Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 553

Initially arriving platelets stick to collagen, form a particle monolayer, and
release platelet activators. Once activated, thrombocytes generate stable bonds to
adhere stably to each other and promote a growing hemostatic clot. Fibrin mesh
created by blood coagulation constructs a support to stabilize the platelet cluster.
The platelet mass grows as additional platelets attach to previously aggregated
thrombocytes. More or less rapidly moving, discoid platelets must slow down
to reach the growing thrombus and become activated, spread platelets. Platelets
accumulate downstream from a constricted vascular segment and developing clot
that causes a stenosis upon local changes in blood flow [ 1016 ]. Platelets join the
developing plug and emit extensions of their plasma membrane to attach to the
growing clot. Then, they become activated.
During platelet adhesion and aggregation of primary hemostasis, platelets
transmit contractile forces developed by the actomyosin cytoskeleton to the
extracellular matrix that provoke a 30 to 40% reduction in plug volume to maintain
the integrity of the primary hemostatic plug, independently of thrombin and fibrin
generation [ 1017 ].
Platelets release thrombin and soluble agonists for further platelet activation
(ADP, thromboxane-A2, etc.). Simultaneously, stimulated platelets trigger activa-
tion of

α 2B β 3 -integrin and platelet aggregation. Platelet integrins are activated due
to contact with a wounded vessel wall to ensure firm adhesion and aggregation.
Platelet integrins interact with collagen and von Willebrand factor. Integrin- α 2B β 3

interacts with collagen-bound von Willebrand factor, fibrinogen, and fibronectin,
whereas α 2 β 1 -integrin binds to collagen fibers. Various plasma clotting factors then

respond to form fibrin strands that strengthen the platelet plug.
The kindlin family consists of 3 known members (Kind1-Kind3) that are
located at integrin-associated adhesion sites. Whereas kindlin-1 and -2 are widely
expressed, kindlin-3 is exclusively produced in hematopoietic cells. It abounds
particularly in megakaryocytes and platelets. Similarly to cytoskeletal talin that
is also involved and associates with the tail of

β -integrin whatever the signaling

pathway, kindlin-3 activates platelet β 3 -integrins by binding to their

cytoplasmic domain (but at a more distal site than that targeted by talin) [ 1018 ].
Primary hemostasis is initiated when platelets adhere to collagen fibers, using
α 2 β 1 -integrin, a platelet collagen receptor. 132 This adhesion is stabilized by von
Willenbrand factor that bridges platelet GP1b-GP9-GP10 complexes and collagen
fibrils. Platelets are then activated and secrete granule contents into the plasma.
The GP1b-GP5-GP9 receptor complex consists of 4 components: GP1b

β 1 -and

α ,

GP1 , GP5, and GP9 glycoproteins. It allows interaction of resting platelets with ac-

tivated leukocytes via

β

α M β 2 -integrin and activated endothelial cells via P-selectin.

132 A.k.a. glycoproteic complex GP1a-GP2a. Tethering and rolling of platelet on the vascular wall
depend on bonds between platelets and wall elements. Bond formation is firstly reversible with fast
association and dissociation rates. Connections between von Willenbrand factor and glycoproteins
initiate activation of

α 2B β 3 -integrins (GP2b-GP3a) with slow rates of bond formation and
destruction, and mediate irreversible adhesion [ 1019 ].