An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. Its influence on glycoprotein IIb-IIIa complex function.

Abstract

Much discussion has concerned the central role of ADP in platelet aggregation. We now describe a patient (M. L.) with an inherited bleeding disorder whose specific feature is that ADP induces a limited and rapidly reversible platelet aggregation even at high doses. Platelet shape change and other hemostatic parameters were unmodified. A receptor defect was indicated, for, while epinephrine normally lowered cAMP levels of PGE,-treated (M. L.) platelets, ADP was without effect. The binding of [3H12-methylthio-ADP de-creased from 836±126 molecules/platelet for normals to 30±17 molecules/platelet for the patient. Flow cytometry confirmed that ADP induced a much lower fibrinogen binding to (M. L.) platelets. Nonetheless, the binding in whole blood of activation-dependent monoclonal antibodies showed that some activation of GP HIb-Ma complexes by ADP was occurring. Platelets of a patient with type I Glanzmann's thrombasthenia bound [3H]2-methylthio-ADP and responded normally to ADP in the presence of PGE1. Electron microscopy showed that ADP-induced aggregates of (M. L.) platelets were composed of loosely bound shapechanged platelets with few contact points. Thus this receptor defect has a direct influence on the capacity of platelets to bind to each other in response to ADP. (J. Clin. Invest. 1995. 95:1612-1622

Historical perspective on ADP-induced platelet activation

“…In the 1980s, by the use of 2-azido-ADP that could be photoactivated [94] and also a strong aggregating ADP analogue, 2-methylthioadenosine labelled with 32 P (2-MeS-ADP), Macfarlane and colleagues [95] obtained values ranging from 400 to 1,200 sites per platelet for the receptor that inhibits adenylyl cyclase (P2Y 12 ). More recently, using the latter analogue, Gachet et al [96] reported 600±125 specific binding sites per platelet, and Nurden and co-workers [97] found 826±126 per platelet. Both these latter two groups described patients with low numbers of these binding sites who exhibited a congenital impairment of ADP-induced platelet aggregation, but normal shape change.…”

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

“…ADP is an important component of the platelet-dense granules and also an important platelet agonist that stimulates platelets by acting on the G q -coupled P2Y 1 receptor and G i -coupled P2Y 12 receptor. 2,3 Once released, it amplifies the primary responses of other agonists such as collagen and thrombin, leading to enhanced platelet aggregation and stability of the thrombus.…”

“…2,3 Once released, it amplifies the primary responses of other agonists such as collagen and thrombin, leading to enhanced platelet aggregation and stability of the thrombus. 4,5 It is now well established that concomitant signaling through G q -coupled P2Y 1 and G i -coupled P2Y 12 is necessary and sufficient for the integrin GPIIb/IIIa activation. 3 Furthermore, selective G i activation, when coupled with selective G 12/13 stimulation, also results in platelet aggregation.…”

“…6,7 Notably, the P2Y 12 -coupled G i signaling is also crucial for potentiating dense granule secretion, thromboxane A 2 (TXA 2 ) generation, and irreversible aggregation. [8][9][10][11] The P2Y 12 receptor deficiency leads to dysfunctional platelets and results in a bleeding diathesis. [12][13][14] Furthermore, platelets obtained from P2Y 12 Ϫ/Ϫ mice also show prolonged bleeding times and decreased aggregation in response to ADP.…”

“…[8][9][10][11] The P2Y 12 receptor deficiency leads to dysfunctional platelets and results in a bleeding diathesis. [12][13][14] Furthermore, platelets obtained from P2Y 12 Ϫ/Ϫ mice also show prolonged bleeding times and decreased aggregation in response to ADP. 15 The P2Y 12 receptor is the target of antithrombotic drugs like clopidogrel and ticlopidine.…”