Characterisation of a Novel Series of Aprotinin-derived Anticoagulants

1995 ◽  
Vol 74 (02) ◽  
pp. 655-659 ◽  
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.

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

2012 ◽  
Vol 107 (02) ◽  
pp. 253-259 ◽  
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.

scholarly journals Tissue factor–positive neutrophils bind to injured endothelial wall and initiate thrombus formation

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2133-2143 ◽  
Author(s):  
Roxane Darbousset ◽  
Grace M. Thomas ◽  
Soraya Mezouar ◽  
Corinne Frère ◽  
Rénaté Bonier ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Long Time ◽  
Platelet Accumulation

AbstractFor a long time, blood coagulation and innate immunity have been viewed as interrelated responses. Recently, the presence of leukocytes at the sites of vessel injury has been described. Here we analyzed interaction of neutrophils, monocytes, and platelets in thrombus formation after a laser-induced injury in vivo. Neutrophils immediately adhered to injured vessels, preceding platelets, by binding to the activated endothelium via leukocyte function antigen-1–ICAM-1 interactions. Monocytes rolled on a thrombus 3 to 5 minutes postinjury. The kinetics of thrombus formation and fibrin generation were drastically reduced in low tissue factor (TF) mice whereas the absence of factor XII had no effect. In vitro, TF was detected in neutrophils. In vivo, the inhibition of neutrophil binding to the vessel wall reduced the presence of TF and diminished the generation of fibrin and platelet accumulation. Injection of wild-type neutrophils into low TF mice partially restored the activation of the blood coagulation cascade and accumulation of platelets. Our results show that the interaction of neutrophils with endothelial cells is a critical step preceding platelet accumulation for initiating arterial thrombosis in injured vessels. Targeting neutrophils interacting with endothelial cells may constitute an efficient strategy to reduce thrombosis.

scholarly journals Calin from Hirudo medicinalis, an inhibitor of platelet adhesion to collagen, prevents platelet-rich thrombosis in hamsters

Blood ◽  
1995 ◽  
Vol 85 (3) ◽  
pp. 712-719 ◽  
Author(s):  
H Deckmyn ◽  
JM Stassen ◽  
I Vreys ◽  
E Van Houtte ◽  
RT Sawyer ◽  
...  
Keyword(s):  
Platelet Adhesion ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Video Recording ◽  
Hirudo Medicinalis ◽  
Thrombosis Model

Interaction between exposed collagen and platelets and/or von Willebrand factor is believed to be one of the initiating events for thrombus formation at sites of damaged endothelium. Interference with this mechanism may provide an anti-thrombotic potential. Calin, a product from the saliva of the leech Hirudo medicinalis, was tested in vitro and for its in vivo activity in a thrombosis model in hamsters. Calin specifically and dose dependently (IC50:6.5 to 13 micrograms/mL) inhibited human platelet aggregation induced by collagen. In addition, specific platelet adhesion onto microtiter wells coated with collagen and detected with a monoclonal antiglycoprotein IIb/IIIa antibody- conjugated with horseradish peroxidase, could be completely prevented with Calin (IC50:22 micrograms/mL). A dose-response curve was constructed in groups of six hamsters in whom a standardized trauma was induced on the femoral vein. Thrombus formation was followed continuously using video recording and processing of the image obtained upon transillumination of the vessel. Intravenous Calin dose- dependently inhibited platelet-rich thrombus formation in this model with an ED50 of 0.07 mg/kg and complete inhibition with 0.2 mg/kg. No effects were seen on coagulation tests or bleeding times, whereas ex vivo aggregation induced by collagen was inhibited dose dependently. Local application of leech saliva, Calin, hirudin, or the combination of the latter two into the bleeding time wound of hamsters resulted in a mild prolongation of the bleeding time (twofold to threefold). A similar experiment in baboons did not cause any prolongation of the bleeding time. This is in sharp contrast with the long-lasting bleeding after a leech bite itself in both species. Calin from the leech Hirudo medicinalis is able, by binding to collagen, to effectively interfere with platelet-collagen interaction, which results in an antithrombotic effect observed in a platelet-rich thrombosis model in hamsters.

scholarly journals Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg- Gly-Asp-sulfoxide (G4120) in a hamster platelet-rich femoral vein thrombosis model

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1247-1253
Author(s):  
Y Imura ◽  
JM Stassen ◽  
S Bunting ◽  
F Stockmans ◽  
D Collen
Keyword(s):  
Platelet Aggregation ◽  
Intravenous Injection ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Platelet Glycoprotein ◽  
Dependent Manner ◽  
Vein Thrombosis ◽  
Thrombosis Model ◽  
Bolus Intravenous Injection

Platelet aggregation plays an important role in the pathogenesis in arterial thrombotic disorders. The binding of fibrinogen via the Arg- Gly-Asp (RGD) recognition sequence to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor is an essential step of platelet aggregation induced by various physiologic agonists, and RGD-containing peptides that bind to the GPIIb/IIIa receptor inhibit thrombus formation in vivo. L-cysteine, N-(mercaptoacetyl)D-tyrosyl-L- arginylglycyl-L alpha-aspartyl-cyclic (1----5)-sulfide, 5-oxide (G4120), a cyclic RGD-containing synthetic pentapeptide, inhibits adenosine diphosphate (ADP)-induced platelet aggregation with 50% inhibition (IC50) at a concentration of 0.05 microgram/mL in human plasma, 0.12 microgram/mL in hamster plasma, and 11 micrograms/mL in rat plasma. Corresponding values for the linear tetrapeptide Arg-Gly- Asp-Phe (RGDF) were 7 and 100 micrograms/mL in human and hamster plasma. The antithrombotic effects of G4120 and RGDF were evaluated in a hamster model consisting of a mural platelet-rich femoral vein thrombus induced by standardized endothelial cell damage. Bolus intravenous injection of G4120 was followed by a biphasic disappearance of G4120 from plasma with t1/2 alpha of 3.7 minutes and t1/2 beta of 63 minutes, corresponding to a plasma clearance of 5.2 +/- 0.68 mL/min. Bolus intravenous injection of G4120 inhibited ex vivo platelet aggregation with 0.5 mumol/L ADP and in vivo thrombus formation in a dose-dependent manner, with ID50 of 11 and 11 micrograms/kg, respectively. Bolus injection of RGDF inhibited in vivo thrombus formation; 43% inhibition was obtained at a dose of 30 mg/kg. Thus, this hamster platelet-rich femoral vein thrombosis model may be useful for the investigation of the antithrombotic properties of platelet GPIIb/IIIa antagonistic peptides. The cyclic synthetic peptide G4120 appears to have a very potent antithrombotic activity in vivo.

scholarly journals Nobiletin represses change in the levels of blood coagulation markers in the LPS-induced rat DIC model

2020 ◽  
Vol 10 (9) ◽  
pp. 397
Author(s):  
Kimihiko Takada ◽  
Mayuko Takano ◽  
Aiko Kunii ◽  
Kei Harayama ◽  
Akira Ito ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Thrombus Formation ◽  
In Vivo Studies ◽  
Coagulation Cascade ◽  
Operating Table ◽  
Blood Indices ◽  
Renal Glomeruli ◽  
Pai 1

Background: Nobiletin is contained in Shiikuwasa fruit, a popular citrus fruit from Okinawa Prefecture in Japan. Nobiletin reportedly acts as a strong antioxidant, an anti-inflammatory agent, and an anti-cancer agent, and it suppresses the expression of TF which triggers blood coagulation. However, in vivo verification of in vitro reports is necessary. This study used a rat model of LPS-induced microthrombosis based on the in vivo studies as previously reported. Sustained intravenous injection of LPS changed all blood coagulation indicators in the direction of thrombus formation. The aim of this study was to determine if intake of nobiletin could suppress DIC-like symptoms.Methods: Experimental SD rats were fully anesthetized and fixed to an operating table. Either LPS alone or nobiletin (50 mg/kg) plus LPS was given to rats to investigate the repressive effects of nobiletin on the expression of blood coagulation factors.Results: After 4 h of LPS infusion (12.5 mg/kg/h, i.v.), PLT counts and Fbg levels in rat plasma decreased by 80% and 74%, respectively. PT and APTT were extended by 180% and 256%, respectively. TF activity and PAI-1 antigen levels were remarkably increased (54- and 86-fold, respectively vs. control). Pretreatment on nobiletin (50 mg/kg, p.o.) reduced or suppressed fluctuations in blood coagulation indices caused by LPS. TF activity was repressed almost completely by nobiletin pretreatment. After 4 h, PAI-1 antigen levels in nobiletin-treated animals were repressed 82.6% compared to LPS-treated rats. Nobiletin repressed LPS-induced changes in TF and PAI-1 more effectively than other parameters. Further, nobiletin repressed fibrin thrombi  formation in the renal glomeruli induced by LPS treatment.Conclusions: Nobiletin was found to reduce LPS-induced DIC-like symptoms in rats. In the fluctuations of blood indices related to the coagulation cascade, nobiletin suppressed the LPS-induced expression of PAI-1 and TF more effectively than other indices. The binding sites of transcription factors that are activated by LPS-induced signals reside in the promoter areas of TF and PAI-1 gene sequences. Thus, the suppression of TF and PAI-1 expression by nobiletin appears similar to mechanisms previously evaluated during in vitro experiments. Importantly, nobiletin repressed fibrin deposition in the renal glomeruli induced by LPS treatment and improved overall health. Nobiletin may function as an anti-thrombogenic agent when ingested daily. Keywords: nobiletin; LPS; DIC model; blood coagulation; anti-thrombogenic

scholarly journals Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg- Gly-Asp-sulfoxide (G4120) in a hamster platelet-rich femoral vein thrombosis model

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1247-1253 ◽  
Author(s):  
Y Imura ◽  
JM Stassen ◽  
S Bunting ◽  
F Stockmans ◽  
D Collen
Keyword(s):  
Platelet Aggregation ◽  
Intravenous Injection ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Platelet Glycoprotein ◽  
Dependent Manner ◽  
Vein Thrombosis ◽  
Thrombosis Model ◽  
Bolus Intravenous Injection

Abstract Platelet aggregation plays an important role in the pathogenesis in arterial thrombotic disorders. The binding of fibrinogen via the Arg- Gly-Asp (RGD) recognition sequence to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor is an essential step of platelet aggregation induced by various physiologic agonists, and RGD-containing peptides that bind to the GPIIb/IIIa receptor inhibit thrombus formation in vivo. L-cysteine, N-(mercaptoacetyl)D-tyrosyl-L- arginylglycyl-L alpha-aspartyl-cyclic (1----5)-sulfide, 5-oxide (G4120), a cyclic RGD-containing synthetic pentapeptide, inhibits adenosine diphosphate (ADP)-induced platelet aggregation with 50% inhibition (IC50) at a concentration of 0.05 microgram/mL in human plasma, 0.12 microgram/mL in hamster plasma, and 11 micrograms/mL in rat plasma. Corresponding values for the linear tetrapeptide Arg-Gly- Asp-Phe (RGDF) were 7 and 100 micrograms/mL in human and hamster plasma. The antithrombotic effects of G4120 and RGDF were evaluated in a hamster model consisting of a mural platelet-rich femoral vein thrombus induced by standardized endothelial cell damage. Bolus intravenous injection of G4120 was followed by a biphasic disappearance of G4120 from plasma with t1/2 alpha of 3.7 minutes and t1/2 beta of 63 minutes, corresponding to a plasma clearance of 5.2 +/- 0.68 mL/min. Bolus intravenous injection of G4120 inhibited ex vivo platelet aggregation with 0.5 mumol/L ADP and in vivo thrombus formation in a dose-dependent manner, with ID50 of 11 and 11 micrograms/kg, respectively. Bolus injection of RGDF inhibited in vivo thrombus formation; 43% inhibition was obtained at a dose of 30 mg/kg. Thus, this hamster platelet-rich femoral vein thrombosis model may be useful for the investigation of the antithrombotic properties of platelet GPIIb/IIIa antagonistic peptides. The cyclic synthetic peptide G4120 appears to have a very potent antithrombotic activity in vivo.

Protein Inhibitor of Coagulation Factor Xa (PifXa): A New Protein-Based Specific Factor Xa Inhibitor Is An Effective, Reversible Inhibitor of Blood Coagulation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1095-1095
Author(s):  
Mette Sondrup Andersen ◽  
Aage Kristian Olsen Alstrup ◽  
Julie Kirstine Andersen ◽  
Søren Risom Kristensen ◽  
Kåre Lehmann Nielsen
Keyword(s):  
Blood Coagulation ◽  
Bleeding Time ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Specific Factor ◽  
Low Molecular Weight ◽  
University Patents

Abstract Abstract 1095 Heparin was discovered in 1916 and put into clinical trials in 1935. Despite advent of several anticoagulants during the last 75 years, heparin still remains the most widely used anticoagulant. None the less, several drawbacks of heparin exist i) it is difficult to determine the correct dosage, ii) heparins binds many different targets in humans, iii) side effects such as Heparin Induced Thrombocytopenia (HIT) is known (Hirsh J et al, Chest 2001). Consequently, intense emphasis have been put on finding new and improved inhibitory agents towards specific factors in the blood coagulation. Especially factor Xa (fXa) is considered an interesting target for inhibitors due to its central place in the coagulation cascade (Gross PL and Weitz, JI, Clinical Pharmacology and therapeutics 2009). Here we present a novel direct specific inhibitor of fXa, PifXa (protein inhibitor of coagulation factor Xa), which has been isolated from potato tubers. The inhibitor of the legume Kunitz type protein family was able to inhibit the activity of fXa using a mixed mode of inhibition with an apparent Ki of 2.5 nM, as determined using a low molecular weight substrate. Noteworthy, no inhibition of thrombin could be detected. Furthermore, the effect of the inhibitor could be detected using the activated partial thromboplastin time (aPTT) assay, which suggests that PifXa is not only capable of inhibiting free fXa but also complex/clot-bound fXa. Other known specific fXa inhibitors such as the pentasaccharide fondaparinux (Arixtra, GlaxoSmithKline) and low molecular weight heparin (LMWH) give rise to little or no effect in the aPTT assay. This observation has been attributed to the fact that these inhibitors only inhibit free fXa (Hirsh J et al, Chest 2001). PifXa was capable of significantly prolonging the tail bleeding time, but did not increase the bleeding amount significantly compared to the control in in vivo experiments conducted in rats. Hence, PifXa is highly specific towards the blood coagulation cascade, but do not interfere with the platelet plug formation in contrast to heparin, that can interfere with the thrombin induced platelet activation (Day, J et al, J of Cardiothoracic and Vascular Anesthesia 2004). Indeed, inhibition of activation of the platelets by PifXa could not be detected in in vitro experiments using platelet aggreometry. Furthermore, PifXa given in combination with the anti-platelet drug acetylsalicylic acid increased both the bleeding time and amount in the in vivo rat experiment significantly, demonstrating an additive effect of PifXa and the antiplatelet drug. The combined effect exceeded that of both heparin and fondaparinux. In contrast to other specific factor Xa inhibitors, the effect of PifXa, being a protein, can be fully reversed by addition of a specific polyclonal antibody. That this is in fact possible was demonstrated in vitro. The specificity of the inhibitor combined with the possibility to reverse the effect makes PifXa an interesting candidate drug during cardio pulmonary bypass where the general inconvenient requirement for IV administration of protein drugs is tolerable, a large dose of anticoagulants in a limited period of time is necessary, and thus administration of an antidote to reverse the effect at the end of the procedure is desired. Disclosures: Andersen: Aalborg University: Patents & Royalties. Nielsen:Aalborg University: Patents & Royalties.

Comparison of the In Vivo Anticoagulant Properties of Standard Heparin and the Highly Selective Factor Xa Inhibitors Antistasin and Tick Anticoagulant Peptide (TAP) in a Rabbit Model of Venous Thrombosis

1991 ◽  
Vol 65 (03) ◽  
pp. 257-262 ◽  
Author(s):  
George P Vlasuk ◽  
Denise Ramjit ◽  
Tsuneo Fujita ◽  
Christopher T Dunwiddie ◽  
Elka M Nutt ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Rabbit Model ◽  
Factor Xa ◽  
Clot Formation ◽  
Factor Xa Inhibitors ◽  
Venous Stasis ◽  
Thrombosis Model ◽  
Tick Anticoagulant Peptide

SummaryAn in vivo thromboplastin (TP)-induced venous stasis thrombosis model in rabbits was used to compare the efficacy of standard heparin with the selective factor Xa inhibitors, recombinant tick anticoagulant peptide (rTAP) and recombinant antistasin (rATS), in prophylactic prevention of thrombus formation. Heparin significantly reduced TP-induced clot formation at doses of 55 and 100 U kg−1 h−1 yielding clot weights of 9 ± 4 and 6 ± 2%, respectively. Clot formation was significantly decreased by i.v. infusions of rTAP at doses of 21, 37 and 64 Μg kg−1 min−1 resulting in normalized clot weights of 13 ± 3, 8 ± 2 and 2 ± 1%, respectively. rATS was approximately 10-fold more potent than rTAP, reducing normalized clot weights to 16 ± 5, 2 ± 1 and 1 ± 0.8% at rATS doses of 1.25, 2.5 and 5.0 Μg kg−1 min−1, respectively. These data suggest that factor Xa-mediated inhibition of coagulation with rTAP and rATS is as effective as conventional anticogulant treatment with heparin in preventing venous thrombosis.

scholarly journals Antithrombotic properties of Ixolaris, a potent inhibitor of the extrinsic pathway of the coagulation cascade

2006 ◽  
Vol 96 (07) ◽  
pp. 7-13 ◽  
Author(s):  
Rômulo Nazareth ◽  
Luana Tomaz ◽  
Susana Ortiz-Costa ◽  
Geórgia Atella ◽  
José Ribeiro ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Ixodes Scapularis ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Heparin Binding ◽  
Extrinsic Pathway ◽  
Thrombosis Model ◽  
Salivary Gland Protein ◽  
Antithrombotic Effects

SummaryIxolaris is a two-Kunitz tick salivary gland protein identified in Ixodes scapularis that presents extensive sequence homology t TFPI.It binds to FXa or FX as scaffolds and inhibits tissue factor/ FVIIa complex (extrinsic Xnase). Differently from TFPI, ixolaris does not bind to the active site cleft of FXa. Instead, comple formation is mediated by the FXa heparin-binding exosite,which may also results in decreased FXa activity into the prothrombi nase complex.In this report,we show that recombinant 125I-ixo laris interacts with rat and human FX in plasma and prolongs the prothrombin time (PT) and activated partial thromboplastin time (aPTT) in vitro.We have also investigated the effects of ixo laris in vivo, using a venous thrombosis model. Subcutaneous (s.c.) or intravenous (i.v.) administration of ixolaris in rats caused a dose-dependent reduction in thrombus formation, with complete inhibition attained at 20 µg/kg and 10 µg/kg, re spectively. Antithrombotic effects were observed 3 h after s.c. administration of ixolaris and lasted for 24 h thereafter. Ex vivo experiments showed that ixolaris (up to 100 µg/kg) did not affect the aPTT,while the PT was increased by ∼0.4-fold at the hig hest ixolaris concentration. Remarkably, effective antithrom botic doses of ixolaris (20 µg/kg) was not associated with bleed ing which was significant only at higher doses of the anticoagulant (40 µg/kg).Our experiments demonstrate that ixolaris is an effective and possibly safe antithrombotic agen in viv .

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