Glycoproteins Promote Hemostasis

Hemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel. Platelets play one of the major roles in the hemostatic process. When platelets are activated, they express glycoprotein receptors that interact with other platelets, producing aggregation and adhesion. Advances in understanding platelet function and thrombotic syndromes have resulted from studies of the major component glycoproteins of the platelet plasma membrane.

Platelet Membrane Glycoproteins

The membrane glycoproteins (GP) of human platelets act as receptors that mediate two important functions, adhesion to the subendothelial matrix and platelet-platelet cohesion, or aggregation.

• Plasma Membrane Glycoproteins

Platelet surface-oriented GP contains a large number of disulfide bonds. The three glycoproteins, GPIb, GPIc, and GPIIb, are composed of larger subunits called alpha chains, and disulfide bonds with smaller subunits called beta chains. The other three glycoproteins, GPIa, GPIIa, and GPIIIa, are single polypeptide chains containing a large number of in-chain disulfide bonds. GPIIb and GPIII A exist in calcium-dependent heterodimers complex. The complex integrity is essential for GPIIB-IIIA fibrinogen receptor activity in platelets, and GPIIB-IIIA can mediate platelet cohesion.

• Platelet Integrins: GlycoproteinsⅡb-Ⅲa, Ⅰc-Ⅱa and Ⅰa-Ⅱa

The membrane glycoprotein complexes, GPⅡb-Ⅲa, GPⅠc-Ⅱa and GPⅠa-Ⅱa, are prototypes of a superfamily of adhesion receptors, the integrins. GPⅡb-Ⅲa is an activation dependent receptor for fibrinogen that mediates platelet-platelet cohesion.

Fig.1 Glycoprotein GPⅡb/Ⅲa. (Beardsley, 1990)

Platelet glycoprotein VI (GPVI) plays a crucial role in collagen-induced activation and aggregation of platelets. Here, the properties and hemostatic function of GPVI are summarized.

Structure and Properties of the Platelet Surface Receptor Glycoprotein GPVI

GPVI was characterized as a 60-65 kDa type I transmembrane glycoprotein belonging to the immunoglobulin superfamily that is uniquely expressed in platelets and megakaryocytes. GPVI contains an extracellular chain with two collagen-binding Ig-C2-like domains formed by disulfide bonds, a transmembrane region, and a 51 amino acid cytoplasmatic tail. GPVI is expressed on platelets surface in monomeric and dimeric forms. GPVI mediates platelet interactions with fibrin promoting further (platelet-dependent) generation of thrombin and binds to immobilized fibrinogen under flow conditions followed by consecutive platelet activation.

GPVI in Hemostasis

GPVI is essential for platelet adhesion and aggregation on immobilized collagen under high shear rates with ensuing thrombus formation, as it mediates the activation of several further adhesive receptors, including integrins α_IIbβ₃ and α₂β₁. Furthermore, GPVI mediates collagen-induced Ca²⁺-dependent scrambling of plasma membrane phospholipids with consecutive platelet surface expression of procoagulant phosphatidylserine (PS). PS exposed at the outer membrane platelet surface facilitates the assembly of tenase and prothrombinase complexes followed by the formation of factor Xa and thrombin. In addition, GPVI promotes thrombus growth and stabilization by binding to fibrinogen and fibrin with subsequent induction of thrombin generation.

Fig.2 Strategies targeting platelet glycoprotein VI. (Borst, 2021)

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References

1. Beardsley, D.S. Platelet membrane glycoproteins: role in primary hemostasis and component antigens. The Yale journal of biology and medicine. 1990, 63(5): 469.
2. Borst, O.; Gawaz, M. Glycoprotein VI-novel target in antiplatelet medication. Pharmacology & therapeutics. 2021, 217: 107630.

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