Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans.

BACKGROUND: Blocking of glycoprotein VI-dependent pathways by interfering in vascular collagen sites is commonly seen as an attractive target for an antiplatelet therapy of acute atherosclerotic diseases such as myocardial infarction or stroke. Revacept (soluble dimeric glycoprotein VI-Fc fusion protein) has been shown to reduce platelet adhesion by blocking vascular collagen in plaques or erosion and to be safe in preclinical studies. A dose-escalating clinical phase I study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Revacept in humans. METHODS AND RESULTS: In a first-in-humans study, 30 healthy men received a single intravenous administration of 10, 20, 40, 80, or 160 mg Revacept. The serum concentration-time courses of each dosage of Revacept showed a narrow variation and a concentration and time dependence. Revacept did not significantly affect the bleeding time. Collagen-induced platelet aggregation was dose-dependently inhibited up to 48 hours at lower doses and for 7 days after higher dose levels. In contrast, ADP- or thrombin receptor activating peptide-dependent platelet aggregation remained unaltered. There were no relevant drug-related adverse events or drug-related changes in laboratory parameters (biochemistry, hematology, and coagulation parameters). There were no drug-related changes in blood pressure, pulse rate, or ECG parameters (including 24-hour Holter monitoring). No anti-Revacept antibodies were detected. CONCLUSION: This phase I study demonstrated that Revacept is a safe and well-tolerated new antiplatelet compound with a clear dose-dependent pharmacokinetic profile with specific, dose-related inhibition of platelet aggregation despite completely unaltered general hemostasis. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT 01042964. URL: eudract.ema.europa.eu. Identifier: 2005-004656-12.

Platelet glycoprotein polymorphisms as risk factors for thrombosis.

Both blood platelets and genetics contribute to the development of acute ischemic arterial diseases. A careful analysis of the various clinical association studies supports a modest increased risk for coronary artery disease events in carriers of the PIA2 polymorphism of GPIIIa. Investigations with both platelets and stable cells lines have shown the PIA2 polymorphism is prothrombotic. Only a handful of studies have been performed for platelet GPla (integrin alpha2) and GPIb-IX-V, but there is support for the 807 T/C polymorphism of GPIa and the met145 and VNTR B/C genotype of GPIbalpha as risk factors in younger age groups. And isolated reports suggest other platelet polymorphisms (GPIIb, FcgammaRIIa, P-selectin, alpha2 adrenergic receptor, transforming growth factor [TGF]beta) are risk factors for arterial disease or produce a prothrombotic phenotype. Platelet glycoprotein polymorphisms should be added to the list of genetic risk factors for arterial thrombosis, particularly in younger patients and women.