ADP Plays a Key Role in Thrombogenesis in Rats

1988 ◽  
Vol 59 (02) ◽  
pp. 225-230 ◽  
Author(s):  
J P Maffrand ◽  
A Bernat ◽  
D Delebassée ◽  
G Defreyn ◽  
J P Cazenave ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Vascular Wall ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Silk Thread ◽  
Dense Granules ◽  
Prolonged Bleeding Time ◽  
Venous Shunt

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

YM150, An Oral Direct Factor Xa Inhibitor: Combination with Aspirin or Clopidogrel In Arteriovenous Shunt Thrombosis In Rats

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3318-3318
Author(s):  
Yoshiyuki Iwatsuki ◽  
Chinatsu Sakata ◽  
Yumiko Moritani
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Control Level ◽  
Factor Xa ◽  
Antiplatelet Agents ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Silk Thread

Abstract Abstract 3318 Background: YM150, an oral direct factor Xa inhibitor, is currently in clinical development for the prevention of venous thromboembolism in patients undergoing orthopedic surgery, prevention of stroke in patients with atrial fibrillation, and prevention of ischemic events after recent acute coronary syndrome (ACS). The antiplatelet agents aspirin or clopidogrel will likely be co-prescribed with YM150 in ACS. Here, we report the effects of YM150 in combination with aspirin or clopidogrel on thrombus formation, bleeding, platelet aggregation, and coagulation in rats. Methods: The antithrombotic effect was estimated in a rat arteriovenous shunt model. The shunt was formed by attaching a polyethylene tube containing a silk thread to the carotid artery and the contralateral carotid vein. Blood was allowed to circulate in this shunt for 15 min, and then the silk thread was withdrawn from the tube to assess the thrombus weight. YM150, aspirin, or clopidogrel was orally administered 0.5, 1, or 2 h before shunt formation, respectively. At the same time as shunt formation, an incision was made at the sole of the left foot using a template bleeding device (Surgicutt®) to measure bleeding time. To avoid interference with the thrombosis model, blood samples to assess platelet aggregation and prothrombin time were obtained from separate animals at the same time point as shunt formation in the thrombus study. Platelet aggregation was induced using 10 μg/mL of collagen and 5 μM of adenosine 5`-diphosphate (ADP) to assess the effects of aspirin and clopidogrel, respectively. Results: YM150 alone inhibited thrombus formation, with significance at 10 mg/kg and more (P < 0.05). Respective thrombus weights in the control, 3, 10, and 30 mg/kg groups of YM150 were 4.8, 3.6, 2.4, and 2.0 mg. Aspirin alone inhibited thrombus formation, with significance at 100 mg/kg and more (P < 0.01). Respective thrombus weights in the control, 30, 100, and 300 mg/kg group of aspirin were 6.2, 4.2, 2.8, and 1.5 mg. Clopidogrel alone inhibited thrombus formation, with significance at 1 mg/kg and more (P < 0.01). Respective thrombus weights in the control, 0.3, 1, and 3 mg/kg group of clopidogrel were 4.8, 3.6, 2.9, and 1.3 mg. When administered concomitantly with 100 mg/kg of aspirin, YM150 (3, 10, 30 mg/kg) further inhibited thrombogenesis, with significance at 30 mg/kg of YM150 (P < 0.05) and thrombus weights of 2.4, 1.5, and 1.3 mg, respectively. When administered concomitantly with 1 mg/kg of clopidogrel, YM150 (3, 10, 30 mg/kg) further inhibited thrombogenesis, with significance at 30 mg/kg of YM150 (P < 0.05) and thrombus weights of 3.0, 2.0, and 1.5 mg, respectively. Collagen-induced platelet aggregation was reduced to 16.7% of the control level by 100 mg/kg of aspirin, and ADP-induced platelet aggregation was reduced to 74.4% of the control level by 1 mg/kg of clopidogrel. These effects were not changed in the presence of YM150. Prothrombin time and bleeding time were not prolonged by any of the agents alone, and further, these parameters were not affected by combined use of YM150 with either aspirin or clopidogrel. Conclusions: The thrombosis study suggests that both the platelet aggregation and coagulation cascade participate in thrombus formation in this model since both antiplatelet agents and the anticoagulant YM150 were effective. Thus, the thrombosis induced in this model can be considered similar to arterial thrombosis in humans where both platelets and fibrin are involved. Taken together, YM150 is a promising antithrombotic agent that augments the effects of antiplatelet agents against arterial thrombosis without increasing bleeding risk. Disclosures: Iwatsuki: Astellas Phama Inc.: Employment. Sakata:Astellas Phama Inc.: Employment. Moritani:Astellas Phama Inc.: Employment.

Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

1994 ◽  
Vol 71 (01) ◽  
pp. 095-102 ◽  
Author(s):  
Désiré Collen ◽  
Hua Rong Lu ◽  
Jean-Marie Stassen ◽  
Ingrid Vreys ◽  
Tsunehiro Yasuda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bolus Injection ◽  
Cell Injury ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Thrombotic Occlusion ◽  
Antithrombotic Effects

SummaryCyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor.The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time.TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.

Essential Athrombia

1975 ◽  
Vol 33 (02) ◽  
pp. 278-285 ◽  
Author(s):  
Şeref Inceman ◽  
Yücel Tangün
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Platelet Factor ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Aggregation Response ◽  
Platelet Disorder ◽  
Fibrinogen Content

SummaryA constitutional platelet function disorder in a twelve-year-old girl characterized by a lifelong bleeding tendency, prolonged bleeding time, normal platelet count, normal clot retraction, normal platelet factor 3 activity and impaired platelet aggregation was reported.Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1–4 μM), although a small wave of primary aggregation was obtained by very large ADP concentrations (25–50 μM). The platelets were also unresponsive to epinephrine, thrombin and diluted collagen suspensions. But an almost normal aggregation response occurred with strong collagen suspensions. The platelets responded to Ristocetin. Pelease of platelet ADP was found to be normal by collagen and thrombin, but impaired by kaolin. Platelet fibrinogen content was normal.The present case, investigated with recent methods, confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, described in 1955 and 1962 under the name of “essential athrombia.”

Acquired Disorder of Platelet Function Associated with Autoantibodies against Membrane Glycoprotein IIb-IIIa Complex - 1. Glycoprotein Analysis

1991 ◽  
Vol 65 (05) ◽  
pp. 491-496 ◽  
Author(s):  
M Meyer ◽  
C M Kirchmaier ◽  
A Schirmer ◽  
P Spangenberg ◽  
Ch Ströhl ◽  
...  
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Adhesion ◽  
Bleeding Time ◽  
Membrane Glycoprotein ◽  
Membrane Glycoproteins ◽  
Abnormal Behaviour ◽  
Thrombocytopenic Purpura ◽  
Immunoelectrophoretic Analysis ◽  
Prolonged Bleeding Time

SummaryA patient with idiopathic thrombocytopenic purpura developed after splenectomy a thrombasthenia-like severe haemor-rhagic diathesis characterized by a normal or subnormal platelet count, prolonged bleeding time, strongly reduced platelet adhesion to glass and defective platelet aggregation in response to ADP and collagen. In contrast to hereditary thrombasthenia membrane glycoproteins (GP) lib and Ilia were normally present in the patient’s platelets. Immunoelectrophoretic analysis revealed an abnormal behaviour of the patient’s GP IIb-IIIa complex. Autoantibodies against GP IIb-IIIa were detected in Triton-extracted washed platelets. Incubation of normal platelets with plasma from the patient resulted in a similar immunoelectrophoretic abnormality of the GP IIb-IIIa complex indicating that bound autoantibodies (IgG) are responsible for the abnormal immunoelectrophoretic behaviour of the patient’s GP IIb-IIIa complex. Platelet fibrinogen was severely reduced similar to classical thrombasthenia suggesting that the GP IIb-IIIa complex is involved in platelet fibrinogen storage.

Antiplatelet Effect of FK633, a Platelet Glycoprotein Ilb/IIIa Antagonist, on Thrombus Formation and Vascular Patency after Thrombolysis in the Injured Hamster Carotid Artery

1997 ◽  
Vol 77 (03) ◽  
pp. 562-567 ◽  
Author(s):  
Takehiro Kaida ◽  
Hiroyuki Matsuno ◽  
Masayuki Niwa ◽  
Osamu Kozawa ◽  
Hideo Miyata ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Vascular Injury ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Separate Experiment ◽  
Platelet Glycoprotein ◽  
Neointima Formation ◽  
Vascular Patency ◽  
Injured Artery

SummaryThe antithrombotic and restenosis-preventing effects of FK633, an inhibitor of platelet aggregation via binding to the glycoprotein (GP) Ilb/IIIa receptor, were studied. IC50 value of FK633 against platelet aggregation ex vivo induced by 2.5 |iM adenosine diphosphate (ADP) was 5.4 X 10"7 M as determined using hamster platelet rich plasma. The inhibitory effect was also investigated in vivo on thrombus formation at the carotid arterial wall injured by a modified catheter. As a control, the left carotid artery was injured and the time required to develop a thrombotic occlusion (3.9 ±1.1 min, mean ± S.E.M., n = 18) was determined. Then, the right carotid artery of the same animal was injured while a continuous intravenous (i.v.) infusion of FK633 was administered at doses of 0 (saline), 0.1,0.3 or 1.0 mg/kg/h. The time to occlusion was dose-dependently prolonged. In a separate experiment, 10% of the total tPA dose (0.52 mg/kg) was injected into the injured artery as a bolus and the remaining was infused i.v. at a constant rate for 30 min. When FK633 (0.3 or 1.0 mg/kg/h) was infused together with tPA, late patency of the reperfused artery was much improved as compared with that of treatment with tPA alone. Bleeding time, measured at the end of the tPA infusion, was markedly prolonged when the higher dose of FK633 (1.0 mg/kg/h) was coadministered, however coadministration of the lower dose of FK633 (0.3 mg/kg/h) was almost without prolongation on the bleeding time, despite a significant effect on the vascular patency after thrombolysis. Next, neointima formation was evaluated 2 weeks after the vascular injury. When FK633 (0.3 mg/kg/h) was continuously infused i. v. by an implanted osmotic pump for 3,7 or 14 days after the vascular injury, the neointimal area formation was significantly suppressed in the treatment groups for 7 or 14 days. These findings suggest that FK633 inhibits platelet activation in the injured artery and improves vascular patency after thrombolysis with tPA with a concomitant suppression of neointima formation.

Increased Ristocetin Induced Binding of Factor VIII to Platelets in Von Willebrand’s Disease (vWd)

1979 ◽  
Author(s):  
Z.M. Ruggeri ◽  
F.I. Pareti ◽  
P.M. Mannucci ◽  
T.S. Zimmerman
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Bleeding Time ◽  
Human Platelet ◽  
Bleeding Tendency ◽  
Platelet Factor ◽  
Induce Platelet Aggregation ◽  
Prolonged Bleeding Time ◽  
Crossed Immunoelectrophoresis ◽  
Ristocetin Cofactor

Initial reports of ristocetin-induced platelet aggregation (RIPA) demonstrated it to be decreased in some patients with vWd. We now report 20 patients (from five unrelated families) in whom RIP A was increased, apparently as the result of an increased ristocetin-induced binding of Factor VIIIrelated antigen (VIIIR:Ag) to platelets. All the patients had a life-long bleeding tendency, with prolonged bleeding time, and an abnormal two-dimensional crossed immunoelectrophoresis (2DCIE). Increased RIPA was demonstrated by measuring the minimum ristocetin concentration necessary to induce platelet aggregation. This was 0.42 mg/ml á 0.11 SD in the patients, and 0.91 á 0.097 SD in 17 normals (t = 13.83; P < 0.001). VIIIR:Ag binding to platelets occurred at ristocetin concentrations (0.4 mg/mI) which were ineffective in normals (who required >0.6 mg/mI). In contrast, the VIIIR:Ag of other patients with abnormal 2DCIE and markedly decreased RIP A did not bind to platelets at ristocetin concentrations as high as I mg/ml. It has been previously demonstrated that 30% to 60% of normal VIIIR:Ag binds to isolated human platelet membranes in the absence of ristocetin or any other agent, and that binding is restricted to the larger forms of VIIIR:Ag. However, VIIIR:Ag from the patients with increased RIPA, including two with normal ristocetin cofactor activity, showed decreased or undetectable binding as did all other patients with abnormal 2DCIE. This study suggests that ristocetin induced platelet Factor VIII interaction does not accurately reflect the “bleeding time factor” defect in vWd.

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.

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

AbstractA 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.

scholarly journals Comparative Study on the Effect of Carbenicillin, Inhibitors of Platelet Function and Heparin on Experimental Thrombus Formation

1977 ◽  
Author(s):  
R. Zimmermann ◽  
K. Andrassy ◽  
C. Zeltsch ◽  
D. Lange ◽  
F. Hof
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Platelet Aggregation Inhibitors ◽  
Venous System ◽  
Arterial System ◽  
Antithrombotic Activity ◽  
Lower Extent ◽  
Aggregation Inhibitors ◽  
Blood Elements

Previous studies documented an impairment of haemostasis by synthetic penicillins (Thromb. Haem. 34: 115, 1976) and penicillin (Lancet II : 1039, 1976). Therefore the antithrombotic activity of synthetic penicillin. (carbenicillin)(C) was compared with that of aspirin (ASA), dipyridamole (DIPY) and heparin in 150 rabbits. Thrombus formation was induced by standardized endothelial lesions. The dose of C was adjusted to a 4.2 fold prolongation of bleeding time, similar to that seen in clinical patients. Analysis and composition of thrombi was done by measurement of incorporation of labeled blood elements (51cr labeled platelets, 125J-fibrinogen and 59Fe labeled red cells). The ‘specific thrombus/blood ratio’ with values of 19.1 and 50.9 (51cr) in venous and arterial thrombi evidenced the significance of platelets in this model. In the venous system C reduced formation of thrombi by 43%, ASA by 34%, ASA and DIPY by 55% and heparin by 90%. In the arterial system C inhibited thrombus formation by 89%, ASA by 15%, ASA and DIPY by 46% and heparin by 60%. It is concluded, that C effectively prevents thrombus formation in the arterial system and to lower extent in the venous system. The results prove the importance of platelets in arterial thrombogenesis and the efficacy of platelet aggregation inhibitors in preventing thrombi in the arterial system. In comparison with other known antiplatelet drugs it seems, that C is the most effective platelet aggregation inhibitor to date.

Ex vivo evaluation of anti-GPVI antibody in Cynomolgus monkeys: Dissociation between anti-platelet aggregatory effect and bleeding time

2006 ◽  
Vol 96 (08) ◽  
pp. 167-175 ◽  
Author(s):  
Yutaka Matsumoto ◽  
Hisao Takizawa ◽  
Kazuhiro Nakama ◽  
Xiaoqi Gong ◽  
Yoshihisa Yamada ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Inhibitory Effect ◽  
Bleeding Tendency ◽  
Fab Fragment ◽  
Dose Escalation Study ◽  
Cynomolgus Monkeys ◽  
Induced Aggregation

SummaryRecent progress in the understanding of thrombus formation has suggested an important role of glycoprotein (GP)VI. In contrast to its pivotal role in collagen-induced platelet activation, it has been suggested that its blockade does not induce massive bleeding tendency. To demonstrate the dissociation between inhibitory effect on platelet aggregation and bleeding by GPVI blockade, we examined the effects of Fab fragment of OM2, an anti-human GPVI monoclonal antibody on ex vivo collagen-induced platelet aggregation and skin bleeding time after intravenous injection in cynomolgus monkeys. In a dose-escalation study, OM2 potently (>80%) inhibited collagen-induced platelet aggregation at the cumulative dose of 0. 2 mg/kg with a slight prolongation of bleeding time (1. 3 times baseline value). Furthermore, at 18. 8 mg/kg, the highest dose tested, prolongation of bleeding time was still mild (1. 9 times). In contrast, abciximab, Fab fragment of anti-GPIIb/IIIa antibody prolonged bleeding time by 5. 0 times at 0. 35 mg/kg, the lowest effective dose on platelet aggregation. Ina pharmacodynamic study,a bolus injection of OM2 at 0. 4 mg/kg produced potent inhibition of collagen-induced aggregation up to six hours after injection, showing longer half-life than that of abciximab. The injection of OM2 Fab did not induce thrombocytopenia and GPVI depletion in monkeys. These results suggest that blockade of GPVI by antibody can exerta potent inhibitory effect on collagen-induced platelet aggregation with a milder prolongation of bleeding time than blockade of GPIIb/IIIa. This study indicates that OM2 has the potential to be developed as a new class of therapeutic tool.

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