Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa.
This study evaluated shedding of the platelet collagen receptor, glycoprotein VI (GPVI) in human plasma. Collagen or other ligands induce metalloproteinase-mediated GPVI ectodomain shedding, generating approximately 55-kDa soluble GPVI (sGPVI) and approximately 10-kDa platelet-associated fragments. In the absence of GPVI ligands, coagulation of platelet-rich plasma from healthy persons induced GPVI shedding, independent of added tissue factor, but inhibitable by metalloproteinase inhibitor, GM6001. Factor Xa (FXa) common to intrinsic and tissue factor-mediated coagulation pathways was critical for sGPVI release because (1) shedding was strongly blocked by the FXa-selective inhibitor rivaroxaban but not FIIa (thrombin) inhibitors dabigatran or hirudin; (2) Russell viper venom that directly activates FX generated sGPVI, with complete inhibition by enoxaparin (inhibits FXa and FIIa) but not hirudin; (3) impaired GPVI shedding during coagulation of washed platelets resuspended in FX-depleted plasma was restored by adding purified FX; and (4) purified FXa induced GM6001-inhibitable GPVI shedding from washed platelets. In 29 patients with disseminated intravascular coagulation, mean plasma sGPVI was 53.9 ng/mL (95% confidence interval, 39.9-72.8 ng/mL) compared with 12.5 ng/mL (95% confidence interval, 9.0-17.3 ng/mL) in thrombocytopenic controls (n = 36, P < .0001), and 14.6 ng/mL (95% confidence interval, 7.9-27.1 ng/mL) in healthy subjects (n = 25, P = .002). In conclusion, coagulation-induced GPVI shedding via FXa down-regulates GPVI under procoagulant conditions. FXa inhibitors have an unexpected role in preventing GPVI down-regulation.
Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Commercial Road, Melbourne, Australia.
Mohammad
M
Al-Tamimi
George
G
Grigoriadis
Huy
H
Tran
Eldho
E
Paul
Patricia
P
Servadei
Michael C
MC
Berndt
Elizabeth E
EE
Gardiner
Robert K
RK
Andrews
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000378:metabolism / Q000473:pathology; D017984:Enoxaparin / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D008875:Middle Aged; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology
D017984:Enoxaparin; D005343:Fibrinolytic Agents; D006629:Hirudins; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D045726:Metalloproteases; D013917:Thrombin; D015951:Factor Xa