Influence of Recombinant Human Erythropoietin on Platelet Function and Coagulation Factors

Abstract

Reports on the effect of recombinant human erythropoietin (r-HUEPO) on the platelet activity are conflicting. In the present study platelet function and coagulation factors were investigated in 20 patients with end-stage renal failure on maintenance hemodialysis. The patients were randomized into two groups and, in a crossover design, investigated during intravenous and subcutaneous administration of rHUEPO. The two groups started with a different administration form (intravenously in group 1 and subcutaneously in group 2), and each mode of treatment was given for 3 months. At entrance into the study the platelets were hyperaggregable to exogenous stimulation with collagen (COL) in both groups. Group 1 developed increasing platelet sensitivity to adenosine diphosphate (ADP; 0.01 < p < 0.025) during intravenous treatment. Concomitantly, three episodes of arteriovenous fistula thrombosis occurred. In group 2 one event of fistula thrombosis occurred despite there being no change in platelet reactivity to ADP. After 3 months on r-HUEPO, the platelet reactivity to ADP decreased significantly in both groups, but also the reactivity to COL declined significantly: 0.01 < p < 0.025 (group 1) versus 0.001 < p < 0.005 (group 2). The platelet reactivity to ristocetin remained unchanged in group 1 but decreased significantly in group 2. In group 1 fibrinogen was increased significantly (0.001 < p < 0.005) at the time of the clotting events. The factor VIIL·coagulant activity increased, but antithrombin III, activated factors X and XIII, activated protein C, activated thromboplastin time, and partial prothrombin time remained unchanged. Furthermore, 4 patients in group 1 and 2 patients in group 2 required an increased dose of heparin after 2-3 months of investigation. Thus, r-HUEPO seemed to influence platelet function. Enhanced activity was observed during intravenous administration. Eventually, platelet reactivity to ex vivo stimulation decreased in both groups. Thus, intravascular hemostatic activation seemed to occur following r-HUEPO administration. An increase in hematocrit is probably of importance, but according to the present data, transient platelet activation may also be a contributory factor.

Effects of Epoetin Alfa on Hemostasis in Chronic Renal Failure

“…It is unlikely that these changes in coagulation factors were clinically significant given the variability of the data and the absence of a well-established association between these changes and an increased risk of thrombosis. There were no consistent changes in the thrombin time [17], reptilase time [17], prothrombin time (PT) or partial thromboplastin time (PTT) [8,13,17,18,21,23,30,31,40] in these studies. For the latter two parameters, both increases [21] and decreases [31] in PT and PTT have been noted, although the values remained within the reference ranges for a normal population.…”

“…The improvement in platelet aggregation following Epoetin alfa therapy was postulated to involve increased intracellular calcium mobilization [38]. Only one study reported a decrease in platelet aggregation following Epoetin alfa administration [8]. The authors speculated that differences in the technical performance of the platelet aggregation assays may explain the variance of their data from that of other investigators.…”

“…The majority of the papers (12 of 17) reported no change in fibrinogen levels, while 4 of 17 papers reported increases and 1 of 17 papers reported decreases in fibrinogen levels. The four papers in which fibrinogen levels were increased were from three groups of investigators [8,17,46,49]; the references by Aunsholt et al [8,46] appear to represent duplicate publications of the same (or similar) data. The latter investigators reported a 20% increase in fibrinogen levels following intravenous, but not subcutaneous, administration of Epoetin alfa.…”

“…200% [8,17,22]. The single study that reported no change in VIII:c was difficult to interpret, since only the abstract was published in English [19].…”

“…The single study that reported no change in VIII:c was difficult to interpret, since only the abstract was published in English [19]. Aunsholt et al [8] found that factors Xa and XIIa did not change with Epoetin alfa therapy. It is unlikely that these changes in coagulation factors were clinically significant given the variability of the data and the absence of a well-established association between these changes and an increased risk of thrombosis.…”