- Email: [email protected]
Arterial and venous thromboembolism with fatal outcome and resistance to activated protein C
Months since
starting EPO therapy
Figure: Changes In haemoglobin over time is the first recorded in each month months after the start of EPO.
Haemoglobin shown
during the 30
elevated before he started on cyclosporin (31.3-66.3 mg/L, normal < 10 mg/L), and although now reduced it remains above the normal range after treatment (15-6-33-3 mg/L). Inflammation in a retained graft has been proposed as a mechanism for EPO resistance. 1,2 Previous reports have shown the beneficial effect of graft nephrectomy.2 The successful treatment documented in this patient may represent suppression of occult chronic rejection and associated inflammation by cyclopsorin. Alternatively, the marrow failure may have been T-cell mediated, perhaps triggered by the presence of the graft and effected through mechanisms similar to those seen in some cases of aplastic anaemia in which marrow dysfunction also responds to cyclosporin.3,4 M K Almond, D Tailor, S M Kelsey, J Cunningham Departments of Nephrology and Haematology, The Royal London Hospital and Medical College, Whitechapel, London E1 1BB, UK
1 Almond MK, Tailor D, Marsh FP, Raftery MJ, Cunningham J. High erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme. J Am Soc Nephrol 1993; 4: 423. 2 Page B, Zitouni Z, Zingraff J. Resistance to rHuEpo and kidney graft rejection in patients on haemodialysis. Nephrol Dial Transplant 1993; 9: 961. 3 Bjorkholm M. Aplastic anaemia: pathogenic mechanisms and treatment with special reference to immunomodulation. J Intern Med 1992; 231: 575-82. 4 Hinterberger-Fischer M, Hocker P, Seewan H, Hinterberger W. Oral cyclosporin-A is effective treatment for untreated and also for previously immunosuppressed patients with severe bone marrow failure. Eur J Haematol 1989; 43: 136-42.
thrombosis3-5 and its prevalence in a thrombosis cohort is about 10-fold higher than prevalences of other inherited anticoagulant protein deficiencies.5 The prevalence of APC resistance in the general population seems high in that APC resistance is found in 3-7% of healthy control populations.4,5 We have recorded APC resistance in three patients in whom peripheral arterial vascular reconstructions have occluded. One of these cases was a 32-year-old man with pronounced APC resistance and arterial and venous thromboembolic complications. He presented with a three-month history of unexplained intermittent claudication of his left leg. Angiography showed occlusion of the left popliteal artery about 4 cm above the knee joint. Conservative treatment was tried but the claudication progressed and surgical reconstruction was carried out. The occluded artery was of normal width, but palpation revealed arteriosclerotic thickening of the wall. A short-vein graft bypass was done with standard surgical procedures. Ten hours postoperatively, the graft occluded and thrombectomy was done. The patient was given intravenous heparin. On the fifth postoperative day, the graft reoccluded and a second vein graft bypass was carried out. Before this reoperation, plasma samples were taken for analysis of possible abnormalities of the coagulation system. Heparin was continued and postoperative duplex examination revealed a well-functioning graft and open popliteal veins. The patient was mobilised and discharged from hospital on the ninth postoperative day. One day after hospital discharge, the patient suddenly developed nausea and dyspnoea, lost consciousness, and died. Deep venous thrombosis of the left leg and a large embolus occluding the main pulmonary artery were found at necropsy. The second vein graft vascular reconstruction was examined and found to be open. Analysis of the coagulation values yielded normal plasma concentrations of protein C, protein S, and antithrombin. In the APC resistance test, the APC ratio (APC time/APT time) was 1-6, well below the lower normal limit of less than 2.5 Since both parents and one brother were also found to have APC resistance it is possible that the patient had compound heterozygous APC resistance. Because APC resistance is a major risk factor for venous thromboembolism, it seems valid to suspect that the severe APC resistance contributed to the vascular occlusions and the fatal thromboembolic
complications. Controlled studies evaluating the risk for postoperative thromboembolic complications in individuals with APC resistance are required. The recent identification of APC resistance as a risk factor for venous thrombosis has raised questions such as whether it is worthwhile screening preoperatively for APC resistance and whether APC-resistant individuals require prolonged or intensified anticoagulant prophylaxis and treatment. B
Lindblad, PJ Svensson, B Darhlbäck
Departments of Surgery, Coagulation Disorders, and Clinical Chemistry, Malmö General Hospital, Lund University, 214 01 Malmö, Sweden
Arterial and venous thromboembolism with fatal outcome and resistance to activated protein C
1
SIR—We
2
have described a previously unrecognised mechanism for thrombophilia, which is characterised by a defect in anticoagulant response to activated protein C (APC).1 After its activation on the endothelial surface by the thrombinthrombomodulin complex, protein C inhibits the coagulation cascade through proteolytic degradation of coagulation factors Va and VIlla. APC resistance is inherited as an autosomal dominant trait. It is caused by deficient anticoagulant APCcofactor activity found to be a property of unactivated factor V.2 APC resistance seems an important risk factor for venous
3
4
5
Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-08. Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci USA 1994; 91: 1396-400. Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-93. Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-06. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-22.
917
starting EPO therapy
Figure: Changes In haemoglobin over time is the first recorded in each month months after the start of EPO.
Haemoglobin shown
during the 30
elevated before he started on cyclosporin (31.3-66.3 mg/L, normal < 10 mg/L), and although now reduced it remains above the normal range after treatment (15-6-33-3 mg/L). Inflammation in a retained graft has been proposed as a mechanism for EPO resistance. 1,2 Previous reports have shown the beneficial effect of graft nephrectomy.2 The successful treatment documented in this patient may represent suppression of occult chronic rejection and associated inflammation by cyclopsorin. Alternatively, the marrow failure may have been T-cell mediated, perhaps triggered by the presence of the graft and effected through mechanisms similar to those seen in some cases of aplastic anaemia in which marrow dysfunction also responds to cyclosporin.3,4 M K Almond, D Tailor, S M Kelsey, J Cunningham Departments of Nephrology and Haematology, The Royal London Hospital and Medical College, Whitechapel, London E1 1BB, UK
1 Almond MK, Tailor D, Marsh FP, Raftery MJ, Cunningham J. High erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme. J Am Soc Nephrol 1993; 4: 423. 2 Page B, Zitouni Z, Zingraff J. Resistance to rHuEpo and kidney graft rejection in patients on haemodialysis. Nephrol Dial Transplant 1993; 9: 961. 3 Bjorkholm M. Aplastic anaemia: pathogenic mechanisms and treatment with special reference to immunomodulation. J Intern Med 1992; 231: 575-82. 4 Hinterberger-Fischer M, Hocker P, Seewan H, Hinterberger W. Oral cyclosporin-A is effective treatment for untreated and also for previously immunosuppressed patients with severe bone marrow failure. Eur J Haematol 1989; 43: 136-42.
thrombosis3-5 and its prevalence in a thrombosis cohort is about 10-fold higher than prevalences of other inherited anticoagulant protein deficiencies.5 The prevalence of APC resistance in the general population seems high in that APC resistance is found in 3-7% of healthy control populations.4,5 We have recorded APC resistance in three patients in whom peripheral arterial vascular reconstructions have occluded. One of these cases was a 32-year-old man with pronounced APC resistance and arterial and venous thromboembolic complications. He presented with a three-month history of unexplained intermittent claudication of his left leg. Angiography showed occlusion of the left popliteal artery about 4 cm above the knee joint. Conservative treatment was tried but the claudication progressed and surgical reconstruction was carried out. The occluded artery was of normal width, but palpation revealed arteriosclerotic thickening of the wall. A short-vein graft bypass was done with standard surgical procedures. Ten hours postoperatively, the graft occluded and thrombectomy was done. The patient was given intravenous heparin. On the fifth postoperative day, the graft reoccluded and a second vein graft bypass was carried out. Before this reoperation, plasma samples were taken for analysis of possible abnormalities of the coagulation system. Heparin was continued and postoperative duplex examination revealed a well-functioning graft and open popliteal veins. The patient was mobilised and discharged from hospital on the ninth postoperative day. One day after hospital discharge, the patient suddenly developed nausea and dyspnoea, lost consciousness, and died. Deep venous thrombosis of the left leg and a large embolus occluding the main pulmonary artery were found at necropsy. The second vein graft vascular reconstruction was examined and found to be open. Analysis of the coagulation values yielded normal plasma concentrations of protein C, protein S, and antithrombin. In the APC resistance test, the APC ratio (APC time/APT time) was 1-6, well below the lower normal limit of less than 2.5 Since both parents and one brother were also found to have APC resistance it is possible that the patient had compound heterozygous APC resistance. Because APC resistance is a major risk factor for venous thromboembolism, it seems valid to suspect that the severe APC resistance contributed to the vascular occlusions and the fatal thromboembolic
complications. Controlled studies evaluating the risk for postoperative thromboembolic complications in individuals with APC resistance are required. The recent identification of APC resistance as a risk factor for venous thrombosis has raised questions such as whether it is worthwhile screening preoperatively for APC resistance and whether APC-resistant individuals require prolonged or intensified anticoagulant prophylaxis and treatment. B
Lindblad, PJ Svensson, B Darhlbäck
Departments of Surgery, Coagulation Disorders, and Clinical Chemistry, Malmö General Hospital, Lund University, 214 01 Malmö, Sweden
Arterial and venous thromboembolism with fatal outcome and resistance to activated protein C
1
SIR—We
2
have described a previously unrecognised mechanism for thrombophilia, which is characterised by a defect in anticoagulant response to activated protein C (APC).1 After its activation on the endothelial surface by the thrombinthrombomodulin complex, protein C inhibits the coagulation cascade through proteolytic degradation of coagulation factors Va and VIlla. APC resistance is inherited as an autosomal dominant trait. It is caused by deficient anticoagulant APCcofactor activity found to be a property of unactivated factor V.2 APC resistance seems an important risk factor for venous
3
4
5
Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-08. Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci USA 1994; 91: 1396-400. Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-93. Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-06. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-22.
917