Initiation of platelet adhesion is the first step in the formation of the platelet plug. Circulating platelets are arrested and subsequently activated by exposed collagen and vWF. It is not entirely clear which type of collagen is responsible for adhesion and activation; collagen types I and III are abundant in vascular epithelia but several other types incluing IV are present (Farndale 2006). Several collagen binding proteins are expressed on platelets, including integrin alpha2 beta1, GPVI, and GPIV. Integrin alpha2 beta1, known on leukocytes as VLA-2, is the major platelet collagen receptor (Kunicki et al. 1988). It requires Mg2+ to interact with collagen and may require initiation mediated by the activation of integrin alphaIIb beta3 (van de Walle 2007). Binding occurs via the alpha2 subunit I domain to a collagen motif with the sequence Gly-Phe-Hyp-Gly-Glu-Arg (Emsley 2000). Binding of collagen to alpha2 beta1 generates intracellular signals that contribute to platelet activation. These facilitate the engagement of the lower-affinity collagen receptor, GPVI (Keely 1996), the key receptor involved in collagen-induced platelet activation. The GPVI receptor is a complex of the GPVI protein with a dimer of Fc epsilon R1 gamma (FceRI gamma). The Src family kinases Fyn and Lyn constitutively associate with the GPVI:FceRIgamma complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in FceRI gamma, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. vWF protein is a polymeric structure of variable size. It is secreted in two directions, by the endothelium basolaterally and into the bloodstream. Shear-induced aggregation is achieved when vWF binds via its A1 domain to GPIb (part of GPIb-IX-V), and via its A3 domain mediating collagen binding to the subendothelium. The interaction between vWF and GPIb is regulated by shear force; an increase in the shear stress results in a corresponding increase in the affinity of vWF for GPIb.