Platelet collagen receptors: a new target for inhibition?
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.
Clemetson
K J
KJ
Theodor Kocher Institute, University of Berne, Switzerland. clemetson@tki.unibe.ch
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D008297:Male; D008958:Models, Molecular; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D038981:Receptors, Collagen; D013329:Structure-Activity Relationship; D019851:Thrombophilia / Q000097:blood / Q000235:genetics; D014688:Venoms / Q000737:chemistry
D000925:Anticoagulants; D016023:Integrins; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D038981:Receptors, Collagen; D014688:Venoms; D003094:Collagen