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

Abstract

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 endogeneously 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. [Arteriosclerosis and Thrombosis 1991;ll:733-744)

Double Dieulafoy's lesions of the stomach in a patient with chronic renal failure on long-term hemodialysis

“…The pathophysiology that underlies a bleeding tendency in patients with CRF appears to involve platelet dysfunction and an imbalance of the mediators of normal endothelial function by the accumulation of uremic substances (7,8). Consistent with this, all bleeding events in the patient reported here occurred within 24 hours before a hemodialysis session.…”

Elevated fibrinogen fragment levels in uremic plasma inhibit platelet function and expression of glycoprotein IIb‐IIIa

“…Although it can be argued that the concentration of FF recovered from uremic plasma was significantly higher than FF isolated from an equal volume of normal plasma, the fact that FF from identical volumes of plasma were added and that FF from uremic plasma caused inhibition is noteworthy and it further supports the hypothesis that elevated levels of FF may be partly responsible for platelet dysfunction in uremic patients. Moreover, our findings also suggest that the improvement of hemostatic function observed following HD [14,18,19,27,[35][36][37] might be due, in part, to a reduction in the circulating FF levels as a result of dialysis.…”

“…Mechanisms causing platelet dysfunction in uremic patients are not fully delineated; however, both platelet abnormalities [5][6][7] as well as the presence of plasma factors that adversely affect platelets have been implicated. For example, urea [27,28], guanidinosuccinic acid [29], phenols [30], and uremic MM [31] have been incriminated as factors that may cause impaired platelet function. In an exhaustive study in search of peptidic MM, Kaplan et al [9] identified several fragments of fibrinogen in uremic serum.…”

“…1, lanes 2 and 3). This is interesting considering the fact that an improvement in hemostatic function has been reported following HD by many investigators [14,18,19,27,[35][36][37].…”

Lipid Composition of Platelets in Patients with Uremia

“…Platelets of patients with uremia are abnormal in many ways [1, 2, 3, 4, 5, 6]. Decreased adhesion to subendothelium [1, 2], impaired formation of thromboxane [3, 4] and abnormal aggregation response to agonists [2, 3, 4, 5, 6] have been well documented.…”