Platelet ADP receptors contribute to the initiation of intravascular coagulation.
While the adenosine 5'-diphosphate (ADP) pathway is known to enhance thrombus formation by recruiting platelets and leukocytes to the primary layer of collagen-adhering platelets, its role for the initiation of coagulation has not been revealed. Ex vivo inhibition of the P2Y12 ADP receptor by clopidogrel administration diminished the rapid exposure of tissue factor (TF), the major initiator of coagulation, in conjugates of platelets with leukocytes established by the contact of whole blood with fibrillar collagen. Under in vitro conditions, the P2Y12 and P2Y1 ADP receptors were both found to be implicated in the exposure of TF in collagen-activated whole blood. Immunoelectron-microscopy revealed that collagen elicited the release of TF from its storage pools within the platelets. Functional activation of the intravascular TF was reduced by inhibition of the ADP receptors, partially due to the disruption of the platelet-neutrophil adhesions. Injection of collagen into the venous system of mice increased the number of thrombin-antithrombin complexes, indicative for the formation of thrombin in vivo. In P2Y1-deficient mice, the ability of collagen to enhance the generation of thrombin was impaired. In conclusion, the platelet ADP pathway supports the initiation of intravascular coagulation, which is likely to contribute to the concomitant formation of fibrin at the site of the growing thrombus.
Leon
Catherine
C
Institut für Klinische Chemie, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany.
Alex
Meike
M
Klocke
Antje
A
Morgenstern
Eberhard
E
Moosbauer
Christine
C
Eckly
Anita
A
Spannagl
Michael
M
Gachet
Christian
C
Engelmann
Bernd
B
D000328:Adult; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D000077144:Clopidogrel; D003094:Collagen / Q000494:pharmacology; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000097:blood; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D010973:Platelet Adhesiveness / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000097:blood* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D058472:Receptors, Purinergic P2Y1; D012016:Reference Values; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000502:physiology; D013927:Thrombosis / Q000097:blood; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
C546382:P2RY1 protein, human; C546383:P2ry1 protein, mouse; D010975:Platelet Aggregation Inhibitors; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D003094:Collagen; D013925:Thromboplastin; D000077144:Clopidogrel; D013917:Thrombin; D015951:Factor Xa; D013988:Ticlopidine