Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice

Coronary artery thrombosis is often initiated by abrupt disruption of the a therosclerotic plaque and activation of platelets on the subendothelial lay ers in the disrupted plaque. The extracellular matrix protein collagen is t he most thrombogenic constituent of the subendothelial layer; therefore, a selective inhibition of the collagen activation pathway in platelets may pr ovide strong antithrombotic protection while preserving other platelet func tions. Here we demonstrate that treatment of mice with a monoclonal antibod y against the activating platelet collagen receptor glycoprotein VI (GPVI; JAQ1) results in specific depletion of the receptor from circulating platel ets and abolished responses of these cells to collagen and collagen-related peptides (CRPs). JAQ1-treated mice were completely protected for at least 2 wk against lethal thromboembolism induced by infusion of a mixture of col lagen (0.8 mg/kg) and epinephrine (60 mug/ml). The tail bleeding times in J AQ1-treated mice were only moderately increased compared with control mice probably because the treatment did not affect platelet activation by other agonists such as adenosine diphosphate or phorbol myristate acetate. These results suggest that GPVI might become a target for long-term prophylaxis o f ischemic cardiovascular diseases and provide the first evidence that it i s possible to specifically deplete an activating glycoprotein receptor from circulating platelets in vivo.