Increased platelet-collagen interaction associated with double homozygosity for receptor polymorphisms of platelet GPIa and GPIIIa.
OBJECTIVE
There is considerable controversy regarding the clinical role of the single-nucleotide polymorphisms (SNPs) of the platelet glycoprotein receptor GPIa C807T and the Pl(A1/A2) of GPIIIa as cardiovascular risk factors. We hypothesized that two combined SNPs in their homozygous prothrombotic forms could clarify their pathophysiological impact.


RESULTS
We identified a family with a striking history of premature cardiovascular events and a high frequency of the prothrombotic form of the two SNPs. From this family, the platelets of a healthy, 27-year-old propositus with this double homozygosity were compared with three matched male neutral gene variant controls. The propositus had shortened PFA-100 closure times and an increased platelet aggregation response to collagen. Platelet deposition to collagen was augmented under the blood flow conditions of a high shear rate model (1600 s(-1)). Platelet adhesion on collagen monomers was induced in a static system, leading to the promotion of subsequent procoagulant activity.


CONCLUSIONS
The combined homozygous prothrombotic SNPs of GPIa and GPIIIa are associated with an increased platelet-collagen interaction and procoagulant activity that can be readily demonstrated in several independent systems. Our patient may serve as a useful model for the functional consequences of two combined, potentially procoagulant, platelet SNPs.
Pontiggia
Luca
L
Department of Medicine, Laboratory for Thrombosis Research, Kantonsspital Baden, Switzerland.
Lassila
Riitta
R
Pederiva
Stephanie
S
Schmid
Hans-Rudolf
HR
Burger
Mirjam
M
Beer
Juerg H
JH
D000328:Adult; D001791:Blood Platelet Disorders / Q000097:blood / Q000453:epidemiology / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D003094:Collagen / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006720:Homozygote; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics* / Q000378:metabolism*; D039661:Integrin beta3 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence
D039421:Integrin alpha2; D039661:Integrin beta3; D003094:Collagen