IMPAIRED FUNCTION OF PLATELET MEMBRANE GLYCOPROTEIN-IIB-IIIA IN END-STAGE RENAL-DISEASE

Impaired platelet function and a bleeding tendency are well-recognized complications of chronic renal failure. Because the fibrinogen recept or GPIIb-IIIa plays a central role in platelet aggregation and adhesio n to the subendothelium, it was reasoned that a defect in this recepto r may underlie the impaired platelet function in uremia. To test this hypothesis, the function of this receptor in the platelets of 11 uremi c patients was studied. Aggregation studies were performed with flow c ytometric techniques with anti-GPIIb-IIIa conformation-specific monocl onal antibodies (mAb) (anti-LIBS1 and anti-PMI-1). Antifibrinogen and antithrombospondin mAb were used to characterize fibrinogen binding to GPIIb-IIIa and the release of alpha-granules, respectively. Platelets from patients with chronic renal failure showed significantly decreas ed binding of conformation-dependent anti-LIBS1 mAb after ADP, phorbol myristate acetate, or RGD-peptide stimulation compared with normal co ntrols, suggesting a defect related to the ability of the fibrinogen r eceptor to undergo a conformational change. Moreover, antifibrinogen a nd antithrombospondin binding to activated platelets were reduced in u remic patients, implying impairment of both ligand-binding and alpha-g ranule release. Hemodialysis partially restored GPIIb-IIIa function, w hich may account for the observed effects of this therapy in restoring platelet aggregation. These findings indicate that platelets of patie nts with chronic renal failure reveal an aggregation defect at least p artially due to an intrinsic GPIIb-IIIa dysfunction and the presence o f a putative uremic toxin that inhibits fibrinogen binding to GPIIb-II Ia.