Thrombin-induced hyperactivity of platelets of young stroke patients: involvement of thrombin receptors in the subject-dependent variability in Ca2+ signal generation.
Activated platelets are implicated in the development of premature arterial vascular diseases, in particular ischemic stroke. Since elevated cytosolic [Ca(2+)](i) is an integrative marker of platelet activation, we determined the generation of Ca(2+) signal in stimulated platelets from 26 young patients recuperating from stroke, 20 patients with symptomatic peripheral arterial disease, and 56 healthy volunteers. Even in the presence of aspirin, the platelets from various individuals showed highly different thrombin-induced Ca(2+) responses. On average, the thrombin-induced Ca(2+) response was increased for platelets from either patient group in comparison to the controls (P <0.04). Relatively more stroke patients had high-responsive platelets (27%, 7/26) than patients with peripheral arterial disease (10%, 2/20) or healthy subjects (4%, 2/56). The average prothrombinase activities of platelets from patients and controls were similar, but 3 out of 6 patients with increased thrombin-induced Ca(2+) responses also exhibited high prothrombinase activity. In a follow-up study, the subject-dependent thrombin-induced Ca(2+) response was found to correlate strongly with the platelet response to protease-activated receptor 1 (PAR1) agonist (r = 0.91), but was not linked to the Pl(A1/2) polymorphism. It is concluded that a significant part of young patients with stroke have platelets with hyperactivity toward thrombin, which is not normalised by aspirin treatment. Furthermore, the subject-dependent variation in thrombin-induced signalling is likely to involve PAR1-mediated platelet activation.
Vanschoonbeek
Kristof
K
Dept of Human Biology, Cardiovascular Research Institute of Maastricht, University of Maastricht, Maastricht, The Netherlands.
Feijge
Marion A H
MA
Keuren
Jeffrey F W
JF
Coenraad Hemker
H
H
Lodder
Jan J
JJ
Hamulyák
Karly
K
van Pampus
Elisabeth C M
EC
Heemskerk
Johan W M
JW
D000328:Adult; D001483:Base Sequence; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D039421:Integrin alpha2 / Q000235:genetics; D039661:Integrin beta3 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000235:genetics; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D011110:Polymorphism, Genetic; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000819:agonists / Q000097:blood*; D020521:Stroke / Q000097:blood* / Q000235:genetics; D013917:Thrombin / Q000494:pharmacology*; D013925:Thromboplastin / Q000378:metabolism
D039421:Integrin alpha2; D039661:Integrin beta3; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D004247:DNA; D013925:Thromboplastin; D013917:Thrombin