Original Paper

Nephron 1992:62:284-288

Department of Medicine C Aalborg Hospital, DK-9000 Aalborg (Denmark)

Key Words Fibrinolytic capacity Recombinant human erythropoietin Uremia

Fibrinolytic Capacity in Hem odialysis Patients Treated with Recombinant Human Erythropoietin

Abstract A major adverse effect of recombinant human erythropoietin (r-HuEPO) in hemodiaiyzed patients are thrombotic events. Several reports on platelet function during r-HuEPO treatment have been published but less is known about fibrinolysis. In the present study, the fibrinolytic capacity was studied in 20 patients on maintenance hemodialysis and treated with r-HuEPO. The patients were randomized into two groups and investigated in a crossover design. r-EluEPO was administred intravenously and subcutaneously in each group and was given for 3 months, respectively. Plasma tissue plasminogen activator (t-PA) and released t-PA remained unaffected by r-HuEPO in both groups throughout the study. Tissue plasminogen activator inhibitor (PAI) increased in a cyclic way reaching peak values 4-6 weeks after the start of investigation and again 4-6 weeks after changing therapy. The increase in PAI was significant in the two groups (0.025> p > 0.01). Tissue plasminogen antigen was low in the uremic patients. The influence of r-HuEPO on this parameter was not investigated. Compensatory changes in plasma levels of factor XII procoagulant activity, activated protein C and of «i-antiplasmin were not observed. Thrombotic events occurred in 4 patients at peak values of PAI. Six patients required an increase in heparin dose simultaneously with the increase in PAI. Thus, r-HuEPO seemed to affect the fibrinolytic capacity of uremic patients.

Introduction Recombinant human erythropoietin (r-HuEPO) is effec­ tive in correcting renal anemia. However, the replacement therapy is associated with an increased risk of thrombosis [I], The rise in hematocrit is followed by a correction of the bleeding time and a transient increase in platelet count and function [2,3],

Accepted: January 10.1992

In end-stage renal failure, the fibrinolytic capacity has been reported to be markedly impaired, but improves dur­ ing a dialysis session [4-6]. In the present study, the fibrino­ lytic capacity was monitored during r-HuEPO replacement therapy focusing on tissue plasminogen activator (t-PA) and its inhibitor (PAI).

G udrun Steffensen, M O Department o f Medicine C Aalborg Hospital D K-9000 A alborg (Denmark)

© 1992 S. K arger AG, Basel 0028--2766/92/ 0623-0284S2.75/0

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N. A. Auiisholt G. Ah Ibom G. Steffensen T. Glud

Twenty patients with end-stage renal failure, mean age 47.5 years (range 23-69), were investigated. The patients were treated with main­ tenance hemodialysis 2 or 3 times weekly for a period of 12-38 months. All gave their informed consent. The study was approved by the local Ethical Committee. The patients met the following criteria: hematocrit below 26%, no iron deficiency, no clinical or biochemical signs of aluminum intoxica­ tion and anemia was of solely uremic origin. The patients had no significant clinical signs of secondary hyperparathyroidism. The pa­ tients were normotensive or had hypertension that was medically well controlled (diastolic blood pressure < 100 mm Hg). Mean predialysis serum creatinine level was 1,017 mmol/l. Drugs known to affect hemostasis were not administered 2 weeks prior to the investigation. All drugs except antihypertensive agents were unchanged during the study period. Six patients needed adjustment to their antihypertensive therapy. S tu d y Design

The study period was 6 months. The patients were randomized into two groups in a crossover study. Group I started treatment with r-HuEPO (Cilag, Denmark) intravenously for 3 months and then changed to a subcutanous administration foranother3 months. Group 2 was initially treated subcutaneously for 3 months followed by a 3-month period of intravenous administration. r-HuEPO was given after each hemodialysis. The r-HuEPO dose was increased stepwise every 4 weeks: in group I with 25 IU /kg/dose from 50 to 150 IU/kg thrice weekly and in group 2 with 20 IU /kg/dose from 40 to 80 IU/kg twice weekly. After 3 months of investigation, the patients changed from one administration form to the other. The intravenous dose was reduced by 50% and given sucutaneously twice weekly. The subcuta­ neous dose was increased by 50% and given intravenously thrice weekly. The doses were adjusted so as to reach a target hemoglobin level of 6.7-7.0 mmol/l. Hemoglobin, hematocrit and platelet count were determined weekly during the trial. Fibrinogen, plasma t-PA and released t-PA were determined every other week. Released t-PA was measured by performing stasis for 10 min using a cuff pressure of > 10 mm Hg on each patient's diastolic blood pressure. PAI was also determined every 2nd week. Factor XII procoagulant activity, activated protein C and a;-antiplasmin were investigated monthly. t-PA antigen was measured once before the study and performed after stasis as described above.

Methods Blood samples for assaying coagulation factors were drawn in tubes containing citrate as anticoagulant. t-PA and PAI were drawn in tubes containing trisodium citrate. Blood samples were drawn each morning at 9 a.m. after 0.5 h of rest. Smoking was not allowed. Hemodialysis was performed after blood drawnings. t-PA and PAI were measured amidolytically according to methods previously de­ scribed [7, 8] using chromogenic substrate S-2251 (Kabi-Vitrum, Sweden). The extent of the inter- and intra-assay variations of t-PA was 6.4 and 8.7%, respectively, and of PAI 7.2 and 7.9%, respectively. Anti-t-PA was analyzed by an immunoradiometric assay as described by Holmberg et al. [9].

Activated protein C and a-antiplasmin were assayed amidolyti­ cally using chromogenic substrate (Behring, USA). Factor X11 procoagulant activity was determined in specific factordeficient plasma (Dade, Kibo). Statistics

For statistical analysis, Wilcoxon’s test for paired data was used. Series of nonpaired data were analyzed by the Kruskal-Wallis analysis followed by Dunn’s lest. The Level of significance was considered at p 1 U/ml) and was unaffected by r-HuEPO therapy in either group (fig. 1). After stasis, the release of t- PA was abnormally low (normal range > 10 U/ml) and reflected significant changes during the trial (fig. 1). The prestudy levels of released t-PA were for some unknown reason significantly different between the groups (p < 0.01). The level of t-PA antigen was 5.45 ng/ml (range 2.0-18.1). The PAI response was equal in both groups (fig. 2; normal range< 10 AU/ml). During r-HuEPO replace­ ment therapy, PAI gradually increased to a peak level after 6 weeks of treatment (0.01 < p -arginine vasopressin lowers pro­ tein C' activity in uremics. Nephron 1989:53: 6 - 8.

20 Jorgensen M. Moretnsen JZ, Madsen AG. Thorsen S. Jacobsen B: A family with reduced plas­ minogen activator activity in blood associated with recurrent venous thrombosis. Scand J Haematol 1982;29:217-223. 21 Macdougall 1C. Davies ME. Hutton RD, Coles GA, Williams JD: Reduction in protein C and protein S levels after treatment with recombi­ nant erythrypoietin (EPO). 26th Congr Eur Dial Transplant Assoc. Goteborg, June 1989, p 206. 22 van Hinsbergbergh VWM, Bertina RM. van Wijngaar den A, van Tilburg NH, Emeis JJ, Haverkate F: Activated protein C decreases plasminogen activator inhibitor activity in endo­ thelial cell-conditioned medium. Blood 1985; 65:444-451.

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Fibrinolytic Capacity of Hemodialysis Patients Treated with r-HuEPO

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12 Nishimoto K, Yamagami S, Katoh Y, ct al: Coagulation and fibrinolysis in chronic renal failure: Change in tissue-type plasminogen acti­ vator activity. Trans Am Soc Artiflnlem Organs 1986;32:478-481. 13 Winter M. Needham J, Mackie I. Cameron JS: Impaired vessel wall response to venous occlu­ sion in patients with chronic renal failure on maintenance hemodialysis. Clin Nephrol 1984; 6:307-313. 14 Rijken DC, Wijngaards G, Welbergen .1: Rela­ tionship between tissue plasminogen activator and activators in blood and vessel wall. Thromb Res 1980;18:815-830. 15 Ästed B, Pandolfi M: On release and synthesis of fibrinolysis activators in human organ cul­ ture. Eur J Clin Biol Res 1972:17:261-267.

Fibrinolytic capacity in hemodialysis patients treated with recombinant human erythropoietin.

A major adverse effect of recombinant human erythropoietin (r-HuEPO) in hemodialyzed patients are thrombotic events. Several reports on platelet funct...
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