[Signal transduction in blood platelets].
When a blood vessel is disrupted, subendothelial structures such as collagen come into contact with circulating blood platelets. These will adhere and recruit additional platelets to form a platelet aggregate which will close the leak, but which can, under certain circumstances, give rise to the formation of a thrombus. In this work our personal contribution to a better understanding of this process is given. We could demonstrate the presence of an antibody interfering with the platelet-collagen interaction in two patients with a bleeding problem. One of the antibodies is directed against glycoprotein (GP) Ia, a known collagen receptor, the other one recognizes a less well characterized protein of 85-90 kD. It therefore can be concluded that activation of blood platelets requires the simultaneous interaction of collagen with multiple receptors. Activation of platelets following binding of an agonist in many instances involves activation of phospholipase C via a GTP-binding protein or G-protein. We have further studied this by using a direct stimulator of G-proteins, AlF4-, which in platelets indeed activates phospholipase C, together with other systems. Furthermore, we could demonstrate that activation of phospholipase C in a GTP-dependent manner also occurs in platelet cytosol, indicating that the action of G-proteins is not restricted to membrane-linked phenomena. Activation of phospholipase C gives rise to the formation of inositol phosphates, of which mainly inositol 1, 4, 5 trisphosphate increases intracellular Ca(2+)-levels. Following this, the Ca(2+)-dependent phospholipase A2 releases arachidonic acid from the membranes. In platelets arachidonic acid is metabolised to another platelet activator: thromboxane A2. We have studied the effects of the inhibition of this aggregation-amplifying pathway by using specific inhibitors of the synthesis of thromboxane A2 and of thromboxane A2 receptor antagonists both in vitro and in vivo. One of the conclusions that were reached from these studies was that theoretically the combination of these two classes of drugs should yield a significant stronger antiplatelet effect than either class used alone. We could later on confirm this hypothesis, which stimulated some pharmaceutical companies to look for dual action compounds, of which we have studied two so far.(ABSTRACT TRUNCATED AT 400 WORDS)
Deckmyn
H
H
Centrum voor Trombose en Vasculair Onderzoek, K.U. Leuven.
D001792:Blood Platelets / Q000502:physiology*; D002352:Carrier Proteins; D003094:Collagen / Q000502:physiology; D005784:Gene Amplification; D006801:Humans; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D038981:Receptors, Collagen; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000096:biosynthesis; D010738:Type C Phospholipases / Q000378:metabolism
D002352:Carrier Proteins; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D038981:Receptors, Collagen; D013928:Thromboxane A2; D003094:Collagen; D010738:Type C Phospholipases
Signaaltransductie in bloedplaatjes.