- Email: [email protected]
PLATELET PRESERVATION BY APROTININ DURING CARDIOPULMONARY BYPASS
644
By the next day his abdomen was acutely tender and laparotomy revealed extensive distal small-bowel ischaemia; there was a good pulse in the ileocolic artery, but thrombus in the distal branches. Thrombectomy through a distal arteriotomy produced some improvement, but 60 cm or so of terminal ileum required resection. Postoperatively renal and hepatic insufficiency and a small-bowel fistula developed, all of which resolved. Histology of the mesenteric arteries in the resected specimen showed thrombus containing numerous cholesterol clefts. This condition seems well recognised by cardiologists and the outcome is not always fatal, as demonstrated by our case. Drost et all reported 7 similar cases following left heart catheterisation, with 4 late deaths not directly associated with cholesterol embolism. However, if severe renal damage has been sustained by the cholesterol embolisation the outcome is almost inevitably fatal, and in such a case it is doubtful if extensive cardiac surgery should be undertaken. Department of Surgery, Leicester Royal Infirmary,
D. S. MACPHERSON
Leicester LE2 7LX
Groby Road Hospital,
M. J. GOLDBERG
Leicester
H, Buis B, Haan D, Hillers JA. Cholesterol embolism as a complication of left heart catheterisation. Br Heart J 1984; 52: 339-42.
1. Drost
PLATELET PRESERVATION BY APROTININ DURING CARDIOPULMONARY BYPASS
SIR,-Remarkable reductions in postoperative blood loss after cardiopulmonary bypass (CPB) have been achieved by prophylactic
aprotinin.’,2 From the very start of CPB the surgeon sees the benefit of aprotinin in reduced capillary bleeding from the stemal wound. The mode of action of aprotinin, however, is unclear: aprotinin is primarily a plasmin inhibitor whereas the increased bleeding tendency in CPB patients is thought to be mainly a platelet defect. This prompted us to measure the adhesive capacity of platelets collected during CPB by looking at specific antibody binding to platelet membrane glycoprotein Ib (GP Ib), the von Willebrand receptor. Blood from 14 CPB patients, randomised to aprotinin or placebo treatment during CPB, was collected before CPB, after 5 min of CPB, and at the end of bypass. Blood was drawn into acid-citrate dextrose (17:3 v:v) and centrifuged at 180 g for 10 min at room temperature. Platelet-rich plasma was gel-filtered on ’Sepharose CL2B’, equilibrated, and developed with calcium-free Tyrode’s buffer containing apyrase and albumin. The void volume containing platelets was concentrated by centrifugation (680g for 10 min). 125I -labelled monoclonal antibodies against platelet GP Ib were incubated for 45 min with 108 platelets in 01 ml Tyrode’s
buffer. Platelets were separated from the unbound antibodies by layering the suspension onto 20 % sucrose and centrifugation (9500 g for 5 min) and the activity of the pellet was counted. GP Ib antibody binding on platelets of control patients decreased within 5 min of CPB, whereas there was no decrease in the aprotinin-treated patients. Plasmin activity, as measured by the plasma concentration of fibrinogen degradation products (Bpl2-45), was at that time low in both patient groups. Bpl2-45 concentrations increased after 30 min of CPB in the untreated but not in the aprotinin-treated patients. These results suggest a specific effect of aprotinin on the platelet membrane at the start of bypass. However, inhibition of plasmin cannot be excluded as the reason for platelet GP Ib preservation by aprotinin. At the start of CPB, when fibrin-degradation product plasma levels are not yet increased, plasmin activity might be restricted to the platelet surface by conversion of membrane-bound plasminogen.’ In these circumstances plasmin can induce degradation of the GP Ib receptor.4 Our results demonstrate that the improved haemostasis observed during and after CPB in patients treated with aprotinin can be attributed to preserved adhesive capacity of platelets. Thorax
Centre, University Hospital Groningen, 9700 RB Groningen, Netherlands; and Departments of Cardiopulmonary Surgery and Haematology, Onze Lieve Vrouwe Gasthuis, Amsterdam
Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass Ann Thorac Surg 1987 44: 640-45. 2. Royston D, Bidstrup BP, Taylor KM, Sapsford RN Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987, ii: 1289-91. 3. Miles LA, Ginsberg MA, White JG, Plow EF. Plasminogen interacts with human platelets through two distinct mechanisms. Clin Invest 1986; 77: 2001-09. 4. Adelman B, Michelson AD, Loscaizo J, et al. Plasmin effect on platelet glycoprotein IB-von willebrand factor interactions. Blood 1985; 65: 32-40. 1.
van
BLOOD PRESSURE, ERYTHROPOIETIN, AND NITRIC OXIDE
SIR,-Dr Raine (Jan 16, p 97) and subsequent correspondents (Feb 13, p 351) describe hypertensive encephalopathy after the administration of erythropoietin to patients with anaemia secondary to renal failure. It is suggested that elevated blood viscosity following the rise in haemoglobin may be a cause of the increase in blood pressure. We propose another mechanism. Nitric oxide is produced by endothelial cells1 and is a potent natural vasodilator.2 Its companion secretory product of the endothelial cell, prostacyclin, is produced in excess during renal failure.3.4 Production of nitric oxide may be increased in renal failure, either as an endogenous response mechanism to the hypertension of renal disease or secondary to an unknown mechanism which also causes prostacyclin increase. The patients described with hypertensive encephalopathy already had preexisting hypertension of some degree. Haemoglobin is known to bind nitric oxideand the rise in haemoglobin caused by erythropoietin therapy may trap the nitric oxide produced by endothelial cells. This would permit unopposed contraction of vascular smooth muscle cells in the face of the pre-existing, yet previously endogenously controlled, hypertension, thus giving rise to hypertensive crisis. If this hypothesis is correct, such patients should respond rapidly to nitroglycerin, which mimics the action of nitric oxide. Wellcome Foundation Ltd,
Langley Court, Beckenham, Kent BR3 3BS
time
(min)
platelet membrane from patients on CPB. . = untreated (placebo); . = aprotmin. At 5 min of CPB and at end of CPB significant differences were observed. Results as mean (SEM). **p < 0-02, *p < 0-05 (Wilcoxon signed-rank test). on
JOHN MARTIN SALVADOR MONCADA
Fernge AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524-26 2. Editorial. EDRF. Lancet 1987; ii: 137-38. 3. Remuzzi G, Misiani R, Marchesi D, et al. Haemolytic-uraemic syndrome: Deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 1978; ii: 871-72. 4. Deckmyn H, Proesmans W, Vermyen J. Prostacyclin production by whole blood from children: Impairment in the hemolytic uremic syndrome and excessive formation in chronic renal failure. Thromb Res 1983; 30: 13-18. 5. Martin W, Smith JA, White DG. The mechanisms by which haemoglobin inhibits the relaxation of rabbit aorta induced by nitrovasodilators, nitric oxide or bovine retractor penis inhibitor factor. Br J Pharmacol 1986; 89: 562-71. 1. Palmer RMJ,
GP Ib antigen
W. VAN OEVEREN L. EIJSMAN K. J. ROOZENDAAL CH. R. H. WILDEVUUR
By the next day his abdomen was acutely tender and laparotomy revealed extensive distal small-bowel ischaemia; there was a good pulse in the ileocolic artery, but thrombus in the distal branches. Thrombectomy through a distal arteriotomy produced some improvement, but 60 cm or so of terminal ileum required resection. Postoperatively renal and hepatic insufficiency and a small-bowel fistula developed, all of which resolved. Histology of the mesenteric arteries in the resected specimen showed thrombus containing numerous cholesterol clefts. This condition seems well recognised by cardiologists and the outcome is not always fatal, as demonstrated by our case. Drost et all reported 7 similar cases following left heart catheterisation, with 4 late deaths not directly associated with cholesterol embolism. However, if severe renal damage has been sustained by the cholesterol embolisation the outcome is almost inevitably fatal, and in such a case it is doubtful if extensive cardiac surgery should be undertaken. Department of Surgery, Leicester Royal Infirmary,
D. S. MACPHERSON
Leicester LE2 7LX
Groby Road Hospital,
M. J. GOLDBERG
Leicester
H, Buis B, Haan D, Hillers JA. Cholesterol embolism as a complication of left heart catheterisation. Br Heart J 1984; 52: 339-42.
1. Drost
PLATELET PRESERVATION BY APROTININ DURING CARDIOPULMONARY BYPASS
SIR,-Remarkable reductions in postoperative blood loss after cardiopulmonary bypass (CPB) have been achieved by prophylactic
aprotinin.’,2 From the very start of CPB the surgeon sees the benefit of aprotinin in reduced capillary bleeding from the stemal wound. The mode of action of aprotinin, however, is unclear: aprotinin is primarily a plasmin inhibitor whereas the increased bleeding tendency in CPB patients is thought to be mainly a platelet defect. This prompted us to measure the adhesive capacity of platelets collected during CPB by looking at specific antibody binding to platelet membrane glycoprotein Ib (GP Ib), the von Willebrand receptor. Blood from 14 CPB patients, randomised to aprotinin or placebo treatment during CPB, was collected before CPB, after 5 min of CPB, and at the end of bypass. Blood was drawn into acid-citrate dextrose (17:3 v:v) and centrifuged at 180 g for 10 min at room temperature. Platelet-rich plasma was gel-filtered on ’Sepharose CL2B’, equilibrated, and developed with calcium-free Tyrode’s buffer containing apyrase and albumin. The void volume containing platelets was concentrated by centrifugation (680g for 10 min). 125I -labelled monoclonal antibodies against platelet GP Ib were incubated for 45 min with 108 platelets in 01 ml Tyrode’s
buffer. Platelets were separated from the unbound antibodies by layering the suspension onto 20 % sucrose and centrifugation (9500 g for 5 min) and the activity of the pellet was counted. GP Ib antibody binding on platelets of control patients decreased within 5 min of CPB, whereas there was no decrease in the aprotinin-treated patients. Plasmin activity, as measured by the plasma concentration of fibrinogen degradation products (Bpl2-45), was at that time low in both patient groups. Bpl2-45 concentrations increased after 30 min of CPB in the untreated but not in the aprotinin-treated patients. These results suggest a specific effect of aprotinin on the platelet membrane at the start of bypass. However, inhibition of plasmin cannot be excluded as the reason for platelet GP Ib preservation by aprotinin. At the start of CPB, when fibrin-degradation product plasma levels are not yet increased, plasmin activity might be restricted to the platelet surface by conversion of membrane-bound plasminogen.’ In these circumstances plasmin can induce degradation of the GP Ib receptor.4 Our results demonstrate that the improved haemostasis observed during and after CPB in patients treated with aprotinin can be attributed to preserved adhesive capacity of platelets. Thorax
Centre, University Hospital Groningen, 9700 RB Groningen, Netherlands; and Departments of Cardiopulmonary Surgery and Haematology, Onze Lieve Vrouwe Gasthuis, Amsterdam
Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass Ann Thorac Surg 1987 44: 640-45. 2. Royston D, Bidstrup BP, Taylor KM, Sapsford RN Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987, ii: 1289-91. 3. Miles LA, Ginsberg MA, White JG, Plow EF. Plasminogen interacts with human platelets through two distinct mechanisms. Clin Invest 1986; 77: 2001-09. 4. Adelman B, Michelson AD, Loscaizo J, et al. Plasmin effect on platelet glycoprotein IB-von willebrand factor interactions. Blood 1985; 65: 32-40. 1.
van
BLOOD PRESSURE, ERYTHROPOIETIN, AND NITRIC OXIDE
SIR,-Dr Raine (Jan 16, p 97) and subsequent correspondents (Feb 13, p 351) describe hypertensive encephalopathy after the administration of erythropoietin to patients with anaemia secondary to renal failure. It is suggested that elevated blood viscosity following the rise in haemoglobin may be a cause of the increase in blood pressure. We propose another mechanism. Nitric oxide is produced by endothelial cells1 and is a potent natural vasodilator.2 Its companion secretory product of the endothelial cell, prostacyclin, is produced in excess during renal failure.3.4 Production of nitric oxide may be increased in renal failure, either as an endogenous response mechanism to the hypertension of renal disease or secondary to an unknown mechanism which also causes prostacyclin increase. The patients described with hypertensive encephalopathy already had preexisting hypertension of some degree. Haemoglobin is known to bind nitric oxideand the rise in haemoglobin caused by erythropoietin therapy may trap the nitric oxide produced by endothelial cells. This would permit unopposed contraction of vascular smooth muscle cells in the face of the pre-existing, yet previously endogenously controlled, hypertension, thus giving rise to hypertensive crisis. If this hypothesis is correct, such patients should respond rapidly to nitroglycerin, which mimics the action of nitric oxide. Wellcome Foundation Ltd,
Langley Court, Beckenham, Kent BR3 3BS
time
(min)
platelet membrane from patients on CPB. . = untreated (placebo); . = aprotmin. At 5 min of CPB and at end of CPB significant differences were observed. Results as mean (SEM). **p < 0-02, *p < 0-05 (Wilcoxon signed-rank test). on
JOHN MARTIN SALVADOR MONCADA
Fernge AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524-26 2. Editorial. EDRF. Lancet 1987; ii: 137-38. 3. Remuzzi G, Misiani R, Marchesi D, et al. Haemolytic-uraemic syndrome: Deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 1978; ii: 871-72. 4. Deckmyn H, Proesmans W, Vermyen J. Prostacyclin production by whole blood from children: Impairment in the hemolytic uremic syndrome and excessive formation in chronic renal failure. Thromb Res 1983; 30: 13-18. 5. Martin W, Smith JA, White DG. The mechanisms by which haemoglobin inhibits the relaxation of rabbit aorta induced by nitrovasodilators, nitric oxide or bovine retractor penis inhibitor factor. Br J Pharmacol 1986; 89: 562-71. 1. Palmer RMJ,
GP Ib antigen
W. VAN OEVEREN L. EIJSMAN K. J. ROOZENDAAL CH. R. H. WILDEVUUR