Hemostatic Elastin-like Polypeptides for Clot Stabilization
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Solution Overview
Problem
Current hemostatic systems face challenges in achieving effective hemostasis due to difficulties in obtaining specific high-affinity binders that discriminate between gelled fibrin and circulating fibrinogen, leading to inadequate clot formation and stability, especially in trauma-induced coagulopathy.
Innovation Solution
Development of hemostatic elastin-like polypeptides (hELPs) comprising Q-block and K-block sequences that are recognized by human transglutaminase factor XIIIa, allowing for covalent crosslinking into fibrin networks, enhancing clot mechanical properties, resistance to plasmin degradation, and accelerating gelation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If synthetic polymers or particles are used to target fibrin, then hemostatic control can be achieved, but it is difficult to obtain specific high-affinity binders that discriminate between gelled fibrin and circulating fibrinogen
Solution Approach 1:
The invention extracts and utilizes the natural enzymatic recognition mechanism of FXIIIa for Q-block and K-block sequences. Instead of attempting to create synthetic binders that discriminate between fibrin and fibrinogen, the patent employs the endogenous transglutaminase enzyme's inherent specificity for these peptide sequences, which are naturally present in fibrin but not fibrinogen.
Solution Approach 2:
The invention introduces Q-block and K-block peptide sequences as intermediary elements that mediate the interaction between the hemostatic system and fibrin. These peptide sequences serve as recognition sites for FXIIIa, enabling specific targeting of fibrin networks without requiring complex synthetic binders.
2Reliability
If fibrin networks are formed through natural coagulation, then clot formation occurs, but clot stability and mechanical properties are insufficient under trauma-induced coagulopathy conditions
Solution Approach 1:
The invention incorporates Q-block and K-block sequences into the hemostatic agent in advance, preparing them for immediate recognition and crosslinking by FXIIIa upon contact with fibrin. This preliminary configuration ensures rapid clot stabilization without requiring additional activation steps or complex in vivo processing.
Solution Approach 2:
The invention creates a composite hemostatic system combining synthetic or recombinant polypeptides containing Q-block and K-block sequences with natural fibrin networks. This composite approach enhances the mechanical properties and stability of the clot by integrating engineered peptide structures with the native fibrin matrix through FXIIIa-mediated crosslinking.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
hELPs improve clot biophysical properties, reduce pore sizes, and accelerate gelation, providing enhanced hemostatic efficacy and stability under conditions of dilutive coagulopathy, thereby addressing the limitations of existing hemostatic systems.
Implementation Method 1
Fb networks are subsequently stabilized through covalent cross-links formed by a reaction between lysine and glutamine residues catalysed by activated clotting-associated transglutaminase, FXIIIa
Implementation Method 2
a reaction between lysine and glutamine residues catalysed by activated clotting-associated transglutaminase, FXIIIa
Implementation Method 3
The knobs non-covalently bind to sites referred to as holes A and B on the distal ends of neighbouring Fb/Fg, allowing Fb to self-associate in a half-staggered conformation and form protofibrils
Implementation Method 4
Fb networks form when activated thrombin cleaves fibrinopeptides from the precursor protein fibrinogen (Fg), revealing sequences known as knobs A and B
Data Source
AI summary
The present invention relates to a hemostatic elastin-like polypeptide comprising a glutamine embedded in a Q-block sequence and, optionally, a lysine embedded in a K-block sequence. Under physiological setting, the Q-block sequence and the K-block sequence are recognized by human transglutaminase factor XIIIa and crosslinked with fibrin networks. The present invention also relates to the medical use of the polypeptide, to a nucleic acid sequence encoding the polypeptide, to an expression vector comprising the nucleic acid sequence, and to a cell comprising the nucleic acid sequence or the expression vector.