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Bilateral renal vein thrombosis and venous sinus thrombosis in a neonate with factor V mutation (FV Leiden)
THE JOURNAL OF PEDIATRICS Volume 132, Number 1 12. Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr 1991;12:439-47. 13. Gasché C, Reinisch W, Lochs H, et al. Anemia of Crohn’s disease: importance of inadequate erythropoietin production and iron-deficiency. Dig Dis Sci 1994;39:1930-4. 14. Thompson A, Brust R, Ali M, et al. Iron deficiency in inflammatory bowel disease. Dig Dis Sci 1978;23:705-9. 15. Fuchs D, Hausen A, Reibnegger G, et al. Immune activation and the anaemia associated with chronic inflammatory disorders. Eur J Haematol 1991;46:65-70. 16. Jelkmann WEB, Fandrey J, Frede S, Pagel H. Inhibition of erythropoietin production by cytokines. Ann N Y Acad Sci 1994;71:300-9. 17. Baer AN, Dessypris EN, Goldwasser E, Krantz SB. Blunted erythropoietin re-
POHL
18.
19.
20.
21.
22.
sponse to anaemia in rheumatoid arthritis. Br J Haematol 1987;66:559-64. Johannsen H, Jelkmann W, Wiedemann G, et al. Erythropoietin/haemoglobin relationship in leukaemia and ulcerative colitis. Eur J Haematol 1989;43:201-6. Fantini F, Gattinara M, Gerloni V, et al. Severe anemia associated with active systemic-onset juvenile rheumatoid arthritis successfully treated with recombinant human erythropoietin: a pilot study. Arthritis Rheum 1992;35:724-6. Sundal E, Businger J, Kappeler A. Treatment of transfusion-dependent anaemia of chronic renal failure with recombinant human erythropoietin. Nephrol Dial Transplant 1991;6:955-65. Komatsu Y, Ito K. Erythropoietin associated hypertension among pediatric dialysis patients. Adv Perit Dial 1992;8:448-52. Campos A, Garin EH. Therapy of renal anemia in children and adolescents with re-
23.
24.
25.
26.
ET AL.
combinant human erythropoietin (rHuEPO). Clin Pediatr 1992;31:94-9. Shannon KM, Mentzer WC, Abels RI, et al. Enhancement of erythropoiesis by recombinant human erythropoietin in low birth weight infants: a pilot study. J Pediatr 1992;120:586-92. Carnielli V, Montini G, Da Riol R, et al. Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants. J Pediatr 1992;121:98-102. Markowitz J, Grancher K, Rosa J, et al. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993;16:373-80. Motil KJ, Grand RJ, Davis-Kraft L, et al. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993;105:681-91.
B
Bilateral renal vein thrombosis and venous sinus
thrombosis in a neonate with factor V mutation (FV Leiden)
Martin Pohl, MD, Lothar B. Zimmerhackl, MD, Florian Heinen, MD, Anton H. Sutor, MD, Reinhard Schneppenheim, MD, and Matthias Brandis, MD Bilateral renal vein thrombosis and venous sinus thrombosis were diagnosed within 3 weeks of birth in a full-term neonate. Heterozygosity for a factor V mutation leading to resistance against the anticoagulatory properties of activated protein C was found. Heparin therapy led to resolution of the thrombotic manifestations. With long-term oral anticoagulation, no relapse or other thrombotic event occurred during infancy. (J Pediatr 1998;132:159-61)
Renal vein thrombosis is a rare but well-defined entity in neonatal medicine. Physical factors such as hemoconcentration or localFrom University Children´s Hospital, Albert-Ludwig University, Freiburg, Germany and the University Children´s Hospital, Christian-Albrecht University, Kiel, Germany Submitted for publication Aug. 5, 1996; accepted Jan. 15, 1997. Reprint requests: Martin Pohl, MD, Children´s Hospital, University of Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/81009
ly impaired blood flow have been primarily held responsible for the development of this condition.1 Neonatal venous sinus thrombosis may be induced by severe birth asphyxia.2 The role of hereditary coagulation disorders in both conditions has not been defined. Heterozygous carriers of factor VR506Q (FV Leiden) have a sevenfold risk of thrombosis, whereas the risk for homozygous individuals is increased 80-fold.3 An allele frequency of 5% in the healthy population and of 21% in patients with deep vein thrombosis (excluding patients with
malignant disease) renders APC resistance the most important known hereditary risk factor for thrombosis formation.4 We report neonatal renal vein thrombosis and sinus venous thrombosis in an infant heterozygous for FV Leiden. APC FV MRI MAG-3
Activated protein C Factor V Magnetic resonance imaging Mercaptoacetyltriglycine
CASE REPORT A 2990 gm full-term male infant was born after an uneventful pregnancy by cesarean section prompted by variable decelerations in fetal heart rate recordings to a gravida 2, para 1 with meconiumstained amniotic fluid. Apgar score was 3/8/9 in the first, fifth, and tenth minute, and arterial umbilical pH was 7.24. Mechanical ventilation was performed for 159
POHL
ET AL.
THE JOURNAL
OF PEDIATRICS JANUARY 1998
based assay for APC resistance with anticoagulant therapy was within normal limits on two separate investigations. Mutation analysis of the factor V gene identified a heterozygous FV Leiden mutation (G1691A) and implicated APC resistance as the origin of thrombophilia.
DISCUSSION
Figure. Sagittal MRI image with selective venous flow enhancement showing the absence of venous flow in the superior sagittal sinus between the coronary suture and the venous confluent.
14 hours, but breathing posed no problem thereafter. Infection was not found and no venous or arterial catheters were inserted. On the third day, microscopic hematuria, proteinuria, and thrombocytopenia were noted. Left renal enlargement on ultrasound led to the suspicion of renal vein thrombosis. Low-dose heparin therapy was started, but symptoms progressed to renal failure presenting with anuria, elevation of serum creatinine, and raised blood pressure. The patient was then transferred to the Freiburg University Children´s Hospital. Color-coded duplex sonography established the diagnosis of bilateral renal vein thrombosis. Heparin therapy was initiated (35 to 40 IE/kg per hour). Thrombolytic therapy was not begun because diuresis resumed early with anticoagulant therapy alone. Acute peritoneal dialysis was performed for 5 days until renal excretion was sufficient to lower renal retention values. After significant improvement of renal blood flow as documented by duplex sonography, heparin therapy was stopped on the fourteenth day of life, when the diagnosis of hereditary thrombophilia was not yet known. On day 19 two clonic seizures of focal origin in the left hemisphere occurred. Computed tomography and magnetic resonance imaging scans showed thrombosis of the superior sagittal sinus (Figure). 160
Heparin therapy was resumed and now maintained for 50 days. When stopped, oral anticoagulation with phenprocoumon had reached therapeutic levels. Seizures did not recur, and cranial MRI scans showed almost complete restitution of cerebral venous flow without evidence of parenchymal lesions. In view of the severe thrombotic manifestations, continuous oral anticoagulation (international normalized ratio approximately 2.3) despite the patient’s young age was recommended. No relapse or other thrombotic event occurred during infancy. At the age of 6 months, compensated renal failure (creatinine clearance, 30 ml/min/1.73 m2) as sequelae of renal vein thrombosis persisted. Renal isotope scan (MAG-3) revealed impaired partial function of the left kidney (28% of total MAG3 uptake) and ultrasound showed a small left kidney. Urinalysis, blood pressure, and the developmental status were normal. At the age of 13 months the patient could walk alone, used several words, and interacted adequately with his parents. Laboratory studies for congenital defects leading to venous thrombosis documented normal activities for antithrombin III (87% to 98%, measured repeatedly by an amidolytic assay), protein C (72% measured amidolytically and 75% coagulometrically), and protein S (total protein S 139%, immunologic assay). The aPTT-
Neonatal renal vein thrombosis and neonatal venous sinus thrombosis are both considered to be caused by exogenous factors.1 The perinatal circulatory depression indicated by the variable decelerations in the fetal heart rate and the Apgar score of 3 in the first minute or the raised extrathoracic venous pressure produced by the mechanical ventilation may have contributed to, but are unlikely to explain, venous thrombosis. Neither is the mild continuous ambulatory peritoneal dialysis regimen leading to a continuous slow weight reduction within 5 days to a minimum weight still above the birth weight likely to constitute a sufficiently strong risk factor toward thrombosis. The continuous medical care during the neonatal period allows the exclusion of other clinically apparent exogenous risk factors. We therefore cannot answer the question whether renal and cerebral thrombosis had formed simultaneously with only disparate clinical presentation or sequentially. The occurrence of both thrombotic conditions in a full-term neonate of normal birth weight, without other strongly predisposing factors, points toward FVR506Q mutation (FV Leiden) as a possible cause. Recently, inferior vena cava thrombosis,5 purpura fulminans,6 and three cases of renal vein thrombosis7 in otherwise healthy neonates with this FV mutation have been reported. To our knowledge no other cases of neonatal venous thrombosis associated with this mutation have been published to date. We believe there must be an increasing recognition of this hereditary thrombophilia in neonatal thrombosis as has been observed in adults, where a considerable percentage of venous thrombosis is at least partially associated with FV Leiden.5,6,8 Clearly, other hereditary or
THE JOURNAL OF PEDIATRICS Volume 132, Number 1 exogenous factors may contribute to clot formation,1,9 but predisposition by FVR506Q mutation must be taken into consideration. Mutation analysis is required for the exclusion of G1691A transition because more than 95% of APC resistance is due to FV Leiden, and mutation analysis is more reliable than testing for APC resistance.10 Long-term management of infants with known hereditary thrombophilia is a considerable clinical problem. The individual risk for recurrent thrombosis is impossible to evaluate because too few endogenous factors are identified and future constellations of environmental factors are unpredictable. Without controlled treatment studies, statistical evidence for best treatment options is not available. The considerable variability of clinical penetrance of homozygous or heterozygous FVR506Q mutation adds to the unpredictability of future thrombotic complications. Rosendaal et al.3 do not recommend lifelong anticoagulant prophylaxis for adult homozygous or heterozygous patients, but favor short-term prophylaxis in risk situations. In children the highest incidence of thromboembolic complications has been found during the first year of life.7 Because many endogenous throm-
POHL
bogenetic factors have not been identified to date and the occurrence of additional exogenous risk factors is unpredictable, we believe that thrombophilia producing multiple neonatal thrombosis in the absence of other identifiable strongly predisposing factors is severe enough to warrant prudent oral anticoagulation during infancy. Because of the multitude of possible influencing factors, every case needs careful individual consideration when deciding on prophylactic treatment. Evidence for best treatment options does not exist and must be produced by future controlled treatment studies. We thank the nursing staff for their dedicated care of this patient and their assistance in diagnostic and treatment procedures.
4.
5.
6.
7.
8.
REFERENCES 1. Ives HE, Daniel TO. Vascular diseases of the kidney: renal vein thrombosis. In: Brenner BM, Rector FC, editors. The kidney. Philadelphia: WB Saunders; 1991. p. 1530-4. 2. Voorhuis TM, Lipper EG, Lee BCP, Vannucci RC, Auld PAM. Occlusive vascular disease in asphyxiated newborn infants. J Pediatr 1984;105:92-6. 3. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in
9.
10.
ET AL.
patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85(6):1504-8. Koster T, Rosendaal FR, De Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503-6. Kodish E, Potter C, Kirschbaum NE, Foster PA. Activated protein C resistance in a neonate with venous thrombosis. J Pediatr 1995;127:645-8. Pipe SW, Schmaier AH, Nichols WC, Ginsburg D, Bozynski MEA, Castle VP. Neonatal purpura fulminans in association with factor V R506 Q mutation. J Pediatr 1996;128:706-9. Nowak-Göttl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kurlemann G, et al. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996;92:992-8. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330:517-22. Zöller B, Berntsdotter A, De Frutos PG, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995;85(15):3518-23. De Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994;72(6):880-6.
161
POHL
18.
19.
20.
21.
22.
sponse to anaemia in rheumatoid arthritis. Br J Haematol 1987;66:559-64. Johannsen H, Jelkmann W, Wiedemann G, et al. Erythropoietin/haemoglobin relationship in leukaemia and ulcerative colitis. Eur J Haematol 1989;43:201-6. Fantini F, Gattinara M, Gerloni V, et al. Severe anemia associated with active systemic-onset juvenile rheumatoid arthritis successfully treated with recombinant human erythropoietin: a pilot study. Arthritis Rheum 1992;35:724-6. Sundal E, Businger J, Kappeler A. Treatment of transfusion-dependent anaemia of chronic renal failure with recombinant human erythropoietin. Nephrol Dial Transplant 1991;6:955-65. Komatsu Y, Ito K. Erythropoietin associated hypertension among pediatric dialysis patients. Adv Perit Dial 1992;8:448-52. Campos A, Garin EH. Therapy of renal anemia in children and adolescents with re-
23.
24.
25.
26.
ET AL.
combinant human erythropoietin (rHuEPO). Clin Pediatr 1992;31:94-9. Shannon KM, Mentzer WC, Abels RI, et al. Enhancement of erythropoiesis by recombinant human erythropoietin in low birth weight infants: a pilot study. J Pediatr 1992;120:586-92. Carnielli V, Montini G, Da Riol R, et al. Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants. J Pediatr 1992;121:98-102. Markowitz J, Grancher K, Rosa J, et al. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993;16:373-80. Motil KJ, Grand RJ, Davis-Kraft L, et al. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993;105:681-91.
B
Bilateral renal vein thrombosis and venous sinus
thrombosis in a neonate with factor V mutation (FV Leiden)
Martin Pohl, MD, Lothar B. Zimmerhackl, MD, Florian Heinen, MD, Anton H. Sutor, MD, Reinhard Schneppenheim, MD, and Matthias Brandis, MD Bilateral renal vein thrombosis and venous sinus thrombosis were diagnosed within 3 weeks of birth in a full-term neonate. Heterozygosity for a factor V mutation leading to resistance against the anticoagulatory properties of activated protein C was found. Heparin therapy led to resolution of the thrombotic manifestations. With long-term oral anticoagulation, no relapse or other thrombotic event occurred during infancy. (J Pediatr 1998;132:159-61)
Renal vein thrombosis is a rare but well-defined entity in neonatal medicine. Physical factors such as hemoconcentration or localFrom University Children´s Hospital, Albert-Ludwig University, Freiburg, Germany and the University Children´s Hospital, Christian-Albrecht University, Kiel, Germany Submitted for publication Aug. 5, 1996; accepted Jan. 15, 1997. Reprint requests: Martin Pohl, MD, Children´s Hospital, University of Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/81009
ly impaired blood flow have been primarily held responsible for the development of this condition.1 Neonatal venous sinus thrombosis may be induced by severe birth asphyxia.2 The role of hereditary coagulation disorders in both conditions has not been defined. Heterozygous carriers of factor VR506Q (FV Leiden) have a sevenfold risk of thrombosis, whereas the risk for homozygous individuals is increased 80-fold.3 An allele frequency of 5% in the healthy population and of 21% in patients with deep vein thrombosis (excluding patients with
malignant disease) renders APC resistance the most important known hereditary risk factor for thrombosis formation.4 We report neonatal renal vein thrombosis and sinus venous thrombosis in an infant heterozygous for FV Leiden. APC FV MRI MAG-3
Activated protein C Factor V Magnetic resonance imaging Mercaptoacetyltriglycine
CASE REPORT A 2990 gm full-term male infant was born after an uneventful pregnancy by cesarean section prompted by variable decelerations in fetal heart rate recordings to a gravida 2, para 1 with meconiumstained amniotic fluid. Apgar score was 3/8/9 in the first, fifth, and tenth minute, and arterial umbilical pH was 7.24. Mechanical ventilation was performed for 159
POHL
ET AL.
THE JOURNAL
OF PEDIATRICS JANUARY 1998
based assay for APC resistance with anticoagulant therapy was within normal limits on two separate investigations. Mutation analysis of the factor V gene identified a heterozygous FV Leiden mutation (G1691A) and implicated APC resistance as the origin of thrombophilia.
DISCUSSION
Figure. Sagittal MRI image with selective venous flow enhancement showing the absence of venous flow in the superior sagittal sinus between the coronary suture and the venous confluent.
14 hours, but breathing posed no problem thereafter. Infection was not found and no venous or arterial catheters were inserted. On the third day, microscopic hematuria, proteinuria, and thrombocytopenia were noted. Left renal enlargement on ultrasound led to the suspicion of renal vein thrombosis. Low-dose heparin therapy was started, but symptoms progressed to renal failure presenting with anuria, elevation of serum creatinine, and raised blood pressure. The patient was then transferred to the Freiburg University Children´s Hospital. Color-coded duplex sonography established the diagnosis of bilateral renal vein thrombosis. Heparin therapy was initiated (35 to 40 IE/kg per hour). Thrombolytic therapy was not begun because diuresis resumed early with anticoagulant therapy alone. Acute peritoneal dialysis was performed for 5 days until renal excretion was sufficient to lower renal retention values. After significant improvement of renal blood flow as documented by duplex sonography, heparin therapy was stopped on the fourteenth day of life, when the diagnosis of hereditary thrombophilia was not yet known. On day 19 two clonic seizures of focal origin in the left hemisphere occurred. Computed tomography and magnetic resonance imaging scans showed thrombosis of the superior sagittal sinus (Figure). 160
Heparin therapy was resumed and now maintained for 50 days. When stopped, oral anticoagulation with phenprocoumon had reached therapeutic levels. Seizures did not recur, and cranial MRI scans showed almost complete restitution of cerebral venous flow without evidence of parenchymal lesions. In view of the severe thrombotic manifestations, continuous oral anticoagulation (international normalized ratio approximately 2.3) despite the patient’s young age was recommended. No relapse or other thrombotic event occurred during infancy. At the age of 6 months, compensated renal failure (creatinine clearance, 30 ml/min/1.73 m2) as sequelae of renal vein thrombosis persisted. Renal isotope scan (MAG-3) revealed impaired partial function of the left kidney (28% of total MAG3 uptake) and ultrasound showed a small left kidney. Urinalysis, blood pressure, and the developmental status were normal. At the age of 13 months the patient could walk alone, used several words, and interacted adequately with his parents. Laboratory studies for congenital defects leading to venous thrombosis documented normal activities for antithrombin III (87% to 98%, measured repeatedly by an amidolytic assay), protein C (72% measured amidolytically and 75% coagulometrically), and protein S (total protein S 139%, immunologic assay). The aPTT-
Neonatal renal vein thrombosis and neonatal venous sinus thrombosis are both considered to be caused by exogenous factors.1 The perinatal circulatory depression indicated by the variable decelerations in the fetal heart rate and the Apgar score of 3 in the first minute or the raised extrathoracic venous pressure produced by the mechanical ventilation may have contributed to, but are unlikely to explain, venous thrombosis. Neither is the mild continuous ambulatory peritoneal dialysis regimen leading to a continuous slow weight reduction within 5 days to a minimum weight still above the birth weight likely to constitute a sufficiently strong risk factor toward thrombosis. The continuous medical care during the neonatal period allows the exclusion of other clinically apparent exogenous risk factors. We therefore cannot answer the question whether renal and cerebral thrombosis had formed simultaneously with only disparate clinical presentation or sequentially. The occurrence of both thrombotic conditions in a full-term neonate of normal birth weight, without other strongly predisposing factors, points toward FVR506Q mutation (FV Leiden) as a possible cause. Recently, inferior vena cava thrombosis,5 purpura fulminans,6 and three cases of renal vein thrombosis7 in otherwise healthy neonates with this FV mutation have been reported. To our knowledge no other cases of neonatal venous thrombosis associated with this mutation have been published to date. We believe there must be an increasing recognition of this hereditary thrombophilia in neonatal thrombosis as has been observed in adults, where a considerable percentage of venous thrombosis is at least partially associated with FV Leiden.5,6,8 Clearly, other hereditary or
THE JOURNAL OF PEDIATRICS Volume 132, Number 1 exogenous factors may contribute to clot formation,1,9 but predisposition by FVR506Q mutation must be taken into consideration. Mutation analysis is required for the exclusion of G1691A transition because more than 95% of APC resistance is due to FV Leiden, and mutation analysis is more reliable than testing for APC resistance.10 Long-term management of infants with known hereditary thrombophilia is a considerable clinical problem. The individual risk for recurrent thrombosis is impossible to evaluate because too few endogenous factors are identified and future constellations of environmental factors are unpredictable. Without controlled treatment studies, statistical evidence for best treatment options is not available. The considerable variability of clinical penetrance of homozygous or heterozygous FVR506Q mutation adds to the unpredictability of future thrombotic complications. Rosendaal et al.3 do not recommend lifelong anticoagulant prophylaxis for adult homozygous or heterozygous patients, but favor short-term prophylaxis in risk situations. In children the highest incidence of thromboembolic complications has been found during the first year of life.7 Because many endogenous throm-
POHL
bogenetic factors have not been identified to date and the occurrence of additional exogenous risk factors is unpredictable, we believe that thrombophilia producing multiple neonatal thrombosis in the absence of other identifiable strongly predisposing factors is severe enough to warrant prudent oral anticoagulation during infancy. Because of the multitude of possible influencing factors, every case needs careful individual consideration when deciding on prophylactic treatment. Evidence for best treatment options does not exist and must be produced by future controlled treatment studies. We thank the nursing staff for their dedicated care of this patient and their assistance in diagnostic and treatment procedures.
4.
5.
6.
7.
8.
REFERENCES 1. Ives HE, Daniel TO. Vascular diseases of the kidney: renal vein thrombosis. In: Brenner BM, Rector FC, editors. The kidney. Philadelphia: WB Saunders; 1991. p. 1530-4. 2. Voorhuis TM, Lipper EG, Lee BCP, Vannucci RC, Auld PAM. Occlusive vascular disease in asphyxiated newborn infants. J Pediatr 1984;105:92-6. 3. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in
9.
10.
ET AL.
patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85(6):1504-8. Koster T, Rosendaal FR, De Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503-6. Kodish E, Potter C, Kirschbaum NE, Foster PA. Activated protein C resistance in a neonate with venous thrombosis. J Pediatr 1995;127:645-8. Pipe SW, Schmaier AH, Nichols WC, Ginsburg D, Bozynski MEA, Castle VP. Neonatal purpura fulminans in association with factor V R506 Q mutation. J Pediatr 1996;128:706-9. Nowak-Göttl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kurlemann G, et al. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996;92:992-8. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330:517-22. Zöller B, Berntsdotter A, De Frutos PG, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995;85(15):3518-23. De Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994;72(6):880-6.
161