UREMIC PATIENTS HAVE DECREASED SHEAR-INDUCED PLATELET-AGGREGATION MEDIATED BY DECREASED AVAILABILITY OF GLYCOPROTEIN IIB-IIIA RECEPTORS

Bleeding and platelet dysfunction are prominent features of uremia. Sh ear-induced platelet aggregation (SIPA) involves the interaction of vo n Willebrand factor (VWF) with platelet membrane glycoproteins (GP) Ib and IIb-IIIa, the same receptor-ligand pair involved in in vivo adhes ion and aggregation of platelets in the arterial circulation. We have used a modified rotational cone-plate viscometer to measure SIPA and c alcium flux in platelets. Flow cytometric analysis of the surface expr ession of GP Ib and IIb-IIIa was performed using fluorescein isothiocy anate-conjugated monoclonal antibodies CD42b and CD41a, respectively. Uremic patients showed decreased SIPA (controls, 43% +/- 2% [mean +/- SEM]; chronic renal failure patients, 36% +/- 3%; chronic hemodialysis patients, 26% +/- 2%; P < 0.0001) along with a decrease in GP IIb-III a (controls, chronic renal failure patients, and chronic hemodialysis patients, 840 +/- 25, 649 +/- 42, 661 +/- 38 mean fluorescence intensi ty, respectively; P < 0.0001). Glycoprotein Ib in uremic patients was not significantly different from normal. Chronic hemodialysis patients also demonstrated increased platelet-bound fibrinogen (P < 0.0001) an d platelet-bound vWF (P = 0.01). Calcium flux and thromboxane B-2 gene ration during SIPA of uremic platelets were normal. However, uremic pl asma showed twice the normal concentration of vWF (P < 0.0001) and sod ium dodecyl sulfate agarose gel electrophoresis revealed the presence of fibrinogen fragments. Mixing experiments demonstrated an inhibitory effect of uremic plasma on SIPA of normal platelets (decreased from 3 9% +/- 3% at baseline to 31% a 3% after incubation in uremic plasma) a long with an activation-independent increase in platelet-bound fibrino gen and platelet-bound vWF. When uremic platelets were incubated in no rmal plasma, their SIPA increased (from 12% +/- 5% at baseline to 18% +/- 4% after incubation in normal plasma; P = 0.002), although it did not return to normal. These results suggest that the uremic platelet d ysfunction results from decreased GP IIb-IIIa availability due to rece ptor occupancy by fibrinogen fragments (and possibly vWF fragments). ( C) 1996 by the National Kidney Foundation, Inc.