Summary
Congenital deficiency of the P2Y12 ADP receptor is a newly discovered rare autosomal recessive disorder of platelets (1-3). P2Y12 belongs to the seven-transmembrane-domain receptor family and signals through Gi. P2Y12 deficiency gives rise to a mild bleeding syndrome marked by excessive posttraumatic and postsurgical blood loss. In laboratory testing, platelet aggregation to ADP is much reduced in intensity and rapidly reversible at all concentrations. A test for abnormal P2Y12 function is the failure of ADP to inhibit the rise in cAMP levels after platelet stimulation with prostaglandin E1. Platelet shape change and Ca2+ fluxes occur in this disease because of the normal presence of a second ADP receptor, P2Y1. Under physiological conditions, P2Y1 starts the platelet response to ADP, but P2Y12 is required for large aggregates to form and be sustained. ADP is a cofactor of aggregation induced by most other physiologic stimuli and P2Y12 deficiency also leads to a reduced platelet response with low agonist doses of collagen and thrombin. Under conditions simulating blood flow, large macroaggregates do not form on collagen, a major substrate for platelet adhesion. Interestingly, heterozygotes may show a mild abnormality of platelet function similar to that seen in storage pool disease (4, 5). A French patient was the first to be characterized for a molecular defect and shown to have a nonexpressed P2Y12 allele and a second allele with a 2-bp deletion within codon 240. This led to a 28 residue frame-shift and a stop codon (3). This report was followed by the detection of a different 2-bp deletion common to 3 Italian patients. This was homozygous and also led to a truncated and nonexpressed protein. Finally, a patient has just been reported who was a compound heterozygote with two missense mutations that resulted in loss of function of P2Y12 despite a normal expression (4). Treatment in this disorder is blood transfusion when bleeding is excessive but this is rare. The disorder is of particular interest as the platelet function response mimics that given on platelets by widely used antithrombotic drugs (clopidogrel, ticlopidine). P2Y12 is also found in brain (glial cells) but the functional significance of this is unknown.*Author: Dr A. Nurden (October 2003)*.
