Arteriosclerosis and Thrombosis, Vol 11, 733-744, Copyright © 1991 by American Heart Association

ARTICLES

Defects in platelet adhesion and aggregate formation in uremic bleeding disorder can be attributed to factors in plasma

JJ Zwaginga, MJ IJsseldijk, PG de Groot, J Vos, RL de Bos Kuil and JJ Sixma
Department of Hematology, University Hospital, Utrecht, The Netherlands.

Uremia is associated with bleeding diathesis. Platelet adhesion to the subendothelium is inhibited by a factor in uremic plasma that may play a role in the disturbed hemostasis of uremic patients. In the formation of the hemostatic plug, platelet adherence is followed by stimulus- induced platelet aggregation and reinforcement by thrombin-generated fibrin. To study these processes in uremic blood, a newly developed thrombosis model was used. Perfusates anticoagulated with low-molecular- weight heparin were circulated over a matrix of stimulated cultured endothelial cells. By stimulation of the endothelial cells, tissue factor was synthesized and deposited in the matrix. When this tissue factor rich-matrix was exposed to flowing blood, local thrombin was formed via activation of the extrinsic coagulation pathway. With this system, platelet adhesion, thrombin-dependent platelet activation, and fibrin formation can all be studied at the same surface. In addition to an adhesion defect, decreased aggregate formation was also found in uremic perfusates. Normal platelets in uremic plasma showed similar results, which indicates that a factor in uremic plasma caused this adhesion and aggregation defect. Platelet aggregation in the system was dependent on endogenously formed thrombin. Fibrinopeptide A generation, however, was normal in uremic perfusates; therefore, uremic plasma has a normal capacity to form thrombin. Resuspension of washed uremic platelets in control plasma did not reverse the aggregation defect in perfusions. In contrast, aggregometer studies with isolated uremic platelets could not detect an abnormal response to threshold concentrations of exogenous thrombin. Thus, uremic toxin(s) cause defective aggregate formation in flow, but not necessarily in the aggregometer. This apparent discrepancy may be due to the higher shear forces in the flow system, which may prevent aggregate formation that is allowed in the aggregometer. Another explanation, that uremic platelets are less responsive to locally formed thrombin than they are to exogenously added thrombin, seems less likely.

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