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. METHODS AND 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.