The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity.
The role of the platelet glycoprotein (GP) Ib-V-IX receptor in thrombin activation of platelets has remained controversial although good evidence suggests that blocking this receptor affects platelet responses to this agonist. The mechanism of expression of procoagulant activity in response to platelet agonists is also still obscure. Here, the binding site for thrombin on GPIb is shown to have a key role in the exposure of negatively charged phospholipids on the platelet surface and thrombin generation, in response to thrombin, which also requires protease-activated receptor-1, GPIIb-IIIa, and platelet-platelet contact. Von Willebrand factor binding to GPIb is not essential to initiate development of platelet procoagulant activity. Inhibition of fibrinogen binding to GPIIb-IIIa also failed to block platelet procoagulant activity. Both heparin and low molecular weight heparin block thrombin-induced platelet procoagulant activity, which may account for part of their clinical efficacy. This study demonstrates a new, critical role for platelet GPIb in hemostasis, showing that platelet activation and coagulation are tightly interwoven, which may have implications for alternative therapies for thrombotic diseases.
Dörmann
D
D
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Experimental and Clinical Haemostasis, University of Münster, Germany.
Clemetson
K J
KJ
Kehrel
B E
BE
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D002122:Calcium Chloride / Q000494:pharmacology; D002450:Cell Communication; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005165:Factor V / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism / Q000494:pharmacology; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011516:Prothrombin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D029742:Caenorhabditis elegans Proteins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; C023592:glycocalicin; C022475:prothrombinase complex; D005165:Factor V; D011516:Prothrombin; D005340:Fibrinogen; D006493:Heparin; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; D017346:Protein Serine-Threonine Kinases; D013917:Thrombin; D015951:Factor Xa; D002122:Calcium Chloride