Further studies on the platelet-inhibitory effect of guanidinosuccinic acid and its role in uremic bleeding

Abstract

The average guanidinosuccinic acid (GSA) level in the serum of seventeen uremic subjects was found to be 2.53 mg per cent (0.15 mM) with a range of 0.86 to 5.4 mg per cent; serum GSA was less than 0.15 mg per cent in each of seventeen normal subjects. Measured GSA levels are sufficient to account for the inhibition of adenosine diphosphate (ADP)-induced platelet factor 3 (PF-3) activation, which we have previously demonstrated in citrated uremic plasma. GSA levels and the degree of inhibitio of ADP-induced PF-3 activation decreased in parallel in the serum and plasma of uremic patients undergoing peritoneal dialysis. In vitro inhibition of ADP-induced PF-3 activation did not occur with urea, creatinine, guanidinoacetic acid or arginine. GSA inhibited the second wave of platelet aggregation induced by ADP or by epinephrine and reduced the degree of aggregation induced by collagen suspensions. At increased concentrations of ADP and l-epinephrine the second wave of aggregation (attributed to release of endogenous platelet ADP) was again demonstrated. The aggregation of uremic citrated platelet-rich plasma (C-PRP) required nearly twice as much ADP as did normal C-PRP for either the second wave of aggregation or a maximal aggregation response. Acetyl salicylic acid (ASA) at equimolar concentrations was as effective as GSA in inhibiting both ADP-induced PF-3 activation and platelet aggregation, but the two inhibitors differed in several respects. Exposure to GSA makes the dense tubular system of normal platelets more prominent and inhibits the internal transformation characteristic of their response to ADP; these ultrastructural changes correlate with the inhibition of the second wave of aggregation. Thus, GSA at levels found in the serum of uremic patients can account for a number of the in vitro abnormalities of uremic platelet function and may be partly responsible for the bleeding syndrome of uremia.