Both the high affinity thrombin receptor (GPIb-IX-V) and GPIIb/IIIa are implicated in expression of thrombin-induced platelet procoagulant activity.
Platelets activated by alpha-thrombin express surface procoagulant activity (PCA) that accelerates the conversion of prothrombin to alpha-thrombin. Following activation with 10 nM alpha-thrombin, the PCA of normal platelets was approximately five-fold higher than that of Bernard-Soulier platelets (lacking GPIb). Normal platelet PCA was inhibited approximately 50% by activation in the presence of the anti-GPIb MoAbs LJIb10 or TM60. Moreover, normal platelet PCA was completely abrogated in the presence of a combination of both LJIb10 and c7E3, a MoAb directed against alphaIIbbeta3 (GPIIb/IIIa). In contrast. PCA expressed by Bernard Soulier or Glanzmann platelets was not inhibited by either LJIb10 or c7E3 MoAb. The platelet activating peptide SFLLRN at 10 microM, a concentration which fully activates platelet aggregation and Ca2+ mobilization, generated PCA activity one fifth of that generated by alpha-thrombin at 10 nM but anti-PAR1 antibodies did not affect thrombin-induced PCA expression. These results demonstrate that GPIb mediates, at least in part, the thrombin-induced activation of platelets that leads to PCA, and that alphaIIbbeta3 is also involved in PCA generation, but these results do not support a major role for PAR1 in this activation.
Dicker
I B
IB
DuPont Pharmaceuticals Company, Wilmington, DE 19880-0400, USA. ira.b.dicker@dupontpharma.com
Pedicord
D L
DL
Seiffert
D A
DA
Jamieson
G A
GA
Greco
N J
NJ
D000328:Adult; D001606:Bernard-Soulier Syndrome / Q000097:blood; D001779:Blood Coagulation Factors / Q000096:biosynthesis* / Q000235:genetics; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000502:physiology*; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013915:Thrombasthenia / Q000097:blood; D013917:Thrombin / Q000494:pharmacology*; D013925:Thromboplastin / Q000378:metabolism
D001779:Blood Coagulation Factors; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C049426:platelet procoagulant factor; C082835:thrombin receptor peptide (42-47); D013925:Thromboplastin; D013917:Thrombin