1361
REFERENCES 1. Fung YC. Biodynamics: circulation. New York:
Springer-Verlag,
1984:
77-165. 2. Miller A, Stonebridge PA, Jepsen SJ, et al. Continued experience with intraoperative angioscopy for monitoring infrainguinal bypass grafting. Surgery 1991; 109: 286-93. 3. LoGerfo FW, Nowak MD, Quist WC. Structural details of boundary layer separation in a model of human carotid bifurcation under steady and pulsatile flow conditions. J Vasc Surg 1985; 2: 263-69. 4. Segadal L, Matre K. Blood velocity distribution in the human ascending aorta. Circulation 1987; 76: 90-100. 5. Karino T, Goldsmith HL, Motomiya M, Mabuchi S, Sohara Y. Flow patterns in vessels of simple and complex geometries. In: Leonard EF, Turitto VT, Vroman L, eds. Blood in contact with natural and artificial surfaces. New York: Academy Press, 1987: 422-41. 6. Frazin L, Lanza G, Mehlman D, et al. Rotational blood flow in the thoracic aorta. Clin Res 1990; 38: 331A. 7. Hung TH. Pulsating spiral blood flow in curved arteries. In: Norman J, ed. Cardiovascular science and technology, basic and applied. Louisville, Kentucky: Oxymoron Press, 1989: 124-26. 8. Uchida Y, Tomaru T, Nakamure F, Furuse A, Fujimori Y, Hasegawa K. Percutaneous coronary angioscopy in patients with ischemic heart disease. Am Heart J 1987; 114: 1216-22.
ADDRESSES
Vascular UK (P. A. Vascular Surgery, Yale
Surgery Unit, Royal Infirmary, Stonebridge, FRCSE) and Division of University School of Medicine, New Haven, Connecticut, USA (C. M. Brophy, MD). Correspondence to Mr P. A. Stonebridge, Vascular Surgery Unit, Royal Infirmary, Edinburgh EH3 9YW, UK.
Edinburgh,
Erythropoietin and spontaneous platelet aggregation in haemodialysis patients
Erythropoietin significantly, reversibly, and reproducibly increased in-vitro whole-blood spontaneous platelet aggregation in 15 patients on haemodialysis. During erythropoietin treatment, spontaneous platelet aggregation was significantly higher in these subjects than in non-uraemic controls; concomitant treatment with 300 mg aspirin platelet hyperaggregability. daily reversed thrombosis may promote by an effect Erythropoietin on
haemodialysis patients with anaemia (haemoglobin below 8-5 g/dl) solely attributable to renal failure were treated with erythropoietin (Boehringer Mannheim, Livingston, UK) at an initial weekly dose of 120 IU/kg. They were randomly assigned 15
platelet function.
Erythropoietin is an effective treatment for anaemia in chronic renal failure; side-effects, particularly hypertension and thrombosis, have generally been attributed to changes in blood viscosity, cardiac output, and peripheral resistance associated with increased haemoglobin concentrations. More direct effects of erythropoietin have also been suggested.2,3 Adhesion, aggregation, and activation of platelets are central to the initiation of thrombus formation. Despite evidence for defective platelet function in uraemia,44 haemodialysis patients have an increased risk of thrombosis in arteriovenous fistulas and their overall cardiovascular mortality is high.5 In vitro, platelets tend to aggregate spontaneously both in whole blood6 and in platelet-rich plasma—a tendency which is increased in patients at risk of thrombosis. We measured in-vitro whole-blood spontaneous platelet aggregation in 15 haemodialysis patients who were treated with erythropoietin, and studied the effects of withdrawal and resumption of erythropoietin and ofcotreatment with aspirin or dipyridamole.
subcutaneous or intravenous treatment. After correction of anaemia a target haemoglobin concentration of 10-12 g/dl was maintained for 8 weeks (first maintenance phase), then treatment was withdrawn. When haemoglobin had fallen to pretreatment values the patients were again treated with erythropoietin by the alternative route (second maintenance phase). Platelet studies were done before treatment and during and between each maintenance
phase. patients on haemodialysis and 4 on continuous ambulatory peritoneal dialysis (CAPD) who were stable on erythropoietin therapy for at least 2 months underwent platelet aggregation studies before, and 4-8 weeks after, the start of treatment with 300 mg enteric-coated aspirin daily. 4 haemodialysis and 2 CAPD patients who had a history of allergy to aspirin or of peptic ulceration were similarly studied before and after the start of treatment with 100 mg dipyridamole daily. 10 haemodialysis patients, who had haemoglobin concentrations above 9-0 g/dl, and 23 healthy volunteers were studied as untreated uraemic and normal controls, and platelet aggregation was also measured in 3 iron-deficient haemodialysis patients (serum ferritin below 100 gg/1) who received 10
iron dextran as
an
alternative treatment.
5 ml venous blood was taken before routine dialysis at 0900-1000 h, and was anticoagulated with 3-8% trisodium citrate (9:1 by volume). Platelets were counted before and after 6 min gentle rotation at 37°C. The fall in platelet count was used to determine the percentage of platelets that spontaneously aggregated.6 Results are expressed as median (range). Wilcoxon’s rank-sum test was used to analyse matched-paired data in erythropoietin-treated patients, and the Mann-Whitney U test to compare patients with untreated haemodialysis and normal controls.
All 15 patients responded to erythropoietin: haemoglobin increased from 6-8 (5-3-8-1) g/dl before treatment to 11-11 (101-128) g/dl in the first maintenance phase, fell to 6-9 (4-8-8-3) g/dl during withdrawal, and rose again to 10-7 (9-6-13-2) g/dl after the second phase of treatment. The 10 haemodialysis controls had similar haemoglobin concentrations to erythropoietin-treated patients during the first and second maintenance phases, but significantly higher concentrations (10-6 [9’1-12’4] g/dl; p 0-05; figure). After erythropoietin, spontaneous platelet aggregation was significantly increased (first maintenance 64 (38-91)%; second maintenance 71 (21-92)%; p < 0-01; figure). This difference was not influenced by the mode of erythropoietin administration. The 10 haemodialysis controls with haemoglobin concentrations above 9 g/dl showed intermediate results, with spontaneous platelet aggregation of 41-5 (36-91) %-less than patients on the first (p 0-003) and second (p 0-013) maintenance phases, but higher than patients during withdrawal of erythropoietin (p 0-013) and in normal controls (p 0-034; figure). The 3 patients treated with iron dextran had greater spontaneous platelet aggregation (41, 18, and 27% to 47, 75, and 36%, respectively) and a small rise in haemoglobin concentration (7-2,9-1, and 8-4 g/dl to9-l,l 1-3, and 9.1g/dl, respectively). Of the 14 patients on erythropoietin who also received 300 mg aspirin daily, 2 were withdrawn because of recurrent =
=
=
=
1362
Spontaneous platelet aggregation
in
subjects and controls.
NC=normal controls; HC=haemodialysis controls; S denotes subjects investigated, SB=before, SE1=during first maintenance phase, and SE2 during second maintenance phase, and D denotes haemodialysis and CAPD subjects investigated for the effects of antiplatelet drugs during erythropoietin treatment, D1 =before, and DA=after, addition of aspirin, and D2=before, and DD=after, addition of dipyridamole. vsDA HC,tp
REFERENCES 1. Fung YC. Biodynamics: circulation. New York:
Springer-Verlag,
1984:
77-165. 2. Miller A, Stonebridge PA, Jepsen SJ, et al. Continued experience with intraoperative angioscopy for monitoring infrainguinal bypass grafting. Surgery 1991; 109: 286-93. 3. LoGerfo FW, Nowak MD, Quist WC. Structural details of boundary layer separation in a model of human carotid bifurcation under steady and pulsatile flow conditions. J Vasc Surg 1985; 2: 263-69. 4. Segadal L, Matre K. Blood velocity distribution in the human ascending aorta. Circulation 1987; 76: 90-100. 5. Karino T, Goldsmith HL, Motomiya M, Mabuchi S, Sohara Y. Flow patterns in vessels of simple and complex geometries. In: Leonard EF, Turitto VT, Vroman L, eds. Blood in contact with natural and artificial surfaces. New York: Academy Press, 1987: 422-41. 6. Frazin L, Lanza G, Mehlman D, et al. Rotational blood flow in the thoracic aorta. Clin Res 1990; 38: 331A. 7. Hung TH. Pulsating spiral blood flow in curved arteries. In: Norman J, ed. Cardiovascular science and technology, basic and applied. Louisville, Kentucky: Oxymoron Press, 1989: 124-26. 8. Uchida Y, Tomaru T, Nakamure F, Furuse A, Fujimori Y, Hasegawa K. Percutaneous coronary angioscopy in patients with ischemic heart disease. Am Heart J 1987; 114: 1216-22.
ADDRESSES
Vascular UK (P. A. Vascular Surgery, Yale
Surgery Unit, Royal Infirmary, Stonebridge, FRCSE) and Division of University School of Medicine, New Haven, Connecticut, USA (C. M. Brophy, MD). Correspondence to Mr P. A. Stonebridge, Vascular Surgery Unit, Royal Infirmary, Edinburgh EH3 9YW, UK.
Edinburgh,
Erythropoietin and spontaneous platelet aggregation in haemodialysis patients
Erythropoietin significantly, reversibly, and reproducibly increased in-vitro whole-blood spontaneous platelet aggregation in 15 patients on haemodialysis. During erythropoietin treatment, spontaneous platelet aggregation was significantly higher in these subjects than in non-uraemic controls; concomitant treatment with 300 mg aspirin platelet hyperaggregability. daily reversed thrombosis may promote by an effect Erythropoietin on
haemodialysis patients with anaemia (haemoglobin below 8-5 g/dl) solely attributable to renal failure were treated with erythropoietin (Boehringer Mannheim, Livingston, UK) at an initial weekly dose of 120 IU/kg. They were randomly assigned 15
platelet function.
Erythropoietin is an effective treatment for anaemia in chronic renal failure; side-effects, particularly hypertension and thrombosis, have generally been attributed to changes in blood viscosity, cardiac output, and peripheral resistance associated with increased haemoglobin concentrations. More direct effects of erythropoietin have also been suggested.2,3 Adhesion, aggregation, and activation of platelets are central to the initiation of thrombus formation. Despite evidence for defective platelet function in uraemia,44 haemodialysis patients have an increased risk of thrombosis in arteriovenous fistulas and their overall cardiovascular mortality is high.5 In vitro, platelets tend to aggregate spontaneously both in whole blood6 and in platelet-rich plasma—a tendency which is increased in patients at risk of thrombosis. We measured in-vitro whole-blood spontaneous platelet aggregation in 15 haemodialysis patients who were treated with erythropoietin, and studied the effects of withdrawal and resumption of erythropoietin and ofcotreatment with aspirin or dipyridamole.
subcutaneous or intravenous treatment. After correction of anaemia a target haemoglobin concentration of 10-12 g/dl was maintained for 8 weeks (first maintenance phase), then treatment was withdrawn. When haemoglobin had fallen to pretreatment values the patients were again treated with erythropoietin by the alternative route (second maintenance phase). Platelet studies were done before treatment and during and between each maintenance
phase. patients on haemodialysis and 4 on continuous ambulatory peritoneal dialysis (CAPD) who were stable on erythropoietin therapy for at least 2 months underwent platelet aggregation studies before, and 4-8 weeks after, the start of treatment with 300 mg enteric-coated aspirin daily. 4 haemodialysis and 2 CAPD patients who had a history of allergy to aspirin or of peptic ulceration were similarly studied before and after the start of treatment with 100 mg dipyridamole daily. 10 haemodialysis patients, who had haemoglobin concentrations above 9-0 g/dl, and 23 healthy volunteers were studied as untreated uraemic and normal controls, and platelet aggregation was also measured in 3 iron-deficient haemodialysis patients (serum ferritin below 100 gg/1) who received 10
iron dextran as
an
alternative treatment.
5 ml venous blood was taken before routine dialysis at 0900-1000 h, and was anticoagulated with 3-8% trisodium citrate (9:1 by volume). Platelets were counted before and after 6 min gentle rotation at 37°C. The fall in platelet count was used to determine the percentage of platelets that spontaneously aggregated.6 Results are expressed as median (range). Wilcoxon’s rank-sum test was used to analyse matched-paired data in erythropoietin-treated patients, and the Mann-Whitney U test to compare patients with untreated haemodialysis and normal controls.
All 15 patients responded to erythropoietin: haemoglobin increased from 6-8 (5-3-8-1) g/dl before treatment to 11-11 (101-128) g/dl in the first maintenance phase, fell to 6-9 (4-8-8-3) g/dl during withdrawal, and rose again to 10-7 (9-6-13-2) g/dl after the second phase of treatment. The 10 haemodialysis controls had similar haemoglobin concentrations to erythropoietin-treated patients during the first and second maintenance phases, but significantly higher concentrations (10-6 [9’1-12’4] g/dl; p 0-05; figure). After erythropoietin, spontaneous platelet aggregation was significantly increased (first maintenance 64 (38-91)%; second maintenance 71 (21-92)%; p < 0-01; figure). This difference was not influenced by the mode of erythropoietin administration. The 10 haemodialysis controls with haemoglobin concentrations above 9 g/dl showed intermediate results, with spontaneous platelet aggregation of 41-5 (36-91) %-less than patients on the first (p 0-003) and second (p 0-013) maintenance phases, but higher than patients during withdrawal of erythropoietin (p 0-013) and in normal controls (p 0-034; figure). The 3 patients treated with iron dextran had greater spontaneous platelet aggregation (41, 18, and 27% to 47, 75, and 36%, respectively) and a small rise in haemoglobin concentration (7-2,9-1, and 8-4 g/dl to9-l,l 1-3, and 9.1g/dl, respectively). Of the 14 patients on erythropoietin who also received 300 mg aspirin daily, 2 were withdrawn because of recurrent =
=
=
=
1362
Spontaneous platelet aggregation
in
subjects and controls.
NC=normal controls; HC=haemodialysis controls; S denotes subjects investigated, SB=before, SE1=during first maintenance phase, and SE2 during second maintenance phase, and D denotes haemodialysis and CAPD subjects investigated for the effects of antiplatelet drugs during erythropoietin treatment, D1 =before, and DA=after, addition of aspirin, and D2=before, and DD=after, addition of dipyridamole. vsDA HC,tp
