Procoagulant and prothrombotic activation of human erythrocytes by phosphatidic acid

2010 ◽  
Vol 299 (2) ◽  
pp. H347-H355 ◽  
Author(s):  
Ji-Yoon Noh ◽  
Kyung-Min Lim ◽  
Ok-Nam Bae ◽  
Seung-Min Chung ◽  
Sang-Wook Lee ◽  
...  
Keyword(s):  
Phosphatidic Acid ◽  
Thrombus Formation ◽  
Biological Activities ◽  
Human Erythrocytes ◽  
Erythrocyte Aggregation ◽  
Dependent Manner ◽  
Disease States ◽  
Thrombosis Model ◽  
Intracellular Ca

Increased phosphatidic acid (PA) and phospholipase D (PLD) activity are frequently observed in various disease states including cancers, diabetes, sepsis, and thrombosis. Previously, PA has been regarded as just a precursor for lysophosphatidic acid (LPA) and diacylglycerol (DAG). However, increasing evidence has suggested independent biological activities of PA itself. In the present study, we demonstrated that PA can enhance thrombogenic activities in human erythrocytes through phosphatidylserine (PS) exposure in a Ca2+-dependent manner. In freshly isolated human erythrocytes, treatment of PA or PLD induced PS exposure. PA-induced PS exposure was not attenuated by inhibitors of phospholipase A2or phosphatidate phosphatase, which converts PA to LPA or DAG. An intracellular Ca2+increase and the resultant activation of Ca2+-dependent PKC-α appeared to underlie the PA-induced PS exposure through the activation of scramblase. A marginal decrease in flippase activity was also noted, contributing further to the maintenance of exposed PS on the outer membrane. PA-treated erythrocytes showed strong thrombogenic activities, as demonstrated by increased thrombin generation, endothelial cell adhesion, and erythrocyte aggregation. Importantly, these procoagulant activations by PA were confirmed in a rat in vivo venous thrombosis model, where PA significantly enhanced thrombus formation. In conclusion, these results suggest that PA can induce thrombogenic activities in erythrocytes through PS exposure, which can increase thrombus formation and ultimately contribute to the development of cardiovascular diseases.

Phosphatidic Acid Enhances Procoagulant Activity and Thrombosis through Phosphatidylserine Exposure in Human Erythrocytes.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3846-3846
Author(s):  
Ji-Yoon Noh ◽  
Kyung-Min Lim ◽  
Jin-Ho Chung
Keyword(s):  
Phosphatidic Acid ◽  
Thrombus Formation ◽  
Biological Activities ◽  
Biological Significance ◽  
Human Erythrocytes ◽  
Disease States ◽  
Thrombosis Model ◽  
Intracellular Calcium Level

Abstract The increased phospholipase D (PLD) activity and phosphatidic acid (PA) level are frequently observed in various disease states including cancers, diabetes, inflammation, sepsis, and thrombosis. While PA has been previously regarded as a precursor for lysophosphatidic acid (LPA) and diacylglycerol (DAG), increasing evidence suggests the biological activities of PA, itself. Here we demonstrated that the PA can enhance procoagulant activities in human erythrocytes and thrombus formation mediated through phosphatidylserine (PS) exposure. Conspicuously, the PS exposure by PA was substantially greater than that of LPA and we examined its mechanism of action in an effort to elucidate the biological significance of PA. In human erythrocytes, PA treatment resulted in PS exposure without microvesicle generation or hemolysis as determined by flow cytometry. These effects were not attenuated by inhibitors of phospholipase A2 and phosphatidate phosphatase, that convert PA to LPA and DAG, respectively, suggesting that PA directly induced PS exposure. PA exposed erythrocytes showed significantly high intracellular calcium level and resultant protein kinase C (PKC) a activation. Consistent with these findings, the activity of scramblase was enhanced by PA treatment, while that of flippase was inhibited. Furthermore, PA-exposed erythrocytes were aggregated, accelerated thrombin generation, and increased adherence to endothelial cells, implying PA treatment enhanced the thrombogenic activities of erythrocytes indeed. Of note, these procoagulant activations by PA were confirmed in rat in vivo venous thrombosis model. These results suggest that PA can contribute to enhanced thrombosis, mediated through PS exposure on erythrocytes. With this study, we believe a novel insight was given into the role of PA in cardiovascular diseases.

“M-AAA-Thrombin”, a New Thrombin Mutant with Potent Anticoagulant and Antiplatelet Properties.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4154-4154
Author(s):  
Kazuya Hosokawa ◽  
Tomoko Ohnishi ◽  
Hiroyuki Matsuda ◽  
Kousuke Kashima ◽  
Takehiko Koide
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Antiplatelet Agent ◽  
Dependent Manner ◽  
In Vivo Experiments ◽  
Thrombosis Model ◽  
Venous Shunt ◽  
Prolonged Aptt ◽  
Antithrombotic Efficacy

Abstract Thrombosis is a major cause of morbidity and mortality, and thrombin is a major inducer of thrombus formation. Thus several antithrombotic agents targeting thrombin have been developed. We previously reported an anticoagulant and antiplatelet thrombin derivative, ‘M-anhydrothrombin’ prepared by chemical modifications. In this study, we prepared a new thrombin mutant, specificity of which was highly modulated with substantially improved antithrombotic efficacy. The thrombin mutant designated “AAA-Thrombin” in which Lys65, His43 and Ser205 in B-chain have been replaced by Ala revealed higher affinity and specificity for factor VIII with no enzymatic activity. AAA-Thrombin prolonged APTT much more than anhydrothrombin in a dose dependent manner without affecting PT and TT. Platelet aggregation induced by activation of PAR-1 was also effectively suppressed by AAA-Thrombin. “M-AAA-Thrombin” prepared by further chemical modification of carboxyl groups in AAA-Thrombin enhanced its antithrombotic efficacy. M-AAA-Thrombin (250nM) prolonged APTT approx. two times, and suppressed platelet aggregation by PAR-1 activation, while AAA-Thrombin did not at the same concentration. M-AAA-Thrombin also suppressed ristocetin-induced platelet aggregation. In vivo experiments, M-AAA-Thrombin demonstrated significant antithrombotic property in the arterio-venous shunt thrombosis model and the FeCl3-induced carotid artery thrombosis model in guinea pigs. These results indicate that M-AAA-Thrombin would be a candidate for quite an innovative anticoagulant and antiplatelet agent for both arterial and venous thromboses. Further optimization of mutagenesis and modification, in terms of efficacy and safety is in progress in our laboratory.

scholarly journals A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin αIIbβ3

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Ding ◽  
Tong-dan Liu ◽  
Zhou-ling Xie ◽  
Qi Zhao ◽  
Yuan Cao ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Antiplatelet Agents ◽  
Bleeding Risk ◽  
Dependent Manner ◽  
Antithrombotic Effect ◽  
Thrombosis Model ◽  
Prolonged Bleeding Time ◽  
Cutting Model

Integrin αIIbβ3 plays a crucial role in the process of platelet aggregation. Three integrin αIIbβ3 antagonists (abciximab, eptifibatide, and tirofiban) have been approved by FDA for clinical use. Unfortunately, they all showed severe side effects such as thrombocytopenia and bleeding risk. Thus, researches on the development of more effective and safer antiplatelet agents are needed. In this manuscript we reported a novel naphthalenic derivative compound ND-1 with potent antithrombotic effect and lower bleeding risk. ND-1 inhibited ADP-, collagen-, thrombin-, and U46619-induced platelet aggregation with IC50 values of 1.29, 14.46, 12.84, and 40.24 μM, respectively. Mechanism studies indicated that ND-1 inhibited the binding of fibrinogen to integrin αIIbβ3 in a dose-dependent manner with an IC50 value of 3.12 μM. ND-1 inhibited P-selectin expression induced by ADP, collagen, thrombin, and U46619 on the surface of platelets. Additionally, this compound reduced platelets spreading to the immobilized fibrinogen. In vivo, ND-1 potently decreased thrombus formation in an arteriovenous shunt thrombosis model in rats and slightly prolonged bleeding time in a tail cutting model in mice. Taken together, our results reveal that ND-1 is a novel antagonist of αIIbβ3 with strong antithrombotic effect and lower bleeding risk.

Tetrahydrocurcumin Downregulates MAPKs/cPLA2 Signaling and Attenuates Platelet Thromboxane A2 Generation, Granule Secretion, and Thrombus Growth

2021 ◽  
Author(s):  
Weiqi Li ◽  
Yongjie Ma ◽  
Chunmei Zhang ◽  
Binlin Chen ◽  
Xiandan Zhang ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Biological Activities ◽  
Thromboxane A2 ◽  
Mapk Signaling ◽  
Inhibitory Effects ◽  
Platelet Factor ◽  
Thrombosis Model ◽  
Granule Secretion

AbstractPlatelet granule secretion plays a key role in atherothrombosis. Curcumin, a natural polyphenol compound derived from turmeric, exerts multiple biological activities. The current study sought to investigate the efficacy of tetrahydrocurcumin (THC, the major active metabolite of curcumin) on platelet granule secretion in vitro and thrombus formation in vivo. We found that THC significantly attenuated agonist-induced granule secretion in human gel-filtered platelets in vitro, including CD62P and CD63 expression and platelet factor 4, CCL5, and adenosine triphosphate release. These inhibitory effects of THC were partially mediated by the attenuation of cytosolic phospholipase A2 (cPLA2) phosphorylation, leading to a decrease in thromboxane A2 (TxA2) generation. Moreover, the MAPK (Erk1/2, JNK1/2, and p38 MAPK) signaling pathways were downregulated by THC treatment, resulting in reduced cPLA2 activation, TxA2 generation, and granule secretion. Additionally, THC and curcumin attenuated murine thrombus growth in a FeCl3-induced mesenteric arteriole thrombosis model in C57BL/6J mice without prolonging the tail bleeding time. THC exerted more potent inhibitory effects on thrombosis formation than curcumin. Through blocking cyclooxygenase-1 activity and thus inhibiting platelet TxA2 synthesis and granule secretion with aspirin, we found that THC did not further decrease the inhibitory effects of aspirin on thrombosis formation. Thus, through inhibiting MAPKs/cPLA2 signaling, and attenuating platelet TxA2 generation, granule secretion, and thrombus formation, THC may be a potent cardioprotective agent.

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 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.

Antithrombotic Effects of Recombinant Human Soluble Thrombomodulin in a Rat Model of Vascular Shunt Thrombosis

1994 ◽  
Vol 72 (03) ◽  
pp. 421-425 ◽  
Author(s):  
Mayumi Ono ◽  
Katsuhiko Nawa ◽  
Yasumasa Marumoto
Keyword(s):  
Rat Model ◽  
Protein C ◽  
Thrombus Formation ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Soluble Thrombomodulin ◽  
Thrombosis Model ◽  
Shunt Thrombosis ◽  
Av Shunt

SummaryThrombomodulin on endothelial cells is a cofactor for thrombin-catalyzed activation of protein C. We have investigated the anticoagulant function of recombinant human soluble thombomodulin (rsTM) in a rat model of arterio-venous (AV)-shunt thrombosis. A bolus injection of rsTM 30 s before the induction of AV-shunt thrombosis inhibited the thrombus formation in a dose-dependent manner. The dose of anticoagulant that inhibited thrombus formation by 50% was 0.4 mg/kg rsTMα, 0.15 mg/kg rsTMβ, and 13 U/kg heparin. Recently, we characterized three monoclonal antibodies (moAbs) against human TM whose epitopes are located in the TM epidermal growth factor-like domain (Nawa et al., 1994). moAb 2A2 inhibited thrombin binding to rsTM, and abolished both TM functions as a cofactor in thrombin-catalyzed activation of protein C and as an anticoagulant by modifying thrombin-induced fibrinogen clotting and platelet aggregation. moAb 1F2 preserved the latter activities as an anticoagulant, but inhibited cofactor activity. moAb 10A3 had no inhibitory effect on either activity. Analysis of the in vivo anticoagulant mechanism of rsTM was facilitated by the availability of these moAbs. After incubation at rsTM/moAb molar ratios of 1:1.25, the effect of the mixtures were examined in the AV-shunt thrombosis model. An injection of 0.8 mg/kg rsTMα or 0.4 mg/kg rsTMβ resulted in a significant reduction on thrombus formation, as expected. moAb 10A3 had no effect on rsTM activity. However, co-injection of rsTM with moAb 1F2 resulted in a significant decrease of the inhibitory activity on thrombus formation. moAb 2A2 essentially abolished the inhibitory effect of rsTM. These moAb effects were observed for both rsTMα and β. These results suggest that the protein C activation accelerated by the injection of rsTM plays an important role for inhibiting thrombus formation in the AV-shunt thrombosis model.

Effects of NO-Donors on Thrombus Formation and Microcirculation in Cerebral Vessels of the Rat

1996 ◽  
Vol 76 (01) ◽  
pp. 111-117 ◽  
Author(s):  
Yasuto Sasaki ◽  
Junji Seki ◽  
John C Giddings ◽  
Junichiro Yamamoto
Keyword(s):  
Blood Flow ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Red Cell ◽  
Cell Velocity ◽  
Red Cell Velocity ◽  
The Mean ◽  
Wall Shear ◽  
Dose Dependent

SummarySodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction

FUNDC2 regulates platelet activation through AKT/GSK-3β/cGMP axis

2018 ◽  
Vol 115 (11) ◽  
pp. 1672-1679 ◽  
Author(s):  
Qi Ma ◽  
Weilin Zhang ◽  
Chongzhuo Zhu ◽  
Junling Liu ◽  
Quan Chen
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Mitochondrial Protein ◽  
Dependent Manner ◽  
Clot Retraction ◽  
Akt Phosphorylation ◽  
Gsk 3Β

Abstract Aims AKT kinase is vital for regulating signal transduction in platelet aggregation. We previously found that mitochondrial protein FUNDC2 mediates phosphoinositide 3-kinase (PI3K)/phosphatidylinositol-3,4,5-trisphosphate (PIP3)-dependent AKT phosphorylation and regulates platelet apoptosis. The aim of this study was to evaluate the role of FUNDC2 in platelet activation and aggregation. Methods and results We demonstrated that FUNDC2 deficiency diminished platelet aggregation in response to a variety of agonists, including adenosine 5′-diphosphate (ADP), collagen, ristocetin/VWF, and thrombin. Consistently, in vivo assays of tail bleeding and thrombus formation showed that FUNDC2-knockout mice displayed deficiency in haemostasis and thrombosis. Mechanistically, FUNDC2 deficiency impairs the phosphorylation of AKT and downstream GSK-3β in a PI3K-dependent manner. Moreover, cGMP also plays an important role in FUNDC2/AKT-mediated platelet activation. This FUNDC2/AKT/GSK-3β/cGMP axis also regulates clot retraction of platelet-rich plasma. Conclusion FUNDC2 positively regulates platelet functions via AKT/GSK-3β/cGMP signalling pathways, which provides new insight for platelet-related diseases.

scholarly journals Antithrombotic Effect of Crotalin, a Platelet Membrane Glycoprotein Ib Antagonist From Venom of Crotalus atrox

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1582-1589
Author(s):  
Mei-Chi Chang ◽  
Hui-Kuan Lin ◽  
Hui-Chin Peng ◽  
Tur-Fu Huang
Keyword(s):  
Platelet Aggregation ◽  
Latent Period ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Platelet Membrane ◽  
Dependent Manner ◽  
Glycoprotein Ib ◽  
Platelet Surface ◽  
Dose Dependent

A potent platelet glycoprotein Ib (GPIb) antagonist, crotalin, with a molecular weight of 30 kD was purified from the snake venom ofCrotalus atrox. Crotalin specifically and dose dependently inhibited aggregation of human washed platelets induced by ristocetin with IC50 of 2.4 μg/mL (83 nmol/L). It was also active in inhibiting ristocetin-induced platelet aggregation of platelet-rich plasma (IC50, 6.3 μg/mL). 125I-crotalin bound to human platelets in a saturable and dose-dependent manner with a kd value of 3.2 ± 0.1 × 10−7 mol/L, and its binding site was estimated to be 58,632 ± 3,152 per platelet. Its binding was specifically inhibited by a monoclonal antibody, AP1 raised against platelet GPIb. Crotalin significantly prolonged the latent period in triggering platelet aggregation caused by low concentration of thrombin (0.03 U/mL), and inhibited thromboxane B2formation of platelets stimulated either by ristocetin plus von Willebrand factor (vWF), or by thrombin (0.03 U/mL). When crotalin was intravenously (IV) administered to mice at 100 to 300 μg/kg, a dose-dependent prolongation on tail bleeding time was observed. The duration of crotalin in prolonging tail bleeding time lasted for 4 hours as crotalin was given at 300 μg/kg. In addition, its in vivo antithrombotic activity was evidenced by prolonging the latent period in inducing platelet-rich thrombus formation by irradiating the mesenteric venules of the fluorescein sodium-treated mice. When administered IV at 100 to 300 μg/kg, crotalin dose dependently prolonged the time lapse in inducing platelet-rich thrombus formation. In conclusion, crotalin specifically inhibited vWF-induced platelet agglutination in the presence of ristocetin because crotalin selectively bound to platelet surface receptor-glycoprotein Ib, resulting in the blockade of the interaction of vWF with platelet membrane GPIb. In addition, crotalin is a potent antithrombotic agent because it pronouncedly blocked platelet plug formation in vivo.

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