Nephrol Dial Transplant (1992) 7: 979-982 £ 1992 European Dialysis and Transplant Association-European Renal Association
Nephrology Dialysis Transplantation
Letters Erythropoietin-induced protein S deficiency and vena cava thrombosis Sir, We have been extremely interested in the recent paper by MacDougall et al. [1]. These authors have observed a significant decrease in protein S and protein C levels during the first months of erythropoietin therapy. They suggest that this transient deficiency may contribute to the increased incidence of fistula thrombosis in patients treated with recombinant human erythropoietin (rHuEpo). We would like to make the following remarks. In patients with normal renal function, either protein S or protein C deficiency can be responsible for iterative venous thromboses that often involve deep axes, with high risk for pulmonary embolism [2]. To date, however, only fistula thromboses have been reported in haemodialysed patients treated with rHuEpo [3]. Various factors may account for this discrepancy; these include the relative magnitude of the quantitative deficiency and the haemodynamic abnormalities [4], and the subtle haemostatic disorders [5], both peculiar to uraemia. Nevertheless we feel that in haemodialysed patients treated with rHuEpo, deep vein thrombosis also is likely to occur, as we have observed in the following case. The patient was a 41-year-old white female, who had started on haemodialysis 12 years ago for anti-GBM nephropathy. She had been subsequently transplanted, but had developed chronic rejection which after 3 years resulted in graft loss. During this period she experienced recurring abdominal and pelvic abcesses from appendicular origin and underwent multiple surgical procedures; she also required bilateral hip prostheses for femoral osteonecrosis. After dialysis had been resumed, mild chronic hepatitis B was diagnosed by liver biopsy. Septicaemia originating from the vascular access resulted in staphylococceal hip arthritis and one prosthesis had to be removed, which was then replaced after a 3-month interval. In the postoperative period, a phlebography was performed because of oedema of the knee; venous axes, including inferior vena cava, appeared normal. Six months later, rHuEpo was started (Hb = 7.2g/dl). After 3 months, when Hb had reached 9.5 g/dl and thrombocyte count remained normal (259000/mm 3 ), the patient complained of fever and abdominal pain, then after a few days exhibited painful oedema of lower limbs. Ultrasonic and tomodensitometric examinations disclosed 'fresh' thrombosis involving both iliac veins and subhepatic vena cava. Coagulation studies were first considered normal, but unfortunately at this time only total antigenic protein S (165%) could be assayed. Six months later, however, while the patient was still receiving rHuEpo, free protein S could be measured and was markedly reduced (45%).
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Cessation of Epo was promptly followed by an increase to normal range (115%) of free protein S. These data exclude hepatitis-induced, as well as congenital protein S deficiency, and normal levels were found in other members of the family. Therefore, this transient decrease in protein S appears to be directly related to rHuEpo. Obviously, protein S deficiency may not be considered the single factor involved in the pathogenesis of vena cava thrombosis in this patient. History of severe sepsis and iterative surgery, both visceral and orthopaedic, has certainly favoured pelvic venous thrombosis. Concerning the effect of rHuEpo, the role of increased blood viscosity should not be overlooked. However, haemoglobin has never reached 10 g/dl, whereas higher Hb levels are commonly observed in haemodialysed patients receiving either rHuEpo or blood tranfusions, without being responsible for severe thrombotic complications. To our knowledge, this case would be the first one of vena cava thrombosis under rHuEpo therapy. From the sequence of the clinical events, we conclude that in the present case, erythropoietin-induced protein S deficiency played a paramount role in thrombogenesis. Assessment of protein S and protein C levels should be warranted during the first weeks of treatment with rHuEpo. The opportunity of prescribing preventive oral anticoagulant therapy in some patients remains to be evaluated. Service de Nephrologie and Laboratoire d'Hematologie, Hopital Tenon, Paris, France
B. Viron B.Jaar E. Verdy F. Mignon
1. MacDougall IC, Davies ME, Mallett I et al. Coagulation studies and fistula blood flow during erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant 1991; 6: 862-687 2. Schaefer Al. The hypercoagulable states. Ann Intern Med 1985; 102: 814-828 3. Eschbach JW, Egrie JC, Downing AR et al. Correction of the anemia of end end-stage renal disease with recombinant human erythropoietin. N Engl J Med 1987; 316: 73-78 4. Jahn H, Schohn D, Schmitt R. Etudes hemodynamiques au cours de l'insuffisance renale chronique terminale. Effets des techniques d'epuration extra-renale. Nephrologie 1981; 2: 53-62. 5. Remuzzi G. Bleeding in renal failure. Lancet 1988; 1: 12051207
Sir, We were interested by the paper of Cunningham et al (Nephrol Dial Transplant 1992; 7: 63-68) on dialysate calcium reduction in CAPD patients treated with CaCO 3
Nephrology Dialysis Transplantation
Letters Erythropoietin-induced protein S deficiency and vena cava thrombosis Sir, We have been extremely interested in the recent paper by MacDougall et al. [1]. These authors have observed a significant decrease in protein S and protein C levels during the first months of erythropoietin therapy. They suggest that this transient deficiency may contribute to the increased incidence of fistula thrombosis in patients treated with recombinant human erythropoietin (rHuEpo). We would like to make the following remarks. In patients with normal renal function, either protein S or protein C deficiency can be responsible for iterative venous thromboses that often involve deep axes, with high risk for pulmonary embolism [2]. To date, however, only fistula thromboses have been reported in haemodialysed patients treated with rHuEpo [3]. Various factors may account for this discrepancy; these include the relative magnitude of the quantitative deficiency and the haemodynamic abnormalities [4], and the subtle haemostatic disorders [5], both peculiar to uraemia. Nevertheless we feel that in haemodialysed patients treated with rHuEpo, deep vein thrombosis also is likely to occur, as we have observed in the following case. The patient was a 41-year-old white female, who had started on haemodialysis 12 years ago for anti-GBM nephropathy. She had been subsequently transplanted, but had developed chronic rejection which after 3 years resulted in graft loss. During this period she experienced recurring abdominal and pelvic abcesses from appendicular origin and underwent multiple surgical procedures; she also required bilateral hip prostheses for femoral osteonecrosis. After dialysis had been resumed, mild chronic hepatitis B was diagnosed by liver biopsy. Septicaemia originating from the vascular access resulted in staphylococceal hip arthritis and one prosthesis had to be removed, which was then replaced after a 3-month interval. In the postoperative period, a phlebography was performed because of oedema of the knee; venous axes, including inferior vena cava, appeared normal. Six months later, rHuEpo was started (Hb = 7.2g/dl). After 3 months, when Hb had reached 9.5 g/dl and thrombocyte count remained normal (259000/mm 3 ), the patient complained of fever and abdominal pain, then after a few days exhibited painful oedema of lower limbs. Ultrasonic and tomodensitometric examinations disclosed 'fresh' thrombosis involving both iliac veins and subhepatic vena cava. Coagulation studies were first considered normal, but unfortunately at this time only total antigenic protein S (165%) could be assayed. Six months later, however, while the patient was still receiving rHuEpo, free protein S could be measured and was markedly reduced (45%).
Downloaded from https://academic.oup.com/ndt/article-abstract/7/9/979/1863108 by St Bartholomew's & the Royal London School of Medicine and Denistry user on 22 March 2018
Cessation of Epo was promptly followed by an increase to normal range (115%) of free protein S. These data exclude hepatitis-induced, as well as congenital protein S deficiency, and normal levels were found in other members of the family. Therefore, this transient decrease in protein S appears to be directly related to rHuEpo. Obviously, protein S deficiency may not be considered the single factor involved in the pathogenesis of vena cava thrombosis in this patient. History of severe sepsis and iterative surgery, both visceral and orthopaedic, has certainly favoured pelvic venous thrombosis. Concerning the effect of rHuEpo, the role of increased blood viscosity should not be overlooked. However, haemoglobin has never reached 10 g/dl, whereas higher Hb levels are commonly observed in haemodialysed patients receiving either rHuEpo or blood tranfusions, without being responsible for severe thrombotic complications. To our knowledge, this case would be the first one of vena cava thrombosis under rHuEpo therapy. From the sequence of the clinical events, we conclude that in the present case, erythropoietin-induced protein S deficiency played a paramount role in thrombogenesis. Assessment of protein S and protein C levels should be warranted during the first weeks of treatment with rHuEpo. The opportunity of prescribing preventive oral anticoagulant therapy in some patients remains to be evaluated. Service de Nephrologie and Laboratoire d'Hematologie, Hopital Tenon, Paris, France
B. Viron B.Jaar E. Verdy F. Mignon
1. MacDougall IC, Davies ME, Mallett I et al. Coagulation studies and fistula blood flow during erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant 1991; 6: 862-687 2. Schaefer Al. The hypercoagulable states. Ann Intern Med 1985; 102: 814-828 3. Eschbach JW, Egrie JC, Downing AR et al. Correction of the anemia of end end-stage renal disease with recombinant human erythropoietin. N Engl J Med 1987; 316: 73-78 4. Jahn H, Schohn D, Schmitt R. Etudes hemodynamiques au cours de l'insuffisance renale chronique terminale. Effets des techniques d'epuration extra-renale. Nephrologie 1981; 2: 53-62. 5. Remuzzi G. Bleeding in renal failure. Lancet 1988; 1: 12051207
Sir, We were interested by the paper of Cunningham et al (Nephrol Dial Transplant 1992; 7: 63-68) on dialysate calcium reduction in CAPD patients treated with CaCO 3
