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Adenosine Diphosphate (ADP) and ADP Receptor Play a Major Role in
Platelet Activation/Aggregation Induced by Sera From Heparin-Induced
Thrombocytopenia Patients
János Polgár,
Petra Eichler,
Andreas Greinacher, and
Kenneth J. Clemetson
From the Theodor Kocher Institute, University of Berne, Berne,
Switzerland and the Institute for Immunology and Transfusion Medicine,
Ernst-Moritz-Arndt-University, Greifswald, Germany.
The molecular basis for heparin-induced thrombocytopenia (HIT), a
relatively common complication of heparin therapy, is not yet fully
understood. 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-dependent platelet aggregation, resulted in complete loss
of platelet aggregation responses to HIT sera. AR-C66096 also totally
inhibited HIT serum-induced dense granule release, as judged by
measurement of adenosine triphosphate (ATP) release. Apyrase, added to
platelets at a concentration that had only minor effects on
thrombin- or arachidonic acid-induced aggregation, also blocked
completely HIT serum-induced platelet aggregation. Furthermore,
AR-C66096 inhibited platelet aggregation and ATP release induced by
cross-linking Fc RIIA with specific antibodies. These data show that
released ADP and the platelet ADP receptor play a pivotal role in HIT
serum-induced platelet activation/aggregation. The thromboxane receptor
inhibitor, Daltroban, had no effect on HIT serum-induced platelet
activation whereas GPIIb-IIIa antagonists blocked platelet aggregation
but had only a moderate effect on HIT serum-induced dense granule
release. Pretreatment of platelets with chondroitinases
but not with heparinases resulted in concentration dependent 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 associated with heparin therapy.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 549-554
© 1998 by The American Society of Hematology.
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