ADENOSINE-DIPHOSPHATE (ADP) AND ADP RECEPTOR PLAY A MAJOR ROLE IN PLATELET ACTIVATION AGGREGATION INDUCED BY SERA FROM HEPARIN-INDUCED THROMBOCYTOPENIA PATIENTS/

The molecular basis for heparin-induced thrombocytopenia (HIT), a rela tively common complication of heparin therapy, is not yet fully unders tood. We found that pretreatment of platelets with AR-C66096 (formerly FPL 66096), a specific platelet adenosine diphosphate (ADP) receptor antagonist, at a concentration of 100 to 200 nmol/L that blocked ADP-d ependent platelet aggregation, resulted in complete loss of platelet a ggregation responses to HIT sera. AR-C66096 also totally inhibited HIT serum-induced dense granule release, as judged by measurement of aden osine triphosphate (ATP) release. Apyrase, added to platelets at a con centration that had only minor effects on thrombin- or arachidonic aci d-induced aggregation, also blocked completely HIT serum-induced plate let aggregation. Furthermore, AR-C66096 inhibited platelet aggregation and ATP release induced by cross-linking Fc gamma RIIA with specific antibodies. These data show that released ADP and the platelet ADP rec eptor play a pivotal role in HIT serum-induced platelet activation/agg regation. The thromboxane receptor inhibitor, Daltroban, had no effect on HIT serum-induced platelet activation whereas GPIIb-IIIa antagonis ts blocked platelet aggregation but had only a moderate effect on HIT serum-induced dense granule release. Pretreatment of platelets with ch ondroitinases but not with heparinases resulted in concentration depen dent inhibition of HIT serum-induced platelet aggregation. These novel data relating to the mechanism of platelet activation induced by HIT sera suggest that the possibility should be examined that ADP receptor antagonists or compounds that inhibit ADP release may be effective as therapeutic agents for the prevention or treatment of complications a ssociated with heparin therapy. (C) 1998 by The American Society of He matology.