Uremic bleeding: closing the circle after 30 years of controversies?

MORGAGNI IN HIS ‘‘Opera Omnia’’-Epistola AnatomicoMedica XLI-1764, Sermo est de Urinae Suppressione,1 was the first to recognize the remarkable association between bleeding and renal dysfunction, which became a clinical problem in the early days of dialysis, when patients sometimes died from excessive bleeding from the gastrointestinal tract or abdominal organs.2,3 Modern dialysis techniques and the use of erythropoietin to correct anemia4 have reduced the frequency of uremic bleeding, which, however, still limits surgery and invasive procedures in these patients. The cause of uremic bleeding has been the subject of a major debate in the last 30 years. The pathogenesis is considered multifactorial (Table 1); however, platelet-platelet and plateletvessel wall interactions appear to be of crucial importance.5,6 Studies found that, in uremics, skin bleeding time (influenced by platelet and vascular function as well as by red blood cells), although far from ideal, is still a reliable predictor of clinical bleeding.2,7 It has always been difficult to investigate the nature of platelet dysfunction in uremia, because dialysis has a complex influence on platelets and coagulation.8-10 Emblematic is the case of platelet function tests that may be worsened11,12 or improved12-14 at the end of an average dialysis. Circumstantial evidence exists that platelets are activated by the dialysis membrane, becoming refractory to further stimuli, which would explain the paradoxical effect of depuration on platelet function tests.15 In the search for the cause of uremic bleeding, abnormalities of platelet a-granules with lower than normal content of ADP and serotonin14,16 and defective arachidonate metabolism17 have been widely reported, but which of the above-noted actually triggered the clinical syndrome remained controversial.18 More recent evidence implicates acquired defects in specific receptors that impair platelet binding to fibrinogen and von Willebrand factor (vWF),13 although the role of vWF in uremic bleeding has been controversial for more than 20 years.19-22