Page 2107 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 125

MOLECULAR BASIS OF PLATELET FUNCTION

Margaret L. Rand and Sara J. Israels

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The primary physiological role of platelets is to support hemosta- adhesion (Table 125.1). These substrates include collagens, immo-
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sis at sites of vascular injury by forming a plug that arrests blood bilized VWF, fibronectin, laminin, and thrombospondin-1.
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loss (Fig. 125.1). Normally, disc-shaped platelets circulate in the Plasma proteins fibrinogen, vitronectin, and circulating VWF also
bloodstream without adhering to the endothelium of the vessel wall. interact with platelets after binding to matrix components. The roles
When the endothelium is damaged, platelets adhere to the exposed of collagen and VWF are well defined, while the contributions of
subendothelial collagen and, at high shear, to collagen-immobilized other adhesive proteins to the initial attachment of platelets are less
von Willebrand factor (VWF). Platelet adhesion at the site of vessel well established. Studies of mice deficient in individual matrix pro-
wall damage initiates activation events via intracellular signaling teins have been useful in determining the contribution of these
pathways that trigger (1) reorganization of the actin cytoskeleton proteins to the integrated function of the ECM in the formation,
that results in a shape change from discs to irregular spheres with growth, and stabilization of the platelet plug.
filopodia, and enables platelet spreading to increase surface contact; Shear rates in flowing blood, which vary depending on vessel
(2) secretion of dense granule and α granule contents, including caliber, influence the contribution of specific matrix proteins. At low
ADP from the dense granules; (3) formation and release of second shear, platelets can be captured by collagens, but at higher shear rates
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messengers including thromboxane A 2 (TxA 2 ); and (4) exposure of (>1000 s ), VWF becomes critical in ensuring efficient platelet
phosphatidylserine (PS) on the platelet surface, thereby creating a attachment via the receptor glycoprotein (GP)Ibα (Fig. 125.2A) (see
procoagulant activated platelet surface for assembly of coagulation section on Platelet Adhesion Receptors). VWF, secreted from endo-
factor complexes that accelerate the generation of thrombin. Platelet thelial cells and recruited from plasma, binds to type VI collagen in
agonists, including ADP, TxA 2 , and thrombin, bind to their specific the vascular matrix via the VWF A1 domain, and to types I and III
membrane receptors, initiating signaling pathways that convert collagen in both superficial and deeper layers of the matrix via the
integrin αIIbβ3 from a low-affinity resting state to a high-affinity VWF A3 domain. 12
activated state capable of binding its ligands. Divalent fibrinogen and Collagen types I, III, and VI exposed at sites of vascular injury are
multivalent VWF function as bridges between αIIbβ3 on adjacent key substrates for direct platelet adhesion. Collagen is a fibrillar
activated platelets, resulting in aggregation and plug formation. This protein made up of tropocollagen monomers packed into units of
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series of platelet responses is essential for the hemostatic function five to generate microfibrils. Collagens have motifs that are not only
of platelets, and when impaired by congenital or acquired defects, recognized by VWF, but also by the platelet collagen receptors α2β1
bleeding can occur. However, if these same events take place on a and GPVI 5,14 (see section on Platelet Adhesion Receptors). At low
ruptured atherosclerotic plaque, they can lead to the formation of a shear, collagen can function independently of VWF to capture
platelet-rich thrombus that can occlude the arterial lumen and lead to platelets at the matrix surface. However, under high shear, collagen
ischemia. and VWF, with their respective receptors, function in concert. 12,15
This chapter addresses the molecular basis of platelet activation Platelet adhesion is supported by other substrates in the matrix,
and primary hemostatic plug formation. Significant progress has been and by plasma proteins that interact with the matrix. It is likely that
made in defining the molecular mechanisms that govern platelet these proteins fine-tune the primary hemostatic response depending
responses, facilitated by the study of patients with congenital defects on the site or severity of the injury. Plasma proteins including fibro-
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of platelet function and/or number, and by the study of genetically nectin, 7,16 vitronectin, and fibrinogen (and its polymerized product
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modified animals. Recently, the field of platelet biology has expanded fibrin), matrix protein laminin and platelet α granule protein
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to encompass the platelet’s role in inflammation, host defense and thrombospondin-1 all support platelet adhesion in experimental
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tumor progression. What we have learned about the molecular systems. It is likely that most of these proteins play an ancillary role
mechanisms of platelets in the setting of hemostasis and thrombosis in vivo via mechanisms that include enhancing VWF immobilization
is now being applied in new areas to address new questions. in the matrix (laminin), protecting large VWF multimers from
degradation (thrombospondin-1), or bridging between platelet recep-
tors and matrix collagen (fibronectin).
MOLECULAR BASIS OF PLATELET ADHESION
Substrates for Platelet Attachment and Spreading Platelet Adhesion Receptors
Platelet plug formation is initiated by contact of circulating platelets Nomenclature
with proteins in the subendothelial extracellular matrix (ECM).
Normal endothelium maintains an effective barrier that prevents The individual adhesive proteins serve as ligands for specific receptors
circulating platelets from contact with these ECM proteins. In addi- on the platelet surface (Table 125.1). Several nomenclature systems
tion to the physical barrier, endothelial cells actively inhibit platelet have been used to identify the membrane glycoproteins of the platelet,
activation by release of nitric oxide, prostacyclin, and enzymes such that the same receptor may have multiple designations. The
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(CD39/CD73) involved in the metabolism of ADP. At sites of original and still widely used system designates the membrane glyco-
vascular injury, where endothelium is lost or damaged and the ECM proteins according to their electrophoretic mobility upon sodium
becomes exposed to flowing blood, platelets come into close contact dodecyl sulfate polyacrylamide gel electrophoresis; protein separation
with ECM adhesive proteins that promote initial attachment and is on the basis of molecular weight, with higher molecular-weight
subsequent activation. proteins migrating more slowly. Glycoproteins were designated as
The subendothelial matrix can be viewed as a dynamic and GPI, II, III, and so on, with GPI having the highest molecular weight.
mutable interface that provides multiple substrates to support platelet With greater resolution techniques, additional glycoproteins were

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