Methods and compositions for deactivating a blood coagulation interfering compound

Abstract

Disclosed herein are methods and compositions for deactivating a blood coagulation interfering compound. Certain methods disclosed herein comprise mixing a sample with activated carbon to thereby bind and deactivate the blood coagulation interfering compound, and performing a blood or blood component coagulation test on the sample containing the activated carbon, wherein the activated carbon is in a composition with one or more blood or blood component coagulation test reagents or additives before it is mixed with the sample. Also disclosed herein are compositions comprising activated carbon and one or more blood or blood component coagulation test reagents or additives.

Description

Methods and compositions for deactivating a blood coagulation interfering compoundCROSS REFERENCE

[0001] The present application claims priority to Australian provisional application numbers 2023902996, filed 16 September 2023, and 2023903957, filed 6 December 2023, the entire contents of which are herein incorporated by cross reference in their entirety.FIELD OF THE INVENTION

[0002] The invention relates to methods and compositions for deactivating a blood coagulation interfering compound in a sample for blood or blood component coagulation testing. However, it will be appreciated that the invention is not limited to this particular field of use.BACKGROUND

[0003] The following discussion of the prior art is provided to place the invention in an appropriate technical context and enable the advantages of it to be more fully understood. It should be appreciated, however, that any discussion of the prior art throughout the specification should not be considered as an express or implied admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0004] Blood clotting tests are used to investigate abnormalities of the coagulation mechanism responsible for bleeding and clotting disorders. Such tests are typically carried out by mixing a blood or blood component (e.g. plasma) sample with a clot- stimulating reagent and timing how long it takes for a clot to form under defined conditions. Clot detection can be performed with a tilted test tube method or in an instrument which measures increased viscosity, impedance or turbidity (e.g. if the sample is a plasma sample). Blood or plasma clotting times which are longer than a normal range imply a defect in some part of the clotting mechanism.

[0005] Clotting tests are also widely used to monitor the effect of traditional antithrombotic agents, such as heparin and warfarin which prolong the clotting times of such tests in a predictable manner. The new generation of anticoagulants: direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, edoxaban and others also prolong most clotting test results, although generally in a less predictable manner. Dabigatran is an antithrombin whereas the other agents are inhibitors of factor Xa. Other low molecular weight specific enzyme inhibitors such as milvexian which targets factor Xia are in clinical trials. The widespread and increasing use of blood coagulation interfering compounds, such as DOACs, by patients therefore often interferes withscreening tests for the diagnosis of underlying coagulation abnormalities. Accordingly, there is a need for agents which can deactivate blood coagulation interfering compounds, such as DOACs, in patient blood or blood component (e.g. plasma) samples so that the DOACs do not interfere with blood or blood component coagulation tests.

[0006] Activated carbon, or activated charcoal, has been used for many years as an adsorbent for removing unwanted organic compounds and pollutants from fluids and gases. It is commonly used orally for treating gastrointestinal problems and diarrhea. In more recent times it has been used for treating poison and drug overdoses such as paracetamol by haemoperfusion. The blood is usually anticoagulated with heparin and pumped through cartridges containing activated charcoal before being returned to the patient. Early versions of these adsorbent charcoal cartridges caused partial haemolysis, activated other blood cells and bound platelets causing thrombocytopenia. Partial blocking of these unwanted interactions could be achieved with albumin and dextrans. Further safety improvements included coating the activated charcoal particles with polymers such as nitrocellulose, hexamethyl disiloxane, hydroxyethyl methacrylate (HEMA) and other hydrophilic acrylate polymers. However, such coatings tend to slow down the binding of unwanted drugs and reduce the adsorbent capacity of the activated charcoal.

[0007] Activated charcoal has been used in powder or mini-tablet form for pre-treating blood plasma samples in vitro for removing the unwanted effect of DOACs. This sample pretreatment involves mixing a test plasma with activated charcoal in minitablet or powder form, then centrifuging down the used adsorbent and removing the supernatant plasma for immediate testing or storage. Common coagulation screening tests such as the activated partial thromboplastin time (APTT) can then be used to provide a result free of any DOAC prolonging effect. This procedure works well but takes time (10-20 minutes) and is inconvenient for large scale use.

[0008] Accordingly, there is a need for an improved method or procedure which can eliminate the unwanted effect of blood coagulation interfering compounds, such as DOACs, from coagulation test results more quickly and easily.

[0009] It is an object of the present invention to overcome or ameliorate one or more the disadvantages of the prior art, or at least to provide a useful alternative.SUMMARY OF THE INVENTION

[0010] The inventors of the present application have surprisingly found that activated carbon in a composition with one or more blood or blood component coagulation test reagents or additives can be added to blood or blood component samples to deactivate blood coagulation interfering compounds, such as DOACs in a manner whereby coagulant tests can be performed directly on thesamples mixed with the activated carbon, i.e. without the need to remove the activated carbon from the sample by using, e.g., an additional filtration or centrifugation step prior to testing. In particular for testing methods where the clotting endpoint is detected physically by visco-elastic testing, and any other method not affected by the presence of activated carbon. This includes chromogenic tests where the effect of carbon particles can be eliminated by using dual wavelength absorbance measurement.

[0011] The inventors of the present application have further surprising discovered that activated carbon can be added directly to most APTT and various other clotting reagents without causing significant changes in their diagnostic efficacy other than for removal of DOACs. This addition can be achieved, for example, with the minitablets described earlier or with concentrated suspensions of activated charcoal (e.g. DOAC Stop-Liquid).

[0012] The inventors of the present application have further surprisingly discovered that activated carbon, when combined with one or more blood or blood component coagulation test reagents, can be added to blood or blood component samples, or to routine and specialized reagents to deactivate blood coagulation interfering compounds, in particular for small anticoagulant molecules such as DOACs, Ila, XI(a), XII(a) or XII(a) inhibitors. This can be done in a manner that may allow coagulant tests to be performed directly on the samples mixed with the activated carbon or in contact with immobilized activated carbon on a surface, without the need to remove the activated carbon from the sample by using additional steps, such as filtration, centrifugation or magnetic separation prior to testing, in particular for testing methods where the clotting endpoint is detected physically by visco-elastic or sonorheometric (SEER) testing, Clot Wave form Analysis, and other methods not affected by the presence of activated carbon.

[0013] The inventors of the present application have further surprising discovered that activated carbon can be added directly to most APTT and other clotting reagents that generate FXa and / or Flla, without causing significant changes in their diagnostic efficacy other than for removal of small anticoagulants molecules, particularly DOACs. This addition can be achieved, for example, with the minitablets described earlier or with concentrated suspensions of activated charcoal (DOAC Stop- Liquid).

[0014] In a first aspect of the invention there is provided a method of deactivating a blood coagulation interfering compound in a sample for blood or blood component coagulation testing, said method comprising: mixing the sample with activated carbon to thereby bind and deactivate the blood coagulation interfering compound; and performing a blood or blood component coagulation test on the sample containing the activated carbon; wherein the activated carbon is in a composition with one or more blood or blood component coagulation test reagents or additives before it is mixedwith the sample, optionally wherein the activated carbon is in a composition with one or more blood or blood component coagulation test reagents before it is mixed with the sample.

[0015] The following options may be used in conjunction with the first aspect, either individually or in any combination.

[0016] In certain embodiments, from about 0.05 % (w / v) to about 12.5 % (w / v) of the activated carbon is mixed with the sample or reagent, relative to the total volume of the sample, or from about 0.01 % (w / v) to about 12.5 % (w / v), about 0.028 % (w / v) to about 12.5 % (w / v), about 0.046 % (w / v) to about 12.5 % (w / v), about 0.064 % (w / v) to about 12.5 % (w / v), about 0.082 % (w / v) to about 12.5 % (w / v), about 0.1 % (w / v) to about 12.5 % (w / v), about 0.49 % (w / v) to about 12.5 % (w / v), about 0.88 % (w / v) to about 12.5 % (w / v), about 1.27 % (w / v) to about 12.5 % (w / v), about 1.66 % (w / v) to about 12.5 % (w / v), about 2.05 % (w / v) to about 12.5 % (w / v), about 2.44 % (w / v) to about 12.5 % (w / v), about 2.83 % (w / v) to about 12.5 % (w / v), about 3.22 % (w / v) to about 12.5 % (w / v), about 3.61 % (w / v) to about 12.5 % (w / v), about 4 % (w / v) to about 12.5 % (w / v), about 0.01 % (w / v) to about 11.7 % (w / v), about 0.01 % (w / v) to about 10.6 % (w / v), about 0.01 % (w / v) to about 9.5 % (w / v), about 0.01 % (w / v) to about 8.4 % (w / v), about 0.01 % (w / v) to about 7.3 % (w / v), about 0.01 % (w / v) to about 6.2 % (w / v), about 0.01 % (w / v) to about 5.1 % (w / v), about 0.01 % (w / v) to about 4 % (w / v), about 0.1 % (w / v) to about 4 % (w / v), about 0.88 % (w / v) to about 4 % (w / v), about 1.66 % (w / v) to about 4 % (w / v), about 2.44 % (w / v) to about 4 % (w / v), about 3.22 % (w / v) to about 4 % (w / v), about 0.1 % (w / v) to about 3.22 % (w / v), about 0.1 % (w / v) to about 2.44 % (w / v), about 0.1 % (w / v) to about 1.66 % (w / v), or about 0.1 % (w / v) to about 0.88 % (w / v). It may be greater than or equal to about 0.005 % (w / v), 0.01 % (w / v), 0.019 % (w / v), 0.028 % (w / v), 0.037 % (w / v), 0.046 % (w / v), 0.055 % (w / v), 0.064 % (w / v), 0.073 % (w / v), 0.082 % (w / v), 0.091 % (w / v), 0.1 % (w / v), 0.49 % (w / v), 0.88 % (w / v), 1.27 % (w / v), or 1.66 % (w / v). It may be less than or equal to about 12.5 % (w / v), 11.7 % (w / v), 10.6 % (w / v), 9.5 % (w / v), 8.4 % (w / v), 7.3 % (w / v), 6.2 % (w / v), 5.1 % (w / v), 4 % (w / v), 3.61 % (w / v), 3.22 % (w / v), 2.83 % (w / v), or 2.44 % (w / v). In certain embodiments, it may be, for example, about 0.005 % (w / v), 0.01 % (w / v), 0.019 % (w / v), 0.028 % (w / v), 0.037 % (w / v), 0.046 % (w / v), 0.055 % (w / v), 0.064 % (w / v), 0.073 % (w / v), 0.082 % (w / v), 0.091 % (w / v), 0.1 % (w / v), 0.295 % (w / v), 0.49 % (w / v), 0.685 % (w / v), 0.88 % (w / v), 1.08 % (w / v), 1.27 % (w / v), 1.46 % (w / v), 1.66 % (w / v), 1.86 % (w / v), 2.05 % (w / v), 2.24 % (w / v), 2.44 % (w / v), 2.64 % (w / v), 2.83 % (w / v), 3.02 % (w / v), 3.22 % (w / v), 3.42 % (w / v), 3.61 % (w / v), 3.8 % (w / v), 4 % (w / v), 6.2 % (w / v), 7.3 % (w / v), 8.4 % (w / v), 9.5 % (w / v), 10.6 % (w / v), 11.7 % (w / v), or 12.5 % (w / v). In certain specific embodiments, from about 0.05 % (w / v) to about 4 % (w / v), or from about 0.1 % (w / v) to about 2 % (w / v), of the activated carbon is mixed with the sample or reagent, relative to the total volume of the sample. In certainembodiments, from about 0.05 mg / mL to about 40 mg / mL, or from about 1 mg / mL to about 20 mg / mL of activated carbon is mixed with the sample, relative to the total volume of the sample.

[0017] In certain embodiments, the blood coagulation interfering compound is selected from the group consisting of: direct thrombin inhibitors, factor Xia and factor Xa inhibitors. In certain embodiment, the blood coagulation interfering compound is selected from the group consisting of, factor Xa, XI, Xia, XII, Xlla inhibitors or direct thrombin inhibitors. In certain specific embodiments, the blood coagulation interfering compound is a direct oral anticoagulant (DO AC). The DOACs may, for example, be selected from the group consisting of: dabigatran, milvexian, rivaroxaban, apixaban, betrixaban and edoxaban. In certain embodiments, the DOACs may be selected from the group consisting of: dabigatran, milvexian, rivaroxaban, apixaban, betrixaban, edoxaban, milvexian and assundexian. The features of compounds which can be removed by activated carbon may include one or more of the following: low molecular weight (<5kD), positive charge and hydrophobicity.

[0018] In certain embodiments, the activated carbon is in a composition with one or more blood or blood component coagulation test reagents or additives before it is mixed with the sample. The one or more blood or blood component coagulation test reagents or additives may be, for example, selected from the group consisting of Activated partial thromboplastin time (APTT) test reagents, Dilute Russell's viper venom time (dRVVT) test reagents, Prothrombin time (PT) test reagents, Non-activated clotting time (NAPTT) reagents, Surface activated clotting time (SACT) reagents, Activated clotting time (ACT) reagents, Recalcification clotting time (RCT) reagents in regular or in diluted form, Calcium chloride solution and any other solutions such as activated protein C or a protein C activator used to modify any test.

[0019] In certain embodiments, the activated carbon is mixed with and at least partially suspended in the sample.

[0020] In certain embodiments, the blood or blood component coagulation test is selected from the group consisting of Activated partial thromboplastin time (APTT) tests, Dilute Russell's viper venom time (dRVVT) tests, Prothrombin time (PT) tests, Non-activated clotting time (NAPTT) tests, Surface activated clotting time (SACT) tests, Activated clotting time (ACT) tests, or Recalcification clotting time (RCT) tests.

[0021] In certain embodiments, the clotting endpoint of the blood or blood component coagulation test may be detected with a visco-elastic sensing method such as those in Stage clotting instruments, Rotem (IL / Werfen, USA) or Clotpro (Enicor, Germany) devices. Activated carbon containing reagents may provide clotting time results directly, with reduced effect from DOACs without needing pre-treatment. The inventive method is unlike the current practice which requiresaddition of activated carbon to test plasma, preincubation, centrifugation and separation to remove the activated carbon prior to performing the blood or blood component coagulation test.

[0022] In certain embodiments the formation of the enzyme thrombin leading to the fibrin clotting endpoint can be detected using a chromogenic substrate releasing the chromogen paranitro aniline. The yellow paranitroaniline can be detected despite the partial obscuring effect of associated carbon particles by using differential optical absorbance measurements at two wavelengths, for example, at 405nm and 490nm. The paranitroaniline can also be detected by using an electroactive electrode system such as in the Xprecia Stride and Xprecia Prime point of care medical devices (Siemens, Germany). Fluorogenic thrombin substrates can also be used whereby the fluorescent marker of thrombin generation can be detected without interference from carbon particles.

[0023] The inventive method may be particularly advantageous in two-stage clotting tests such as the APTT in which a plasma sample is typically preincubated with an APTT reagent for two to five minutes at 37°C, then recalcified and timed to a clotting endpoint. The APTT reagent contains contact activators such as silica dispersion, kaolin or ellagic acid compounds. These agents activate clotting factors XII, XI and prekallikrein to start off the clotting mechanism. The APTT reagents also contain procoagulant phospholipid to substitute for platelets in the clotting mechanism after recalcification. Neither of these essential components of the reagent seem to be affected by the presence of activated carbon with the reagent.

[0024] In certain embodiments, the activated carbon is in the form of a suspension, i.e. a heterogenous mixture in which solid particles of the activated carbon are suspended in a bulk liquid, and if mixed thoroughly do not settle out (i.e. form a sediment) after a rest (i.e. non-mixing) period of at least 1 minute. These liquid suspensions can be used to dilute the activated charcoal into the coagulation reagents being used in the actual clotting tests.

[0025] In certain embodiments, the suspension further comprises a sugar, carbohydrate or polymer thereof. The sugar may be, for example, a monosaccharide, disaccharide or polysaccharide. In certain embodiments, the sugar is selected from the group consisting of dextrose (glucose), galactose, maltose, maltobiose, sucrose, fructose, glucosamine, trehalose and lactose. In certain embodiments, the sugar is trehalose. The carbohydrate polymer may be dextran, hydroxyethyl starch or similar substituted polymer. In certain embodiments, higher molecular weight polymers may be preferred. The inventors of the present invention have surprisingly discovered that such carbohydrate polymers can prevent the coating of AC to hydrophobic surfaces (e.g. the surface of a plastic vial). AC suspensions typically coat such surfaces either immediately or over time. The resulting lack of visibility can make it difficult to view the contents and pick up samples with a pipettor. With such carbohydrate polymer additives present in the suspension, clear containers madeof polystyrene, polyethylene and siliconized glass can be used for storage and clean dispensing. The carbohydrate polymer can also prevent coating and adhesion of the AC suspension to plastic pipette tips or tubes, thus potentially allowing for more accurate dispensing.

[0026] In certain embodiments the concentration of the sugar, carbohydrate or polymer thereof in the suspension may be from about 0.1 % (w / v) to about 15 % (w / v), or from about 1.4 % (w / v) to about 15 % (w / v), about 1.8 % (w / v) to about 15 % (w / v), about 2.2 % (w / v) to about 15 % (w / v), about 2.6 % (w / v) to about 15 % (w / v), about 3 % (w / v) to about 15 % (w / v), about 3.4 % (w / v) to about 15 % (w / v), about 3.8 % (w / v) to about 15 % (w / v), about 4.2 % (w / v) to about 15 % (w / v), about 4.6 % (w / v) to about 15 % (w / v), about 5 % (w / v) to about 15 % (w / v), about 5.4 % (w / v) to about 15 % (w / v), about 5.8 % (w / v) to about 15 % (w / v), about 6.2 % (w / v) to about 15 % (w / v), about 6.6 % (w / v) to about 15 % (w / v), about 7 % (w / v) to about 15 % (w / v), about 1 % (w / v) to about 14 % (w / v), about 1 % (w / v) to about 13 % (w / v), about 1 % (w / v) to about 13 % (w / v), about 1 % (w / v) to about 12 % (w / v), about 1 % (w / v) to about 11 % (w / v), about 1 % (w / v) to about 10 % (w / v), about 1 % (w / v) to about 9.4 % (w / v), about 1 % (w / v) to about 8.6 % (w / v), about 1 % (w / v) to about 7.8 % (w / v), about 1 % (w / v) to about 7 % (w / v), about 3 % (w / v) to about 7 %(w / v), about 3.8 % (w / v) to about 7 % (w / v), about 4.6 % (w / v) to about 7 % (w / v), about 5.4 %(w / v) to about 7 % (w / v), about 6.2 % (w / v) to about 7 % (w / v), about 3 % (w / v) to about 6.2 %(w / v), about 3 % (w / v) to about 5.4 % (w / v), about 3 % (w / v) to about 4.6 % (w / v), about 0.1 %(w / v) to about 1 % (w / v), or about 3 % (w / v) to about 3.8 % (w / v). It may be greater than or equal to about 0.1 % (w / v), 1 % (w / v), 1.2 % (w / v), 1.4 % (w / v), 1.6 % (w / v), 1.8 % (w / v), 2 % (w / v), 2.2 % (w / v), 2.4 % (w / v), 2.6 % (w / v), 2.8 % (w / v), 3 % (w / v), 3.4 % (w / v), 3.8 % (w / v), 4.2 % (w / v), or 4.6 % (w / v). It may be less than or equal to about 15 % (w / v), 14 % (w / v), 13 % (w / v), 13 % (w / v), 12 % (w / v), 11 % (w / v), 10 % (w / v), 9.4 % (w / v), 8.6 % (w / v), 7.8 % (w / v), 7 % (w / v), 6.6 % (w / v), 6.2 % (w / v), 5.8 % (w / v), 5.4 % (w / v), 4 % (w / v), 3 % (w / v), 2 % (w / v), or 1 % (w / v). In certain embodiments, it may be, for example, about 0.1 % (w / v), 0.2 % (w / v), 0.3 % (w / v), 0.4 % (w / v), 0.5 % (w / v), 0.6 % (w / v), 0.7 % (w / v), 0.8 % (w / v), 0.9 % (w / v), 1 % (w / v), 1.2 % (w / v), 1.4 % (w / v), 1.6 % (w / v), 1.8 % (w / v), 2 % (w / v), 2.2 % (w / v), 2.4 % (w / v), 2.6 % (w / v), 2.8 % (w / v), 3 % (w / v), 3.2 % (w / v), 3.4 % (w / v), 3.6 % (w / v), 3.8 % (w / v), 4 % (w / v), 4.2 % (w / v), 4.4 % (w / v), 4.6 % (w / v), 4.8 % (w / v), 5 % (w / v), 5.2 % (w / v), 5.4 % (w / v), 5.6 % (w / v), 5.8 % (w / v), 6 % (w / v), 6.2 % (w / v), 6.4 % (w / v), 6.6 % (w / v), 6.8 % (w / v), 7 % (w / v), 8.6 % (w / v), 9.4 % (w / v), 10 % (w / v), 11 % (w / v), 12 % (w / v), 13 % (w / v), 13 % (w / v), 14 % (w / v), or 15 % (w / v).

[0027] In certain embodiments, the concentration of the activated carbon in the suspension may be from about 5 mg / mL to about 200 mg / mL, or from about 14 mg / mL to about 200 mg / mL, about 23 mg / mL to about 200 mg / mL, about 32 mg / mL to about 200 mg / mL, about 41 mg / mL to about 200mg / mL, about 50 mg / mL to about 200 mg / mL, about 65 mg / mL to about 200 mg / mL, about 80 mg / mL to about 200 mg / mL, about 95 mg / mL to about 200 mg / mL, about 110 mg / mL to about 200 mg / mL, about 125 mg / mL to about 200 mg / mL, about 140 mg / mL to about 200 mg / mL, about 155 mg / mL to about 200 mg / mL, about 5 mg / mL to about 150 mg / mL, about 50 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL, about 110 mg / mL to about 150 mg / mL, about 50 mg / mL to about 170 mg / mL, about 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 110 mg / mL, or about 50 mg / mL to about 80 mg / mL. It may be greater than or equal to about 5 mg / mL,9.5 mg / mL, 14 mg / mL, 18.5 mg / mL, 23 mg / mL, 27.5 mg / mL, 32 mg / mL, 36.5 mg / mL, 41 mg / mL,45.5 mg / mL, 50 mg / mL, 65 mg / mL, 80 mg / mL, 95 mg / mL, or 110 mg / mL. It may be less than or equal to about 200 mg / mL, 185 mg / mL, 170 mg / mL, 155 mg / mL, or 140 mg / mL. In certain embodiments, it may be, for example, about 5 mg / mL, 9.5 mg / mL, 14 mg / mL, 18.5 mg / mL, 23 mg / mL, 27.5 mg / mL, 32 mg / mL, 36.5 mg / mL, 41 mg / mL, 45.5 mg / mL, 50 mg / mL, 57.5 mg / mL, 65 mg / mL, 72.5 mg / mL, 80 mg / mL, 87.5 mg / mL, 95 mg / mL, 102 mg / mL, 110 mg / mL, 118 mg / mL, 125 mg / mL, 132 mg / mL, 140 mg / mL, 148 mg / mL, 155 mg / mL, 162 mg / mL, 170 mg / mL, 178 mg / mL, 185 mg / mL, 192 mg / mL, or 200 mg / mL. In certain specific embodiments, the concentration of the activated carbon in the suspension is from about 50 mg / mL to about 200 mg / mL.

[0028] In certain embodiments, in particular for addition of AC as a liquid suspension in reagents, the particles of activated charcoal may be less than 50 microns in size, so that the settling is slower and the fluid can be dispensed using regular pipette tips or capillary tubing. The AC may be sieved through a 50 micron mesh to achieve suitable particle size in the final reagent. The reagents containing activated carbon may be mixed gently, for example, with a magnetic stirrer before being dispensed to provide consistent delivery.

[0029] In certain embodiments, the activated carbon is in the form of a tablet, optionally a minitablet, which can be formulated to produce a suspension (e.g. the suspension described hereinbefore) when contacted with a liquid (e.g. the sample).

[0030] In certain embodiments, the tablet further comprises a sugar. The sugar may be, for example, a monosaccharide or a disaccharide. In certain embodiments, the sugar is selected from the group consisting of dextrose (glucose), galactose, maltose, maltobiose, sucrose, fructose, glucosamine, trehalose and lactose. In certain embodiments, the sugar is trehalose.

[0031] In certain embodiments concentration of the sugar in the tablet may be from about 40 % (w / w) to about 95 % (w / w), or from about 42 % (w / w) to about 95 % (w / w), about 44 % (w / w) to about 95 % (w / w), about 46 % (w / w) to about 95 % (w / w), about 48 % (w / w) to about 95 % (w / w), about 50 % (w / w) to about 95 % (w / w), about 54 % (w / w) to about 95 % (w / w), about 58 % (w / w)to about 95 % (w / w), about 62 % (w / w) to about 95 % (w / w), about 66 % (w / w) to about 95 % (w / w), about 70 % (w / w) to about 95 % (w / w), about 74 % (w / w) to about 95 % (w / w), about 78 % (w / w) to about 95 % (w / w), about 82 % (w / w) to about 95 % (w / w), about 86 % (w / w) to about 95 % (w / w), about 90 % (w / w) to about 95 % (w / w), about 40 % (w / w) to about 94 % (w / w), about 40 % (w / w) to about 94 % (w / w), about 40 % (w / w) to about 94 % (w / w), about 40 % (w / w) to about 93 % (w / w), about 40 % (w / w) to about 92 % (w / w), about 40 % (w / w) to about 92 % (w / w), about 40 % (w / w) to about 92 % (w / w), about 40 % (w / w) to about 91 % (w / w), about 40 % (w / w) to about 90 % (w / w), about 40 % (w / w) to about 90 % (w / w), about 50 % (w / w) to about 90 % (w / w), about 58 % (w / w) to about 90 % (w / w), about 66 % (w / w) to about 90 % (w / w), about 74 % (w / w) to about 90 % (w / w), about 82 % (w / w) to about 90 % (w / w), about 50 % (w / w) to about 82 % (w / w), about 50 % (w / w) to about 74 % (w / w), about 50 % (w / w) to about 66 % (w / w), or about 50 % (w / w) to about 58 % (w / w). It may be greater than or equal to about 40 % (w / w), 41 % (w / w), 42 % (w / w), 43 % (w / w), 44 % (w / w), 45 % (w / w), 46 % (w / w), 47 % (w / w), 48 % (w / w), 49 % (w / w), 50 % (w / w), 54 % (w / w), 58 % (w / w), 62 % (w / w), or 66 % (w / w). It may be less than or equal to about 95 % (w / w), 94 % (w / w), 94 % (w / w), 94 % (w / w), 93 % (w / w), 92 % (w / w), 92 % (w / w), 92 % (w / w), 91 % (w / w), 90 % (w / w), 90 % (w / w), 86 % (w / w), 82 % (w / w), 78 % (w / w), or 74 % (w / w). In certain embodiments, it may be, for example, about 40 % (w / w), 41 % (w / w), 42 % (w / w), 43 % (w / w), 44 % (w / w), 45 % (w / w), 46 % (w / w), 47 % (w / w), 48 % (w / w), 49 % (w / w), 50 % (w / w), 52 % (w / w), 54 % (w / w), 56 % (w / w), 58 % (w / w), 60 % (w / w), 62 % (w / w), 64 % (w / w), 66 % (w / w), 68 % (w / w), 70 % (w / w), 72 % (w / w), 74 % (w / w), 76 % (w / w), 78 % (w / w), 80 % (w / w), 82 % (w / w), 84 % (w / w), 86 % (w / w), 88 % (w / w), 90 % (w / w), 91 % (w / w), 92 % (w / w), 92 % (w / w), 92 % (w / w), 93 % (w / w), 94 % (w / w), 94 % (w / w), 94 % (w / w), or 95 % (w / w).

[0032] In certain embodiments, the concentration of the activated carbon in the tablet may be from about 5 % (w / w) to about 40 % (w / w), or from about 6 % (w / w) to about 40 % (w / w), about 7 % (w / w) to about 40 % (w / w), about 8 % (w / w) to about 40 % (w / w), about 9 % (w / w) to about 40 % (w / w), about 10 % (w / w) to about 40 % (w / w), about 12 % (w / w) to about 40 % (w / w), about 14 % (w / w) to about 40 % (w / w), about 16 % (w / w) to about 40 % (w / w), about 18 % (w / w) to about 40 % (w / w), about 20 % (w / w) to about 40 % (w / w), about 22 % (w / w) to about 40 % (w / w), about 24 % (w / w) to about 40 % (w / w), about 26 % (w / w) to about 40 % (w / w), about 28 % (w / w) to about 40 % (w / w), about 30 % (w / w) to about 40 % (w / w), about 5 % (w / w) to about 39 % (w / w), about 5 % (w / w) to about 38 % (w / w), about 5 % (w / w) to about 37 % (w / w), about 5 % (w / w) to about 36 % (w / w), about 5 % (w / w) to about 35 % (w / w), about 5 % (w / w) to about 34 % (w / w), about 5 % (w / w) to about 33 % (w / w), about 5 % (w / w) to about 32 % (w / w), about 5 % (w / w) to about 31 % (w / w), about 5 % (w / w) to about 30 % (w / w), about 10 % (w / w) to about 30 % (w / w), about 14 %(w / w) to about 30 % (w / w), about 18 % (w / w) to about 30 % (w / w), about 22 % (w / w) to about 30 % (w / w), about 26 % (w / w) to about 30 % (w / w), about 10 % (w / w) to about 26 % (w / w), about 10 % (w / w) to about 22 % (w / w), about 10 % (w / w) to about 18 % (w / w), or about 10 % (w / w) to about 14 % (w / w). It may be greater than or equal to about 5 % (w / w), 5.5 % (w / w), 6 % (w / w), 6.5 % (w / w), 7 % (w / w), 7.5 % (w / w), 8 % (w / w), 8.5 % (w / w), 9 % (w / w), 9.5 % (w / w), 10 % (w / w), 12 % (w / w), 14 % (w / w), 16 % (w / w), or 18 % (w / w). It may be less than or equal to about 40 % (w / w), 39 % (w / w), 38 % (w / w), 37 % (w / w), 36 % (w / w), 35 % (w / w), 34 % (w / w), 33 % (w / w), 32 % (w / w), 31 % (w / w), 30 % (w / w), 28 % (w / w), 26 % (w / w), 24 % (w / w), or 22 % (w / w). In certain embodiments, it may be, for example, about 5 % (w / w), 5.5 % (w / w), 6 % (w / w), 6.5 % (w / w), 7 % (w / w), 7.5 % (w / w), 8 % (w / w), 8.5 % (w / w), 9 % (w / w), 9.5 % (w / w), 10 % (w / w), 11 % (w / w), 12 % (w / w), 13 % (w / w), 14 % (w / w), 15 % (w / w), 16 % (w / w), 17 % (w / w), 18 %(w / w), 19 % (w / w), 20 % (w / w), 21 % (w / w), 22 % (w / w), 23 % (w / w), 24 % (w / w), 25 % (w / w),26 % (w / w), 27 % (w / w), 28 % (w / w), 29 % (w / w), 30 % (w / w), 32 % (w / w), 33 % (w / w), 34 %(w / w), 35 % (w / w), 36 % (w / w), 37 % (w / w), 38 % (w / w), 39 % (w / w), or 40 % (w / w).

[0033] In certain embodiments, the sample may be mixed with the activated carbon optionally in the presence of a reagent for a period of from about 30 s to about 1 h, or from about 48 s to about 1 h, about 1.1 min to about 1 h, about 1.4 min to about 1 h, about 1.7 min to about 1 h, about 2 min to about 1 h, about 2.8 min to about 1 h, about 3.6 min to about 1 h, about 4.4 min to about 1 h, about 5.2 min to about 1 h, about 6 min to about 1 h, about 6.8 min to about 1 h, about 7.6 min to about 1 h, about 8.4 min to about 1 h, about 9.2 min to about 1 h, about 10 min to about 1 h, about 30 s to about 55 min, about 30 s to about 50 min, about 30 s to about 45 min, about 30 s to about 40 min, about 30 s to about 35 min, about 30 s to about 30 min, about 30 s to about 25 min, about 30 s to about 20 min, about 30 s to about 15 min, about 30 s to about 10 min, about 2 min to about 10 min, about 3.6 min to about 10 min, about 5.2 min to about 10 min, about 6.8 min to about 10 min, about8.4 min to about 10 min, about 2 min to about 8.4 min, about 2 min to about 6.8 min, about 2 min to about 5.2 min, or about 2 min to about 3.6 min. It may be greater than or equal to about 30 s, 39 s, 48 s, 57 s, 1 min, 1.2 min, 1.4 min, 1.5 min, 1.7 min, 1.8 min, 2 min, 2.5 min, 3 min, 4 min, or 5 min. It may be less than or equal to about 1 h, 55 min, 50 min, 45 min, 40 min, 35 min, 30 min, 25 min, 20 min, 15 min, 10 min, 9 min, 8 min, 7 min, or 6 min. In certain embodiments, it may be, for example, about 30 s, 40 s, 50 s, 60 s, 1.1 min, 1.2 min, 1.4 min, 1.5 min, 1.7 min, 1.8 min, 2 min,2.4 min, 2.8 min, 3.2 min, 3.6 min, 4 min, 4.4 min, 4.8 min, 5.2 min, 5.6 min, 6 min, 6.4 min, 6.8 min, 7.2 min, 7.6 min, 8 min, 8.4 min, 8.8 min, 9.2 min, 9.6 min, 10 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, or 1 h, or more.

[0034] In certain embodiments, the coagulation testing with activated carbon-containing reagents is carried out on plasma samples mainly in viscosity-sensing or impedance measuring instruments, for example, the Stage series of instruments (Staclot ST4, StaR and Sta Max, Diagnostica Stage, France). Activated carbon-containing reagents can also be used on the Ball Coagulometer MC4 (Merlin Medical, Germany), similar physical clot-sensing devices, and also in manual tilt tube clotting tests.

[0035] In certain embodiments, for use in rapid testing instruments, the activated carbon can be provided in a rapidly dispersing form, for example mixed with dried reagents in test strips, capillaries, channels or on surfaces as in for example the Roche Coagucheck or the Abbott iSTAT ACT point of care clotting test strips.

[0036] In certain embodiments, the average particle size of the activated carbon may be from about 5 pm to about 500 pm, or from about 14 pm to about 500 pm, about 23 pm to about 500 pm, about 32 pm to about 500 pm, about 41 pm to about 500 pm, about 50 pm to about 500 pm, about 65 pm to about 500 pm, about 80 pm to about 500 pm, about 95 pm to about 500 pm, about 110 pm to about 500 pm, about 125 pm to about 500 pm, about 140 pm to about 500 pm, about 155 pm to about 500 pm, about 170 pm to about 500 pm, about 185 pm to about 500 pm, about 200 pm to about 500 pm, about 5 pm to about 470 pm, about 5 pm to about 440 pm, about 5 pm to about 410 pm, about 5 pm to about 380 pm, about 5 pm to about 350 pm, about 5 pm to about 320 pm, about 5 pm to about 290 pm, about 5 pm to about 260 pm, about 5 pm to about 230 pm, about 5 pm to about 200 pm, about 50 pm to about 200 pm, about 80 pm to about 200 pm, about 110 pm to about 200 pm, about 140 pm to about 200 pm, about 170 pm to about 200 pm, about 50 pm to about 170 pm, about 50 pm to about 140 pm, about 50 pm to about 110 pm, or about 50 pm to about 80 pm. It may be greater than or equal to about 5 pm, 9.5 pm, 14 pm, 18.5 pm, 23 pm, 27.5 pm, 32 pm, 36.5 pm, 41 pm, 45.5 pm, 50 pm, 65 pm, 80 pm, 95 pm, or 110 pm. It may be less than or equal to about 500 pm, 470 pm, 440 pm, 410 pm, 380 pm, 350 pm, 320 pm, 290 pm, 260 pm, 230 pm, 200 pm, 185 pm, 170 pm, 155 pm, or 140 pm. In certain embodiments, it may be, for example, about 5 pm, 9.5 pm, 14 pm, 18.5 pm, 23 pm, 27.5 pm, 32 pm, 36.5 pm, 41 pm, 45.5 pm, 50 pm, 57.5 pm, 65 pm, 72.5 pm, 80 pm, 87.5 pm, 95 pm, 102 pm, 110 pm, 118 pm, 125 pm, 132 pm, 140 pm, 148 pm, 155 pm, 162 pm, 170 pm, 178 pm, 185 pm, 192 pm, 200 pm, 260 pm, 290 pm, 320 pm, 350 pm, 380 pm, 410 pm, 440 pm, 470 pm, or 500 pm. In certain specific embodiments, the average particle size of the activated carbon is less than about 200 pm, 150 pm, or 100 pm, or wherein the average particle size of the activated carbon is from about 50 pm to about 200 pm. In certain embodiments, for example where a small tube or pipette tip is used to contain and / or transfer thesample, it may be preferable to use activated charcoal having a particle size below about 100 pm, so as to avoid blocking said small tube or pipette tip.

[0037] A skilled person will appreciate that activated charcoal (AC) products may vary significantly in quality and suitability for use in coagulation diagnostics. The AC used for the example experiments described herein was the Darco AC product 242276 from the Sigma / Merck chemical supply company. A skilled person will appreciate that batches of AC to be used according to the invention may need to be subjected to quality control testing in regard to their capacity for binding DOACs and non-interference in plasma or blood samples not containing DOACs.

[0038] In certain embodiments, the activated carbon may have a purity (excluding any moisture content) of from about 95 % to about 100 %, or from about 95.4 % to about 100 %, about 95.8 % to about 100 %, about 96.2 % to about 100 %, about 96.6 % to about 100 %, about 97 % to about 100 %, about 97.3 % to about 100 %, about 97.6 % to about 100 %, about 97.9 % to about 100 %, about98.2 % to about 100 %, about 98.4 % to about 100 %, about 98.7 % to about 100 %, about 99 % to about 100 %, about 99.3 % to about 100 %, about 99.6 % to about 100 %, about 99.9 % to about 100 %, about 95 % to about 100 %, about 95 % to about 100 %, about 95 % to about 100 %, about 95 % to about 100 %, about 95 % to about 100 %, about 95 % to about 99.9 %, about 95 % to about 99.9 %, about 95 % to about 99.9 %, about 95 % to about 99.9 %, about 95 % to about 99.9 %, about 97 % to about 99.9 %, about 97.6 % to about 99.9 %, about 98.2 % to about 99.9 %, about 98.7 % to about 99.9 %, about 99.3 % to about 99.9 %, about 97 % to about 99.3 %, about 97 % to about 98.7 %, about 97 % to about 98.2 %, or about 97 % to about 97.6 %. It may be greater than or equal to about 95 %, 95.2 %, 95.4 %, 95.6 %, 95.8 %, 96 %, 96.2 %, 96.4 %, 96.6 %, 96.8 %, 97 %,97.3 %, 97.6 %, 97.9 %, or 98.2 %. It may be less than or equal to about 100 %, 100 %, 100 %, 100 %, 100 %, 100 %, 99.9 %, 99.9 %, 99.9 %, 99.9 %, 99.9 %, 99.6 %, 99.3 %, 99 %, or 98.7 %. In certain embodiments, it may be, for example, about 95 %, 95.2 %, 95.4 %, 95.6 %, 95.8 %, 96 %,96.2 %, 96.4 %, 96.6 %, 96.8 %, 97 %, 97.1 %, 97.3 %, 97.4 %, 97.6 %, 97.7 %, 97.9 %, 98 %,98.2 %, 98.3 %, 98.4 %, 98.6 %, 98.7 %, 98.9 %, 99 %, 99.2 %, 99.3 %, 99.5 %, 99.6 %, 99.8 %,99.9 %, 99.9 %, 99.9 %, 99.9 %, 100 %, 100 %, 100 %, 100 %, 100 %, or 100 %.

[0039] In a second aspect of the invention there is provided a composition comprising: activated carbon; and one or more blood or blood component coagulation test reagents or additives.

[0040] The following options may be used in conjunction with the second aspect, either individually or in any combination.

[0041] The activated carbon and / or one or more blood or blood component coagulation test reagents or additives may be as hereinbefore described with respect to the first aspect.

[0042] In certain embodiments, the one or more blood or blood component coagulation test reagents or additives are selected from the group consisting of Activated partial thromboplastin time (APTT) test reagents, Dilute Russell's viper venom time (dRVVT) test reagents, Prothrombin time (PT) test reagents, Non-activated clotting time (NAPTT) reagents, Surface activated clotting time (SACT) reagents, Recalcification clotting time (RCT) reagents in regular or in diluted form; and Activated clotting time (ACT) reagents, optionally wherein the one or more blood or blood component coagulation test reagents or additives are selected from the group consisting of APTT reagents, dRVVT reagents, PT reagents, NAPTT reagents, and surface activated clotting time reagents.

[0043] In certain embodiments, the activated carbon may be present in the composition in an amount of from about 0.01 % (w / v) to about 15 % (w / v), or from about 0.028 % (w / v) to about 15 % (w / v), about 0.046 % (w / v) to about 15 % (w / v), about 0.064 % (w / v) to about 15 % (w / v), about 0.082 % (w / v) to about 15 % (w / v), about 0.1 % (w / v) to about 15 % (w / v), about 0.49 % (w / v) to about 15 % (w / v), about 0.88 % (w / v) to about 15 % (w / v), about 1.27 % (w / v) to about 15 % (w / v), about 1.66 % (w / v) to about 15 % (w / v), about 2.05 % (w / v) to about 15 % (w / v), about 2.44 % (w / v) to about 15 % (w / v), about 2.83 % (w / v) to about 15 % (w / v), about 3.22 % (w / v) to about 15 % (w / v), about 3.61 % (w / v) to about 15 % (w / v), about 4 % (w / v) to about 15 % (w / v), about 0.01 % (w / v) to about 13.9 % (w / v), about 0.01 % (w / v) to about 12.8 % (w / v), about 0.01 % (w / v) to about 11.7 % (w / v), about 0.01 % (w / v) to about 10.6 % (w / v), about 0.01 % (w / v) to about 9.5 % (w / v), about 0.01 % (w / v) to about 8.4 % (w / v), about 0.01 % (w / v) to about 7.3 % (w / v), about 0.01 % (w / v) to about 6.2 % (w / v), about 0.01 % (w / v) to about 5.1 % (w / v), about 0.01 % (w / v) to about 4 % (w / v), about 0.1 % (w / v) to about 4 % (w / v), about 0.88 % (w / v) to about 4 % (w / v), about 1.66 % (w / v) to about 4 % (w / v), about 2.44 % (w / v) to about 4 % (w / v), about 3.22 % (w / v) to about 4 % (w / v), about 0.1 % (w / v) to about 3.22 % (w / v), about 0.1 % (w / v) to about 2.44 % (w / v), about 0.1 % (w / v) to about 1.66 % (w / v), or about 0.1 % (w / v) to about 0.88 % (w / v). It may be greater than or equal to about 0.01 % (w / v), 0.019 % (w / v), 0.028 % (w / v), 0.037 % (w / v), 0.046 % (w / v), 0.055 % (w / v), 0.064 % (w / v), 0.073 % (w / v), 0.082 % (w / v), 0.091 % (w / v), 0.1 % (w / v), 0.49 % (w / v), 0.88 % (w / v), 1.27 % (w / v), or 1.66 % (w / v). It may be less than or equal to about 15 % (w / v), 13.9 % (w / v), 12.8 % (w / v), 11.7 % (w / v), 10.6 % (w / v), 9.5 % (w / v), 8.4 % (w / v), 7.3 % (w / v), 6.2 % (w / v), 5.1 % (w / v), 4 % (w / v), 3.61 % (w / v), 3.22 % (w / v), 2.83 % (w / v), or 2.44 % (w / v). In certain embodiments, it may be, for example, about 0.01 % (w / v), 0.019 % (w / v), 0.028 % (w / v), 0.037 % (w / v), 0.046 % (w / v), 0.055 % (w / v), 0.064 % (w / v), 0.073 % (w / v), 0.082 % (w / v), 0.091 % (w / v), 0.1 % (w / v), 0.295 % (w / v), 0.49 % (w / v), 0.685 % (w / v), 0.88 % (w / v), 1.08 % (w / v), 1.27 % (w / v), 1.46 % (w / v), 1.66 % (w / v), 1.86 % (w / v), 2.05 % (w / v), 2.24 % (w / v), 2.44 % (w / v), 2.64 % (w / v), 2.83 % (w / v), 3.02 % (w / v), 3.22 % (w / v), 3.42 % (w / v), 3.61 % (w / v), 3.8 %(w / v), 4 % (w / v), 6.2 % (w / v), 7.3 % (w / v), 8.4 % (w / v), 9.5 % (w / v), 10.6 % (w / v), 11.7 % (w / v), 12.8 % (w / v), 13.9 % (w / v), or 15 % (w / v). In certain specific embodiments, the activated carbon is present in the composition in an amount of from about 0.1 % (w / v) to about 4 % (w / v).

[0044] In certain embodiments, the activated carbon is in the form of a suspension. The suspension may be as hereinbefore described with respect to the first aspect. In certain specific embodiments, the suspension further comprises a sugar or sugar polymer, optionally wherein the sugar comprises dextrose. In certain embodiments the sugar polymer may be high molecular weight hydroxyethyl starch (e.g. Sigma product H6382). In certain embodiments, the concentration of the activated carbon in the suspension is from about 50 mg / mL to about 200 mg / mL.

[0045] In certain embodiments, the average particle size of the activated carbon is less than about 100 pm, or wherein the average particle size of the activated carbon is from about 30 pm to about 60 pm.

[0046] In certain embodiments, the composition according to the second aspect may be used in the method according to the first aspect. In certain embodiments, the method according to the first aspect may use the composition according to the first aspect.

[0047] In a third aspect of the invention there is provided a blood or blood component sample container, comprising: activated carbon.

[0048] The following options may be used in conjunction with the third aspect, either individually or in any combination.

[0049] In certain embodiments, the activated carbon according to the third aspect may be as hereinbefore described with respect to the first aspect.

[0050] In certain embodiments, the blood or blood component sample container further comprises one or more anticoagulant agents. In certain specific embodiments, the one or more anticoagulant agents comprise regular 3.1% citrate, heparin, acid citrate dextrose, EDTA or DOACs.

[0051] In certain embodiments, the blood or blood component sample container is a blood or blood component collection vial, a coagulation test vial (for example, comprising sodium citrate, ACD anticoagulant, sodium heparin or other salt of heparin), a plasma collection vial (comprising, for example, a heparin salt, such as lithium heparin), or a whole blood collection vial (comprising, for example, EDTA).

[0052] In certain embodiments, the activated carbon is in the form of a suspension. The suspension may be as hereinbefore described with respect to the first aspect. In certain specific embodiments, the suspension further comprises a sugar, optionally wherein the sugar comprises trehalose. Incertain embodiments, the suspension further contains a carbohydrate polymer, wherein the polymer comprises hydroxy ethyl starch. In certain embodiments, the concentration of the activated carbon in the suspension is from about 50 mg / mL to about 200 mg / mL.

[0053] In certain embodiments, the average particle size of the activated carbon is less than about 100pm, 50pm, or 20pm, or wherein the average particle size of the activated carbon is from about 20pm to about 50pm, or from about 30 pm to about 60 pm.

[0054] In certain embodiments, the blood or blood component sample container according to the third aspect may comprise the composition according to the second aspect. In certain embodiments, the composition according to the second aspect may be a component of the blood or blood component sample container according to the second aspect.DEFINITIONS

[0055] In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

[0057] Unless the context clearly requires otherwise, throughout the description and the claims, the terms “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.

[0058] The transitional phrase “consisting of’ excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

[0059] The transitional phrase “consisting essentially of’ is used to define a composition, process or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elementsdo not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of’ occupies a middle ground between “comprising” and “consisting of’.

[0060] Where applicants have defined an invention or a portion thereof with an open-ended term such as “comprising”, it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms “consisting essentially of’ or “consisting of’. In other words, with respect to the terms “comprising”, “consisting of’, and “consisting essentially of’, where one of these three terms is used herein, the presently disclosed and claimed subject matter may include the use of either of the other two terms. Thus, in some embodiments not otherwise explicitly recited, any instance of “comprising” may be replaced by “consisting of’ or, alternatively, by “consisting essentially of’.

[0061] Other than in the claims or operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood as modified in all instances by the term “about”. The examples are not intended to limit the scope of the invention.

[0062] In what follows, or where otherwise indicated, “%” will mean “weight %”, “ratio” will mean “weight ratio” and “parts” will mean “weight parts”.

[0063] The terms “predominantly”, “predominant”, and “substantially” as used herein shall mean comprising more than 50% by weight, unless otherwise indicated.

[0064] As used herein, with reference to numbers in a range of numerals, the terms “about,” “approximately” and “substantially” are understood to refer to the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1 % to + 1 % of the referenced number, most preferably -0.1 % to +0.1 % of the referenced number. Moreover, with reference to numerical ranges, these terms should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, from 8 to 10, and so forth.

[0065] The terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.

[0066] As used herein, the term “deactivating”, in the context of “deactivating a blood coagulation interfering compound in a sample for blood or blood component coagulation testing” means to atleast partially inactivate, neutralise or disable a blood coagulation interfering compound such that the blood coagulation interfering compound is unable to interfere with a blood coagulation test. In certain embodiments, it means to bind to the blood coagulation interfering compound such that it is no longer able to interfere with a blood coagulation process, or at least such that its capability to interfere with a blood coagulation process is reduced.

[0067] As used herein, the term “blood coagulation interfering compound” means a compound which is capable of interfering with a blood coagulation process. In certain embodiments, it means an anticoagulant compound.

[0068] As used herein, the term “anticoagulant compound” or “anticoagulant agent” means a compound or agent that prevents, interferes with, and / or reduces a blood coagulation process.

[0069] As used herein, the term “blood or blood component coagulation test reagents” includes any component of a blood or blood component coagulation test kit that reacts with a blood component, or that is involved in or contributes to a reaction (whether physical or chemical) in the blood or blood component coagulation test.

[0070] As used herein the term “blood or blood component coagulation test additives” includes any component of a blood or blood component coagulation test that is not involved and does not contribute to a reaction in the blood or blood component coagulation test. In certain embodiments, the term “blood or blood component coagulation test additives” does not include solvents or carriers such as water.ABBREVIATIONS

[0071] ACD: acid citrate dextrose; AC: activated carbon; ACT: activated clotting time; APTT: activated partial thromboplastin time; Dabiga: Dabigatran base; DOAC: Direct Oral Anticoagulant; dRVVT: dilute Russell’s viper venom time; DCT: DOAC clotting test; Intern: intrinsic thrombo- elastometry; KCT: kaolin clotting time; LS: lupus anticoagulant sensitive; NAPTT: non-activated partial thromboplastin time; PNP: Pooled normal plasma; PT: prothrombin time; RCT: recalcification clotting time; SACT: Surface activated clotting time; SCT: silica clotting time;SEER: sonic estimation of clot elasticity via resonance.

[0072] Preferred features, embodiments and variations of the invention may be discerned from the following Examples which provides sufficient information for those skilled in the art to perform the invention. The following Examples are not to be regarded as limiting the scope of the preceding Summary of the Invention in any way.EXAMPLES

[0073] In all the examples below, blood or blood component coagulation testing was carried out using a Stage ST4 instrument. Since activated carbon tends to settle out, all fluids containing it such as DOAC Stop-Liquid (12.5% AC suspension) were mixed well before use to provide homogeneity. Note that the levels of DOACs used here (1000-2000ng / ml) were far higher than normal therapeutic levels (50-300ng / ml) to demonstrate efficacy even at excess levels.Example 1: Removing Rivaroxaban from normal plasma with various concentrations of activated charcoal in an APTT reagent.

[0074] Activated carbon was effective at a concentration of 5mg / mL in plasma samples over 5-10 minutes at room temperature for the near-complete removal of DOACs. The following experiment was carried out to determine how much activated carbon might be required if it was provided in an APTT reagent for a test with a three minute pre-incubation at 37°C.

[0075] Table 1 shows APTT results with varying concentrations of activated carbon spiked from a 12.5% liquid suspension (DOAC Stop-L) into Haematex Intrinsin APTT reagent (Haematex Research, Australia). Tests were carried out on pooled normal plasma (PNP) containing varying concentrations of rivaroxaban. APTT tests with three minute pre-incubation were carried out on a Stage ST4 clotting instrument. Note that the PNP initially had an APTT of 36.6 sec.Table 1: APTT test results for plasma samples spiked with different concentrations of Rivaroxaban and treated with different amounts of activated carbon in Haematex Intrinsin APTT reagent

[0076] It is apparent in table 1 that activated carbon in the reagent had negligible effect on normal plasma not containing rivaroxaban (first row). In the absence of activated carbon, rivaroxaban prolonged the APTT (column 2). The addition of activated carbon to the APTT reagent greatly reduced the sensitivity to rivaroxaban. The effect of rivaroxaban was almost completely removed by 5mg / mL of activated carbon (column 5) and consequently, this preferred concentration of activated carbon in APTT reagents was adopted for subsequent experiments.Example 2: Activated charcoal in other A PIT reagents for removing Rivaroxaban from normal plasma.

[0077] Tests with activated carbon (AC)in several APTT reagents were carried out as follows. AC was added from a 12.5% suspension to a final concentration of 5mg / mL in three APTT reagents: Synthasil (IL / Werfen, USA), Triniclot S (Stage, France), and Cephen (Hyphen Biomed, France), as well as one surface activated clotting time reagent: phospholipid free reagent, SACT II (Haematex, Sydney). Test plasma samples were prepared by adding 0, 500, 1000 and 2000ng / mL concentrations of rivaroxaban to pooled normal plasma (PNP) samples. Then these plasma samples were tested with each APTT reagent with and without the added activated carbon in the reagent. Tests were carried out using three minute pre-incubations in a Stage ST4 instrument. Results obtained are shown in table 2 below.Table 2: APTT test results for plasma samples spiked with different concentrations of Rivaroxaban (Riva) and treated with different APTT test reagents either with or without 5 mg / mL activated carbon (AC).

[0078] The addition of activated carbon to each reagent had negligible effect on results with PNP alone (Riva=0 ng / mL, row 4). APTT results obtained with no activated carbon in the reagents were significantly prolonged for increasing rivaroxaban concentrations (columns 2, 4, 6 and 8). However, with activated carbon (5 mg / mL) present in each reagent, the results were relatively unaffected by rivaroxaban levels up to 2000ng / mL (columns 3,5,7 and 9).

[0079] These results show that activated carbon can be used in compositions with simple APTT reagents such as Cephens or SACT II to minimize the effect of DOACs in APTT tests.Example 3: Use of an APTT reagent containing activated charcoal to remove various DOACs

[0080] There are several DOACs in clinical use and all DOACs that were tested were readily removed by activated carbon in the APTT reagents as shown in table 3 below. The five different DOACs were included at lOOOng / mL in pooled normal plasma and had variable prolonging effects on APTT results obtained with the two reagents. Dabigatran and betrixaban had the strongest anticoagulant effects. Apixaban had the weakest anticoagulant effect.

[0081] The reagents used were Cephen low phospholipid, lupus anticoagulant sensitive (LS) and the high phospholipid LA resistant version (LR). They were used with no activated charcoal and also after activated carbon had been added from DOAC Stop-L to the reagents at 5mg / mL final concentration.

[0082] All results utilizing the activated carbon additive came back to near normal. Thus, showing that the activated charcoal containing APTT reagents were no longer sensitive to DOACs. Also, that the activated charcoal worked similarly with all available DOACs. In contrast, the prolonging effect of heparin on the APTT results with the two reagents was not altered significantly by the presence of activated carbon. Activated charcoal added to these two APTT reagents was effective for neutralizing all available DOACs and did not affect results on normal and heparinised plasma.Table 3: APTT results for plasma samples spiked with different anticoagulant agents, when mixed with activated carbon (AC) containing or no activated carbon APTT test reagentsExample 4: Effect of activated carbon in an APTT reagent on DOAC removal from various abnormal plasmas

[0083] APTT tests are mainly used to detect clotting factor defects, inhibitors other than DOACs and heparin. DOACs typically confound the detection of such abnormalities. Activated carbon in the reagent removed DOACs from normal plasma, but whether this procedure would also work in abnormal plasmas or if it might affect the underlying plasma defect was tested in the following example.

[0084] Rivaroxaban was added at lOOOng / mL to various pre-tested abnormal plasmas. The results in Table 4 show that the rivaroxaban significantly prolonged APTT results with the regular APTT (Cephen LS) reagent (column 2). Then the samples were tested with the same APTT reagent containing added 5mg / mL activated carbon. The results recorded below (column 3) show that including activated carbon in this APTT reagent did not affect its sensitivity to the usual abnormalities for which it is used. The removal of rivaroxaban by activated carbon in the APTTreagent as shown in column 3 did not affect the subsequent detection of the underlying abnormalities.Table 4: Effect of activated carbon in an APTT reagent on a DOAC removal from various abnormal plasmasExample 5: Activated carbon in a single stage activated clotting time (ACT) reagent

[0085] All the above examples were carried out with the activated carbon within an APTT reagent being mixed with a plasma sample in a pre-incubation step of 3 minutes. This was considered necessary so that the activated carbon had sufficient time to adsorb the DOACs. However, that the use of activated carbon in a single stage clotting test without such preincubation also worked as shown in the following example.

[0086] The APTT reagent Cephen was mixed with an equal volume of 0.025M calcium chloride to form a one stage APTT reagent. This provided a clotting reagent similar to an APTT reagent, but without requiring a preincubation period for activating the contact factors. This could be described as a one stage APTT or an Activated Clotting Time (ACT) test as carried out more usually on whole blood samples. Contact activation in this method can occur only during the actual clotting stage with calcium chloride present.

[0087] The ACT reagent was mixed with 5mg / mL activated carbon from DOAC Stop-L to form AC-ACT. Samples of normal plasma were prepared containing O-lOOOng / mL of either dabigatran or rivaroxaban. Tests were carried out by adding O.lmL ACT reagent with or without activated carbon to 0.05mL of test plasmas and timing to a clotting endpoint at 37°C in the ST4.

[0088] As shown in table 5, the result on PNP without either DOAC was approximately 60 sec with both ACT and AC-ACT reagents. This was almost twice as long as in a regular APTT, due to incomplete activation of contact factors. The ACT showed good sensitivity to dabigatran andrivaroxaban as shown in columns 2 and 5. The tests were then repeated with the AC-ACT reagent. As shown in columns 3 and 6, this modified test was only slightly prolonged by the DOACs.

[0089] Thus, the activated carbon acts very quickly and can be effective for removing the effect of DOACs even in a single stage clotting test. The ACT is sensitive to DOACs and activated carbon can be added directly to this reagent to overcome their prolonging effect.Table 5: The effect of activated carbon in a single stage activated clotting time (ACT) reagentExample 6: Activated carbon in calcium chloride solution reduces the sensitivity of APTT tests for DOACs.

[0090] Plasma samples containing various rivaroxaban and dabigatran concentrations up to 2000ng / mL were prepared as shown in table 6. They were tested with the APTT reagent Cephen, recalcifying initially with regular 25 mM calcium chloride. Then the APTT testing was repeated but using a calcium chloride solution containing 5mg / mL activated carbon suspension. Results obtained are shown in Table 6.Table 6: APTT testing of DOAC spiked plasma samples using the APTT reagent Cephen in calcium chloride solutions with and without activated carbon

[0091] Both rivaroxaban and dabigatran had a prolonging effect on the APTT carried out with regular 25 mM calcium chloride. When the same test was carried out with 5mg / mL activated carbon in the calcium chloride solution, the prolonging effects of both rivaroxaban and dabigatran were greatly reduced. Dabigatran was reduced by 97% and rivaroxaban by 80% by the action of activated carbon in the calcium chloride recalcification step. This shows that even brief exposure of activated carbon to these DOACs during the recalcification step of the APTT has a significant neutralizingeffect. A similar effect was observed in the NAPTT and also in simple Recalcification Clotting Time (RCT results not shown) tests where neither contact activator nor phospholipid were added before the activated carbon-containing calcium chloride solution.Example 7: Anticoagulant solution containing activated carbon suspension (ACD+AC) for obtaining blood and plasma samples reduced in DOACs

[0092] The acid citrate dextrose (ACD) anticoagulant concentrate for blood collection tubes was prepared by dissolving 2.2g trisodium citrate dihydrate (MWt 294, 0.075M), 0.73g anhydrous citric acid (MWt 192, 0.004M) and 2.45g dextrose monohydrate (MWt 180, 0.14M) in 95mL of water. 2.5g activated carbon (25mg / mL Darco, final concentration) was added to this solution and to make the total volume up to lOOmL. The final pH of the solution was 5.0 + / - 0.2.

[0093] The following example suggests that blood samples can be collected directly into citrate anticoagulant tubes containing activated carbon without affecting basic clotting test results. Also, that the activated carbon does adsorb DOACs and related compounds when present, but not heparin (or likely anything similar) which would affect this clotting test.

[0094] Fresh whole blood was obtained by clean venipuncture from a normal healthy donor and collected into plain ACD anticoagulant tubes. Sample volumes of ImL were spiked with 500ng / mL of various DOACs, argatroban and 0.3u / mL of heparin. Then 0.5mL subsamples were treated with 0.02mL of 12.5% activated carbon (DOAC Stop-L) (Final concentration was 5mg / mL of activated carbon) and centrifuged. The remaining initial 0.5mL volumes were centrifuged similarly. Then all the supernatant plasmas were tested with DOAC Test (a dilute Russell’s viper venom-based test highly sensitive to DOACs available from Haematex), APTT tests (with Cephen LR) and observed for haemolysis. Results obtained were shown in Table 7.Table 7: DOAC Test and APTT-LR test results on plasmas from whole blood, spiked with a variety of anticoagulants which was collected into standard (no AC) tubes, or activated carbon (AC) containing blood collection tubes.| Heparin | 23.1 | 23.5 | 268 | 249 |

[0095] Results in both tests were significantly prolonged for the standard (having no activated carbon) tubes (columns 2 and 4) by all additions except for the DOAC test on the heparin plasma. (Note that the DOAC Test is a Russell’s viper venom-based test for DOACs and is intentionally not affected by heparin). When these blood samples were collected into tubes containing activated carbon (columns 3 and 5), the results all normalized except for the heparin-containing sample in the APTT test. There was no haemolysis apparent in any sample.

[0096] These results confirm the almost complete removal of DOACs and argatroban by the activated carbon in whole blood samples. Also, activated carbon shows no effect on plasma from the normal blood sample nor on the heparin-containing sample. If there had been platelet activation by the activated carbon, then heparin would have been partially neutralized by released platelet factor 4 and the APTT would have shortened.

[0097] The procedures disclosed herein may present a practical advantage for use of activated carbon in instruments which employ viscosity-sensing or impedance technology rather than photoelectric clot turbidity detection for a clotting endpoint. The direct addition of activated carbon to a reagent may simplify the use of this DOAC adsorbing medium into routine practice and may allow more rapid interpretation of clotting test results if DOACs are present.

[0098] The inventors have also found that activated carbon can be mixed with acid citrate dextrose (ACD) anticoagulant as used for blood sample collection to provide a similar diagnostic benefit.Use of ACD instead of the conventional 0.109M trisodium citrate was found to provide improved stability of blood collected with activated present. An activated carbon containing liquid suspension concentrate can be added by syringe to capped tubes of patient whole blood samples to adsorb DOACs. This simplifies the DOAC removal process to a single centrifugation step and allows better integration into automated testing.

[0099] It was not known previously if activated carbon suspension would affect the performance of any APTT reagents if added directly to the reagent. Or if the DOAC binding capacity of activated carbon might be affected by other components of APTT reagents. The effect of activated carbon within a plasma / reagent mix on the clot detection system in the Stage clotting instrument was also previously unknown. The inventors of the present application have investigated these possibilities and discovered the previously unknown versatility of activated carbon.[000100] The near complete adsorption of DOACs by activated carbon from plasma occurs in around 2 to 5 minutes typically, which is similar to the time required for the first stage of an APTT test. There appears to be negligible interference by activated carbon in the contact activation process. Normal contact activation and DOAC adsorption can take place together during thispreincubation stage. Also surprisingly, there appears to be no interference with the activity of the procoagulant phospholipid in the reagent in the second stage of the test.[000101] Other two stage clotting tests where activated carbon could be useful for removing DOACs include the kaolin clotting time (KCT), surface activated clotting time (SACT) and silica clotting time (SCT) tests. In the reagents for these tests none or little external phospholipid is provided to make them more sensitive to antiphospholipid antibodies. (These antibodies present as lupus anticoagulants). Another slightly different test, the non activated clotting time (NAPTT) test reagent contains only phospholipid and no contact activator. So, it can be carried out with a variable preincubation time. In these three tests activated carbon in the reagent adsorbs most of the DOAC in a test plasma during the initial phase and provides results unaffected by DOACs. These tests are usually carried out on plasmas but could be applied similarly to whole blood samples, particularly if an appropriate viscosity or impedance-sensing instrument was used.[000102] The activated clotting time (ACT) is a one stage test carried out on whole blood samples, often used in emergency rooms to rapidly identify causes of bleeding. DOACs prolong results from this test and can interfere with diagnosis of bleeding disorders. They are becoming more widely used and patients are often on unknown medications. Therefore, it would be useful to include activated carbon in the test to identify their effects. ACT is a single stage test with no preincubation time and therefore otherwise difficult to accommodate a step with activated carbon.[000103] Other newer whole blood tests such as the Intern (intrinsic thrombo-elastography) on the ROTEM and PROCLOT instruments are similarly affected. The Intern is a test for the intrinsic pathway of coagulation including the contact factors and the reagent is similar to an APTT plus calcium (if the sample contains citrate anticoagulant). Many other point of care clotting devices are being developed and use similar reagents. The combination of activated carbon with the reagents in such devices simplifies such methods. This applies to both liquid reagents as well as to dried reagents within a cassette, strip or capillaries that would be activated by a test sample fluid.[000104] Since most rapid single stage clotting tests are carried out on whole blood samples, the use of activated carbon in whole blood samples was also investigated. To remove DOACs from a patient’s blood sample, one volume of ACD anticoagulant containing 25mg / mL of activated carbon was mixed with nine volumes of fresh patient blood. The final concentration of AC in the blood sample is then 2.5mg / ml. This can be collected by venipuncture into a polystyrene or other biocompatible tube. Or if evacuated and sealed with a rubber septum, it can be used with Vacutainer accessories. The activated carbon can also be added subsequently to whole blood samples from a 12.5% concentrate suspension.[000105] The treated whole blood sample can be used directly in appropriate instrumentation for various clotting tests based on visco-elastic or impedance testing. For collection of DOAC free plasma from this sample, the tubes can be centrifuged within 10 minutes of collection to obtain supernatant plasma free of DOACs and otherwise unaffected by the brief exposure to activated charcoal.[000106] In summary, the above examples demonstrate that activated carbon is a useful additive to various coagulation reagents for the purpose of neutralizing the unwanted effects of DOACs and similar confounding agents which may occur in patient blood and blood component (e.g., plasma) samples.[000107] Disclosed herein are the following forms:A20. A method for deactivating a blood coagulation interfering compound in a sample for blood or blood component coagulation testing, said method comprising: a) mixing the sample with activated carbon to bind and deactivate the blood coagulation interfering compound; and b) performing a blood or blood component coagulation test on a sample containing the activated carbon, wherein the activated carbon is incorporated into the testing process, such as a clotting, chromogenic, Anorogenic, visco-elastic and / or sonorheometric test, by one or more of the following methods: including the activated carbon in a composition with one or more blood or blood component coagulation test reagents, wherein the carbon is mixed with the reagents before they are added to the sample, or by adding the activated carbon directly to the sample, wherein the carbon is mixed with the blood sample itself or applied to a surface in contact with the sample; wherein the test can be performed on a clot mechanical, optical, fluorogcnic detection or POC system.A21. The method of form A20, wherein from about 0.05 mg / mL to about 40 mg / mL, or from about 1 mg / mL to about 20 mg / mL of activated carbon is mixed with the sample, relative to the total volume of the sample.A22. The method of form A20 or A21, wherein the blood coagulation interfering compound is selected from the group consisting of, factor Xa, XI, Xia, XII, Xlla inhibitors or direct thrombin inhibitors.A23. The method of any one of forms A20 to A22, wherein the blood coagulation interfering compound is a direct oral anticoagulant (DO AC).A24. The method of form A23, wherein the DOAC is selected from the group consisting of: dabigatran, rivaroxaban, apixaban, betrixaban, edoxaban, milvexian or assundexian.A25. The method of any one of forms A20 to A24, wherein the one or more blood or blood component coagulation tests are selected from chronometry, chromogenic or fluorescence based blood or blood component coagulation tests.A26. The method of any one of forms A20 to A24, wherein the one or more blood or blood component coagulation tests are selected from the group consisting of thomboelastometry and thromboelastography using cup and pin, resonance, sonorheometry, and sonic estimation of clot elasticity via resonance (SEER).A27. The method of any one of forms A20 to A26, wherein the blood or blood component coagulation test reagents are selected from the group consisting of activated partial thromboplastin time (APTT) test reagents, Staclot LA test reagents, Dilute Russell's viper venom time (dRVVT) test reagents, prothrombin time (PT) test reagents, thrombin ime (TT) test reagents, nonactivated clotting time (NAPTT) reagents, activated clotting time (ACT), surface activated clotting time (SACT) reagents, and / or derived reagents comprising one stage clotting test reagents, fibrin formation test reagents, protein C, protein S, activated protein C resistance (APCR) clotting test reagents and thrombin generation test reagents.A28. The method of any one of forms A20 to A26, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting chromogenic factor VIII or IX reagents, anti-thrombin chromogenic reagents, protein C chromogenic reagents, and anti-Xa chromogenic reagents.A29. The method of any one of forms A20 to A28, wherein the activated carbon is mixed with and at least partially suspended in the sample or immobilized on a surface.A30. The method of any one of forms A20 to A29, wherein the blood or blood component coagulation test is selected from the group consisting of APTTtests, Staclot LA tests, dRVVT tests, PT tests, TT tests, NAPTT tests, and surface activated clotting time tests, or derived tests comprising one stage clotting factor fibrin formation tests, protein C, protein S and APCR clotting tests, and thrombin generation assays.A31. The method of any one of forms A20 to A29, wherein the blood or blood component coagulation tests are selected from the group consisting of chromogenic factor VIII or IX tests, antithrombin chromogenic tests, protein C chromogenic tests and anti-Xa chromogenic tests.A32. The method of any one of forms A20 to A29, wherein the blood or blood component coagulation tests comprise a cartridge system and are measured using a SEER system.A33. A composition comprising: a) activated carbon; and b) one or more blood or blood component coagulation test reagents or additives.A34. The composition of form A33, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting of APTT reagents, Staclot LA reagents, dRVVT reagents, PT reagents, NAPTT reagents, and surface activated clotting time reagents, or derived reagents comprising one stage clotting factor reagents, protein C, protein S and APCR clotting reagents, and thrombin generation reagents.A35. The composition of form A33, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting of chromogenic factor VIII or IX reagents, anti-thrombin chromogenic reagents, protein C chromogenic reagents, and anti-Xa chromogenic reagents.A36. The composition of any one of forms A33 to A35, wherein the activated carbon is present in the composition in an amount of from about 0.1 mg / mL to about 40 mg / mL, or from 1 mg / mL to about 40 mg / mL.A37. A blood or blood component sample container, comprising: activated carbon.A38. The blood or blood component sample container of form A37, wherein the activated carbon is added into the sample container by a manual or automated pretreatment step.A39. The blood or blood component sample container of form A37 or A38, further comprising one or more anticoagulant agents selected from regular citrate, EDTA, DOACs, heparin or acid citrate dextrose.A40. The blood or blood component sample container of any one of forms A37 to A39, wherein the container is a blood or blood component collection vial.A41. The method of any one of any one of forms A20 to A32, composition of any one of forms A33 to A36, or blood or blood component sample container of any one of forms A37 to A40 wherein the activated carbon is in the form of a suspension.A42. The method, composition, or blood or blood component sample container of form A41, wherein the suspension further comprises a sugar or a thixotropic agent, optionally wherein the sugar comprises trehalose or polysaccharides.A43. The method, composition, or blood or blood component sample container of form A41 or A42, wherein the concentration of the activated carbon in the suspension is from about 5 mg / mL to about 200 mg / mL, or from about 50 mg / mL to about 200 mg / mL.A44. The method of any one of forms A20 to A32 and A41 to A43, the composition of any one of forms A33 to A36 and A41 to A43, or blood or blood component sample container of any one of forms A37 to A40, wherein the average particle size of the activated carbon is less than about 100 pm, or from about 60 pm to about 30 pm.[000108] Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms. In particular, features of any one of the various described examples may be provided in any combination in any of the other described examples. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.

Claims

Claims:

1. A method of deactivating a blood coagulation interfering compound in a sample for blood or blood component coagulation testing, said method comprising: mixing the sample with activated carbon to thereby bind and deactivate the blood coagulation interfering compound; and performing a blood or blood component coagulation test on the sample containing the activated carbon; wherein the activated carbon is in a composition with one or more blood or blood component coagulation test reagents or additives before it is mixed with the sample, optionally wherein the activated carbon is in a composition with one or more blood or blood component coagulation test reagents before it is mixed with the sample.

2. The method of claim 1, wherein from about 0.5 mg / mL to about 40 mg / mL, or from about 1 mg / mL to about 20 mg / mL, of the activated carbon is mixed with the sample, relative to the total volume of the sample.

3. The method of claim 1 or 2, wherein the blood coagulation interfering compound is selected from the group consisting of: direct thrombin inhibitors, factor Xia and factor Xa inhibitors.

4. The method of any one of claims 1 to 3, wherein the blood coagulation interfering compound is a direct oral anticoagulant (DO AC).

5. The method of claim 4, wherein the DOAC is selected from the group consisting of: dabigatran, rivaroxaban, apixaban, betrixaban and edoxaban.

6. The method of any one of claims 1-5, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting of Activated partial thromboplastin time (APTT) test reagents, Dilute Russell's viper venom time (dRVVT) test reagents, Prothrombin time (PT) test reagents, Non-activated clotting time (NAPTT) reagents, Activated clotting time (ACT) reagents, Surface activated clotting time (SACT) reagents, and Recalcification clotting time (RCT) reagents in regular or in diluted form.

7. The method of any one of claims 1 to 6, wherein the activated carbon is mixed with and at least partially suspended in the sample.

8. The method of any one of claims 1 to 7, wherein the blood or blood component coagulation test is selected from the group consisting of Activated partial thromboplastin time (APTT) tests,Dilute Russell's viper venom time (dRVVT) tests, Prothrombin time (PT) tests, Non-activated clotting time (NAPTT) tests, Activated clotting time (ACT) tests, Surface activated clotting time (SACT) tests or Recalcification clotting time (RCT) tests.

9. A composition comprising: activated carbon; and one or more blood or blood component coagulation test reagents or additives.

10. The composition of claim 9, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting of APTT reagents, dRVVT reagents, PT reagents, NAPTT reagents, Activated clotting time (ACT) reagents, Surface activated clotting time (SACT) reagents, and Recalcification clotting time (RCT) reagents in regular or in diluted form.

11. The composition of claim 9 or 10, wherein the activated carbon is present in the composition in an amount of from about 1 mg / mL to about 40mg / mL.

12. A blood or blood component sample container, comprising: activated carbon.

13. The blood or blood component sample container of claim 12, further comprising one or more anticoagulant agents.

14. The blood or blood component sample container of claim 12 or 13, wherein the one or more anticoagulant agents comprise regular citrate, EDTA, DOACs, heparin or acid citrate dextrose.

15. The blood or blood component sample container of any one of claim 12 to 14, which is a blood or blood component collection vial.

16. The method of any one of any one of claims 1 to 8, composition of any one of claims 9 to 11, or blood or blood component sample container of any one of claims 12 to 15, wherein the activated carbon is in the form of a suspension.

17. The method, composition, or blood or blood component sample container of claim 16, wherein the suspension further comprises a sugar, optionally wherein the sugar comprises trehalose or polymers of sugars such as dextran and hydroxyethyl starch.

18. The method, composition, or blood or blood component sample container of claim 16 or 17, wherein the concentration of the activated carbon in the suspension is from about 50 mg / mL to about 200 mg / mL.

19. The method of any one of any one of claims 1 to 8 and 16 to 18, composition of any one of claims 9 to 11 and 16 to 18, or blood or blood component sample container of any one of claims 12 to 18, wherein the average particle size of the activated carbon is less than about 100 pm, or wherein the average particle size of the activated carbon is from about 30 pm to about 60 pm.

20. A method for deactivating a blood coagulation interfering compound in a sample for blood or blood component coagulation testing, said method comprising: a) mixing the sample with activated carbon to bind and deactivate the blood coagulation interfering compound; and b) performing a blood or blood component coagulation test on a sample containing the activated carbon, wherein the activated carbon is incorporated into the testing process, such as a clotting, chromogenic, Anorogenic, visco-elastic and / or sonorheometric test, by one or more of the following methods: including the activated carbon in a composition with one or more blood or blood component coagulation test reagents, wherein the carbon is mixed with the reagents before they are added to the sample, or by adding the activated carbon directly to the sample, wherein the carbon is mixed with the blood sample itself or applied to a surface in contact with the sample; wherein the test can be performed on a clot mechanical, optical, fluorogcnic detection or POC system.

21. The method of claim 20, wherein from about 0.05 mg / mL to about 40 mg / mL, or from about 1 mg / mL to about 20 mg / mL of activated carbon is mixed with the sample, relative to the total volume of the sample.

22. The method of claim 20 or 21, wherein the blood coagulation interfering compound is selected from the group consisting of, factor Xa, XI, Xia, XII, Xlla inhibitors or direct thrombin inhibitors.

23. The method of any one of claims 20 to 22, wherein the blood coagulation interfering compound is a direct oral anticoagulant (DO AC).

24. The method of claim 23, wherein the DOAC is selected from the group consisting of: dabigatran, rivaroxaban, apixaban, betrixaban, edoxaban, milvexian or assundexian.

25. The method of any one of claims 20 to 24, wherein the one or more blood or blood component coagulation tests are selected from chronometry, chromogenic or fluorescence based blood or blood component coagulation tests.

26. The method of any one of claims 20 to 24, wherein the one or more blood or blood component coagulation tests are selected from the group consisting of thomboelastometry and thromboelastography using cup and pin, resonance, sonorheometry, and sonic estimation of clot elasticity via resonance (SEER).

27. The method of any one of claims 20 to 26, wherein the blood or blood component coagulation test reagents are selected from the group consisting of activated partial thromboplastin time (APTT) test reagents, Staclot LA test reagents, Dilute Russell's viper venom time (dRVVT) test reagents, prothrombin time (PT) test reagents, thrombin ime (TT) test reagents, nonactivated clotting time (NAPTT) reagents, activated clotting time (ACT), surface activated clotting time (SACT) reagents, and / or derived reagents comprising one stage clotting test reagents, fibrin formation test reagents, protein C, protein S, activated protein C resistance (APCR) clotting test reagents and thrombin generation test reagents.

28. The method of any one of claims 20 to 26, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting chromogenic factor VIII or IX reagents, anti-thrombin chromogenic reagents, protein C chromogenic reagents, and anti-Xa chromogenic reagents.

29. The method of any one of claims 20 to 28, wherein the activated carbon is mixed with and at least partially suspended in the sample or immobilized on a surface.

30. The method of any one of claims 20 to 29, wherein the blood or blood component coagulation test is selected from the group consisting of APTTtests, Staclot LA tests, dRVVT tests, PT tests, TT tests, NAPTT tests, and surface activated clotting time tests, or derived tests comprising one stage clotting factor fibrin formation tests, protein C, protein S and APCR clotting tests, and thrombin generation assays.

31. The method of any one of claims 20 to 29, wherein the blood or blood component coagulation tests are selected from the group consisting of chromogenic factor VIII or IX tests, anti-thrombin chromogenic tests, protein C chromogenic tests and anti-Xa chromogenic tests.

32. The method of any one of claims 20 to 29, wherein the blood or blood component coagulation tests comprise a cartridge system and are measured using a SEER system.

33. A composition comprising:a) activated carbon; and b) one or more blood or blood component coagulation test reagents or additives.

34. The composition of claim 33, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting of APTT reagents, Staclot LA reagents, dRVVT reagents, PT reagents, NAPTT reagents, and surface activated clotting time reagents, or derived reagents comprising one stage clotting factor reagents, protein C, protein S and APCR clotting reagents, and thrombin generation reagents.

35. The composition of claim 33, wherein the one or more blood or blood component coagulation test reagents are selected from the group consisting of chromogenic factor VIII or IX reagents, antithrombin chromogenic reagents, protein C chromogenic reagents, and anti-Xa chromogenic reagents.

36. The composition of any one of claims 33 to 35, wherein the activated carbon is present in the composition in an amount of from about 0.1 mg / mL to about 40 mg / mL, or from 1 mg / mL to about 40 mg / mL.

37. A blood or blood component sample container, comprising: activated carbon.

38. The blood or blood component sample container of claim 37, wherein the activated carbon is added into the sample container by a manual or automated pretreatment step.

39. The blood or blood component sample container of claim 37 or 38, further comprising one or more anticoagulant agents selected from regular citrate, EDTA, DOACs, heparin or acid citrate dextrose.

40. The blood or blood component sample container of any one of claims 37 to 39, wherein the container is a blood or blood component collection vial.

41. The method of any one of any one of claims 20 to 32, composition of any one of claims 33 to 36, or blood or blood component sample container of any one of claims 37 to 40 wherein the activated carbon is in the form of a suspension.

42. The method, composition, or blood or blood component sample container of claim 41, wherein the suspension further comprises a sugar or a thixotropic agent, optionally wherein the sugar comprises trehalose or polysaccharides.

43. The method, composition, or blood or blood component sample container of claim 41 or 42, wherein the concentration of the activated carbon in the suspension is from about 5 mg / mL to about 200 mg / mL, or from about 50 mg / mL to about 200 mg / mL.

44. The method of any one of claims 20 to 32 and 41 to 43, the composition of any one of claims 33 to 36 and 41 to 43, or blood or blood component sample container of any one of claims 37 to 40, wherein the average particle size of the activated carbon is less than about 100 pm, or from about 60 pm to about 30 pm.

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