Active site-blocked factor Xa prevents thrombus formation in the coronary vasculature in parallel with inhibition of extravascular coagulation in a canine thrombosis model

Abstract Factor Xa is a central procoagulant enzyme, linking the intrinsic and extrinsic activation mechanisms to the final common pathway of coagulation. To assess its contribution to pathologic thrombosis, studies were performed in a canine coronary thrombosis model. Thrombus formation was initiated by the application of electric current via a needle electrode placed in the lumen of the left circumflex coronary artery. When 50% occlusion of the vessel developed, the current was stopped and animals received an intravenous bolus of either saline, bovine glutamyl-glycinyl-arginyl-factor Xa (Xai), a competitive inhibitor of factor Xa assembly into the prothrombinase complex, Factor X, or heparin. Animals infused with saline or factor X (300 micrograms/kg) developed total occlusion of the vessel due to a fibrin/platelet thrombus in 70 +/- 11 minutes (36 of 36 animals) and 74 +/- 13 minutes (8 of 8 animals), respectively. In contrast, infusion of Xai prevented thrombus formation completely at a dose of 300 micrograms/kg (8 of 8 animals). As the dose of Xai was decreased, its antithrombotic effect was diminished, with a patency rate of only 2 of 6 animals at a dose of 90 micrograms/kg. Xai at 300 micrograms/kg prevented the accumulation of 125I-fibrinogen/fibrin at the site of the coronary thrombus by approximately 63% and decreased deposition of 111In-labeled platelets by approximately 57%. Hemostatic parameters of animals infused with Xai demonstrated prolongation of the PT and dose- dependent increased extravascular bleeding tendency. These data indicate that factor Xa has a comparably important role in thrombus formation and extravascular hemostasis, and contrast with previous results in this same animal model in which IXai selectively prevented clotting in the coronary vasculature.

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Active site-blocked factor Xa prevents thrombus formation in the coronary vasculature in parallel with inhibition of extravascular coagulation in a canine thrombosis model

Blood ◽

10.1182/blood.v81.8.2059.bloodjournal8182059 ◽

1993 ◽

Vol 81 (8) ◽

pp. 2059-2066

Author(s):

CR Benedict ◽

J Ryan ◽

J Todd ◽

K Kuwabara ◽

P Tijburg ◽

...

Keyword(s):

Thrombus Formation ◽

Coronary Thrombosis ◽

Factor Xa ◽

Competitive Inhibitor ◽

Bleeding Tendency ◽

Factor X ◽

Total Occlusion ◽

Coronary Vasculature ◽

Thrombosis Model ◽

Activation Mechanisms

Factor Xa is a central procoagulant enzyme, linking the intrinsic and extrinsic activation mechanisms to the final common pathway of coagulation. To assess its contribution to pathologic thrombosis, studies were performed in a canine coronary thrombosis model. Thrombus formation was initiated by the application of electric current via a needle electrode placed in the lumen of the left circumflex coronary artery. When 50% occlusion of the vessel developed, the current was stopped and animals received an intravenous bolus of either saline, bovine glutamyl-glycinyl-arginyl-factor Xa (Xai), a competitive inhibitor of factor Xa assembly into the prothrombinase complex, Factor X, or heparin. Animals infused with saline or factor X (300 micrograms/kg) developed total occlusion of the vessel due to a fibrin/platelet thrombus in 70 +/- 11 minutes (36 of 36 animals) and 74 +/- 13 minutes (8 of 8 animals), respectively. In contrast, infusion of Xai prevented thrombus formation completely at a dose of 300 micrograms/kg (8 of 8 animals). As the dose of Xai was decreased, its antithrombotic effect was diminished, with a patency rate of only 2 of 6 animals at a dose of 90 micrograms/kg. Xai at 300 micrograms/kg prevented the accumulation of 125I-fibrinogen/fibrin at the site of the coronary thrombus by approximately 63% and decreased deposition of 111In-labeled platelets by approximately 57%. Hemostatic parameters of animals infused with Xai demonstrated prolongation of the PT and dose- dependent increased extravascular bleeding tendency. These data indicate that factor Xa has a comparably important role in thrombus formation and extravascular hemostasis, and contrast with previous results in this same animal model in which IXai selectively prevented clotting in the coronary vasculature.

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Comparative Studies of an Orally-active Factor Xa Inhibitor, YM-60828, with other Antithrombotic Agents in a Rat Model of Arterial Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615007 ◽

1998 ◽

Vol 79 (02) ◽

pp. 410-416 ◽

Cited By ~ 32

Author(s):

Kazuo Sato ◽

Yumiko Sakai ◽

Fukushi Hirayama ◽

Hiroyuki Koshio ◽

Yuta Taniuchi ◽

...

Keyword(s):

Electrical Stimulation ◽

Arterial Thrombosis ◽

Thrombus Formation ◽

Factor Xa ◽

Test Drug ◽

Antithrombotic Agent ◽

Antithrombotic Activity ◽

Thrombosis Model ◽

Treatment And Prevention ◽

Orally Active

SummaryWe examined the antithrombotic activity of a novel synthetic inhibitor of factor Xa, YM-60828, in an electrically-induced carotid artery thrombosis model in rats. In the first experiment, the antithrombotic activity of YM-60828 after i.v. infusion was compared with those of heparin, darteparin and argatroban. Test drug was administered by i.v. infusion from 30 min before electrical stimulation to the end of the experiment. YM-60828 at 1 mg/kg/h significantly improved patency status, prolonged the time to occlusive thrombus formation and duration of patency. Heparin at 300 U/kg/h also improved these parameters, but were accompanied by a marked increase in systemic coagulation time. In the second experiment, the antithrombotic activity of YM-60828 after oral administration was compared with those of ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate and warfarin. Test drug was orally administered to fasted rats 60 min before electrical stimulation. YM-60828 at 30 mg/kg p.o., but not ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate or warfarin, significantly reduced the incidence of occlusion and improved carotid arterial patency. These results suggest that YM-60828 may be a promising antithrombotic agent for the treatment and prevention of arterial thrombosis which can be given by oral as well as intravenous administration.

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EXPERIMENTAL THROMBUS FORMATION AND HAEMOSTASIS OF DIFFERENT LOW MOLECULAR WEIGHT HEPARINS AND DOSAGES

10.1055/s-0038-1644162 ◽

1987 ◽

Author(s):

R A Zimmerman ◽

C T Rieger ◽

K Hübner ◽

C W Harenber ◽

W Kübler

Keyword(s):

Molecular Weight ◽

Thrombus Formation ◽

Factor Xa ◽

Bleeding Complications ◽

Maximum Effect ◽

Low Molecular Weight ◽

Antithrombotic Effect ◽

Low Molecular Weight Heparins ◽

Antithrombotic Activity ◽

Thrombosis Model

Low molecular weight heparin induces a higher anti factor Xa (a-Xa) and a lower antithrombin activity in plasma in comparison to conventional heparin. From this constellation a more pronounced antithrombotic effect and a minor incidence of bleeding Complications has been suggested.Therefore the antithrombotic activity of heparins was studied in a standardized experimental thrombosis model in rabbits. Three low molecular weight heparins with a mean molecular weight of 4.200 (heparin I),4.000 (heparin II),4.600 Dalton (heparin III) and standard heparin were tested at different dosages in 120 experiments. In the first series the dose of 60 anti Xa units (a-Xa U) given initially and 60 a-Xa U/kg/h induced a reduction of the thrombus size by 40 % (heparin I),37 % (heparin II) and 53 % (heparin III) and a prolongation of the aPTT to 45 (heparin I),66 (heparin II) and 79 sec (heparin III). The a-Xa activity was minor than 0.1 U/ml. In the second series heparins were given to aim at an a-Xa activity of 0.2-0.3 U/ml. Thereby the thrombus formation could be reduced by 84 % (heparin I), 62 % (heparin II) and 39 % (heparin III). aPTT and a-Xa activity were measured at 65.5 sec and 0.22 a-Xa U/ml (heparin I),67.3 sec and 0.3 a-Xa U/ml (heparin II) and 67.5 and 0.31 a-Xa U/ml (heparin III),respectively. In the third series the increase of the a-Xa activity to more than 0.3 U/ml showed no further reduction of the thrombus formation by heparin I, while heparins II and III already at this level reachedthe antithrombotic activity of heparin I.Our data on three different low molecular weight heparins demonstrate that already a heparin level ranging at a minimal a-Xa activity induces a clear and statistically significant antithrombotic effect. A higher heparin dosage with higher a-Xa activity increases the antithrombitic effect. At a level of 0.2-0.3 a-Xa U/ml an obvious and maximum effect could be reached, but the further elevation of the a-Xa activity produced no further antithrombotic action.

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Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

Thrombosis and Haemostasis ◽

10.1160/th11-09-0668 ◽

2012 ◽

Vol 107 (02) ◽

pp. 253-259 ◽

Cited By ~ 106

Author(s):

Toshio Fukuda ◽

Yuko Honda ◽

Chikako Kamisato ◽

Toshiro Shibano ◽

Yoshiyuki Morishima

Keyword(s):

Venous Thrombosis ◽

Prothrombin Complex Concentrate ◽

Bleeding Time ◽

Factor Viia ◽

Thrombus Formation ◽

Factor Xa ◽

Factor Xa Inhibitor ◽

Direct Factor ◽

Thrombosis Model ◽

Haemostatic Agents

SummaryEdoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

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Antithrombotic and Hemorrhagic Effects of DU-176b, a Novel, Potent and Orally Active Direct Factor Xa Inhibitor: A Wider Safety Margin Compared to Heparins and Warfarin.

Blood ◽

10.1182/blood.v104.11.1851.1851 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1851-1851 ◽

Cited By ~ 1

Author(s):

Taketoshi Furugohri ◽

Yuko Honda ◽

Chikako Matsumoto ◽

Koji Isobe ◽

Nobutoshi Sugiyama ◽

...

Keyword(s):

Animal Studies ◽

Bleeding Time ◽

Thrombus Formation ◽

Dose Range ◽

Safety Margin ◽

Vena Cava ◽

Factor Xa ◽

Selective Inhibition ◽

Thrombosis Model ◽

Orally Active

Abstract DU-176b is a novel potent, orally active and selective direct inhibitor of factor Xa (FXa). Direct FXa inhibitors have been reported to exert little effect on bleeding time at antithrombotic doses in animal studies. The aim of the present study was to compare the antithrombotic and hemorrhagic effects of DU-176b with unfractionated heparin (UFH), low molecular weight heparin (LMWH; dalteparin) and warfarin in rat models of thrombosis and hemorrhage. Rats were treated with DU-176b, UFH and LMWH by continuous intravenous infusion for 2 – 2.5 h, and with warfarin orally once daily for 4 days before thrombosis or hemorrhage. Thrombosis was induced by the insertion of a platinum wire into the inferior vena cava and left for 60 min. Tail template bleeding time was measured after an incision on the tail. DU-176b dose-dependently inhibited thrombus formation in the venous thrombosis model. The dose required for 50% inhibition (ED50) was 0.076 mg/kg/h. In contrast, the dose of DU-176b to double template bleeding time (BT2) was 0.75 mg/kg/h, indicating 10-fold dissociation of the doses of antithrombotic and hemorrhagic effects. UFH, LMWH and warfarin also prevented thrombus formation (ED50 = 56 U/kg/h, 66 U/kg/h and 0.16 mg/kg/day, respectively), but prolonged bleeding time at slightly higher doses (BT2 = 73 U/kg/h, 135 U/kg/h and 0.21 mg/kg/day, respectively) than the effective doses. The dissociation of the doses for these compounds was only 1.3, 2.0 and 1.3-fold, respectively. Moreover, the slope of dose-antithrombotic response curve of DU-176b was significantly slighter than those of UFH, LMWH and warfarin, indicating that the therapeutic dose range of DU-176b would be wider than those of the other anticoagulants. These results suggest that direct and selective inhibition of FXa by DU-176b is preferable for the treatment of thrombotic diseases in the aspect of lack of compromising primary hemostasis.

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In Vitro and In Vivo Characterization of a Murine Model of Suppressed Intrinsic Pathway Using a FX Variant: FXRoma.

Blood ◽

10.1182/blood.v110.11.2697.2697 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2697-2697

Author(s):

Elise Roy ◽

Paris Margaritis ◽

Harre D. Downey ◽

Katherine A. High

Keyword(s):

Mouse Model ◽

Thrombus Formation ◽

Bleeding Tendency ◽

Factor X ◽

Wild Type ◽

Intrinsic Pathway ◽

Vessel Occlusion ◽

Tail Clip

Abstract The complex and dynamic interplay between the intrinsic and extrinsic pathways of blood coagulation is incompletely understood. The mediator of prothrombin cleavage, Factor X (FX), plays a pivotal role as part of both the extrinsic and intrinsic tenase complexes. Moreover, the existence of naturally occurring Factor X mutations that can be asymmetrically activated through one but not both of these pathways affords one strategy for analyzing the relationship of the two pathways. The Factor X Roma (FXRoma) variant, originally described in a patient with mild bleeding tendency (severe following trauma, De Stefano et al., 1988), is due to a missense mutation (Thr318←Met) in exon 8. Coagulation testing revealed markedly decreased activity (1–3% wild-type) in the intrinsic pathway as measured by aPTT, but substantially higher activity (30–50% wild-type) in the extrinsic pathway as measured by PT. We chose to generate a mouse model of FX asymmetric activation to further probe the extrinsic-intrinsic pathway physiological relationship in hemostasis and thrombosis. For this, we used both an in vitro and an in vivo approach. We first constructed and purified the mouse homolog of FXRoma (mFXRoma) as well as wild-type mFX. Using a clotting-based assay, mFXRoma exhibited intrinsic and extrinsic activity comparable to that reported for the human mutation (5% and 18%, respectively). The reduced intrinsic and extrinsic activity of mFXRoma was not due to a secretion defect, based on Western blot analysis of supernatant and cell extracts from mFXRoma and mFX stably-transfected human embryonic kidney (HEK-293) cell lines. Mice homozygous for the analogous mutation (Thr315←Met) in exon 8 of the murine FX gene were generated by using a plug-and-socket approach. This resulted in the endogenous mFX exon 8 sequence being replaced with the mutated one, thus affording gene expression under the endogenous promoter. Analysis of mFXRoma homozygous mice showed a 6.4% and 19.2% intrinsic and extrinsic activity relative to wild-type littermates, respectively, confirming our in vitro data. The reduced activity in these mice resulted in a slight reduction in levels of the thrombin-antithrombin (TAT) complex. To determine any physiological defect of this mutation on the two pathways of coagulation, we performed two hemostatic challenges of the macrocirculation (tail clip and FeCl3-induced thrombus formation). In the tail-clip assay, blood loss showed no statistical difference between wild-type (n=5) and mFXRoma (n=6) mice. In contrast, following FeCl3-induced injury on the carotid artery (larger vessel diameter that in the tail), mFXRoma mice (3/3) failed to result in vessel occlusion (up to 30 min of observation), whereas wild-type littermates showed stable vessel occlusion (3/4) within ∼6 min of FeCl3 application. Although the type of injury was different, these data suggest that an impeded intrinsic activity of FX does not appear to affect hemostasis of the macrocirculation at relatively small diameter vessels but is essential for thrombus formation in large diameter vessels, and a relatively normal extrinsic activity does not compensate for this defect. This mouse model will aid in determining the safety and efficacy of therapeutic approaches based on impeding the intrinsic pathway of coagulation.

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The purification and properties of Factor X from pig serum and its role in hypercoagulability in vivo

Biochemical Journal ◽

10.1042/bj1330311 ◽

1973 ◽

Vol 133 (2) ◽

pp. 311-321 ◽

Cited By ~ 1

Author(s):

R. J. Dupe ◽

R. M. Howell

Keyword(s):

Molecular Weight ◽

Thrombus Formation ◽

Gel Filtration ◽

Factor Xa ◽

Factor X ◽

Molecular Weights ◽

Purification And Properties ◽

Initial Adsorption

The molecular weights or shapes of Factor X preparations determined by gel filtration were dependent on the density of the BaSO4 used for the initial adsorption from serum. One form obtained with BaSO4 of density 2g/ml behaved as if it had a molecular weight of 39000 and possessed preformed clotting activity (Factor Xa), whereas that of the form adsorbed with BaSO4 of density 1g/ml had a molecular weight of 69000 and consisted of inactive Factor X precursor. Thus degradation accompanied by activation seems to occur as a result of surface adsorption on high-density BaSO4 and is associated with an interchange of protein between the two bands observed electrophoretically. The clotting and esterase activities measurable in vitro after complete activation were not matched by a corresponding ability to induce thrombus formation and ‘lethality’ in vivo. The most effective preparations of Factor X in this respect possessed preformed activity, which was enhanced in the presence of phospholipid. Factor X lost activity more rapidly in dilute solution, and its concentration at the surface of phospholipid micelles probably decreases loss by dilution in circulating blood.

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Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site

Thrombosis and Haemostasis ◽

10.1160/th09-06-0400 ◽

2010 ◽

Vol 103 (01) ◽

pp. 224-233 ◽

Cited By ~ 13

Author(s):

Jin-an Jiao ◽

Andrew Kelly ◽

Ulla Marzec ◽

Esperanza Nieves ◽

Jorge Acevedo ◽

...

Keyword(s):

Binding Site ◽

Tissue Factor ◽

Thrombus Formation ◽

Treated Group ◽

Factor Ix ◽

Factor Vii ◽

Factor X ◽

Antithrombotic Agent ◽

Vascular Thrombosis ◽

Thrombosis Model

SummaryTissue factor (TF) antagonists targeting the factor VII (FVII) binding domain have been shown to interrupt acute vascular thrombus formation without impairing haemostasis in non-human primates. In this study, we evaluate whether a human/mouse chimeric monoclonal antibody (ALT-836, formerly known as Sunol-cH36) blocking the factor X/factor IX (FX/FIX) binding site of tissue factor could achieve similar clinical benefits in an arterial thrombosis model induced by surgical endarterectomy in chimpanzees. In this model, sequential surgical endarterectomies on right and left superficial femoral arteries were performed 30 days apart in five chimpanzees. A bolus (1 mg/kg) of ALT-836 was injected intravenously immediately preceding the restoration of flow in the endarterectomised femoral artery. Pre-surgical labelling of autologous platelets using 111In-Oxine and post-surgical gamma camera imaging of 111In-platelet deposition at endarterectomy sites was performed. The manipulated arterial segments were harvested for patency analysis 30 days following surgery. The results indicate that ALT-836 was highly effective at reducing acute vascular thrombosis, with no significant variations in surgical blood loss and template-bleeding time in the treated group compared to the control animals. These data suggest that ALT-836 is an effective and safe antithrombotic agent in preventing TF-initiated vascular thrombogenesis without compromising haemostasis.

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CrataBL, a lectin and Factor Xa inhibitor, plays a role in blood coagulation and impairs thrombus formation

Biological Chemistry ◽

10.1515/hsz-2014-0127 ◽

2014 ◽

Vol 395 (9) ◽

pp. 1027-1035 ◽

Cited By ~ 7

Author(s):

Bruno R. Salu ◽

Rodrigo S. Ferreira ◽

Marlon V. Brito ◽

Tatiana F. Ottaiano ◽

José Walber M.C. Cruz ◽

...

Keyword(s):

Arterial Thrombosis ◽

Bleeding Time ◽

Antithrombin Iii ◽

Thrombus Formation ◽

Factor Xa ◽

Artery Occlusion ◽

Control Group ◽

Thrombosis Model ◽

Arterial Thrombus ◽

Induce Cancer Cell Apoptosis

Abstract Arterial thrombosis is an important complication of diabetes and cancer, being an important target for therapeutic intervention. Crataeva tapia bark lectin (CrataBL) has been previously shown to have hypoglycemiant effect and also to induce cancer cell apoptosis. It also showed inhibitory activity against Factor Xa (Kiapp=8.6 μm). In the present study, we evaluated the anti-thrombotic properties of CrataBL in arterial thrombosis model. CrataBL prolongs the activated partial thromboplastin time on human and mouse plasma, and it impairs the heparin-induced potentiation of antithrombin III and heparin-induced platelet activation in the presence of low-dose ADP. It is likely that the dense track of positive charge on CrataBL surface competes with the heparin ability to bind to antithrombin III and to stimulate platelets. In the photochemically induced thrombosis model in mice, in the groups treated with 1.25, 5.0, or 10 mg/kg CrataBL, prior to the thrombus induction, the time of total artery occlusion was prolonged by 33.38%, 65%, and 66.11%, respectively, relative to the time of the control group. In contrast to heparin, the bleeding time in CrataBL-treated mice was no longer than in the control. In conclusion, CrataBL was effective in blocking coagulation and arterial thrombus formation, without increasing bleeding time.

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Characterisation of a Novel Series of Aprotinin-derived Anticoagulants

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649793 ◽

1995 ◽

Vol 74 (02) ◽

pp. 655-659 ◽

Cited By ~ 6

Author(s):

Jean Marie Stassen ◽

Anne-Marie Lambeir ◽

Ingrid Vreys ◽

Hans Deckmyn ◽

Gaston Matthyssens ◽

...

Keyword(s):

Blood Coagulation ◽

Initial Level ◽

Factor Viia ◽

Thrombus Formation ◽

Femoral Vein ◽

Factor Xa ◽

Vascular Trauma ◽

Coagulation Cascade ◽

Thrombosis Model

SummaryUpon vascular damage platelet activation and blood coagulation are initiated. Interference at the initial level of the activation of the coagulation cascade can result in effective inhibition of thrombus formation. The in vivo antithrombotic properties of a series of bovine pancreatic trypsin inhibitor mutants (BPTI, aprotinin) 4C2, 7L22, 5L15, 5L15-PEG, 6L15 and 5L84, as described in the accompanying paper, with a combined inhibitory activity on factor Xa, factor VIIa-tissue factor complex, factor XIa and plasma kallikrein were compared to rTAP, r-hirudin, heparin and enoxaparin in a platelet rich thrombosis model in hamsters.Platelet dependent thrombus deposition was quantified by dedicated image analysis after transillumination of the femoral vein to which a standardised vascular trauma was applied. After increasing intravenous bolus injections all tested agents, except for aprotinin, induced a dose dependent decrease of thrombus formation and a concomitant prolongation of the aPTT. From the linear correlation between these two parameters it was found that 5 out of the 6 tested aprotinin analogues, rTAP and r-hirudin completely inhibited thrombus formation at a therapeutical (2- to 3-fold) aPTT prolongation while 4C2, heparin and enoxaparin only inhibited thrombus formation for 40 to 50 percent at a 2-fold aPTT prolongation. Based on the calculated IC50 values for thrombus formation rTAP was found to be the most active compound in this model.It is concluded that acceptable interference at the initial level of the blood coagulation, e. g. within a therapeutical aPTT prolongation, can significantly inhibit platelet deposition at a site of vascular injury.

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