Laminins are major components of basement membranes, well located to interact with platelets upon vascular injury. Laminin-111 (α₁β₁γ₁) is known to support platelet adhesion but is absent from most blood vessels, which contain isoforms with the α₂, α₄, or α₅ chain. Whether vascular laminins support platelet adhesion and activation and the significance of these interactions in hemostasis and thrombosis remain unknown.

Using an in vitro flow assay, we show that laminin-411 (α₄β₁γ₁), laminin-511 (α₅β₁γ₁), and laminin-521 (α₅β₂γ₁), but not laminin-211 (α₂β₁γ₁), allow efficient platelet adhesion and activation across a wide range of arterial wall shear rates. Adhesion was critically dependent on integrin α₆β₁ and the glycoprotein Ib-IX complex, which binds to plasmatic von Willebrand factor adsorbed on laminins. Glycoprotein VI did not participate in the adhesive process but mediated platelet activation induced by α₅-containing laminins. To address the significance of platelet/laminin interactions in vivo, we developed a platelet-specific knockout of integrin α₆. Platelets from these mice failed to adhere to laminin-411, laminin-511, and laminin-521 but responded normally to a series of agonists. α₆β₁-Deficient mice presented a marked decrease in arterial thrombosis in 3 models of injury of the carotid, aorta, and mesenteric arterioles. The tail bleeding time and blood loss remained unaltered, indicating normal hemostasis.

This study reveals an unsuspected important contribution of laminins to thrombus formation in vivo and suggests that targeting their main receptor, integrin α₆β₁, could represent an alternative antithrombotic strategy with a potentially low bleeding risk.