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 von Willebrand factor (vWF) with platelet membrane glycoproteins (GP) Ib and IIb-IIIa, the same receptor-ligand pair involved in in vivo adhesion and aggregation of platelets in the arterial circulation. We have used a modified rotational cone-plate viscometer to measure SIPA and calcium flux in platelets. Flow cytometric analysis of the surface expression of GP Ib and IIb-IIIa was performed using flourescein isothiocyanate-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 < 0.001) along with a decrease in GP IIb-IIIa (controls, chronic renal failure patients, and chronic hemodialysis patients, 840 +/- 25, 649 +/- 42, 661 +/- 38 mean flourescence intensity, 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 < 0.001) and platelet-bound vWF (p < 0.01). Calcium flux and thromboxane B(2) generation during SIPA of uremic platelets was normal. However, uremic plasma showed twice the normal concentration of vWF (P < 0.001) and sodium 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 39% +/- 3% at baseline to 31% +/- 3% after incubation in uremic plasma) along with an activation-independent increase in platelet-bound fibrinogen and platelet-bound vWF. When uremic platelets were incubated in normal 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 dysfunction results from decreased GP IIb-IIa availability due to receptor occupancy by fibrinogen fragments (and possibly vWF fragments).
Sreedhara
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R
Division of Nephrology, The Long Island College Hospital, Brooklyn, NY, USA.
Itagaki
I
I
Hakim
R M
RM
D002118:Calcium / Q000097:blood; D005260:Female; D005434:Flow Cytometry / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000032:analysis / Q000502:physiology*; D016024:Receptors, Cytoadhesin / Q000032:analysis / Q000502:physiology*; D006435:Renal Dialysis; D013929:Thromboxane B2 / Q000097:blood; D014511:Uremia / Q000097:blood* / Q000628:therapy; D014841:von Willebrand Factor / Q000032:analysis
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016024:Receptors, Cytoadhesin; D014841:von Willebrand Factor; D013929:Thromboxane B2; D002118:Calcium