Fusion proteins of TFPI-alpha and cbp4-beta

Abstract

The invention relates to fusion proteins comprising tissue factor pathway inhibitor alpha (TFPlα) or a functional fragment thereof and, an exogenous protein S binding moiety, especially complement component 4 binding protein beta (C4BPβ), or a functional fragment thereof. The invention further relates to compositions comprising the same, as well as uses thereof, in particular to inhibit coagulation or for treating thrombotic events, vectors encoding such fusion protein and, method of production thereof.

Description

[0001]FUSION PROTEINS FIELD OF THE INVENTION The invention relates to fusion proteins comprising a TFPIα or a functional fragment thereof and an exogenous protein S binding moiety. The invention further relates to compositions comprising the same, as well as uses thereof and vectors encoding such fusion proteins and method of production thereof. BACKGROUND OF THE INVENTION Approximately 1 in 3 deaths are attributable to thrombosis, and many more individuals are at risk of developing life-threatening thrombotic events. Such events arise due to excessive clot formation that occludes blood vessels. Thrombosis is not a single entity. Arterial thrombosis – including myocardial infarction (i.e., heart attacks) and stroke (blood clots in the brain) - occurs due to formation of clots in the arterial system. These clots tend to develop relatively rapidly, most frequently due to rupture of an atherosclerotic plaque. Protection against arterial thrombosis is classically most effectively achieved using antiplatelet agents that reduce the activation of platelets recruited to damaged / ruptured vessels. Venous thrombosis is quite different. Venous thrombosis develops over longer periods of time (hours to weeks). It develops for a multitude of different reasons, but blood stasis within the venous valves due to immobilization or sedentary lifestyle is a frequent component. Additionally, surgery / trauma, cancer, infection, along with a number of both lifestyle and genetic modifiers further influence the risk of venous thrombosis. Venous thrombosis most commonly develops in the deep veins of the leg – there are an estimated 10 million venous thrombotic event per year globally. If a portion of clot detaches, this can cause pulmonary embolism (PE) where a clot gets trapped in the lungs, which can be a primary cause of death resulting from venous thrombosis. In the US and Europe combined there are ~800,000 venous thrombosis related deaths per year. Protection against venous thrombosis (unlike arterial thrombosis) is primarily achieved through the use of anticoagulant drugs that diminish the coagulation cascade. Haemostasis is the physiological response to blood vessel damage. Vascular injury frequently damages the endothelial cell layer that ordinarily lines blood vessels. This exposes subendothelial collagen, which promotes the local recruitment of platelets. Injury also causes the exposure of tissue factor (TF) on the surface of extravascular cells that are not ordinarily exposed to the blood. TF binds to activated factor (F) VII in plasma to form the TF-FVIIa an active protease complex, which activates Factor X (FX). FXa (a serine protease) then activates a small amount of prothrombin to thrombin (a serine protease). Thrombin then propagates its own further generation through the feedback activation of FVIII and FV into protease cofactors that augment further generation of thrombin. Thrombin also catalyzes the proteolytic deposition of fibrin, which forms an extensive local meshwork that consolidates the locally recruited platelets. Together these processes limit bleeding at sites of injury. Coagulation is temporally and spatially regulated by three distinct anticoagulant pathways. First, antithrombin, which primarily inhibits FXa and thrombin. Secondly, the protein C pathway, which reduces the procoagulant functions of FVa and FVIIIa. Together, these two pathways primarily influence the propagation of coagulation. The third pathway is the tissue factor pathway inhibitor (TFPI) pathway, which regulates the initiation of coagulation. TFPI is the only physiological regulator of the initiation of coagulation and is the only anticoagulant capable of shutting down TF function. For many years, the drug warfarin (a vitamin K antagonist), which diminishes the production of functional coagulation factors containing a Gla domain (e.g., FVII, FX, prothrombin, FIX, protein S, protein C) was used for thromboprophylaxis. Although effective, patients receiving warfarin require monitoring to measure the level of anticoagulation so that dosing can be continually adjusted to keep patients within the therapeutic range. Warfarin has a slow onset and offset (4-5 days) of action, which incurs further considerations when starting and stopping therapy. Low molecular weight heparin (LMWH) is another frequently used anticoagulant. LMWH is a mixture of sulphated polysaccharide chains that work by acting as a cofactor for the endogenous anticoagulant, antithrombin, which enhances the efficiency with which it inactivates FXa (and thrombin). Heparin must be administered by injection. Due to its short half-life (~1-2 hours) repeated / frequent dosing is usually given primarily in hospital settings. More recently, a major advance in thromboprophylaxis has been the development of direct oral anticoagulants (DOACs). These are small molecule stoichiometric inhibitors that target either FXa or thrombin, which have largely replaced warfarin to achieve longer-term thromboprophylaxis. In the US, alone the annual spend on DOACs is currently ~$8 billion. All of these therapeutic agents are effective in diminishing the risk of thrombosis. However, there remain limitations. Whenever using an anticoagulant to inhibit or reduce procoagulant reactions, there remains an increase in the risk of bleeding. The incidence of bleeding in DOAC-treated patients is has been evaluated in several studies. The rate of fatal bleeding and major bleeding with DOAC use ranges from 0.06%-0.30% and 1.1%-4%, respectively. The rate of intracranial hemorrhage ranges from 0.09%-0.51%, major gastrointestinal bleeding from 0.35%-2.09%, and clinically relevant non major bleeding from 6.6%-10.24%. Both LMWH and DOACs have comparatively short half-lives (1-2 hours and ~12 hours, respectively). This means that relatively soon after patients are given these agents, there is a period where they may be over-anticoagulated (and therefore at even greater risk of bleeding). Similarly, due to clearance, many patients also experience a period during which they are under-anticoagulated (and therefore not fully protected). This, therefore, necessitates regular and repeated dosing (daily or twice daily). Despite this, individuals may spend as much as half of the time outside of the therapeutic range (either above or below). Another aspect of these anticoagulants is that although they diminish coagulation, none of them actually target or inhibit TF, which is responsible for initiating coagulation. It is an object of the present invention to provide a new means for controlling coagulation which addresses one or more of the problems associated with conventional anticoagulative agents, particularly LMWH and DOACs. In particular, the invention provides a new anticoagulant which acts by inhibiting initiation of coagulation, therefore acting as an inhibitor of coagulation, and which has improved pharmacokinetic properties, allowing a therapeutic effect to be achieved with low doses, preferably (low) nanomolar doses, that are administered less frequently, potentially improving both patient safety and compliance. SUMMARY OF INVENTION The present invention provides a fusion protein comprising a TFPIα or a functional fragment thereof and an exogenous protein S-binding moiety, together with products for use in methods of treating a subject and methods of purifying said fusion protein. The present inventors have identified, fusion proteins which have substantial advantages over conventional medicaments used in the treatment of excessive coagulant conditions. The fusion proteins have the potential to be administered at low therapeutic doses and a plasma half-life which a weekly injection of super TFPI could be sufficient to maintain an individual within the therapeutic range, with no peaks or troughs. The skilled person would recognise there are other significant advantage which will be discussed in more detail below. Accordingly, the invention provides a fusion protein comprising: a) a TFPIα or a functional fragment thereof; and (b) an exogenous protein S binding moiety. Said exogenous protein S binding moiety may bind to protein S with a KDof 1nM or less, preferably 0.5nM or less. Said TFPIα or functional fragment thereof may comprise or consist of one or more of the Kunitz (K) domains K1, K2 and / or K3 domains, wherein optionally: (a) the TFPIα or functional fragment thereof comprises or consists of (i) the K1 domain; (ii) the K2 domain; (iii) the K3 domain; (iv) the K1 and K2 domains; (v) the K1 and K3 domains; (vi) the K2 and K3 domains; or (vii) the K1, K2 and K3 domains; preferably wherein the TFPIα or functional fragment thereof comprises or consists of the K1 and K2 domains; and / or (b) (i) the K1 and K2 domains; and / or (ii) the K2 and K3 domains; are connected by a linker, preferably wherein said linker is the endogenous linker present in TFPIα. Said TFPIα or functional fragment thereof may comprise or consist of an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 1 or a functional fragment thereof. Said TFPIα or functional fragment thereof may comprise: (a) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 2; and / or (b) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 3; and wherein the TFPIα or functional fragment thereof retains the ability to inhibit the TF-FVIIa complex and / or FXa, preferably FXa. Said TFPIα or functional fragment thereof may comprise or consist of an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO:4, which retains the ability to inhibit the TF-FVIIa complex and / or FXa, preferably FXa. Said protein S binding moiety may be a C4BPβ or a functional fragment thereof. Said C4BPβ or functional fragment thereof may comprise an amino acid sequence of at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 5 or a functional fragment thereof. Said C4BPβ or functional fragment thereof may comprise or consist of at least CCP domain, wherein optionally: (a) the C4BPβ or functional fragment thereof comprises or consists of: (i) CCP1; (ii) CCP2; (iii) CCP3; (iv) CCP1 and CCP2; (v) CCP2 and CCP3; (vi) CCP1 and CCP3; or (vii) CCP1, CCP2 and CCP3; preferably wherein the C4BPβ or functional fragment thereof comprises or consists of: CCP1 and CCP2; and / or (b) (i) the CCP1 and CCP2 domains; and / or (ii) the CCP2 and CCP3 domains; are connected by a linker, preferably wherein said linker is the endogenous linker present in C4BPβ. Said C4BPβ or functional fragment thereof may comprise: (a) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 6; and / or (b) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 7; and wherein the C4BPβ or functional fragment thereof may retain the ability to bind protein S. Said C4BPβ or functional fragment thereof may comprise or consist of an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 8, which retains the ability to bind protein S. Said protein S binding moiety may be an antibody which binds to protein S, preferably an scFv. Said fusion protein or functional fragment thereof may comprise: (a) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 10; or (b) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 11. Said fusion protein may decrease fibrin deposition, preferably the fusion protein decreases fibrin deposition in vivo. Said fusion protein may have a plasma half-life of at least 12 hours, preferably at least 24 hours, and more preferably about 48 hours. The invention further provides a conjugate comprising the fusion protein according to the invention, and a conjugate group, wherein optionally the conjugate group is attached to the N-terminus and / or C-terminus of the fusion protein, preferably at the N-terminus. Said conjugate group may comprise a conjugate linker and a conjugate moiety, and optionally wherein: (a) the conjugate linker (i) comprises or consists of a GS linker; or (ii) consists of a single bond; and / or (b) the conjugate moiety is selected from the group consisting of: human serum albumin (HSA); an antibody Fc fragment; or polyethylene glycol (PEG), preferably the conjugate moiety is HSA. The invention further provides a pharmaceutical composition comprising the fusion protein or the conjugate according to the invention and a pharmaceutically acceptable carrier, wherein preferably the fusion protein is comprised within the pharmaceutical composition at a concentration of 25nM or less, preferably 20nM or less, more preferably 15nM or less. The invention further provides a polynucleotide comprising a nucleic acid sequence encoding the fusion protein, the conjugate according to the invention, or an expression vector comprising said polynucleotide, wherein in said expression vector said polynucleotide is operably linked to a promoter. The invention further provides a host cell comprising the fusion protein, the conjugate, the polynucleotide, or expression vector according to the invention wherein optionally said host cell is a mammalian cell or an insect cell. The invention further provides the fusion protein according to the invention for use in a method of treating the human or animal body. The invention further provides the fusion protein, the conjugate, or the pharmaceutical composition according to the invention for use as an inhibitor of coagulation. In particular, the invention provides the fusion protein, the conjugate, or the pharmaceutical composition according to the invention for use as an anticoagulant. Said fusion protein, the conjugate, or the pharmaceutical composition may be for use in the prevention and / or treatment of an excessive coagulant condition, preferably a thrombotic event, more preferably venous thromboembolism, myocardial infarction, or stroke. In particular, said fusion protein, the conjugate, or the pharmaceutical composition may be for use in the prevention and / or treatment of a thrombotic event, more preferably venous thromboembolism, myocardial infarction, or stroke. Said fusion protein, the conjugate, or the pharmaceutical composition for use may be administered to a subject in need thereof in a therapeutically effective amount of 25nM or less, preferably 20nM or less, more preferably 15 nM or less. The invention further provides a method for purifying the fusion protein or the conjugate of claim according to the invention, the method comprising: a) a chelation chromatography step; and b) Ni2+ chelation chromatography; and c) size exclusion chromatography; where steps (a) to (c) are carried out sequentially an optionally wherein: (i) step (a) comprises elution of the fusion protein or conjugate using increasing concentrations of imidazole, optionally wherein the increasing concentrations of imidazole are 10mM, 100mM, and / or 400mM; and / or (ii) step (b) comprises elution of the fusion protein or conjugate using a 30-100mM linear gradient, of imidazole, with the fusion protein eluting at about 200mM imidazole. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: A schematic of the domain organisation and amino acid sequences of TFPIα (A), C4BPβ (B) and super-TFPI (K1K2-C4BP) (C). Figure 2: Purification of Super-TFPI (K1K2-C4BP). (A) Chromatogram of K1K2-C4BP purification by Fast Protein Liquid Chromatography. (B) Western blot analysis of purification fractions from (A). (C) Chromatogram of second Super-TFPI / K1K2-C4BP purification step. (D) Coomassie analysis of second purification. (E) Size exclusion chromatogram of K1K2-C4BP purification. (F) Coomassie analysis for size exclusion chromatography. Figure 3: Super-TFPI / K1K2-C4BP binds to protein S with high affinity. Binding to Protein S plotted as a function of protein S concentration from which binding constants (KD) were derived for each of TFPIα, C4BPβ and super-TFPI (K1K2-C4BP). Figure 4: Super-TFPI(K1K2-C4BP) inhibits FXa with slightly reduced efficiency to TFPI in the absence of protein S. (A) Graph showing FXa inhibition by wildtype TFPIα. (B) Graph showing FXa inhibition by super TFPI (K1K2-C4BP). (C) FXa activity at 30 mins plotted as a function of inhibitor concentration, from which the IC50for FXa inhibition was derived for both TFPIα and super TFPI. Figure 5: Super-TFPI(K1K2-C4BP) inhibits FXa more potently than TFPI in the presence of protein S. A) Graph showing FXa inhibition in the presence of Protein S by wildtype TFPIα. (B) Graph showing FXa inhibition in the presence of Protein S by super TFPI (K1K2-C4BP). (C) FXa activity in the presence of Protein S at 30 mins plotted as a function of inhibitor concentration, from which the IC50for FXa inhibition was derived for both TFPIα and super TFPI. Figure 6: Anticoagulant effect of super-TFPI in vivo. Y axis shows the median fibrin deposition (AU), and the X axis shows the elapsed time (seconds) Figure 7: Super-TFPI(K1K2-C4BP) inhibits FVIIa to reduce thrombin generation comparably to TFPI in the presence of protein S. A) Graph showing thrombin reduction in the presence of 10nM of Protein S by super TFPI (K1K2-C4BP). B) Graph showing thrombin reduction in the presence of 50nM of Protein S by super TFPI (K1K2-C4BP). C) Graph showing thrombin reduction in the presence of 10nM of Protein S by wildtype TFPIα. D) Graph showing thrombin reduction in the presence of 50nM of Protein S by wildtype TFPIα. E) Graph showing thrombin reduction in the absence of Protein S by super TFPI (K1K2-C4BP). F) Graph showing thrombin reduction in the presence of 50nM of Protein S by super TFPI (K1K2-C4BP). DETAILED DESCRIPTION OF THE INVENTION Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Singleton, et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 20 ED., John Wiley and Sons, New York (1994), and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY, Harper Perennial, NY (1991) provide the skilled person with a general dictionary of many of the terms used in this disclosure. The meaning and scope of the terms should be clear; however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts described herein to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims. The headings provided herein are not limitations of the various aspects or embodiments of this disclosure. As used herein, the term "capable of' when used with a verb, encompasses, or means the action of the corresponding verb. For example, "capable of interacting" also means interacting, "capable of cleaving" also means cleaves, "capable of binding" also means binds and "capable of specifically targeting…" also means specifically targets. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure. As used herein, the articles "a" and “an” may refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting. “About” may generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. Preferably, the term “about” shall be understood herein as plus or minus (±) 5%, preferably ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, of the numerical value of the number with which it is being used. The term "consisting of'' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the invention. As used herein the term "consisting essentially of'' refers to those elements required for a given invention. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that invention (i.e., inactive, or non- immunogenic ingredients). Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of” and / or “consisting essentially of” such features. Concentrations, amounts, volumes, percentages, and other numerical values may be presented herein in a range format. It is also to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. A "vector" or "construct" (sometimes referred to as gene delivery or gene transfer "vehicle") refers to a macromolecule or complex of molecules comprising a polynucleotide to be delivered to a host cell, either in vitro or in vivo. A vector can be a linear or a circular molecule. A vector of the invention may be viral or non-viral. All disclosure herein in relation vectors of the invention applies equally to viral and non-viral vectors unless otherwise stated. All disclosure in relation to viral vectors of the invention applies equally and without reservation to adenovirus vectors or pox virus vectors. As used herein, the term "plasmid", refers to a common type of non-viral vector. A plasmid is an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA. Preferably a plasmid is circular and may be double stranded. The terms "nucleic acid cassette,” “nucleic acid construct", "expression cassette" and "nucleic acid expression cassette" are used interchangeably to mean a nucleic acid molecule that is capable of directing transcription. A nucleic acid cassette includes, at the least, a promoter, or a structure functionally equivalent to a promoter and a nucleic acid sequence to be transcribed. Thus, a nucleic acid cassette includes, at the least, a promoter, or a structure functionally equivalent to a promoter and a nucleic acid sequence encoding a protein of interest. In the present invention, a nucleic acid cassette includes, at the least, a promoter, or a structure functionally equivalent to a promoter, and a nucleic acid encoding a therapeutic protein. A nucleic acid cassette may include additional elements, such as an enhancer, and / or a transcription termination signal. As used herein, the term “virus-like particle” (VLP) refers to a particle which resembles a virus, but which does not contain viral nucleic acid and is therefore non-infectious. VLPs commonly contain one or more virus capsid or envelope proteins which are capable of self- assembly to form the VLP. VLPs have been produced from components of a wide variety of virus families (Noad and Roy (2003), Trends in Microbiology, 11:438-444; Grgacic et al., (2006), Methods, 40:60-65). Some VLPs have been approved as prophylactic vaccines, for example Engerix-B (for hepatitis B), Cervarix and Gardasil (for human papilloma viruses). Amino acids are referred to herein using the name of the amino acid, the three-letter abbreviation, or the single letter abbreviation. Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively. As used herein, the terms "protein" and "polypeptide" are used interchangeably herein to designate a series of amino acid residues, connected to each other by peptide bonds between the alpha-amino and carboxyl groups of adjacent residues. The terms "protein", and "polypeptide" refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogues, regardless of its size or function. "Protein" and "polypeptide" are often used in reference to relatively large polypeptides, whereas the term "peptide" is often used in reference to small polypeptides, but usage of these terms in the art overlaps. The terms "protein" and "polypeptide" are used interchangeably herein when referring to a gene product and fragments thereof. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogues of the foregoing. As used herein, the terms “polynucleotides,” "nucleic acid" and "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid, or an analogue thereof. The nucleic acid can be either single-stranded or double-stranded. A single-stranded nucleic acid can be one nucleic acid strand of a denatured double- stranded DNA Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA. In one aspect, the nucleic acid can be DNA. In another aspect, the nucleic acid can be RNA Suitable nucleic acid molecules are DNA, including genomic DNA or cDNA. Other suitable nucleic acid molecules are RNA, including siRNA, shRNA, and antisense oligonucleotides. The terms “transgene” and “gene” are also used interchangeably, and both terms encompass fragments or variants thereof encoding the target protein, specifically an antigen of the invention. The transgenes of the present invention include nucleic acid sequences that have been removed from their naturally occurring environment, recombinant or cloned DNA isolates, and chemically synthesized analogues or analogues biologically synthesized by heterologous systems. Minor variations in the amino acid sequences of the invention are contemplated as being encompassed by the present invention, providing that the variations in the amino acid sequence(s) maintain at least 60%, at least 70%, more preferably at least 80%, at least 85%, at least 90%, at least 95%, and most preferably at least 97% or at least 99% sequence identity to the amino acid sequence of the invention or a fragment thereof as defined anywhere herein. The term homology is used herein to mean identity. As such, the sequence of a variant or analogue sequence of an amino acid sequence of the invention may differ on the basis of substitution (typically conservative substitution) deletion or insertion. Proteins comprising such variations are referred to herein as variants. Proteins of the invention may include variants in which amino acid residues from one species are substituted for the corresponding residue in another species, either at the conserved or non-conserved positions. Variants of protein molecules disclosed herein may be produced and used in the present invention. Following the lead of computational chemistry in applying multivariate data analysis techniques to the structure / property-activity relationships [see for example, Wold et al. Multivariate data analysis in chemistry. Chemometrics- Mathematics and Statistics in Chemistry (Ed.: B. Kowalski); D. Reidel Publishing Company, Dordrecht, Holland, 1984 (ISBN 90-277-1846-6] quantitative activity-property relationships of proteins can be derived using well-known mathematical techniques, such as statistical regression, pattern recognition and classification [see for example Norman et al. Applied Regression Analysis. Wiley-lnterscience; 3rd edition (April 1998) ISBN: 0471170828; Kandel, Abraham et al. Computer-Assisted Reasoning in Cluster Analysis. Prentice Hall PTR, (May 11, 1995), ISBN: 0133418847; Krzanowski, Wojtek. Principles of Multivariate Analysis: A User's Perspective (Oxford Statistical Science Series, No 22 (Paper)). Oxford University Press; (December 2000), ISBN: 0198507089; Witten, Ian H. et al Data Mining: Practical Machine Learning Tools and Techniques with Java Implementations. Morgan Kaufmann; (October 11, 1999), ISBN:1558605525; Denison David G. T. (Editor) et al Bayesian Methods for Nonlinear Classification and Regression (Wiley Series in Probability and Statistics). John Wiley & Sons; (July 2002), ISBN: 0471490369; Ghose, Arup K. et al. Combinatorial Library Design and Evaluation Principles, Software, Tools, and Applications in Drug Discovery. ISBN: 0-8247-0487-8]. The properties of proteins can be derived from empirical and theoretical models (for example, analysis of likely contact residues or calculated physicochemical property) of proteins sequence, functional and three-dimensional structures and these properties can be considered individually and in combination. Amino acids are referred to herein using the name of the amino acid, the three-letter abbreviation, or the single letter abbreviation. The term “protein", as used herein, includes proteins, polypeptides, and peptides. As used herein, the term “amino acid sequence” is synonymous with the term “polypeptide” and / or the term “protein.” In some instances, the term “amino acid sequence” is synonymous with the term “peptide.” The terms "protein" and "polypeptide" are used interchangeably herein. In the present disclosure and claims, the conventional one-letter and three-letter codes for amino acid residues may be used. The 3- letter code for amino acids as defined in conformity with the IUPACIUB Joint Commission on Biochemical Nomenclature (JCBN). It is also understood that a polypeptide may be coded for by more than one nucleotide sequence due to the degeneracy of the genetic code. Amino acid residues at non-conserved positions may be substituted with conservative or non-conservative residues. In particular, conservative amino acid replacements are contemplated. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, or histidine), acidic side chains (e.g., aspartic acid or glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, or cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, or tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, or histidine). Thus, if an amino acid in a polypeptide is replaced with another amino acid from the same side chain family, the amino acid substitution is considered to be conservative. The inclusion of conservatively modified variants in a protein of the invention does not exclude other forms of variant, for example polymorphic variants, interspecies homologs, and alleles. “Non-conservative amino acid substitutions” include those in which (i) a residue having an electropositive side chain (e.g., Arg, His or Lys) is substituted for, or by, an electronegative residue (e.g., Glu or Asp), (ii) a hydrophilic residue (e.g., Ser or Thr) is substituted for, or by, a hydrophobic residue (e.g., Ala, Leu, Ile, Phe or Val), (iii) a cysteine or proline is substituted for, or by, any other residue, or (iv) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, His, Ile or Trp) is substituted for, or by, one having a smaller side chain (e.g., Ala or Ser) or no side chain (e.g., Gly). “Insertions” or “deletions” are typically in the range of about 1, 2, or 3 amino acids. The variation allowed may be experimentally determined by systematically introducing insertions or deletions of amino acids in a protein using recombinant DNA techniques and assaying the resulting recombinant variants for activity. This does not require more than routine experiments for a skilled person. A “fragment” of a polypeptide comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97% or more of the original polypeptide. For example, a fragment may comprise at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200 or more amino acids of the protein from which it is derived. Preferably a fragment may comprise no more than 50, no more than 60, no more than 70, no more than 80, no more than 90, no more than 100, no more than 150, no more than 200, no more than 250 amino acids of the protein from which it is derived. A fragment may be continuous or discontinuous, preferably continuous. The polynucleotides of the present invention may be prepared by any means known in the art. For example, large amounts of the polynucleotides may be produced by replication in a suitable host cell. The natural or synthetic DNA fragments coding for a desired fragment will be incorporated into recombinant nucleic acid constructs, typically DNA constructs, capable of introduction into and replication in a prokaryotic or eukaryotic cell. Usually, the DNA constructs will be suitable for autonomous replication in a unicellular host, such as yeast or bacteria, but may also be intended for introduction to and integration within the genome of a cultured insect, mammalian, plant, or other eukaryotic cell lines. The polynucleotides of the present invention may also be produced by chemical synthesis, e.g., by the phosphoramidite method or the tri-ester method and may be performed on commercial automated oligonucleotide synthesizers. A double-stranded fragment may be obtained from the single stranded product of chemical synthesis either by synthesizing the complementary strand and annealing the strand together under appropriate conditions or by adding the complementary strand using DNA polymerase with an appropriate primer sequence. When applied to a nucleic acid sequence, the term “isolated” in the context of the present invention denotes that the polynucleotide sequence has been removed from its natural genetic milieu and is thus free of other extraneous or unwanted coding sequences (but may include naturally occurring 5' and 3' untranslated regions such as promoters and terminators) and is in a form suitable for use within genetically engineered protein production systems. Such isolated molecules are those that are separated from their natural environment. In view of the degeneracy of the genetic code, considerable sequence variation is possible among the polynucleotides of the present invention. Degenerate codons encompassing all possible codons for a given amino acid are set forth below: Amino Codons Degenerate Codon Acid Cys TGC TGT TGY Ser AGC AGT TCA TCC TCG WSN TCT Thr ACA ACC ACG ACT ACN Pro CCA CCC CCG CCT CCN Ala GCA GCC GCG GCT GCN Gly GGA GGC GGG GGT GGN Asn AAC AAT AAY Asp GAC GAT GAY Glu GAA GAG GAR Gln CAA CAG CAR His CAC CAT CAY Arg AGA AGG CGA CGC CGG MGN CGT Lys AAA AAG AAR Met ATG ATG Ile ATA ATC ATT ATH Leu CTA CTC CTG CTT TTA TTG YTN Val GTA GTC GTG GTT GTN Phe TTC TTT TTY Tyr TAC TAT TAY Trp TGG TGG Ter TAA TAG TGA TRR Asn / Asp RAY Glu / Gln SAR Any NNN One of ordinary skill in the art will appreciate that flexibility exists when determining a degenerate codon, representative of all possible codons encoding each amino acid. For example, some polynucleotides encompassed by the degenerate sequence may encode variant amino acid sequences, but one of ordinary skill in the art can easily identify such variant sequences by reference to the amino acid sequences of the present invention. A “variant” nucleic acid sequence has substantial homology or substantial similarity to a reference nucleic acid sequence (or a fragment thereof). A nucleic acid sequence or fragment thereof is “substantially homologous” (or “substantially identical”) to a reference sequence if, when optimally aligned (with appropriate nucleotide insertions or deletions) with the other nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 70%, 75%, 80%, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or more% of the nucleotide bases. Methods for homology determination of nucleic acid sequences are known in the art. Alternatively, a “variant” nucleic acid sequence is substantially homologous with (or substantially identical to) a reference sequence (or a fragment thereof) if the “variant” and the reference sequence they are capable of hybridizing under stringent (e.g., highly stringent) hybridization conditions. Nucleic acid sequence hybridization will be affected by such conditions as salt concentration (e.g. NaCl), temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. Stringent temperature conditions are preferably employed, and generally include temperatures in excess of 30°C, typically in excess of 37°C and preferably in excess of 45°C. Stringent salt conditions will ordinarily be less than 1000 mM, typically less than 500 mM, and preferably less than 200 mM. The pH is typically between 7.0 and 8.3. The combination of parameters is much more important than any single parameter. Methods of determining nucleic acid percentage sequence identity are known in the art. By way of example, when assessing nucleic acid sequence identity, a sequence having a defined number of contiguous nucleotides may be aligned with a nucleic acid sequence (having the same number of contiguous nucleotides) from the corresponding portion of a nucleic acid sequence of the present invention. Tools known in the art for determining nucleic acid percentage sequence identity include Nucleotide BLAST (as described below). One of ordinary skill in the art appreciates that different species exhibit “preferential codon usage”. As used herein, the term “preferential codon usage” refers to codons that are most frequently used in cells of a certain species, thus favouring one or a few representatives of the possible codons encoding each amino acid. For example, the amino acid threonine (Thr) may be encoded by ACA, ACC, ACG, or ACT, but in mammalian host cells ACC is the most commonly used codon; in other species, different codons may be preferential. Preferential codons for a particular host cell species can be introduced into the polynucleotides of the present invention by a variety of methods known in the art. Introduction of preferential codon sequences into recombinant DNA can, for example, enhance production of the protein by making protein translation more efficient within a particular cell type or species. A “fragment” of a polynucleotide of interest comprises a series of consecutive nucleotides from the sequence of said full-length polynucleotide. By way of example, a “fragment” of a polynucleotide of interest may comprise (or consist of) at least 600 consecutive nucleotides from the sequence of said polynucleotide (e.g., at least 600, 650, 700, 750, 800 850, 900, or 950 consecutive nucleic acid residues of said polynucleotide). Typically, a fragment as defined herein retains the same function as the full-length polynucleotide. As used herein, “conjugate group” means a group of atoms that is directly attached to a fusion protein. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the fusion protein. As used herein, “conjugate linker” means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to a fusion protein. As used herein, “conjugate moiety” means a group of atoms that modifies one or more properties of a molecule compared to the identical molecule lacking the conjugate moiety, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance. As used herein, the term GS linker refers to a short peptide (typically less than 30 amino acids) consisting primarily of stretches of Gly and Ser residues, which comprise a sequence of (Gly-Gly-Gly-Gly-Ser)n where n is any positive integer. Non-limiting examples of GS linkers include GS5 or (GGGGS)1(SEQ ID NO: 12); GS10 or (GGGGS)2(SEQ ID NO: 13); GS15 or (GGGGS)3(SEQ ID NO: 14); GS20 or (GGGGS)4(SEQ ID NO: 15); and GS25 or (GGGGS)5(SEQ ID NO: 16). The terms “decrease” "reduced", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. The terms "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, "reduction" or "inhibition" encompasses a complete inhibition or reduction as compared to a reference level. "Complete inhibition" is a 100% inhibition (i.e., abrogation) as compared to a reference level. The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. The terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 25%, at least 50% as compared to a reference level, for example an increase of at least about 50%, or at least about 75%, or at least about 80%, or at least about 90%, at least about 95%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 250% or more compared with a reference level, or at least about a 1.5-fold, or at least about a 2-fold, or at least about a 2.5-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 1.5-fold and 10-fold or greater as compared to a reference level. In the context of a yield or titre, an "increase" is an observable or statistically significant increase in such level. The terms "individual,” "subject,” and "patient,” are used interchangeably herein to refer to a mammalian subject for whom diagnosis, prognosis, disease monitoring, treatment, therapy, and / or therapy optimisation is desired. The mammal can be (without limitation) a human, non-human primate, mouse, rat, dog, cat, horse, or cow. In a preferred embodiment, the individual, subject, or patient is a human. An “individual” may be an adult, juvenile or infant. An “individual” may be male or female. A "subject in need" of treatment for a particular condition can be an individual having that condition, diagnosed as having that condition, or at risk of developing that condition. A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications or symptoms related to such a condition, and optionally, have already undergone treatment for a condition as defined herein or the one or more complications or symptoms related to said condition. Alternatively, a subject can also be one who has not been previously diagnosed as having a condition as defined herein or one or more or symptoms or complications related to said condition. For example, a subject can be one who exhibits one or more risk factors for a condition, or one or more or symptoms or complications related to said condition or a subject who does not exhibit risk factors. As used herein, the term “healthy individual” refers to an individual or group of individuals who are in a healthy state, e.g., individuals who have not shown any symptoms of the disease, have not been diagnosed with the disease and / or are not likely to develop the disease e.g., a thrombotic event. Preferably said healthy individual(s) is not on medication affecting haemostasis and has not been diagnosed with any other disease. The one or more healthy individuals may have a similar sex, age, and / or body mass index (BMI) as compared with the test individual. Application of standard statistical methods used in medicine permits determination of normal levels of expression in healthy individuals, and significant deviations from such normal levels. Herein the terms “control” and “reference population” are used interchangeably. The term “pharmaceutically acceptable” as used herein means approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. Disclosure related to the various methods of the invention are intended to be applied equally to other methods, therapeutic uses or methods, the data storage medium or device, the computer program product, and vice versa. Tissue factor pathway inhibitor (TFPI) The invention relates to fusion proteins comprising a tissue factor pathway inhibitor (TFPI) or functional fragment thereof. TFPI is a protein involved in the regulation of blood clotting, specifically the extrinsic pathway of coagulation. The extrinsic pathway is initiated when tissue factor (TF) is exposed due to vascular injury. Vascular injury frequently damages the endothelial cell layer that ordinarily lines blood vessels. This exposes subendothelial collagen, which promotes the local recruitment of platelets. Excessive coagulation refers to a disruption or dysfunction of the natural regulatory mechanisms that control blood clotting, leading to an overactivation of the coagulation cascade. The TFPI pathway plays a crucial role in regulating the coagulation process by inhibiting tissue factor-induced coagulation, which is one of the primary triggers for blood clot formation. TFPI is a protein that acts as a key inhibitor of blood clotting. It inhibits the activity of Factor VIIa / TF (Tissue Factor) complex, which is an essential initiator of the coagulation cascade. By inhibiting this complex, TFPI helps prevent excessive clot formation and maintains a delicate balance between clotting and clot dissolution. However, in certain situations, there can be a deficiency or dysfunction of TFPI, leading to an impaired inhibitory function. This can result in a hypercoagulable state, where blood clot formation becomes excessive, increasing the risk of thrombosis. Excessive coagulation in the context of the TFPI pathway can lead to conditions such as deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, and other clot-related complications. TFPI is the only physiological regulator of the initiation of coagulation and is the only anticoagulant capable of shutting down TF function. In humans, TFPI exists in two major alternatively spliced isoforms, TFPIα and TFPIβ. TFPIα comprises three Kunitz (K) domains (K1-3) followed by a highly basic C-terminal tail. TFPIβ comprises only two of the three K domains (K1 and K2). In the exemplary TFPIα of SEQ ID NO: 1, residues 1-28 (inclusive) correspond to a signal peptide; residues 29-53 (inclusive) correspond to an N-terminal domain; residues 54-104 (inclusive) correspond to the K1 domain; residues 105-124 correspond to a linker between the K1 and K2 domains; residues 125-175 (inclusive) correspond to the K2 domain; residues 176-216 correspond to a linker between the K2 and K3 domains; residues 217-267 (inclusive) correspond to the K3 domain; and residues 268-304 (inclusive) correspond to a C-terminal domain. It is within the routine practice of one of ordinary skill in the art to identify the regions of other TFPI (e.g., TFPIα) proteins which correspond to the N- terminal, K1-K3 and C-terminal domains of the human TFPIα protein of SEQ ID NO: 1. As is conventional for signal peptides, the TFPIα signal peptide is removed from the mature protein. Again, it is within the routine practice of one of ordinary skill in the art to identify the regions of TFPIα proteins which correspond to the N-terminal, K1-K3 and C-terminal domains of the human TFPIα protein of SEQ ID NO: 1 in the absence of the signal peptide, and to do the same for other TFPI (e.g., TFPIα) proteins. By way of example, in an amino acid sequence corresponding to SEQ ID NO: 1 without the signal peptide, residues 1-25 (inclusive) correspond to an N-terminal domain; residues 26-76 (inclusive) correspond to the K1 domain; residues 77-96 correspond to a linker between the K1 and K2 domains; residues 97-147 (inclusive) correspond to the K2 domain; residues 148-188 correspond to a linker between the K2 and K3 domains; residues 189-239 (inclusive) correspond to the K3 domain; and residues 240-276 (inclusive) correspond to a C-terminal domain. It is within the routine practice of one of ordinary skill in the art to identify the regions of other TFPI (e.g., TFPIα) proteins which correspond to the N-terminal, K1-K3 and C-terminal domains of the human TFPIα protein of SEQ ID NO: 1. The TFPI may be from any species. Preferably, the TFPI is a mammalian TFPI, more preferably a human TFPI. Thus, the TFPI may be human TFPIα or TFPIβ, preferably human TFPIα. A reference herein to TFPI encompasses both TFPIα and TFPIβ, and particularly human TFPIα and human TFPIβ, unless expressly stated to the contrary. An exemplary TFPIα is defined by SEQ ID NO: 1 (NCBI Reference ID: NP_001316168, version 1, also UniProt Accession No. P10646, version 1, both accessed 19 July 2023). A schematic for human TFPIα is shown in Figure 1A. The TFPI portion of the fusion protein of the invention may be a full-length TFPI or a fragment thereof. Preferably the TFPI portion of the fusion protein of the invention is a fragment of TFPI. A TFPI fragment is typically a functional fragment of TFPI. In other words, a TFPI fragment retains at least one of the functional properties of full-length TFPI, e.g., FXa inhibition and / or inhibition of the TF-FVIIa complex, as discussed herein. A TFPI portion of the fusion protein of the invention may be modified relative to the TFPI from which it is derived, provided that the variant retains at least one of the functional properties of full-length TFPI, e.g., FXa inhibition and / or inhibition of the TF-FVIIa complex, as discussed herein. Full length TFPIα circulates at low concentrations (0.2-0.5nM) but can also be acutely / locally released by activated platelets. Smaller truncated forms of TFPI also circulate, primarily in association with plasma lipoproteins, but with markedly reduced inhibitory function. As a soluble protein, full-length TFPIα exerts its function both in plasma and on cell surfaces exposed to the plasma. Conversely, the inhibitory function of TFPIβ, which contains only K1 and K2 that is glycosylphosphatidylinositol-anchored to the cell surface, is restricted to the surface of cells expressing this isoform. In both TFPIα and TFPIβ, the K1 and K2 domains directly inhibit the TF-FVIIa complex and FXa, respectively. In TFPIα, the K3 domain interacts with its cofactor, protein S, which enhances the rate of FXa inhibition 4- to 10-fold and, therefore, augments its anticoagulant function. The TFPIα or functional fragment thereof may comprise or consist of one or more of the Kunitz (K) domains K1, K2 and / or K3 domains, as defined herein. Thus, the TFPIα or functional fragment thereof may comprise or consist of (i) the K1 domain; (ii) the K2 domain; (iii) the K3 domain; (iv) the K1 and K2 domains; (v) the K1 and K3 domains; (vi) the K2 and K3 domains; or (vii) the K1, K2 and K3 domains.; Preferably, the TFPIα or functional fragment thereof comprises or consists of the K1 and K2 domains. The TFPIα or functional fragment thereof may lack one or more of the K domains, particularly K3. Alternatively, or in addition, the TFPIα or functional fragment thereof may lack the N-terminal domain and / or the C-terminal domain. Alternatively, or in addition, the TFPIα or functional fragment is derived from the mature TFPIα and lacks the signal peptide. In some preferred embodiments, the TFPIα or functional fragment thereof lacks the K3 domain and the C-terminal domain, and optionally also the signal peptide. The K domains present in the TFPIα, or functional fragment thereof may be connected directly without any intervening amino acid(s). Alternatively, and preferably, the TFPIα or functional fragment thereof may comprise one or more linker connecting the K domains. Thus, a TFPIα or functional fragment thereof may comprise a linker connecting: (i) the K1 and K2 domains; and / or (ii) the K2 and K3 domains. Preferably, the TFPIα or functional fragment thereof comprises or consists of the K1 and K2 domains, which are connected by a linker. Any appropriate linker may be used to connect the K domains within a TFPI or functional fragment thereof according to the invention. The linker may be a flexible linker (e.g., allowing effective positioning of the connected K domains). The linker may, for example, be a peptide linker. The peptide linker may comprise (or consist of) 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids. The peptide linker may comprise (or consist of) from 10 to 50 amino acids: preferably from 15 to 45 amino acids, more preferably from 20 to 42 amino acids. Typically, where a linker is present between K domains within the TFPIα or functional fragment, the linker is an endogenous linker present in TFPIα, particularly the linker that would be present between the respective K domains in a wild-type TFPIα (e.g., SEQ ID NO: 1). By way of example, wherein the K1 and K2 domains are present in a TFPIα or functional fragment thereof, the linker may correspond to residues 105-124 (inclusive) of SEQ ID NO: 1 (which is the linker between the K1 and K2 domains in SEQ ID NO: 1, as described herein). Alternatively, or in addition, wherein the K2 and K3 domains are present in a TFPIα or functional fragment thereof, the linker may correspond to residues 176-216 (inclusive) of SEQ ID NO: 1 (which is the linker between the K2 and K1 domains in SEQ ID NO: 1, as described herein). The functional fragment of TFPI may comprise (or consist of) a contiguous sequence of no more than 250 amino acids from TFPI (e.g., SEQ ID NO: 1). For example, the functional fragment of TFPI may comprise (or consist of) no more than 220 amino acids, no more than 210 amino acids, no more than 200 amino acids, or no more than 190 amino acids from TFPI (e.g., SEQ ID NO: 1). Preferably, the contiguous sequence is from the N-terminal portion of TFPI, more preferably excluding the signal peptide, even more preferably comprising the K1 and K2 domains. The functional fragment of TFPI may comprise (or consist of) a contiguous sequence of at least 150 amino acids from TFPI (e.g., SEQ ID NO: 1). For example, the TFPI functional fragment may comprise (or consist of) a contiguous sequence of at least 150, at least 160, at least 170, at least 180, at least 181, at least 182, at least 183, at least 184, at least 185, at least 186, at least 187, at least 188, at least 189, at least 190, at least 191, at least 192, at least 193, at least 194, at least 195, at least 200, or at least 210 amino acids from TFPI (e.g., SEQ ID NO: 1). Preferably, the functional fragment of TFPI comprises (or consists of) a contiguous sequence of at least 185, at least 186, at least 187, at least 188, at least 189, at least 190, at least 200 or at least 210 amino acids from TFPI (e.g., SEQ ID NO: 1). Preferably, the contiguous sequence is from the N-terminal portion of TFPI, more preferably excluding the signal peptide, even more preferably comprising the K1 and K2 domains. The functional fragment of TFPI may comprise (or consist of) a contiguous sequence of from 150 to 250 amino acids from TFPI, from 170 to 220 amino acids from TFPI, from 180 to 220 amino acids, from 180 to 200 amino acids or from 180 to 190 amino acids from TFPI (e.g., SEQ ID NO: 1). Preferably, the contiguous sequence is from the N-terminal portion of TFPI, more preferably excluding the signal peptide, even more preferably comprising the K1 and K2 domains. The TFPIα or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 1 or a functional fragment thereof. Preferably the TFPIα or functional fragment thereof according to the invention will have at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 1 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention has at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 1 or a functional fragment thereof. The TFPIα or functional fragment thereof according to the invention may comprise a K1 domain. Therefore, the TFPIα or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof. Preferably the TFPIα or functional fragment thereof according to the invention will comprise an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof. The TFPIα or functional fragment thereof according to the invention may comprise a K2 domain. Therefore, the TFPIα or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. Preferably the TFPIα or functional fragment thereof according to the invention will comprise an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. Preferably the TFPIα or functional fragment thereof according to the invention comprises a K1 domain and a K2 domain. Therefore, the TFPIα or functional fragment thereof according to the invention comprises (a) an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof and (b) amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof; and (b) an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. Preferably the TFPIα or functional fragment thereof according to the invention will comprise (a) an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof; and (b) an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof; and (b) an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. By way of further example, the TFPIα or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof; and (b) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. By way of further example, the TFPIα or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof; and (b) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. By way of further example, the TFPIα or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof; and (b) an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. By way of further example, the TFPIα or functional fragment thereof according to the invention may comprise (a) the amino acid sequence of SEQ ID NO: 2 or a functional fragment thereof; and (b) the amino acid sequence of SEQ ID NO: 3 or a functional fragment thereof. Regardless of the % identity of the TFPIα or functional fragment comprised in a fusion protein of the invention, said functional fragment retains the ability of TFPI to inhibit the TF- FVIIa complex and / or FXa, as defined herein in the context of fusion proteins of the invention. As described herein, the TFPIα or functional fragment of the invention may comprise one or more endogenous linker present in TFPIα. Thus, the TFPIα or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 4 or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 4or a functional fragment thereof. Preferably the TFPIα or functional fragment thereof according to the invention will comprise or consist of an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 4or a functional fragment thereof. For example, the TFPIα or functional fragment thereof according to the invention may preferably comprise or consist of an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 4or a functional fragment thereof. Regardless of the % identity of the TFPIα or functional fragment comprised in a fusion protein of the invention, said functional fragment retains the ability of TFPI to inhibit the TF- FVIIa complex and / or FXa, as defined herein in the context of fusion proteins of the invention. Protein S Binding Moieties Protein S is an anticoagulant plasma protein. Protein S is synthesized as a 676 amino acid propeptide that is processed to a mature protein of 635 amino acids. Mature protein S contains a phospholipid binding γ-carboxyglutamic acid domain (GLA), a thrombin sensitive region, four Epidermal Growth Factor (EGF)-like domains and a sex hormone binding globule that contains two laminin G (LG)-type domains. An exemplary protein S amino acid sequence is SEQ ID NO: 9 (UniProt Accession No. P07225, version 1, accessed 19 July 2023). Protein S is a cofactor of TPFI. The cofactor function of protein S is at least in part attributed to the ability of protein S to augment the association of TFPIα to the phospholipid surfaces upon which the initiation of coagulation occurs (activated platelets / activates cells). Protein S-TFPIα cofactor function is particularly important given the very low concentrations of TFPIα (0.2-0.5nM). Protein S circulates in the plasma at a concentration of approximately 350nM. In humans, approximately 60% of plasma protein S (approx.200nM) circulates in tight complex with C4b-binding protein (C4BP). Only free protein S (approx.150nM) exerts TFPIα cofactor function, due to overlapping binding sites between C4BP and TFPI K3 in protein S. Although TFPIα function has been comparatively well-characterized in vitro, the role / importance of the TFPIα anticoagulant pathway and the involvement of protein S in vivo is less well understood. The reasons for this are in part due to the embryonic lethality of both Tfpi- / -and Pros1- / -mice, as well as important interspecies differences in both TFPI and protein S between humans and mice. A binding member for protein S (referred to interchangeably herein as a “protein S binding member”) refers to a molecule that selectively binds to protein S. An exogenous protein S binding member is one which is not present in wild-type TPFIα, e.g., in the exemplary TPFIα of SEQ ID NO: 1. Thus, a TPFIα or functional fragment thereof within a fusion protein of the invention may retain its own protein S binding activity, provided that the fusion protein comprises a non-TPFIα moiety which also provides protein S binding activity. Preferably, the TPFIα or functional fragment thereof within a fusion protein of the invention lacks protein S binding activity, i.e., it lacks a K3 domain. Typically, protein S binding members of the invention are selective for (also referred to interchangeably herein as specific for) protein S. The protein S binding members of the invention may bind to soluble protein S, particularly human protein S. The protein S binding members of the invention may have cross-reactivity with murine protein S. By selective, it will be understood that a binding member binds to protein S with no significant cross-reactivity to any other molecule. Cross-reactivity may be assessed by any suitable method. By way of non-limiting example, cross-reactivity of a protein S binding member with a molecule other than protein S may be considered significant if the binding member binds to the other molecule at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 100% as strongly as it binds to protein S. A protein S binding member that binds selectively to protein S may bind to another molecule at less than 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25% or 20% the strength that it binds to protein S. Preferably, the protein S binding member binds to the other molecule at less than 20%, less than 15%, less than 10% or less than 5%, less than 2% or less than 1% the strength that it binds to protein S. Any suitable protein S binding member may be used according to the invention, for example antibodies, small molecules, peptides and peptidomimetics and aptamers. Preferred binding members include C4BP, or fragments or variants thereof. Alternatively, a protein S binding moiety may be an antibody such as an scFv. An exogenous protein S binding member typically has a binding affinity for protein S as defined herein in the context of the fusion proteins of the invention. C4BP Preferred binding members include C4BP, or fragments or variants thereof. C4BP is an octameric protein consisting of either eight covalently linked C4BP-α chains, or seven C4BP-α chains and one C4BP-β chain. Only β chain containing C4BP binds protein S, which binds via CCP1 and CCP2 domains with sub nanomolar affinity (KD 0.1- 0.2nM). C4BP-β chain (also referred to interchangeably herein as C4BPβ) comprises an N- terminal signal peptide, an N-terminal domain, 3 complement control protein (CCP) domains and a C-terminal domain. In the exemplary C4BPβ of SEQ ID NO: 5, residues 1-17 (inclusive) correspond to a signal peptide; residues 18-20 (inclusive) correspond to an N-terminal domain; residues 21- 78 (inclusive) correspond to the CCP1 domain; residues 79-136 (inclusive) correspond to the CCP2 domain; residues 137-193 (inclusive) correspond to the CCP3 domain; and residues 194-252 (inclusive) correspond to a C-terminal domain. It is within the routine practice of one of ordinary skill in the art to identify the regions of other C4BP (e.g., C4BPβ) proteins which correspond to the N-terminal, CCP1-3 and C-terminal domains of the human C4BPβ protein of SEQ ID NO: 5. As is conventional for signal peptides, the C4BPβ signal peptide is removed from the mature protein. Again, it is within the routine practice of one of ordinary skill in the art to identify the regions of C4BPβ proteins which correspond to the N-terminal, CCP1-3 and C-terminal domains of the human C4BPβ protein of SEQ ID NO: 5 in the absence of the signal peptide, and to do the same for other C4BP (e.g., C4BPβ) proteins. By way of example, in an amino acid sequence corresponding to SEQ ID NO: 5 without the signal peptide, residues 1- 3 (inclusive) correspond to an N-terminal domain; residues 4-61 (inclusive) correspond to the CCP1 domain; residues 62-119 (inclusive) correspond to the CCP2 domain; residues 120-176 (inclusive) correspond to the CCP3 domain; and residues 177-235 (inclusive) correspond to a C-terminal domain. It is within the routine practice of one of ordinary skill in the art to identify the regions of other C4BP (e.g., C4BPβ) proteins which correspond to the N-terminal, CCP1- 3, and C-terminal domains of the human C4BPβ protein of SEQ ID NO: 5. The C4BP (e.g., C4BPβ may be from any species). Preferably, the C4BP is a mammalian C4BP (e.g., C4BPβ), more preferably a human C4BP (e.g., C4BPβ). Thus, the C4BP may be human C4BPα or C4BPβ, preferably human C4BPβ. A reference herein to C4BP encompasses both C4BPβ and C4BPα, and particularly human C4BPβ and human C4BPα, unless expressly stated to the contrary. An exemplary C4BPβ is defined by SEQ ID NO: 5 (NCBI Reference ID: NP_000707, version 1, also UniProt Accession No. P20851, version 1, both accessed 19 July 2023). A schematic for human C4BPβ is shown in Figure 1B. The C4BP (e.g., C4BPβ) portion of the fusion protein of the invention may be a full- length C4BP (e.g., C4BPβ) or a fragment thereof. Preferably the C4BP (e.g., C4BPβ) portion of the fusion protein of the invention is a fragment of C4BP (e.g., C4BPβ). A C4BP (e.g., C4BPβ) fragment is typically a functional fragment of C4BP (e.g., C4BPβ). In other words, a C4BP (e.g., C4BPβ) fragment retains at least one of the functional properties of full-length C4BP (e.g., C4BPβ), particularly the ability to bind protein S, as discussed herein. A C4BP (e.g., C4BPβ) portion of the fusion protein of the invention may be modified relative to the C4BP (e.g. C4BPβ) from which it is derived, provided that the variant retains at least one of the functional properties of full-length C4BP (e.g. C4BPβ), specifically the ability to bind protein S, as discussed herein. The C4BP (e.g., C4BPβ) or functional fragment thereof may comprise or consist of one or more of the CCP1, CCP2 and / or CCP3 domains, as defined herein. Thus, the C4BP (e.g. C4BPβ) or functional fragment thereof may comprise or consist of (i) the CCP1 domain; (ii) the CCP2 domain; (iii) the CCP3 domain; (iv) the CCP1 and CCP2 domains; (v) the CCP1 and CCP3 domains; (vi) the CCP2 and CCP3 domains; or (vii) the CCP1, CCP2 and CCP3 domains.; Preferably, the C4BP (e.g. C4BPβ) or functional fragment thereof comprises or consists of the CCP1 and CCP2 domains. The C4BP (e.g., C4BPβ) or functional fragment thereof may lack one or more of the CCP domains, particularly CCP3. Alternatively, or in addition, the C4BP (e.g., C4BPβ) or functional fragment thereof may lack the N-terminal domain and / or the C-terminal domain. Alternatively, or in addition, the C4BP (e.g., C4BPβ) or functional fragment is derived from the mature C4BP (e.g. C4BPβ) and lacks the signal peptide. In some preferred embodiments, the C4BP (e.g., C4BPβ) or functional fragment thereof lacks the CCP3 domain and the C-terminal domain, and optionally also the signal peptide. The CCP domains present in the C4BP (e.g., C4BPβ) or functional fragment thereof may be connected directly without any intervening amino acid(s). Alternatively, the C4BP (e.g., C4BPβ) or functional fragment thereof may comprise one or more linker connecting the C4BP (e.g., C4BPβ) domains. Thus, a C4BP (e.g., C4BPβ) or functional fragment thereof may comprise a linker connecting: (i) the CCP1 and CCP2 domains; and / or (ii) the CCP2 and CCP33 domains. Any appropriate linker may be used to connect the CCP domains within a C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention. The linker may be a flexible linker (e.g., allowing effective positioning of the connected CCP domains). The linker may, for example, be a peptide linker. The peptide linker may comprise (or consist of) 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids. The peptide linker may comprise (or consist of) from 10 to 50 amino acids: preferably from 15 to 45 amino acids, more preferably from 20 to 42 amino acids. When a linker is present between CCP domains within the C4BP (e.g., C4BPβ) or functional fragment, the linker may be an endogenous linker present in C4BP (e.g., C4BPβ) or TFPIα. The functional fragment of C4BP (e.g., C4BPβ) may comprise (or consist of) a contiguous sequence of no more than 150 amino acids from C4BP (e.g., C4BPβ) (e.g., SEQ ID NO: 5). For example, the functional fragment of TFPI may comprise (or consist of) no more than 140 amino acids, no more than 130 amino acids, no more than 125 amino acids, or no more than 120 amino acids from C4BP (e.g., C4BPβ, such as SEQ ID NO: 5). Preferably, the contiguous sequence is from the N-terminal portion of C4BP (e.g., C4BPβ), more preferably excluding the signal peptide, even more preferably comprising the CCP1 and CCP2 domains. The functional fragment of C4BP (e.g., C4BPβ) may comprise (or consist of) a contiguous sequence of at least 80 amino acids from C4BP (e.g., C4BPβ), such as SEQ ID NO: 5). For example, the C4BP (e.g. C4BPβ) functional fragment may comprise (or consist of) a contiguous sequence of at least 80, at least 90, at least 100, at least 110, at least 111, at least 112, at least 113, at least 114, at least 115, at least 116, at least 117, at least 118, at least 119, at least 120, at least 121, at least 122, at least 123, at least 124, at least 125, at least 130, or at least 135 amino acids from C4BP (e.g. C4BPβ, such as SEQ ID NO: 5). Preferably, the functional fragment of C4BP (e.g., C4BPβ) comprises (or consists of) a contiguous sequence of at least 115, at least 116, at least 117, at least 118, at least 119, at least 120, at least 125 or at least 130 amino acids from C4BP (e.g., C4BPβ, such as SEQ ID NO: 5). Preferably, the contiguous sequence is from the N-terminal portion of C4BP (e.g., C4BPβ), more preferably excluding the signal peptide, even more preferably comprising the CCP1 and CCP2 domains. The functional fragment of C4BP (e.g., C4BPβ) may comprise (or consist of) a contiguous sequence of from 100 to 140 amino acids from C4BP (e.g., C4BPβ), from 110 to 130 amino acids from C4BP (e.g. C4BPβ), from 115 to 125 amino acids, from 115 to 120 amino acids or from 117 to 120 amino acids from C4BP (e.g. C4BPβ, such as SEQ ID NO: 5). Preferably, the contiguous sequence is from the N-terminal portion of C4BP (e.g., C4BPβ), more preferably excluding the signal peptide, even more preferably comprising the CCP1 and CCP2 domains. The C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 5 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 5 or a functional fragment thereof. Preferably the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention will have at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 5 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention has at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 5 or a functional fragment thereof. The C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise a CCP1 domain. Therefore, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof. Preferably the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention will comprise an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof. The C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise a CCP2 domain. Therefore, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. Preferably the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention will comprise an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. Preferably the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention comprises a CCP1 domain and a CCP2 domain. Therefore, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention comprises (a) an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof and (b) amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. For example, the C4BP (e.g. C4BPβ) or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof; and (b) an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. Preferably the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention will comprise (a) an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof; and (b) an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. For example, the C4BP (e.g. C4BPβ) or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof; and (b) an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. By way of further example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof; and (b) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. By way of further example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof; and (b) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. By way of further example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise (a) an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof; and (b) an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. By way of further example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise (a) the amino acid sequence of SEQ ID NO: 6 or a functional fragment thereof; and (b) the amino acid sequence of SEQ ID NO: 7 or a functional fragment thereof. Regardless of the % identity of the C4BP (e.g., C4BPβ) or functional fragment comprised in a fusion protein of the invention, said functional fragment retains the ability of C4BP (e.g., C4BPβ) to bind to protein S. As described herein, the C4BP (e.g., C4BPβ) or functional fragment of the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 8 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may comprise or consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 8 or a functional fragment thereof. Preferably the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention will comprise or consist of an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 8 or a functional fragment thereof. For example, the C4BP (e.g., C4BPβ) or functional fragment thereof according to the invention may preferably comprise or consist of an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 8 or a functional fragment thereof. Regardless of the % identity of the C4BP (e.g., C4BPβ) or functional fragment comprised in a fusion protein of the invention, said functional fragment retains the ability of C4BP (e.g., C4BPβ) to bind to protein S. Antibodies The protein S binding moiety may be an antibody which binds to protein S. As used herein, the term antibody encompasses the use of a monoclonal antibody or polyclonal antibody, as well as the antigen-binding fragments of a monoclonal or polyclonal antibody, or a peptide which binds to protein S with specificity. The antibody may be a Fab, F(ab’)2, Fv, scFv, Fd or dAb. Preferably, the protein S binding moiety is a scFv which binds to protein S. ScFv refers to a single-chain variable fragment. scFv is a type of antibody fragment that retains the antigen-binding properties of a full-size antibody while being smaller and structurally simplified. The scFv is engineered by linking the variable regions of the antibody's heavy chain (VH) and light chain (VL) into a single polypeptide chain. Fusion proteins Fusion proteins described herein are those in accordance with the invention. Since the methods of the invention may be used to manufacture fusion proteins and conjugates in accordance with the invention, it will be appreciated that (unless context requires otherwise) features disclosed herein in connection with the fusion proteins and conjugates of the invention should also be taken as disclosed in connection with their use in the methods of the invention, and features disclosed in connection with the methods of the invention should also be taken as disclosed in connection with their use in the compositions or to form fusion proteins and conjugates of the invention. Fusion proteins of the present invention comprise a TFPIα or a functional fragment thereof and an exogenous protein S binding moiety. The terms “fusion protein" and "fusion molecule" are used interchangeably and may refer to a polypeptide comprising a TFPIα, or a functional fragment thereof linked to exogenous protein S binding moiety. Preferably, the TFPIα or a functional fragment thereof is a TFPIα, or a functional fragment thereof as described above. The exogenous protein S binding moiety is preferably as described above. Typically, a fusion protein of the invention possesses one or more of the properties described herein. The TFPIα or a functional fragment and the exogenous protein S binding moiety may be covalently linked (e.g., fused) by recombinant, chemical or other suitable methods. The fusion molecule can be fused at one or several sites through a linker, particularly a peptide linker sequence, examples of which are described herein. Alternatively, the peptide linker may be used to assist in construction of the fusion molecule. Specifically preferred fusion molecules are fusion proteins. Generally fusion molecules also can be comprised of conjugate molecules. Different orientations of the TFPIα or a functional fragment and the exogenous protein S binding moiety are envisaged. Thus, the TFPIα or a functional fragment may be at the N- terminus of the fusion protein and the exogenous protein S binding moiety at the C-terminus. Alternatively, the TFPIα or a functional fragment may be at the C-terminus of the fusion protein and the exogenous protein S binding moiety at the N-terminus. In some preferred embodiments, a fusion protein of the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 10 or a functional fragment thereof. For example, a fusion protein of the invention may comprise or consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 10 or a functional fragment thereof. Preferably a fusion protein of the invention will comprise or consist of an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 10 or a functional fragment thereof. For example, a fusion protein of the invention may preferably comprise or consist of an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 10 or a functional fragment thereof. A schematic for this exemplary fusion protein is shown in Figure 1C. A fusion protein of the invention may be modified to facilitate production and / or purification. By way of non-limiting example, such modifications may include an N- or C-terminal tag, for example to assist in recombinant production and / or purification. Any N- or C-terminal tag may be used, including conventional tags known in the art. Suitable tags sequences include C-terminal hexa-histidine tags and the “C-tag” (the four amino acids EPEA at the C- terminus), which are commonly used in the art to aid purification from heterologous expression systems, e.g., insect cells, mammalian cells, bacteria, or yeast. Other examples of suitable tags include GST and MBP tags, or any other conventional tag which may be used to facilitate increased expression. As exemplified, a His tag is used. In other embodiments, fusion proteins of the invention are purified from heterologous expression systems without the need to use a purification tag. Other modifications that can be made to facilitate production and / or purification include the addition of a protease cleavage site, such as a TEV cleavage site. Thus, a fusion protein of the invention may comprise or consist of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 11 or a functional fragment thereof. For example, a fusion protein of the invention may comprise or consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 11 or a functional fragment thereof. Preferably a fusion protein of the invention will comprise or consist of an amino acid sequence having at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 11 or a functional fragment thereof. For example, a fusion protein of the invention may preferably comprise or consist of an amino acid sequence having at least 90%, at least 95%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 11 or a functional fragment thereof. Conjugates The invention also provides a conjugate comprising a fusion protein of the invention and a conjugate group. Thus, a fusion protein of the invention may be covalently attached to one or more conjugate groups. A conjugate group may be attached to the N-terminus and / or the C- terminus of a fusion protein of the invention. A conjugate group may be attached to one or more non-terminal amino acid within the fusion protein. Where conjugate groups are attached to both the N- and C-termini, different conjugate groups may be attached to the N-terminus and C-terminus, or the same conjugate group may be used for the N-terminus and the C-terminus. Where different conjugate groups are used, they may be selected independently. Where conjugate groups are attached to one or more non-terminal amino acid within the fusion protein, these may be the same as those present at the N-terminus or C-terminus (if present), or different thereto. When present, a conjugate group may preferably be attached to the N-terminus of a fusion protein of the invention. References herein to attachment of a conjugate group to a fusion protein of the invention refers to both attachment of said conjugate group to N-terminus and / or C-terminus, and / or to one or more non-terminal amino acid unless expressly stated to the contrary. A conjugate group may modify one or more properties of the attached double-stranded oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance. Typically, a conjugate group further improves the half-life of a fusion protein of the invention. Without being bound by theory, it is believed that conjugation of a conjugate group to a fusion protein of the invention, increases its molecular weight and reduces renal clearance, allowing the fusion protein to remain in the plasma and complex with protein S. Thus, a conjugate group may have a molecular weight of at least 30kDa, at least 40kDa, at least 50kDa, at least 60kDa, at least 65kDa or more. Preferably, a conjugate group attached to a fusion protein of the present invention is inert and thereby has no effect on the function of the fusion protein of the invention. Any suitable interactions may be used to directly connect the conjugate protein to fusion protein according to the invention. By way of a non-limiting example, such direct connection may be mediated by covalent bonds or non-covalent interactions e.g., electrostatic interactions. A conjugate group may comprise or consist of a conjugate linker and / or a conjugate moiety, such as those described herein. For the avoidance of doubt, any and all disclosure herein in relation to the properties of fusion proteins of the invention applies equally and without reservation to conjugates of the invention comprising such fusion proteins. Thus, a conjugate of the invention typically possesses at least one advantageous property compared with wildtype TFPIα (e.g., the wildtype TFPIα of SEQ ID NO: 1). Non-limiting examples of such advantageous properties included increased binding affinity for protein S, increased inhibition of FXa activity, the ability to decrease fibrin deposition and / or increased plasma half-life. Preferably, conjugates of the invention typically possess any two, any three, or all 4 of these advantageous properties compared with wildtype TFPIα (e.g., the wildtype TFPIα of SEQ ID NO: 1). These properties are discussed in more detail below. Conjugate Moieties Conjugate moieties may be protein or non-protein. Non-limiting examples of protein conjugate moieties include, human serum albumin (HSA), an antibody Fc fragment, such as an IgG Fc fragment. Non-limiting examples of non-protein conjugate moieties include polyethylene glycol (PEG). Conjugate Linkers Conjugate moieties are typically attached to fusion proteins through conjugate linkers. In certain conjugates, the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an amino acid through a single bond). In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units. In certain embodiments, conjugate linkers comprise 1-30 linker-amino acids. In certain embodiments, conjugate linkers comprise 1-10 linker-amino acids, particularly 1-5 amino acids. In certain embodiments, conjugate linkers comprise exactly 4 or 5 amino acids. The conjugate group may be cleavable from the fusion protein of the invention. Thus, certain conjugate linkers may comprise one or more cleavable moieties. In certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety is a group of atoms comprising at least one cleavable bond. Cleavage may be mediated by any suitable process, for example use of a protease or by chemical cleavage. Preferably the conjugate group is not cleavable from the fusion protein of the invention. Thus, certain conjugate linkers may not comprise any cleavable moieties. Any appropriate linker may be used to connect the conjugate protein to fusion protein according to the invention. The linker may be a flexible linker or non-flexible linker, preferably a flexible linker. By way of a non-limiting example, such linkers may include so-called “GS” or “Glycine-Serine” linkers, as described herein. By way of non-limiting example, for example a GS linker typically takes the format (Gly4Ser)n, where n is a positive integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. The conjugate protein may be bound at any suitable location on a fusion protein according to the invention. By way of a non-limiting example, such suitable locations may include the N-terminus or the C-terminus of a fusion protein of the invention, most preferably the N-terminus. Complexes Complexes comprising a fusion protein or conjugate of the invention and a binding target are also provided. Any suitable binding target may be used to form a pre-made complex with a fusion protein of the invention. Preferably the binding target is Protein S or a functional fragment thereof. It will be appreciated that such complexes can be made in by a variety of methods which include combining a fusion protein or conjugate of the invention and the binding target at the desired molar ratio in a suitable buffer, or co-expressing a fusion protein or conjugate of the invention and a binding target in the same host cell or organism, allowing them to naturally form a complex during expression. Such complexes may be suitable for multiple purposes. By way of a non-limiting example such a complex may be useful as a laboratory reagent. In a further example, such a complex may be applied therapeutically, for example as part of a formulation given to a subject. For the avoidance of doubt, any and all disclosure herein in relation to the properties of fusion proteins of the invention applies equally and without reservation to complexes of the invention comprising such fusion proteins. Advantageous properties of the fusion proteins Fusion proteins (and conjugates) of the invention typically possess at least one advantageous property compared with wildtype TFPIα (e.g., the wildtype TFPIα of SEQ ID NO: 1). Non-limiting examples of such advantageous properties included increased binding affinity for protein S, increased inhibition of FXa activity, the ability to decrease fibrin deposition and / or increased plasma half-life. Preferably, fusion proteins (and conjugates) of the invention typically possess any two, any three, or all 4 of these advantageous properties compared with wildtype TFPIα (e.g., the wildtype TFPIα of SEQ ID NO: 1). These properties are discussed in more detail below. Binding affinity for protein S In the present disclosure, “KD” refers to the dissociation constant or equilibrium constant. The disassociation constant is a measure of the binding affinity between two molecules, such as a protein and its target molecule. In the present disclosure, the KDvalue refers to the affinity of the fusion protein (and conjugates), specifically the exogenous protein S binding moiety, according to the invention to bind to protein S. Suitably, the KDvalue of a protein may be measured by any appropriate technique, examples of which are known in the art and within the routine practice of one of ordinary skill in the art. Non-limiting examples of suitable techniques include surface plasmon resonance, isothermal titration calorimetry, fluorescence-based techniques such as fluorescence polarisation, microscale thermophoresis, bio-layer interferometry and radioligand binding assays. As exemplified herein, KDvalues may be calculated using ELISA. The exogenous protein S binding moiety typically binds to protein S with a KD of about 1nM or less, such as about 0.9nM or less, about 0.8nM or less, about 0.7nM or less, about 0.6nM or less, about 0.5nm or less, about 0.4nM or less, about 0.3nM or less, about 0.2nM or less or even about 0.1nM or less. As a result, the fusion protein of the invention typically binds to protein S with a KDof about 1nM or less, such as about 0.9nM or less, about 0.8nM or less, about 0.7nM or less, about 0.6nM or less, about 0.5nm or less, about 0.4nM or less, about 0.3nM or less, about 0.2nM or less or even about 0.1nM or less. Preferably, the exogenous protein S binding moiety binds to protein S with a KDof preferably about 0.5nM or less. For example, the exogenous protein S binding moiety according to the present invention binds to protein S with a KDof preferably about 0.5nm or less, about 0.4nM or less, about 0.3nM or less, about 0.2nM or less or even about 0.1nM or less. As a result, the fusion protein of the invention preferably binds to protein S with a KDof preferably about 0.5nm or less, about 0.4nM or less, about 0.3nM or less, about 0.2nM or less or even about 0.1nM or less. Comparatively, previous publications have identified that wildtype TFPIα found within the human body binds to protein S with an affinity of approximately 1µM. As demonstrated herein, fusion proteins of the invention typically bind to protein S with an affinity approximately 3 orders of magnitude higher that of wildtype TFPIα. The higher binding affinity demonstrated by the fusion protein according to the invention indicates its potential as a treatment for excessive coagulant conditions. Without being bound by theory, the high binding affinity of the fusion proteins (or conjugates) of the invention for protein S is believed to be associated with an increased plasma half-life, making the fusion proteins (or conjugates) of the invention suitable for clinical use at increased dosing intervals. Thus, a fusion protein (or conjugate) of the invention typically has at least 10 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, at least 750 times, at least 1000 times greater binding affinity for protein S compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1. Inhibition of FXa activity TFPI acts by inhibiting FXa activity. Thus, a fusion protein (or conjugate) of the invention has FXa inhibitory activity. A fusion protein (or conjugate) of the invention may be at least as effective in inhibiting FXa, preferably more effective in inhibiting FXa activity compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1. A fusion protein (or conjugate) of the invention may be more effective in inhibiting FXa activity compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1, in the presence of protein S. A fusion protein (or conjugate) of the invention may be less effective in inhibiting FXa, activity compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1, provided that the inhibition of FXa by said fusion protein (or conjugate) of the invention has a potential therapeutic effect. For example, a fusion protein (or conjugate) of the invention may have no more than 3-fold lower, no more than 2.5-fold lower, no more than 2-fold lower, no more than 1.5 lower, or less FXa inhibitory activity compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1. In other words, the FXa inhibitory activity of a fusion protein (or conjugate) of the invention may be essentially equivalent (e.g. statistically indistinguishable) from that of wildtype TFPIα, e.g. the TFPIα of SEQ ID NO: 1. Without being bound by theory, it is believed that administration of a fusion protein (or conjugate) of the invention which has essentially equivalent FXa inhibitory activity compared with wildtype TFPIα, e.g. the TFPIα of SEQ ID NO: 1 may be clinically beneficial compared with the administration of wildtype TFPIα (e.g. the TFPIα of SEQ ID NO: 1) as its increased plasma half-life allows it to persist within the patient for longer, exerting its therapeutic effect. The inhibition of FXa activity refers to the blocking or suppression of the enzymatic activity of Factor Xa, which is a key component in the blood clotting cascade. Factor Xa is responsible for converting prothrombin to thrombin, a critical step in the formation of blood clots. Suitably, there are several mechanisms that may be used to inhibit FXa activity such as direct factor Xa inhibitors or indirect factor Xa inhibitors. Direct factor Xa inhibitors directly bind to and inhibit the activity of Factor Xa. For example, direct Factor Xa inhibitors include rivaroxaban, apixaban, edoxaban, and betrixaban. Indirect factor Xa inhibitors that indirectly inhibit the activity of Factor Xa by targeting other components of the coagulation cascade. For example, Indirect factor Xa inhibitors include heparin and low-molecular-weight heparin (LMWH). A fusion protein (or conjugate) of the present invention may inhibit FXa activity more potently in the presence of protein S compared with a corresponding TFPIα or functional fragment thereof (e.g., SEQ ID NO: 1 or a functional fragment thereof) which is not fused with the exogenous protein S binding moiety. In other words, protein S may have a greater enhancing effect on the activity of a fusion protein (or conjugate) of the compared with the enhancing effect of protein S on wildtype TFPIα. Inhibition of a protein, such as FXa, may be measured by a variety of methods dependent on the specific protein such as enzyme activity assays, binding assays, western blotting, immunoprecipitation, cell-based assays, or mass spectrometry. Suitable techniques are well-known in the art and within the routine practice of one of ordinary skill in the art. Inhibition of a protein, such as FXa, may be quantified using units such as IC50(half- maximal inhibitory concentration), Ki (inhibition constant), percent inhibition, enzyme kinetics parameters and / or binding affinity. By way of non-limiting example, inhibition of FXa activity may be quantified by IC50. IC50is the concentration of the inhibitor required to inhibit the protein activity or function by 50%. It is an indicator of the potency of an inhibitor or drug compound in inhibiting the activity or function of a target protein or enzyme. For example, a low IC50value indicates that a lower concentration of the inhibitor is required to achieve a significant inhibitory effect. Alternatively, a high IC50value indicates that a higher concentration of the inhibitor is needed to achieve the same level of inhibition. This suggests a lower potency or efficacy of the inhibitor in inhibiting the target protein or enzyme. IC50values may be calculated using FXa activity assays such as those exemplified herein (using an FXa concentration of 0.5nM). A fusion protein (or conjugate) of the present invention may inhibit FXa activity with an IC50of 12nM or less. This corresponds to the concentration of a fusion protein (or conjugate) of the present invention needed to cause 50% inhibition of FXa, i.e. it is the IC50value of the fusion protein (or conjugate) itself. For example, the fusion protein in accordance with the present invention inhibits FXa with an IC50of about 20nM or less, 15nM or less, 12nM or less, 11nM or less, 10nM or less, about 9nM or less, about 8nM or less, about 7nM or less, about 6nM or less, about 5nM or less, about 4nM or less, about 3nM or less, about 2nM or less or about 1nM or less. Preferably, the fusion protein (or conjugate) in accordance with the present invention may inhibit FXa activity with an IC50of 15 nM, preferably 12nM or less. For example, the fusion protein (or conjugate) in accordance with the present invention may inhibit FXa activity with an IC50of about 15nM or less, about 14 nM or less, about 13nM or less, about 12.5nM or less, about 12nM or less, about 11.5nM or less, about 11.2nM or less or less. More preferably, the fusion protein (or conjugate) in accordance with the present invention may inhibit FXa activity with an IC50of about 12nM or less. For example, the fusion protein (or conjugate) in accordance with the present invention inhibits FXa activity with an IC50of about 11.5nM or less, about 11.4nM or less, about 11.3nM or less, or about 11.2nM or less. A fusion protein (or conjugate) of the present invention may inhibit FXa activity with an IC50of between 0-15nM. For example, the fusion protein (or conjugate) in accordance with the present invention inhibits FXa activity with an IC50of about 0-15nM, 0-14nM, 0-13nM, 0-12nM, 0-11nM, 0-10nM, 0-9nM, 0-8nM, 0-7nM, 0-6nM, 0-5nM, 0-4nM, 0-3nM, 0-2nM, 0-1nM, 0.01-10nM, 0.01-9nM, 0.01-8nM, 0.01-7nM, 0.01-6nM, 0.01-5nM, 0.01-4nM, 0.01-3nM, 0.01-2nM, 0.01- 1nM, 0.05-10nM, 0.05- 9nM, 0.05-8nM, 0.05-7nM, 0.05-6nM, 0.05-5nM, 0.05-4nM, 0.05-3nM, 0.05-2nM, 0.05-1nM, 0.1-10nM, 0.1- 9nM, 0.1-8nM, 0.1-7nM, 0.1-6nM, 0.1-5nM, 0.1-4nM, 0.1- 3nM, 0.1-2nM, 0.1-1nM, 0.5-10nM, 0.5- 9nM, 0.5-8nM, 0.5-7nM, 0.5-6nM, 0.5-5nM, 0.5-4nM, 0.5-3nM, 0.5-2nM, 0.5-1nM. Preferably the fusion protein (or conjugate) in accordance with the present invention inhibits FXa activity with an IC50of about 0.1-15nM, more preferably of about 0.1-12nM. Typically, a fusion protein (or conjugate) of the present invention inhibits FXa activity with an IC50of about 12nM or less in the absence of protein S, such as with an IC50of about 11.5nM or less, about 11nM or less, or about 10nM or less. A fusion protein (or conjugate) ofthe present invention may inhibit FXa activity with an IC50 of from about 7.5nM to about 12nM,such as from about 10nM to about 12nM, from about 10nM to about 11.5nM or from about 10.5nM to about 11.5nM in the absence of protein S. As exemplified herein, protein S may have a greater enhancing effect on the activity of a fusion protein (or conjugate) of the invention compared with the enhancing effect of protein S on wildtype TFPIα. Thus, IC50values may be defined as the concentration of protein S that half-maximally enhances a fusion protein (or conjugate) of the invention. Typically, protein S may enhance the FXa inhibitory activity of a fusion protein (or conjugate) of the present invention with an IC50of about 7.5nM or less, such as with an IC50of about 6.5 nM or less, about 5.5nM or less, about 4.5nM or less, about 3.5nM or less, about 2.5nM or less, about 1.5nM or less or about 0.5nM or less. Protein S may enhance the FXa inhibitory activity of a fusion protein (or conjugate) of the present invention with an IC50of from about 0.01nM to about 7.5nM, such as from about 0.05nM to about 7.5nM, from about 0.1nM to about 7.5nM, from about 0.01nM to about 6nM, from about 0.05nM to about 6nM, from about 0.1nM to about 6nM, from about 0.01nM to about 5nM, such as from about 0.05nM to about 5nM, or from about 0.1nM to about 5nM. Preferably, Protein S may enhance the FXa inhibitory activity of a fusion protein (or conjugate) in accordance with the present invention with an IC50about 0.01nM to about 7.5nM, more preferably an IC50about 0.1nM to about 5nM (using an FXa concentration of 0.5nM). Previous publications have identified Protein S may enhance the FXa inhibitory activity of wildtype TFPIα (e.g., the TFPIα of SEQ ID NO: 1) with an IC50of approximately 10 to 30nM. Herein, the present inventors have quantified that Protein S may enhance the FXa inhibitory activity of wildtype TFPIα with an IC50form protein S as low as 12nM. However, the inventors have surprisingly demonstrated that Protein S had a greater enhancing effect on the activity of a fusion protein (or conjugate) of the invention compared with the enhancing effect of protein S on wildtype TFPIα (e.g., the TFPIα of SEQ ID NO: 1), as evidenced by IC50values of reduced magnitude (e.g.5nM). Thus, Protein S enhances the FXa inhibitory activity of a fusion protein (or conjugate) of the invention typically by at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold or greater than wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1. Inhibition of TF-FVIIa activity TFPI can also act as a FXa-dependent inhibitor of TF-FVIIa. Thus, following inhibition of FXa activity, TFPI typically inhibits TF-FVIIa activity to reduce thrombin generation. Thus, a fusion protein (or conjugate) of the invention can act as a FXa-dependent inhibitor of TF-FVIIa. The inhibition of TF-FVIIa activity refers to the blocking or suppression of the complex TF-VIIa activity, which is a key component in the blood clotting cascade. The complex TF-VIIa is made up of tissue factor (TF) and Factor VIIa (VIIa). TF-VIIa is responsible for activating Factor X (FX) and converting it to its active form, FXa, a critical step in the formation of blood clots. Suitably, there are several mechanisms that may be used to inhibit TF-VIIa activity such as direct TF-VIIa inhibitors or indirect TF-VIIa inhibitors. Direct TF-VIIa inhibitors directly bind to and inhibit the activity of TF-VIIa. Indirect TF-VIIa inhibitors that indirectly inhibit the activity of TF-VIIa by targeting other components of the coagulation cascade. For example, Indirect TF-VIIa inhibitors include heparin and low-molecular-weight heparin (LMWH). A fusion protein (or conjugate) of the invention may be at least about as effective at inhibiting TF-FVIIa activity compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1. A fusion protein (or conjugate) of the invention may be less effective at inhibiting TF-FVIIa activity compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1, but may have other advantageous properties, thus providing a clinical benefit over wildtype TFPIα even if its TF-FVIIa inhibitory activity is lower than that of wildtype TFPIα. By way of non-limiting example, a fusion protein (or conjugate) of the invention may be retained within a patient for longer than wildtype TFPIα, thus providing a clinical benefit over wildtype TFPIα even if its TF-FVIIa inhibitory activity is lower than that of wildtype TFPIα. A fusion protein (or conjugate) of the present invention may inhibit TF-VIIa activity at least about comparably in the presence of protein S compared with a corresponding TFPIα or functional fragment thereof (e.g., SEQ ID NO: 1 or a functional fragment thereof) which is not fused with the exogenous protein S binding moiety. A fusion protein (or conjugate) of the invention may be less effective at inhibiting TF-FVIIa activity in the presence of protein S compared with wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1, but may have other advantageous properties, thus providing a clinical benefit over wildtype TFPIα even if its TF-FVIIa inhibitory activity is lower than that of wildtype TFPIα. By way of non-limiting example, a fusion protein (or conjugate) of the invention may be retained within a patient for longer than wildtype TFPIα, thus providing a clinical benefit over wildtype TFPIα even if it is less effective at inhibiting TF-FVIIa activity in the presence of protein S compared with wildtype TFPIα. Inhibition of a complex, such as TF-VIIa, may be measured by a variety of methods dependent on the specific complex such as enzyme activity assays, binding assays, western blotting, immunoprecipitation, cell-based assays, or mass spectrometry. Suitable techniques are well-known in the art and within the routine practice of one of ordinary skill in the art. Inhibition of a complex, such as TF-VIIa, may be quantified using units such as IC50(half-maximal inhibitory concentration), Ki (inhibition constant), percent inhibition, enzyme kinetics parameters and / or binding affinity. By way of non-limiting example, inhibition of TF-VIIa activity may be quantified by IC50.IC50is the concentration of the inhibitor required to inhibit the protein activity or function by 50%. By way of another non-limiting example, inhibition of TF-VIIa activity may be quantified by measuring the reduction of thrombin generation over a period of time. The decrease in thrombin generation may be compared with an appropriate control or reference. By way of non-limiting example, a fusion protein (or conjugate) of the invention may decrease thrombin generation at least comparably to a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety. By way of a further non-limiting example, a therapeutic dose of fusion protein (or conjugate) of the invention may decrease thrombin generation in a patient compared with a therapeutic dose of a conventional anticoagulant, such as LMWH or a DOAC. By way of a further non-limiting example, a therapeutic dose of fusion protein (or conjugate) of the invention may decrease thrombin generation in a patient compared with an untreated patient. The decrease may be as defined herein. A fusion protein (or conjugate) of the present invention may reduce thrombin generation wherein thrombin generation is decreased by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% or lower. A fusion protein (or conjugate) of the present invention may reduce thrombin generation wherein thrombin generation is decreased by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold or higher. A fusion protein (or conjugate) of the present invention may increase the lag time for thrombin generation (i.e. the duration required for the initiation of thrombin generation, corresponding to the initiation phase of coagulation targeted by TFPI (e.g., TFPIα)). Typically, a fusion protein (or conjugate) of the present invention may increase the lag time for thrombin generation by 2-fold at similar concentrations or concentrations preferably less than at least 3-fold higher than wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1. Previous publications have established that the wildtype TFPIα (e.g., the TFPIα of SEQ ID NO: 1) exhibits a dose-dependent reduction in thrombin generation. For example, in Hakeng et al (Proc Natl Acad Sci. 2006;103(9):3106-1, herein incorporated by reference), wildtype TFPIα decreased thrombin generation with an IC50of approximately 2nM during assays initiated by 1.4pM Tissue Factor (TF). The present inventors have shown that a fusion protein (or conjugate) according to the present invention decreases thrombin generation by at least an approximately similar amount when compared with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety. Thus, a fusion protein (or conjugate) of the invention may preferably decrease TF-VIIa activity in the presence of protein S comparably to wildtype TFPIα, e.g., compared with the TFPIα of SEQ ID NO: 1. A fusion protein (or conjugate) of the invention may be at least as effective in decreasing TF-VIIa activity in the presence of protein S compared with the ability of wildtype TFPIα to decrease TF-VIIa activity in the presence of protein S. Decrease in fibrin deposition. Fibrin is a fibrous protein, is a major component of blood clots and provides a mesh- like structure that stabilizes the clot. Fibrin is formed through the proteolytic cleavage of fibrinogen by the enzyme thrombin. The fusion protein (or conjugate) in accordance with the present invention may decrease fibrin deposition, preferably it decreases fibrin deposition in vivo. The decrease in fibrin deposition may be compared with an appropriate control or reference. By way of non-limiting example, a fusion protein (or conjugate) of the invention may decrease fibrin deposition compared with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety. By way of a further non-limiting example, a therapeutic dose of fusion protein (or conjugate) of the invention may decrease fibrin deposition in a patient compared with a therapeutic dose of a conventional anticoagulant, such as LMWH or a DOAC. By way of a further non-limiting example, a therapeutic dose of fusion protein (or conjugate) of the invention may decrease fibrin deposition in a patient compared with an untreated patient. The decrease may be as defined herein. By way of non-limiting example, a fusion protein (or conjugate) of the invention may decrease fibrin deposition by at least about 20%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, or more. The decrease may encompass complete inhibition. Said decrease in fibrin deposition may be compared with an appropriate control or reference, such as those described herein. Increased plasma half-life A fusion protein (or conjugate) of the invention typically has at least equivalent plasma half-life compared with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety. Preferably, a fusion protein (or conjugate) of the invention may have an increased plasma half-life compared with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety. Without being bound by theory, it is believed that fusion of the exogenous protein S binding moiety to TFPI (e.g., TFPIα) or functional fragment thereof typically creates a fusion protein that will form an obligate complex with protein S. The resulting complex has a molecular weight of at least 100 kDa, e.g., at least 100 kDa, at least 105 kDa, at least 110 kDa, at least 115 kDa, at least 120 kDa, or more (the combined molecular weight of the fusion protein and protein S). This molecular weight reduces renal clearance of the fusion protein, and so increases the half-life, particularly the plasma half-life of the fusion protein. A fusion protein (or conjugate) of the invention may have a decreased renal clearance compared with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety, wherein the decrease is as defined herein. By way of non-limiting example, a fusion protein of the invention may have renal clearance that is decreased by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% or lower. As used herein, decreased renal clearance encompasses a complete inhibition, such that the fusion protein may require metabolising before it can be cleared by the kidneys. As described herein, a fusion protein of the present invention may further be attached to a conjugate group, producing a conjugate of the invention. Attachment of a conjugate group to a fusion protein of the invention forms a resulting conjugate which is larger than the fusion protein formed by the exogenous protein S binding moiety and TFPI (e.g., TFPIα) or functional fragment thereof. Accordingly, when such conjugates are bound to protein S, the resulting complex typically has a molecular weight that is greater than that of an equivalent fusion protein (without a conjugate group) bound to protein S. Thus, such complexes typically have a molecular weight of at least 100 kDa, e.g., at least 100 kDa, at least 110 kDa, at least 120 kDa, at least 130 kDa, at least 140kDa, at least 150 kDa, at least 160kDa, at least 170kDa, or more (the combined molecular weight of the conjugate and protein S). It will be appreciated that the larger molecular weight of the resulting complex as described herein may have advantageous effects on both renal clearance and plasma half-life. A fusion protein of the Invention that is further bound to a conjugate group may have further decreased renal clearance (e.g. renal clearance rate) compared with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety and compared with a fusion protein of the invention without a conjugate protein bound. By way of non-limiting example, a conjugate of the invention may have renal clearance that is decreased by at least about 2-fold, at least about 5-fold, at least about 10- fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, at least about 55-fold, at least about 60-foldor higher. As used herein, decreased renal clearance encompasses a complete inhibition, such that the fusion protein may require metabolising before it can be cleared by the kidneys. A fusion protein of the present invention may a plasma half-life of at least 12 hours. For example, the fusion protein may have a plasma half-life of at least 12 hours, at least 16 hours, at least 20 hours, at least 24 hours, at least 28 hours, at least 32 hours, at least 36 hours, at least 40 hours, at least 44 hours or at least 48 hours, or more. Preferably, a fusion protein of the invention has a plasma half-life of at least 24 hours. By way of non-limiting example, a fusion protein of the present invention preferably may a plasma half-life of at least 24 hours, at least 28 hours, at least 32 hours, at least 36 hours, at least 40 hours, at least 44 hours or at least 48 hours. More preferably, a fusion protein of the invention may have a plasma half-life of about 48 hours. For example, the fusion protein may have a plasma half-life of about 43 hours, about 44 hours, about 45 hours, about 46 hours, about 47 hours, about 48 hours, about 49 hours, about 50 hours, about 51 hours, about 52 hours or about 53 hours. A conjugate of the present invention may have an increased plasma-life compared with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety and / or compared with an equivalent fusion protein of the invention without a conjugate group. By way of non-limiting example, a conjugate of the invention may have a plasma half-life of at least 12 hours, at least 16 hours, at least 20 hours, at least 24 hours, at least 28 hours, at least 32 hours, at least 36 hours, at least 40 hours, at least 44 hours or at least 48 hours, or more. Preferably, a conjugate of the invention has a plasma half-life of at least 24 hours. By way of non-limiting example, a fusion protein of the present invention preferably may a plasma half-life of at least 24 hours, at least 28 hours, at least 32 hours, at least 36 hours, at least 40 hours, at least 44 hours or at least 48 hours. More preferably, a fusion protein of the invention may have a plasma half-life of about 48 hours. For example, the fusion protein may have a plasma half-life of about 43 hours, about 44 hours, about 45 hours, about 46 hours, about 47 hours, about 48 hours, about 49 hours, about 50 hours, about 51 hours, about 52 hours or about 53 hours. Previous publications regarding common treatments for excessive coagulant conditions such warfarin, heparin and LMWH recognise limitations with the current treatment options. For example, warfarin has a slow onset and offset of action, 4-5 days. Although effective, patients receiving warfarin require monitoring to measure the level of anticoagulation so that dosing can be continually adjusted to keep patients within the therapeutic range. LMWH has a short half-life of approximately 1-2 hours and DOACs have a relatively short half- life of approximately 12 hours. As a result of their relatively short half-lives, and the doses required, relatively soon after patients are given these agents, there is a period where they may be over-anticoagulated (and therefore at risk of bleeding). Similarly, due to clearance, many patients also experience a period during which they are under-anticoagulated (and therefore not fully protected). This, therefore, necessitates regular and repeated dosing (daily or twice daily). Despite this, individuals may spend as much as half of the time outside of the therapeutic range (either above or below). The extended half-life of fusion proteins (and conjugates) in accordance with the present invention strikes a balance between too long and too short a half-life, which provides advantageous properties for clinical use. As discussed in more detail below, the properties of the fusion proteins (and conjugates) of the invention have the potential to allow longer intervals between doses (i.e., less frequent dosing), and / or to allow smaller concentrations of the fusion protein (or conjugate) to be administered. By way of non-limiting example, these properties potentially allow a weekly dosing schedule that is sufficient to maintain an individual within the therapeutic range, with no peaks or troughs of over-coagulation or under-coagulation. Polynucleotides and Vectors The present invention also provides a polynucleotide that encodes a fusion protein (or conjugate) of the invention. The term polynucleotide encompasses both DNA and RNA sequences. A polynucleotide of the invention may be used for recombinant expression of the fusion protein (or conjugate), or as a DNA / RNA vaccine. A polynucleotide of the invention may optionally be codon optimised for expression in a particular cell type, for example, eukaryotic cells (e.g., mammalian cells, yeast cells, insect cells or plants cells) or prokaryotic cells (e.g., E. coli). The term “codon optimised” refers to the replacement of at least one codon within a base polynucleotide sequence with a codon that is preferentially used by the host organism in which the polynucleotide is to be expressed. Typically, the most frequently used codons in the host organism are used in the codon- optimised polynucleotide sequence. Methods of codon optimisation are well known in the art. It will be understood by a skilled person that numerous different polynucleotides can encode the same polypeptide as a result of the degeneracy of the genetic code. It is also understood that skilled persons may, using routine techniques, make nucleotide substitutions that do not affect the polypeptide sequence encoded by the nucleic acid molecules to reflect the codon usage of any particular host organism in which the polypeptides are to be expressed. Therefore, unless otherwise specified, a “polynucleotide that encodes the fusion protein (or conjugate) of the invention” includes all polynucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The Invention provides a polynucleotide comprising a nucleic acid sequence encoding the fusion protein (or conjugate) of the invention, or an expression vector comprising said polynucleotide wherein in said expression vector said polynucleotide is operably linked to a promoter. The vector(s) may be a viral vector. Such a viral vector may be an adenovirus, a lentivirus, a poxvirus vector (such as a modified vaccinia Ankara (MVA)), or an adeno associated virus (AAV). Viral vectors are usually non-replicating or replication impaired vectors, which means that the viral vector cannot replicate to any significant extent in normal cells (e.g., normal human cells), as measured by conventional means – e.g., via measuring DNA synthesis and / or viral titre. Non-replicating or replication impaired vectors may have become so naturally (i.e., they have been isolated as such from nature) or artificially (e.g., by breeding in vitro or by genetic manipulation). There will generally be at least one cell-type in which the replication- impaired viral vector can be grown – for example, modified vaccinia Ankara (MVA) can be grown in CEF cells. In one embodiment, the vector is selected from a human or simian adenovirus or a poxvirus vector. Typically, the viral vector is incapable of causing a significant infection in an animal subject, typically in a mammalian subject such as a human or other primate. The vector(s) may be a DNA vector, such as a DNA plasmid. The DNA vector is typically capable of expression in a mammalian cell expression system. The vector may be suitable for expression in a bacterial and / or insect host cell or expression system, such as any of those exemplified herein. A non-limiting example of a suitable expression vector is a Pet15b vector, which may be optionally modified to encode a C-terminal tag, such as a hexa-histidine tag and / or a protease cleavage site, such as a TEV protease cleavage site. The vector(s) may be an RNA vector, such as a MRNA vector or a self-amplifying RNA vector (e.g., as in Geall, A.J. et al., Proc Natl Acad Sci USA 2012; 109(36) pp. 14604-9; incorporated herein by reference). The present invention may be a phage vector, such as an AAV / phage hybrid vector as described in Hajitou et al., Cell 2006; 125(2) pp.385-398; herein incorporated by reference. Vectors of the present invention also include virus-like particles (VLP), soluble proteins and / or fusion proteins comprising the antigens as described herein. Methods for generating VLPs are known in the art (see, for example, Brune et al. Sci. Rep. (2016), 19(6):19234, which is incorporated by reference in its entirety) and can readily be applied to the present invention. References herein to vectors of the invention may apply equally to VLP, soluble proteins and / or fusion proteins of the invention. The DNA and / or RNA vector(s) of the invention may be capable of expression in eukaryotic and / or prokaryotic cells, typically insect cells and / or mammalian cells. Typically, in the vector(s) the polynucleotide of the invention is operably linked to a suitable promoter. The polynucleotide may also be linked to a suitable terminator sequence. Suitable promoter and terminator sequences are well known in the art. The choice of promoter will depend on where the ultimate expression of the polynucleotide will take place. In general, constitutive promoters are preferred, but inducible promoters may likewise be used. The construct produced in this manner includes at least one part of a vector, in particular, regulatory elements. The vector is preferably capable of expressing the nucleic acid in a given host cell. Any appropriate host cell may be used, such as mammalian, bacterial, insect, yeast, and / or plant host cells. In addition, cell-free expression systems may be used. Such expression systems and host cells are standard in the art. The fusion proteins (and conjugates) of the invention may include a signal sequence (also referred to as a leader sequence), for example to assist in recombinant production and / or secretion. Any suitable signal sequence may be used, including conventional leader sequences known in the art. Suitable leader sequences include the endogenous signal sequences of TFPIα and / or C4BPβ, as described herein, or exogenous signal sequences, such as Bip leader sequences, which are commonly used in the art to aid secretion from insect cells and human tissue plasminogen activator leader sequence (Tpa), which is routinely used in viral, and DNA based vaccines and for protein vaccines to aid secretion from mammalian cell expression platforms. Alternatively, the fusion proteins of the invention may be the mature form in which the N-terminal signal peptide has been removed. The fusion proteins (and conjugates) of the invention may additionally comprise an N- or C-terminal tag, for example to assist in recombinant production and / or purification. Any N- or C-terminal tag may be used, including conventional tags known in the art. Suitable tags sequences include C-terminal hexa-histidine tags and the “C-tag” (the four amino acids EPEA at the C-terminus), which are commonly used in the art to aid purification from heterologous expression systems, e.g., insect cells, mammalian cells, bacteria, or yeast. Other examples of suitable tags include GST and MBP tags, or any other conventional tag which may be used to facilitate increased expression. In other embodiments, the epitopes / antigens, and fusion proteins (or conjugates) of the invention are purified from heterologous expression systems without the need to use a purification tag. The nucleic acid molecules of the Invention may be made using any suitable process known in the art. Thus, the nucleic acid molecules may be made using chemical synthesis techniques. Alternatively, the nucleic acid molecules of the invention may be made using molecular biology techniques. Vector(s) of the present invention may be designed in silico, and then synthesised by conventional polynucleotide synthesis techniques. The invention further provides a host cell comprising the fusion protein (or conjugate) according to the present invention, or the polynucleotide or expression vector according to the present invention, wherein optionally said host cell is a mammalian cell or an insect cell. In some preferred embodiments the host cell is an insect cell, preferably a Drosophila melanogaster cell, particularly an S2 cell or S2 derivative. Pharmaceutical Compositions and Formulations As described herein, the present inventors are the first to provide a fusion protein comprising a TFPI (e.g., TFPIα) or a functional fragment thereof and an exogenous protein S binding moiety, and conjugates comprising such fusion proteins. Said fusion proteins (and conjugates) have utility as a pharmaceutical composition in view of its half-life and magnitude of its ability to inhibit FXa. Accordingly, the invention provides a pharmaceutical composition comprising the fusion protein (or conjugate) according to the invention and a pharmaceutically acceptable carrier. Alternatively, or in addition the vaccine of the invention can further be combined with one or more of a salt, excipient, diluent, adjuvant, immunoregulatory agent and / or antimicrobial compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or with organic acids such as acetic, oxalic, tartaric, maleic, and the like. Salts formed with the free carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropyl amine, trimethylamine, 2- ethylamino ethanol, histidine, procaine, and the like. Administration of pharmaceutical compositions (e.g., those a comprising fusion protein or conjugate as defined herein and / or the polynucleotide as defined herein, and / or an expression vector) is generally by conventional routes e.g., intravenous, subcutaneous, intraperitoneal, or mucosal routes. The administration may be by parenteral injection, for example, a subcutaneous, intradermal, or intramuscular injection. Compositions comprising fusion proteins (or conjugates) of the invention may be particularly suited to administration by injection, for example intravenously, intramuscularly, intradermally, or subcutaneously. Accordingly, pharmaceutical compositions (e.g., those a comprising fusion protein or conjugate as defined herein and / or the polynucleotide as defined herein, and / or an expression vector) of the invention are typically prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid prior to injection may alternatively be prepared. The preparation may also be emulsified, or the peptide encapsulated in liposomes or microcapsules. Liquid compositions may be sterilised by filtration through a sterile filter using aseptic techniques before filling into suitable sterile containers (e.g., vials or ampoules) and sealing. Alternatively, if solution stability is adequate, the solution in its sealed containers may be sterilised by autoclaving. Additives such as preservative or bactericidal, suspending, or emulsifying agents and or local anaesthetic agents may be dissolved in the vehicle. Solid formulations (e.g., dry powders), which are dissolved or suspended in a suitable vehicle prior to use, may be prepared by filling pre-sterilised ingredients into a sterile container using aseptic technique in a sterile area. Alternatively, the ingredients may be dissolved into suitable containers using aseptic technique in a sterile area. The product is then lyophilised, and the containers are sealed aseptically. Parenteral suspensions, suitable for intramuscular, subcutaneous, or intradermal injection, are prepared in substantially the same manner, except that the sterile components are suspended in the sterile vehicle, instead of being dissolved and sterilisation cannot be accomplished by filtration. The components may be isolated in a sterile state or alternatively it may be sterilised after isolation, e.g., by gamma irradiation. The active ingredients (such as a fusion protein or conjugate as defined herein and / or the polynucleotide as defined herein, and / or an expression vector) are often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the vaccine may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, Ph buffering agents, and / or adjuvants which enhance the effectiveness of the vaccine. Generally, the carrier is a pharmaceutically acceptable carrier. Non-limiting examples of pharmaceutically acceptable carriers include water, saline, and phosphate-buffered saline. In some embodiments, however, the composition is in lyophilized form, in which case it may include a stabilizer, such as BSA. In some embodiments, it may be desirable to formulate the composition with a preservative, such as thiomersal or sodium azide, to facilitate long term storage. Examples of buffering agents include, but are not limited to, sodium succinate (Ph 6.5), and phosphate buffered saline (PBS; Ph 6.5 and 7.5). Additional formulations which are suitable for other modes of administration include suppositories and, in some cases, oral formulations or formulations suitable for distribution as aerosols. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%. Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. The dosage ranges for administration of the compositions of the present invention are those to produce the desired therapeutic effect. A therapeutically effective dose refers to an amount of the fusion protein to be used in a composition of the present invention which prevents, ameliorates, or treats the symptoms accompanying a disease or condition referred herein. Therapeutic efficacy and toxicity of the compound are typically determined in the art by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50(the dose therapeutically effective in 50% of the population) and LD50(the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. In general terms, it will be appreciated that the dosage range and interval required for a given pharmaceutical depends on the precise nature of the composition, the route of administration, the nature of the formulation, the age of the patient, the nature, extent or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician. In some preferred embodiments, the fusion protein is contained within the pharmaceutical composition at a concentration of 25nM or less, or 20nM or less, , such as 24nM or less, 23nM or less, 22nM or less, 21nM or less, 20nM or less, 19nM or less, 18nM or less, 17nM or less, 16nM or less, 15nM or less, 14nM or less, 13nM or less, 12nM or less, 11nM or less, 10nM or less, 9nM or less, 8nM or less, 7 nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, or 1nM or less, preferably 20nM or less, more preferably 15nM or less, even more preferably 10nM or less. The invention also provides a kit comprising a composition as described herein and instructions for therapeutic administration of said composition to a subject in need thereof. More precisely, the invention relates to a kit comprising a composition of the invention and instructions for therapeutic administration of said composition to an individual in need thereof As used herein, the term “instructions” refers to a publication, a recording, a diagram, or any other medium of expression which can be used to communicate how to perform a method or use of the invention, such as therapeutic administration of said composition to an individual in need thereof. Said instructions can, for example, be affixed to a container which comprises said composition or said kit. Therapeutic Indications The invention provides a fusion protein, conjugate, pharmaceutical composition, polynucleotide, or expression vector as described herein for use in a method of treating the human or animal body. The invention also provides the use of a fusion protein, conjugate, polynucleotide, or expression vector as described herein in the manufacture of a medicament for use in a method of treating the human or animal body. The invention further provides a method of treatment of the human or animal body, in a patient in need thereof, said method comprising administering a therapeutically effective amount of a fusion protein, conjugate, pharmaceutical composition, polynucleotide, or expression vector as described herein to said patient. The invention also provides a fusion protein, conjugate, pharmaceutical composition, polynucleotide, or expression vector as described herein for use as an inhibitor of coagulation. The invention also provides the use of a fusion protein, conjugate, polynucleotide, or expression vector as described herein in the manufacture of a medicament that is an inhibitor of coagulation. The invention further provides a method of treatment for the inhibition of coagulation, in a patient in need thereof, said method comprising administering a therapeutically effective amount of a pharmaceutical composition, fusion protein, conjugate, polynucleotide, or expression vector as described herein to said patient. The invention also provides a fusion protein, conjugate, pharmaceutical composition, polynucleotide, or expression vector as described herein for use as an anticoagulant. Thus, a fusion protein, conjugate, pharmaceutical composition, polynucleotide, or expression vector as described herein may be useful in treating conditions associated with excessive coagulation, by inhibiting coagulation. Such conditions would be readily identified by one of ordinary skill in the art. The invention also provides the use of a fusion protein, conjugate, polynucleotide, or expression vector as described herein in the manufacture of an anticoagulant medicament. The invention further provides a method of anticoagulant treatment in a patient in need thereof, said method comprising administering a therapeutically effective amount of a pharmaceutical composition, fusion protein, conjugate, polynucleotide, or expression vector as described herein to said patient. An anticoagulant refers to medication that inhibits or prevents the formation of blood clots. Common examples of anticoagulants include warfarin, heparin and LMWH, and DOACs such as enoxaparin, rivaroxaban, apixaban, and dabigatran. The invention also provides a fusion protein, conjugate, pharmaceutical composition, polynucleotide, or expression vector as described herein, for use in the prevention and / or treatment of an excessive coagulant condition. The invention also provides the use of a fusion protein, conjugate, polynucleotide, or expression vector as described herein in the manufacture of a medicament for use in the prevention and / or treatment of an excessive coagulant condition. The invention further provides a method of preventing and / or treating of an excessive coagulant condition, said method comprising administering a therapeutically effective amount of a pharmaceutical composition, fusion protein, conjugate, polynucleotide, or expression vector as described herein to a patient in need thereof. The term “excessive coagulant condition” encompasses thrombotic events, preferably venous thromboembolism, myocardial infarction, and stroke. Patients at elevated risk of similar conditions may also be treated according to the present invention. Excessive coagulant conditions, also known as hypercoagulable or prothrombotic conditions, are medical conditions or factors that increase the risk of abnormal blood clot formation (thrombosis) in the circulatory system. These conditions can lead to various complications, such as deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, and heart attack. According to the invention, the excessive coagulant conditions may be selected from Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), strokes, Myocardial Infarction (Heart Attack), Ischemic Stroke, Transient Ischemic Attack (TIA), Portal Vein Thrombosis, Mesenteric Artery Thrombosis, Renal Vein Thrombosis, or Retinal Artery or Vein Occlusion. In the context of the therapeutic uses and methods, the terms “subject,” “patient” and “individual” are used interchangeably to refer to any animal subject that would benefit from anticoagulant treatment. Typical animal subjects are mammals, such as primates, for example, humans. The treatments and preventative therapies of the present invention are applicable to a variety of different subjects of different ages. In the context of humans, the therapies are applicable to children (e.g., infants, children under 5 years old, older children or teenagers) and adults. In the context of other animal subjects (e.g., mammals such as primates), the therapies are applicable to immature subjects and mature / adult subjects. Ans. As used herein, the term “treatment” or “treating” embraces therapeutic or preventative / prophylactic measures against an excessive coagulant condition, and / or therapeutic or preventative / prophylactic use as an anticoagulant. As used herein, the term “preventing” includes preventing the initiation of coagulation and / or reducing the severity or intensity of coagulation. When used in a therapeutic application as described herein, a fusion protein or conjugate of the invention may be provided in any appropriate form, e.g., as a fusion protein, conjugate, vector, DNA plasmid, RNA vector or other form, as described herein. Any and all disclosure in relation to therapeutic applications of fusion proteins of the invention applies equally and without reservation to any form of the fusion protein. As described herein, the fusion proteins and conjugates of the present invention advantageously allow for micro-dosing, whereas conventional anticoagulants require dosing in larger amounts which can lead to dosing outside the therapeutic window. Previous publications have shown that common treatments for excessive coagulant conditions such warfarin, heparin and LMWH use dosages in the millimolar (mM) range. The fusion proteins (and conjugates) in accordance with the present invention advantageously allow for the use of nanomolar (nM) dosages, preferably doses in the low nM range (e.g. 50nM or less, particularly 25nM or less, as described herein) and hence allows for micro-dosing. Micro- dosing allows for precise control over the amount of anticoagulant administered, minimizing the risk of over-coagulation and may help to maintain more stable and consistent anticoagulation levels over time. As described herein, the fusion proteins and conjugates of the present invention may advantageously have at least approximately equivalent or increased potency when compared to with a corresponding TFPI (e.g., TFPIα) or functional fragment thereof which is not fused with the exogenous protein S binding moiety. Thus, preferably the fusion protein, conjugate, polynucleotide or expression vector as described herein is administered at a therapeutically effective concentration of 25nM or less, such as 24nM or less, 23nM or less, 22nM or less, 21nM or less, 20nM or less, 19nM or less, 18nM or less, 17nM or less, 16nM or less, 15nM or less, 14nM or less, 13nM or less, 12nM, or less, 11nM or less, 10nM or less, 9nM or less, 8nM or less, 7 nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, or 1nM or less, preferably 25nM or less, more preferably 20nM or less, even more preferably 15nM or less. The fusion protein, conjugate, polynucleotide, or expression vector as described herein may be administered once every day, every other day, twice a week, once a week, once every two weeks, once every month or more. The frequency of administration of the fusion protein, conjugate, polynucleotide, or expression vector as described herein is typically lower than the frequency of administration of a conventional anticoagulant, such as LMWH or a DOAC. Preferably the fusion protein, conjugate, polynucleotide, or expression vector as described herein is administered once or twice a week, more preferably once a week. As discussed herein, for common treatments for excessive coagulant conditions such DOACs, heparin and LMWH, there is a period where they may be over-anticoagulated (and therefore at risk of bleeding). Similarly, due to clearance, many patients also experience a period during which they are under-anticoagulated (and therefore not fully protected). This, therefore, necessitates regular and repeated dosing (daily or twice daily). Previous publications have revealed that individuals may spend as much as 50% of the time outside of the therapeutic range (either above or below). The fusion protein, conjugate, polynucleotide, or expression vector as described herein may decrease the time spent outside of the therapeutic range (either above or below). By way of non-limiting example, the amount of time that a patient treated according to the present invention may spend outside of the therapeutic range (either above or below) may be reduced to less than 20% of the time, such as less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, or less. Preferably, the amount of time that a patient treated according to the present invention may spend outside of the therapeutic range (either above or below) may be reduced to less than 10%. Purification Methods The invention further provides methods for the purification of a fusion protein or conjugate in accordance with the present invention. The method of purification may be used to manufacture a fusion protein or conjugate used in products for use according to the invention. In particular, the invention provides a method for purifying a fusion protein or conjugate according to the invention, preferably a fusion protein, the method comprising: (a) a chelation chromatography step; and (b) Ni2+chelation chromatography; and (c) size exclusion chromatography; where steps (a) to (c) are carried out sequentially. Proteins suitable for purification using a method of the invention may be the same as those considered elsewhere in the present specification in the context of the fusion protein (or conjugate) of the invention. The methods of the invention involve a first purification step utilising chelation chromatography. A second purification step utilising Ni2+chelation and finally a third gel filtration / size exclusion chromatography purification step Step (a) of the method may comprise elution of the fusion protein bound to immobilised Cu2+using increasing concentrations of imidazole. By way of example, the increasing concentrations of imidazole may be 10mM, 100mM, and / or 400mM. Step (b) of the method may comprise elution of the fusion protein using a step or linear gradient of imidazole, typically a linear gradient. Preferably a 30-100mM imidazole gradient is used, with the fusion protein eluting from a column containing immobilised Ni2+at about 100- 200mM imidazole. Step (c) typically involves gel filtration of the material isolated from step (b) after concentration (e.g., on spin concentrators). Separation of the fusion protein according to size will isolate the fusion protein from any remaining trace contaminants of different molecular weight. SEQUENCE HOMOLOGY An amino acid modification according to the invention may be a substitution, deletion, addition, or other modification, including post-translational modification, unless the relevant disclosure explicitly says otherwise. Preferably said modifications are amino acid substitutions. In other words, the amino acid at a specified position within the antigen of the invention is substituted by a naturally occurring or non-naturally occurring amino acid that is different to the amino acid present at that position in the sequence from which the antigen of the invention is derived. Alternatively, the amino acid at a specified position within the antigen of the invention may be modified post-translationally. Post-translational modifications include glycosylation’s, acetylation’s, acylation’s, de-aminations, phosphorylisations, isoprenylisations, glycosyl phosphatidyl inositolisations and further modifications known to a person skilled in the art. The modification of one or more amino acid position as described herein may be performed, for example, by specific mutagenesis, or any other method known in the art. In embodiments in which one or more amino acid position is substituted relative to the corresponding antigen from which the antigen of the invention is derived, the substitution may be a conservative substitution or a non-conservative substitution. A conservative substitution is defined as substitution by an amino acid pertaining to the same physiochemical group to the amino acid present in the antigen from which the antigen of the invention is derived. A non- conservative amino acid substitution is defined as substitution by an amino acid pertaining to a different physiochemical group to the amino acid present in the antigen from which the antigen of the invention is derived. In more detail, amino acids are, in principle, divided into different physiochemical groups. Aspartate and glutamate belong to the negatively charged amino acids. Histidine, arginine, and lysine belong to the positively charged amino acids. Asparagine, glutamine, serine, threonine, cysteine, and tyrosine belong to the polar amino acids. Glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, and tryptophan belong to the non-polar amino acids. Aromatic side groups are to be found among the amino acids histidine, phenylalanine, tyrosine, and tryptophan. Thus, as a non-limiting example, a conservative substation may involve the substitution of a non-polar amino acid by another non-polar amino acid, such as substituting leucine with isoleucine. As another non- limiting example, a non-conservative substitution may involve the substation of a non-polar amino acid (e.g., leucine) with a negatively charged amino acid (e.g., aspartate), a positively charged amino acid (e.g. arginine), or a polar amino acid (e.g. asparagine). Conventional methods for determining amino acid sequence identity are known in the art. The terms “sequence identity” and “sequence homology” are considered synonymous in this specification. By way of example, a polypeptide of interest may comprise an amino acid sequence having at least 70, 75, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 99 or 100% amino acid sequence identity with the amino acid sequence of a reference polypeptide. There are many established algorithms available to align two amino acid sequences. Typically, one sequence acts as a reference sequence, to which test sequences may be compared. The sequence comparison algorithm calculates the percentage sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Alignment of amino acid sequences for comparison may be conducted, for example, by computer implemented algorithms (e.g., GAP, BESTFIT, FASTA or TFASTA), or BLAST and BLAST 2.0 algorithms. The BLOSUM62 table shown below Is an amino acid substitution matrix derived from about 2,000 local multiple alignments of protein sequence segments, representing highly conserved regions of more than 500 groups of related proteins (Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-10919, 1992; incorporated herein by reference). Amino acids are indicated by the standard one-letter codes. The percent identity is calculated as: Total number of identical matches __________________________________________ x 100 [length of the longer sequence plus the number of gaps Introduced into the longer sequence in order to align the two sequences] BLOSUM62 table A R N D C Q E G H I L K M F P S T W Y V A 4 R -1 5 N -2 0 6 D -2 -2 1 6 C 0 -3 -3 -3 9 Q -1 1 0 0 -3 5 E -1 0 0 2 -4 2 5 G 0 -2 0 -1 -3 -2 -2 6 H -2 0 1 -1 -3 0 0 -2 8 I -1 -3 -3 -3 -1 -3 -3 -4 -3 4 L -1 -2 -3 -4 -1 -2 -3 -4 -3 2 4 K -1 2 0 -1 -3 1 1 -2 -1 -3 -2 5 M -1 -1 -2 -3 -1 0 -2 -3 -2 1 2 -1 5 F -2 -3 -3 -3 -2 -3 -3 -3 -1 0 0 -3 0 6 P -1 -2 -2 -1 -3 -1 -1 -2 -2 -3 -3 -1 -2 -4 7 S 1 -1 1 0 -1 0 0 0 -1 -2 -2 0 -1 -2 -1 4 T 0 -1 0 -1 -1 -1 -1 -2 -2 -1 -1 -1 -1 -2 -1 1 5 W -3 -3 -4 -4 -2 -2 -3 -2 -2 -3 -2 -3 -1 1 -4 -3 -211 Y -2 -2 -2 -3 -2 -1 -2 -3 2 -1 -1 -2 -1 3 -3 -2 -2 2 7 V 0 -3 -3 -3 -1 -2 -2 -3 -3 3 1 -2 1 -1 -2 -2 0 -3 -1 4 In a homology comparison, the identity may exist over a region of the sequences that is at least 10 amino acid residues in length (e.g., at least 15, 20, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500 or 520 amino acid residues in length) – e.g., up to the entire length of the reference sequence. Substantially homologous polypeptides have one or more amino acid substitutions, deletions, or additions. In many embodiments, those changes are of a minor nature, for example, involving only conservative amino acid substitutions. Conservative substitutions are those made by replacing one amino acid with another amino acid within the following groups: Basic: arginine, lysine, histidine; Acidic: glutamic acid, aspartic acid; Polar: glutamine, asparagine; Hydrophobic: leucine, isoleucine, valine; Aromatic: phenylalanine, tryptophan, tyrosine; Small: glycine, alanine, serine, threonine, methionine. Substantially homologous polypeptides also encompass those comprising other substitutions that do not significantly affect the folding or activity of the polypeptide; small deletions, typically of 1 to about 30 amino acids (such as 1-10, or 1-5 amino acids); and small amino- or carboxyl-terminal extensions, such as an amino-terminal methionine residue, a small linker peptide of up to about 20-25 residues, or an affinity tag. SEQUENCE INFORMATION SEQ ID NO 1: Full amino acid sequence of TFPIα SEQ ID NO 2: K1 domain amino acid sequence SEQ ID NO 3: K2 domain amino acid sequence SEQ ID NO 4: TFP1 amino acid sequence used in the Super-TFPI fusion SEQ ID NO 5: Full C4BPβ amino acid sequence SEQ ID NO 6: CCP1 domain amino acid sequence SEQ ID NO 7: CCP2 domain amino acid sequence SEQ ID NO 8: C4BP beta amino acid sequence used in the exemplified Super-TFPI fusion SEQ ID NO 9: Protein S amino acid sequence SEQ ID NO 10: Exemplary Super-TFPI fusion protein SEQ ID NO 11: Exemplary Super-TFPI fusion protein with purification modifications SEQ ID NO 12: GS linker SEQ ID NO 13: GS linker SEQ ID NO 14: GS linker SEQ ID NO 15: GS linker SEQ ID NO 16: GS linker Where an initial Met amino acid residue or a corresponding initial codon is indicated in any of the following SEQ ID Nos, said residue / codon is optional. SEQ ID NO 1: Full amino acid sequence of TFPIα MIYTMKKVHALWASVCLLLNLAPAPLNADSEEDEEHTIITDTELPPLKLMHSFCAFKADDGPCKAIMKRFFFNIF TRQCEEFIYGGCEGNQNRFESLEECKKMCTRDNANRIIKTTLQQEKPDFCFLEEDPGICRGYITRYFYNNQTKQC VKNM Bold = signal peptide Italics = N-terminal domain Underlined = K1 domain Double-underlined = K2 domain Dash-underlined = K3 domain Italics and bold = C-terminal domain SEQ ID NO 2: K1 domain amino acid sequence AFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMC SEQ ID NO 3: K2 domain amino acid sequence CFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNIC SEQ ID NO 4: TFP1 amino acid sequence used in the Super-TFPI fusion DSEEDEEHTIITDTELPPLKLMHSFCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKM CTRDNANRIIKTTLQQEKPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDG PNGFQVDNYGTQLNAVNNSLTPQSTKVPSLFEFHGPSW Underlined = K1 domain Double-underlined = K2 domain SEQ ID NO 5: Full C4BPβ amino acid sequence MFFWCACCLMVAWRVSASDAEHCPELPPVDNSIFVAKEVEGQILGTYVCIKGYHLVGKKTLFCNASKEWDNTTTE LKESGMTMEELKYSLELKKAELKAKLL Bold = signal peptide Italics = N-terminal domain Underlined = CCP1 domain Double-underlined = CCP2 domain Dash-underlined = CCP3 domain Italics and bold = C-terminal domain SEQ ID NO 6: CCP1 domain amino acid sequence EHCPELPPVDNSIFVAKEVEGQILGTYVCIKGYHLVGKKTLFCNASKEWDNTTTECRL SEQ ID NO 7: CCP2 domain amino acid sequence GHCPDPVLVNGEFSSSGPVNVSDKITFMCNDHYILKGSNRSQCLEDHTWAPPFPICKS SEQ ID NO 8: C4BP beta amino acid sequence used in the exemplified Super-TFPI fusion SDAEHCPELPPVDNSIFVAKEVEGQILGTYVCIKGYHLVGKKTLFCNASKEWDNTTTECRLGHCPDPVLVNGEFS SSGPVNVSDKITFMCNDHYILKGSNRSQCLEDHTWAPPFPICKS Underlined = CCP1 domain Double-underlined = CCP2 domain SEQ ID NO 9: Protein S amino acid sequence MRVLGGRCGALLACLLLVLPVSEANFLSKQQASQVLVRKRRANSLLEETKQGNLERECIEELCNKEEAREVFEND PETDYFYPKYLVCLRSFQTGLFTAARQSTNAYPDLRSCVNAIPDQCSPLPCNEDGYMSCKDGKASFTCTCKPGWQ GEKCEFDINECKDPSNINGGCSQICDNTPGSYHCSCKNGFVMLSNKKDCKDVDECSLKPSICGTAVCKNIPGDFE CECPEGYRYNLKSKSCEDIDECSENMCAQLCVNYPGGYTCYCDGKKGFKLAQDQKSCEVVSVCLPLNLDTKYELL YLAEQFAGVVLYLKFRLPEISRFSAEFDFRTYDSEGVILYAESIDHSAWLLIALRGGKIEVQLKNEHTSKITTGG DVINNGLWNMVSVEELEHSISIKIAKEAVMDINKPGPLFKPENGLLETKVYFAGFPRKVESELIKPINPRLDGCI RSWNLMKQGASGIKEIIQEKQNKHCLVTVEKGSYYPGSGIAQFHIDYNNVSSAEGWHVNVTLNIRPSTGTGVMLA LVSGNNTVPFAVSLVDSTSEKSQDILLSVENTVIYRIQALSLCSDQQSHLEFRVNRNNLELSTPLKIETISHEDL QRQLAVLDKAMKAKVATYLGGLPDVPFSATPVNAFYNGCMEVNINGVQLDLDEAISKHNDIRAHSCPSVWKKTKN S Bold = signal peptide SEQ ID NO 10: Exemplary Super-TFPI fusion protein DSEEDEEHTIITDTELPPLKLMHSFCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKM CTRDNANRIIKTTLQQEKPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDG PNGFQVDNYGTQLNAVNNSLTPQSTKVPSLFEFHGPSWSDAEHCPELPPVDNSIFVAKEVEGQILGTYVCIKGYH Italics = N-terminal domain (from TFPIα) Underlined = K1 domain (from TFPIα) Double-underlined = K2 domain (from TFPIα) Bold = N-terminal domain (from C4BPβ) Dash-underlined = CCP1 domain (from C4BPβ) Wavy-underlined = CCP2 domain (from C4BPβ) SEQ ID NO 11: Exemplary Super-TFPI fusion protein with purification modifications DSEEDEEHTIITDTELPPLKLMHSFCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKM CTRDNANRIIKTTLQQEKPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDG PNGFQVDNYGTQLNAVNNSLTPQSTKVPSLFEFHGPSWSDAEHCPELPPVDNSIFVAKEVEGQILGTYVCIKGYH Italics = N-terminal domain (from TFPIα) Underlined = K1 domain (from TFPIα) Double-underlined = K2 domain (from TFPIα) Bold = N-terminal domain (from C4BPβ) Dash-underlined = CCP1 domain (from C4BPβ) Wavy-underlined = CCP2 domain (from C4BPβ) Italics and bold = TEV protease site Dotted-underlined = His tag SEQ ID NO 12: GS linker GGGGS SEQ ID NO 13: GS linker GGGGSGGGGS SEQ ID NO 14: GS linker GGGGSGGGGSGGGGS SEQ ID NO 15: GS linker GGGGSGGGGSGGGGSGGGGS SEQ ID NO 16: GS linker GGGGSGGGGSGGGGSGGGGSGGGGS EXAMPLES The invention will be further clarified by the following examples, which are intended to be purely exemplary of the invention and are in no way limiting. Example 1: Design and Construction of K1K2-C4BP The K1K2-C4BP fusion protein was strategically designed, leveraging comprehensive understanding of TFPIα functionality. The fusion protein was designed with specific requirements for the K1 and K2 domains of TFPIα, known for their role in inhibiting TF-VIIa and FXa, as well as the necessity for the remaining part of the molecule to interact effectively with protein S. The fusion protein's sequence was designed such that the amino acid sequence merged the TFPI K1 and K2 domains seamlessly with the CCP1 and CCP2 domains of C4BP beta. The fusion protein's sequence was then transformed into a codon-optimized sequence, optimizing it for efficient expression in a host organism. Subsequently, this codon-optimized sequence was employed to construct the fusion protein, allowing for its cloning into an expression vector and thus enabling recombinant expression in transfected cells. The K1K2-C4BP fusion protein was successfully designed and constructed. Example 2: Purification of the fusion protein Methods and Results First Purification of Super-TFPI (K1K2-C4BP). Chromatogram of K1K2-C4BP purification by Fast Protein Liquid Chromatography Conditioned media from stably transfected S2 insect cells were passed over a chelating column. Proteins which did not bind to the column are specified as flow through (FT). Fractions, containing separated proteins, are eluted at increasing concentrations of Imidazole (10mM, 100mM, 400mM). This Fast Protein Liquid Chromatography was the first purification step (Figure 2A). Western blot analysis of purification fractions from Fast Protein Liquid Chromatography Fractions eluted from the Fast Protein Liquid Chromatography were analysed by Western Blot using anti-His antibodies which recognises super-TFPI / K1K2-C4BP. The band intensity indicates relative amount of K1K2-C4BP within the fraction (Figure 2B). The predicted molecular weight of K1K2-C4BP is ≈50 kDa, with most being present in the 10mM Imidazole fraction. The box indicates the elution fraction that was further purified (Figure 2B). Second Super-TFPI / K1K2-C4BP purification step The fraction eluted from 10mM Imidazole of the first purification step was further purified using Ni2+-chelating column. Proteins were eluted at 30mM, 30-100mM linear gradient, and 200mM of Imidazole (Figure 2C). Coomassie analysis of second purification. Fractions from the second purification step were analysed by SDS-PAGE and Instant Blue staining, with K1K2-C4BP being eluted in the 200mM Imidazole fractions (Figure 2D). Third Super-TFPI / K1K2-C4BP purification step. Size exclusion chromatogram of K1K2- C4BP purification. The 200mM Imidazole fractions from the second purification step were loaded on a size exclusion chromatography which separates proteins based on their size. Larger proteins elute first, with the peak indicating the K1K2-C4BP protein (Figure 2E). Super-TFPI was successfully isolated with a very high degree of purity for characterisation (Figure 2E). Coomassie analysis for size exclusion chromatography. Fractions from the third purification step were analysed by SDS-PAGE and Instant Blue staining. Analysis revealed most K1K2-C4BP are within F-I fractions, shown by the density of the stained bands (Figure 2F). The box indicates fractions used for functional analyses (Figure 2F). Example 3: A fusion protein according to the present invention binds to Protein S with high affinity Methods The fusion protein according to the present invention, super-TFPI herein after, was assessed to quantify its predicted ability to interact with protein S with high affinity using ELISA-style plate binding assays. Super-TFPI / K1K2-C4BP (triangle, Figure 3), C4BP β-chain (circle, Figure 3) or WT TFPIα (square, Figure 3) were immobilised in a 96-well plate. Thereafter, increasing concentrations (0-5nM) of human protein S was applied and binding detected with anti-protein S antibody. Binding was plotted as a function of protein S concentration from which binding constants (KD) were derived. Results Super-TFPI / K1K2-C4BP binds protein S with very high affinity (KD 0.5nM), very similar to C4BP β-chain (Figure 3). Conversely, under these conditions, TFPIα does not bind detectably, prior studies suggest it binds with low affinity (KD ~1µM), specifically with an affinity ~3 orders of magnitude lower that super-TFPI (Figure 3). Super-TFPI binds with very high affinity to Protein S. Example 4: A fusion protein according to the present invention inhibits FXa in the absence of Protein S Methods The ability of super-TFPI to inhibit FXa was assessed by performing FXa activity assays in the presence of increasing TFPIα or super-TFPI concentrations (Figure 4). The ability of either TFPI (Figure 4A) or Super-TFPI (K1K2-C4BP) (Figure 4B) to inhibit FXa was assayed using a FXa activity assay into which increasing concentrations of TFPI or super-TFPI were titrated. Proteolysis of a chromogenic substrate was monitored over time. With increasing concentrations of both inhibitors there was a dose-dependent reduction in FXa activity. FXa activity at 30 mins was plotted as a function of inhibitor concentration, from which the IC50 for FXa inhibition was derived (Figure 4C). Results Both TFPIα and super-TFPI dose-dependently reduced FXa activity. These data reveal that super-TFPI is a slightly weaker inhibitor of FXa (in the absence of protein S) with an IC5011.1nM compared to TFPIα with an IC50of 4.9nM. This is likely due to the absence of the K3 domain and C-terminal tail that (although not involved directly in FXa inhibition) contribute modestly to the inhibitory process. However, the data was measured in artificial conditions that are not representative of the real host cell conditions (i.e., the absence of Protein S). Therefore, these data may not accurately represent how super TFPI will perform in the human host. To obtain a more accurate set of performance data, further, more representative, conditions were trialled. Example 5: A fusion protein according to the present invention inhibits FXa potently in the presence of Protein S Methods To better recreate a more representative set of conditions the efficiency with which protein S augments the inhibitory function of either TFPIα or super-TFPI was quantified (Figure 5). These conditions better represent the natural system found within the human body and are therefore more exemplary of real-world conditions. FXa activity assays were performed in the presence of a single concentration of either TFPIα (Figure 5B) or super-TFPI (Figure 5A). Into this, increasing concentrations of protein S were titrated to assess the efficiency with which protein S enhances the inhibitory function of either TFPIα or super-TFPI. FXa activity was then plotted as a function of protein S concentration to derive the IC50, which corresponds to the concentration of protein S that half- maximally enhances TFPIα or super-TFPI (Figure 5). Results It was found that protein S enhances TFPIα with an IC50of 12nM (i.e. the concentration of protein S required to half-maximally enhance TFPIα) (which is slightly lower than we have previously reported (20-30nM). However, super-TFPI was enhanced with an IC50of 5nM (i.e. super-TFPI requires lower concentrations of protein S for it to be maximally enhanced), consistent with the higher affinity of super-TFPI for protein S and revealing that super-TFPI is more efficiently enhanced by protein S than TFPIα (Figure 5). Example 6: A fusion protein according to the present invention has an anticoagulant effect in vivo. Methods Super TFPI was then used in a murine model of thrombosis to evaluate its anticoagulant effect (Figure 6). A laser-injury model was used in which the cremaster muscle arterioles are exteriorised and placed under the objective of a microscope. Mice were injected with antibodies to label platelets and fluorescently labelled fibrinogen to enable visualisation of fibrin deposited. A standardised injury using a laser was focussed onto the vessel through the microscope objective and then platelet and fibrin depositions (markers of thrombus formation) were monitored in real time by video microscopy. In these initial assays, assessment of whether super-TFPI can function as an anticoagulant in vivo was completed. To do this, mice were injected with an inhibitory antibody (14D1) that blocks all endogenous murine TFPI and fibrin deposition measured (Figure 6). Results From the laser injury model (data presented are median of 12 thrombi) an increase in fibrin deposition over time was observed when no super TFPI was introduced. Conversely, when these same experiments were performed in mice receiving the 14D1 antibody and 4nM (final plasma concentration) super-TFPI, there is a profound decrease in the amount of fibrin deposited (Figure 6). These data reveal that super-TFPI can exert a profound anticoagulant effect in mice and can diminish fibrin deposition in vivo. Example 7: A fusion protein according to the present invention inhibits TF-VIIa in the presence of Protein S comparably to TFPIα. Methods Thrombin generation assays were performed using protein S depleted plasma with coagulation initiated using 1pM TF.0-10nM super-TFPI was added (Figures 7A & 7B) or 0- 10nM WT TFPI (Figures 7C & 7D) with either 10nM protein S (Figures 7A & 7C) or 50nM protein S (Figures 7B & 7D). Thrombin generation was measured over time. Super TFPI exhibited potent anticoagulant function seen by the reduction in thrombin generation in the presence of protein S (albeit modestly less potently than WT TFPI. Similar experiments using super-TFPI in the absence of protein S (Figure 7E) or presence of 50nM protein S (Figure 7F) demonstrate that super TFPI function is almost completely dependent upon protein S cofactor function. The reduction of thrombin generation, an indicator of the inhibition TF-VIIa activity, was then plotted on graphs representative of super-TFPI and TFPIα in the presence of varying concentrations of Protein S. Results Both TFPIα and super-TFPI reduced thrombin generation. These data reveal that super-TFPI is a slightly weaker TF-VIIa inhibitor than TFPIα. However, the difference between the super-TFPI and TFPIα was minimal meaning that super-TFPI reduced thrombin generation and hence inhibited TF-VIIa with a similar and comparable effect to TFPIα (Figure 7).

Claims

CLAIMS 1. A fusion protein comprising: a) a TFPIα or a functional fragment thereof; and b) an exogenous protein S binding moiety.

2. The fusion protein according to claim 1, wherein the exogenous protein S binding moiety binds to protein S with a KDof 1nM or less, preferably 0.5nM or less.

3. The fusion protein according to claim 1 or 2, wherein the TFPIα or functional fragment thereof comprises or consists of one or more of the Kunitz (K) domains K1, K2 and / or K3 domains, wherein optionally: (a) the TFPIα or functional fragment thereof comprises or consists of (i) the K1 domain; (ii) the K2 domain; (iii) the K3 domain; (iv) the K1 and K2 domains; (v) the K1 and K3 domains; (vi) the K2 and K3 domains; or (vii) the K1, K2 and K3 domains; preferably wherein the TFPIα or functional fragment thereof comprises or consists of the K1 and K2 domains; and / or (b) (i) the K1 and K2 domains; and / or (ii) the K2 and K3 domains; are connected by a linker, preferably wherein said linker is the endogenous linker present in TFPIα.

4. The fusion protein according to any of the preceding claims, wherein the TFPIα or functional fragment thereof comprises or consists of an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 1 or a functional fragment thereof.

5. The fusion protein according to any of the preceding claims, wherein the TFPIα or functional fragment thereof comprises: (a) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 2; and / or (b) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 3; and wherein the TFPIα or functional fragment thereof retains the ability to inhibit the TF-FVIIa complex and / or FXa, preferably FXa.

6. The fusion protein according to any of the preceding claims, wherein the TFPIα or functional fragment thereof comprises or consists of an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO:4, which retains the ability to inhibit the TF-FVIIa complex and / or FXa, preferably FXa.

7. The fusion protein according to any of the preceding claims, wherein the protein S binding moiety is C4BPβ or a functional fragment thereof.

8. The fusion protein according to claim 7, wherein the C4BPβ or functional fragment thereof comprises an amino acid sequence of at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 5 or a functional fragment thereof.

9. The fusion protein according to claim 7 or 8, wherein the C4BPβ or functional fragment thereof comprises or consists of at least CCP domain, wherein optionally: (a) the C4BPβ or functional fragment thereof comprises or consists of: (i) CCP1; (ii) CCP2; (iii) CCP3; (iv) CCP1 and CCP2; (v) CCP2 and CCP3; (vi) CCP1 and CCP3; or (vii) CCP1, CCP2 and CCP3; preferably wherein the C4BPβ or functional fragment thereof comprises or consists of: CCP1 and CCP2; and / or (b) (i) the CCP1 and CCP2 domains; and / or (ii) the CCP2 and CCP3 domains; are connected by a linker, preferably wherein said linker is the endogenous linker present in C4BPβ.

10. The fusion protein according to claim 9, wherein the C4BPβ or functional fragment thereof comprises: (a) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 6; and / or (b) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 7; and wherein the C4BPβ or functional fragment thereof retains the ability to bind protein S.

11. The fusion protein according to any one of claims 7 to 10, wherein the C4BPβ or functional fragment thereof comprises or consists of an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 8, which retains the ability to bind protein S.

12. The fusion protein according to any one of claims 1 to 6, wherein the protein S binding moiety is an antibody which binds to protein S, preferably an scFv.

13. The fusion protein according any one of the preceding claims, wherein the fusion protein or functional fragment thereof comprises: (a) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO: 10; or (b) an amino acid sequence having at least 80% sequence identity, preferably at least 90% sequence identity, to the amino acid sequence of SEQ ID NO:

11.

14. The fusion protein according to any of the preceding claims, which decreases fibrin deposition, preferably which decreases fibrin deposition in vivo.

15. The fusion protein according to any one of the preceding claims, which has a plasma half-life of at least 12 hours, preferably at least 24 hours, more preferably about 48 hours.

16. A conjugate comprising the fusion protein of any one of the preceding claims, and a conjugate group, wherein optionally the conjugate group is attached to the N- terminus and / or C-terminus of the fusion protein, preferably at the N-terminus.

17. The conjugate according to claim 16, wherein the conjugate group comprises a conjugate linker and a conjugate moiety, and optionally wherein: (a) the conjugate linker (i) comprises or consists of a GS linker; or (ii) consists of a single bond; and / or (b) the conjugate moiety is selected from the group consisting of: human serum albumin (HSA); an antibody Fc fragment; or polyethylene glycol (PEG), preferably the conjugate moiety is HSA.

18. A pharmaceutical composition comprising the fusion protein of any one of claims 1 to 15 or the conjugate of claim 16 or 17 and a pharmaceutically acceptable carrier, wherein preferably the fusion protein is comprised within the pharmaceutical composition at a concentration of 25nM or less, preferably 20nM or less, more preferably 15nM or less.

19. A polynucleotide comprising a nucleic acid sequence encoding the fusion protein of any one of claims 1 to 15, the conjugate of claim 16 or 17, or an expression vector comprising said polynucleotide, wherein in said expression vector said polynucleotide is operably linked to a promoter.

20. A host cell comprising the fusion protein of any one of claims 1 to 15, the conjugate of claim 16 or 17, or the polynucleotide or expression vector of claim 19, wherein optionally said host cell is a mammalian cell or an insect cell.

21. The fusion protein according to any one of claims 1 to 15, the conjugate of claim 16 or 17, or the pharmaceutical composition of claim 18 for use in a method of treating the human or animal body.

22. The fusion protein according to any one of claims 1 to 15, the conjugate of claim 16 or 17, or the pharmaceutical composition of claim 18 for use as an inhibitor of coagulation.

23. The fusion protein, conjugate, or pharmaceutical composition for use of claim 22, for use in the prevention and / or treatment of a thrombotic event, preferably venous thromboembolism, myocardial infarction or stroke.

24. The fusion protein, conjugate, or pharmaceutical composition for use of claim 22 or 23, wherein the fusion protein or conjugate is administered to a subject in need thereof in a therapeutically effective amount of 25nM or less, preferably 20nM or less, more preferably 15 nM or less.

25. A method for purifying the fusion protein according to claim 1 to 15, or the conjugate of claim 16 or 17, the method comprising: a) a chelation chromatography step; and b) Ni2+chelation chromatography; and c) size exclusion chromatography;where steps (a) to (c) are carried out sequentially and optionally wherein:(i) step (a) comprises elution of the fusion protein or conjugate using increasingconcentrations of imidazole, optionally wherein the increasing concentrations of imidazole are 10mM, 100mM, and / or 400mM; and / or(ii) step (b) comprises elution of the fusion protein or conjugate using a 30-100mMlinear gradient, of imidazole, with the fusion protein eluting at about 200mM imidazole.

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