Uremic Platelet Dysfunction: Past and Present Gines Escolar, MD, PhD*, Maribel Díaz-Ricart, PhD, and Aleix Cases, MD, PhD Address Servicio de Hemoterapia y Hemostasia and Servicio de Nefrología, Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. E-mail: gescolar@clinic.ub.es Current Hematology Reports 2005, 4:359–367 Current Science Inc. ISSN 1540-3408 Copyright © 2005 by Current Science Inc. Introduction Patients with chronic renal failure frequently show complex hemostatic disorders, the most frequent being bleeding episodes. Hemorrhagic complications were more frequent and severe before dialysis procedures were available, but they still persist. Some of the spontaneous bleeding symptoms reported in uremic patients include cutaneous purpura, easy bruising, epistaxis, gingival bleeding, and hematuria. Less frequent but more severe bleeding complications affect internal organs. Gastrointestinal hemorrhage, associated with mucosal ulceration or telangiectasiae, was formerly the most common cause of death in this group of patients. Retro- peritoneal hemorrhages have also been observed, often associated with other underlying conditions. Subdural hematoma after brain trauma, hypertension, or anticoag- ulation has been reported in 6% to 16% of hemodialysis patients. The prognosis of cerebrovascular hemorrhage is variable, with a high mortality rate (approximately 90%) in patients requiring emergency surgery. The observation that hemorrhages occurred in patients with normal and even elevated levels of coagula- tion factors suggested from the very beginning that bleed- ing in the uremic condition was related to a platelet dysfunction. The introduction of routine hemodialysis in the 1970s seemed to improve hemorrhagic symptoms, but did not completely correct the bleeding diathesis. Unfortunately, hemodialysis requires the use of anti- coagulants to keep blood fluid in the circuits, and these anticoagulants were found to contribute to increased bleeding in uremic patients and to enhance the risk of gastric bleeding or subdural hematoma in those with hypertension. Anemia from reduced production of erythropoietin (EPO) is commonly present in patients with chronic renal failure. It was recognized very early that anemia complicated the bleeding tendency in uremic patients. Treatment with EPO was introduced in the mid-1980s and has had a very favorable impact, not only reducing the frequency of bleeding but also improving patients’ overall quality of life. Despite the positive impact derived from the introduction of hemodialysis and EPO treatments, the underlying bleeding diathesis of uremic patients is still manifested when invasive procedures (eg, placement of vascular accesses, biopsy, or surgery) are carried out. These observations are consistent with the concept that a certain platelet dysfunction is still present in uremic patients. Platelet Dysfunction in Uremic Patients Excessive hemorrhage was long ago identified in patients with chronic renal failure and rapidly was related to the uremic/azotemic condition [1–3]. Clinically significant hemorrhages are usually not spontaneous, however; bleed- ing in uremic patients is more evident when invasive procedures are conducted [4]. From very early observa- tions, the bleeding in patients with uremia was thought to be related to altered platelet function [5,6,7•]. Platelet dysfunction in uremic disease was identified by a prolonged bleeding time and poor platelet retention on glass microbeads [1,8,9]. Other signs of this altered func- tion were subsequently observed: Uremic patients develop an acquired platelet dysfunction that results in bleeding complications. The pathogenesis of this hemostatic dysfunction is multifactorial and includes effects of circulating toxins, alterations of the vessel wall, anemia, and other factors, complicated by unwanted effects of hemodialysis procedures. This review seeks to place in perspective the evolution of knowledge on uremic platelet dysfunction. It examines how investigations of the altered hemostasis in these patients have led to a better under- standing of the mechanisms involved and how these advances have contributed to the development of effective therapeutic strategies. It also comments upon the fact that elevated rates of thrombotic complications are apparently emerging as the bleeding tendency is better controlled. Emphasized is the delicate balance of hemostasis in the uremic condition, in which deficient hemostasis paradoxi- cally coexists with accelerated atherosclerosis and an enhanced risk of thrombosis.