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Antithrombotic Effect of Crotalin, a Platelet Membrane Glycoprotein
Ib Antagonist From Venom of Crotalus atrox
Mei-Chi Chang,
Hui-Kuan Lin,
Hui-Chin Peng, and
Tur-Fu Huang
From the Team of Biomedical Science, Chang-Gung Institute of Nursing,
Taoyuan, Taiwan; and the Pharmacological Institute, College of
Medicine, National Taiwan University, Taipei, Taiwan.
A potent platelet glycoprotein Ib (GPIb) antagonist, crotalin, with
a molecular weight of 30 kD was purified from the snake venom of
Crotalus 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 B2
formation 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.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1582-1589
© 1998 by The American Society of Hematology.
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