Platelet Collagen Receptors: A New Target for Inhibition?

Abstract

Collagen is a major component of extracellular matrix and a wide variety of types exist. Cells recognise collagen in different ways depending on sequence and structure. They can recognise predominantly primary sequence, they may require triple-helical structure or they can require fibrillar structures. Since collagens are major constituents of the subendothelium that determine the thrombogenicity of the injured or pathological vessel wall, a major role is induction of platelet activation and aggregation as the start of repair processes. Platelets have at least two direct and one indirect (via von Willebrand factor) receptors for collagen, and collagen has specific recognition motifs for these receptors. These receptors and recognition motifs are under intensive investigation in the search for possible methods to control platelet activation in vivo. A wide range of proteins has been identified and, in part, characterised from both haematophageous insects and invertebrates but also from snake venoms that inhibit platelet activation by collagen or induce platelet activation via collagen receptors on platelets. These will provide model systems to test the effect of inhibition of specific collagen-platelet receptor interactions for both effectiveness as well as for side effects and should provide assay systems for the development of small molecule inhibitors. Since platelet inhibitors for long-term prophylaxis of cardiovascular diseases are still in clinical trials there are many unanswered questions about long-term effects both positive and negative. The major problem which still has to be definitively solved about these alternative approaches to inhibition of platelet activation is whether they will show advantages in terms of dose-response curves while offering decreased risks of bleeding problems. Preliminary studies would seem to suggest that this is indeed the case.

Dynamics of GPIIb/IIIa-mediated platelet-platelet interactions in platelet adhesion/thrombus formation on collagen in vitro as revealed by videomicroscopy

“…[2][3][4]8,14 In addition, such assays have helped to define the roles of platelet receptors that have been reported to participate in platelet adhesion to collagen or collagen-induced intracellular signaling, including ␣ 2 ␤, GPV, GPVI, GPIV, and proteins of Mr 68 000/72 000, 65 000, and 47 000. 7,14,17,19 Such studies have not, however, provided information on the cell-biologic dynamics of platelet adhesion and thrombus formation.…”

“…[2][3][4][5] Platelet-collagen interactions are complex, with the presence of multiple platelet receptors for collagen leading to differences in behavior as a function of collagen type; collagen architecture (monomeric or fibrillar); availability of soluble adhesive glycoproteins such as von Willebrand factor, fibronectin, and fibrinogen; the presence of divalent cations and their concentrations; and shear forces. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Nonetheless, the central paradigm is that platelet interactions with collagen occur in a sequential manner in which platelet adhesion, platelet activation and spreading, and platelet-platelet interactions follow one another in series.…”

Variable protection of β3-integrin–deficient mice from thrombosis initiated by different mechanisms

“…In contrast, tissue factor injection most likely results more directly in fibrin formation, which may then trap platelets in an ␣IIb␤3-independent manner, perhaps in part through an interaction of platelet GPIb with von Willebrand factor adherent to fibrin. [18][19][20] The decrease in platelet count in wild-type mice after injecting collagen ϩ epinephrine likely reflects 2 separate processes, platelet adhesion to collagen fibrils (through ␣2␤1, GPVI, and perhaps other receptors 21,22 ) and ␣IIb␤3-mediated platelet-platelet interactions resulting from the release of ADP, thromboxane A 2 , and perhaps other agents from the adherent platelets. The partial protection against thrombocytopenia in the ␤3-null mice is consistent with this interpretation given that their platelets are not deficient in collagen receptors, but they are unable to support ␣IIb␤3-mediated platelet-platelet interactions.…”

Structural Basis for the Platelet-Collagen Interaction

“…Interaction of circulating platelets with collagen is a multistage process involving several receptors in which the activatory collagen receptor glycoprotein VI (GpVI) 2 plays a central role (1)(2)(3). GpVI has been identified as an anti-thrombotic target (4), and for this potential to be exploited, an understanding of the molecular mechanism by which GpVI recognizes and is activated by collagen is essential.…”