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Factor V Leiden mutation and the risk of thrombo-embolic disease in pregnancy: a case report
European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 197–198
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Case Report
Factor V Leiden mutation and the risk of thrombo-embolic disease in pregnancy: a case report Danie J. Schneider, Petrus S. Steyn*, Erna P.G. Mansvelt Department of Obstetrics and Gynaecology and Department of Haematology, University of Stellenbosch Medical School, Tygerberg Hospital, Parow, South Africa Received 23 March 1999; received in revised form 1 October 1999; accepted 27 October 1999
Abstract Factor V Leiden mutation is a risk factor for the development of thrombo-embolic episodes in pregnancy. A case is presented of a pregnant woman with repeated episodes of venous thrombosis with a complicated clinical course. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Leiden mutation; Pregnancy; Thrombotic episodes
1. Introduction A single-point mutation in the gene coding for factor V, known as Factor V Leiden, modifies the normal cleavage site at arginine 506 for activated protein C. This renders activated factor V resistant to inactivation by protein C and leads to a three- to six-fold increased risk for the development of venous thrombo-embolism [1]. In a selected population of pregnant women with venous thrombo-embolism, the incidence of activated protein C resistance (APCR) is as high as 46% [2]. There is a relatively low incidence of venous thrombo-embolism during pregnancy in South Africa and the prevalence of the FV Leiden mutation is still unknown in this country. A case of recurrent venous thrombo-embolism and subsequent management difficulties in a young primiparous woman is presented. 2. Case report Mrs EB, a 20-year-old primigravida, booked in a rural *Corresponding author. Tel.: 127-21-938-4432; fax: 127-21-9333084. E-mail address: [email protected] (P.S. Steyn)
town at 13 weeks pregnancy, confirmed with an early ultrasound. There was no previous or family history of thrombosis, intra-uterine growth restriction or pre-eclampsia. She presented at 20 weeks gestation to the rural practitioner with swelling of the left leg and an ultrasound evaluation of the leg confirmed the presence of a thrombus in the left femoral vein. The patient was managed on intravenous heparin for 1 week and was discharged on the oral anticoagulant warfarin, 7.5 mg daily. She subsequently moved to a coastal town and at 30 weeks gestation presented to another hospital with another deep vein thrombosis on the left side. The diagnosis was again confirmed ultrasonically in the left femoral vein. She also had a drug-induced hepatitis from paracetamol overuse. The prothrombin time, expressed as the international normalised ratio (INR), was prolonged beyond the highest detectable level. Paradoxically to the thrombosis, she had a severe bleeding tendency and developed a hematoma of the parotid gland. Her warfarin was discontinued, she was treated with fresh frozen plasma and parenteral vitamin K and was subsequently placed on subcutaneous low molecular weight heparin, 40 mg twice daily. She was then referred to our tertiary care unit, where she first presented at 34 weeks of gestation. At that stage there was no residual sequela of the thrombosis. Her liver function tests
0301-2115 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00265-1
198
D. J. Schneider et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 197 – 198
had normalised. She continued on subcutaneous low molecular weight heparin. She was admitted to hospital at 36 weeks for intravenous heparinisation. In spite of increasing dosage, therapeutic levels as monitored by the activated partial thromboplastin time (APTT) could not be attained. A factor VIII assay revealed a FVIII activity of 303% (303 mg / ml), a probable explanation for her heparin resistance. She also had a persistently low platelet count of around 100 000 / ml. Collagen screening and anticardiolipin antibodies were negative. Heparin induced thrombotic thrombocytopaenia was regarded as an unlikely cause because her platelet count remained constant. Protein S assay was within normal limits and protein C was decreased. Antithrombin III level and APCR could not be determined at this stage due to heparin therapy. At 38 weeks she developed a fever of unknown origin and labour was induced at term. She was eventually delivered by caesarean section due to poor progress of labour. A healthy baby boy of 3189 g was delivered with good Apgar scores. Heparin was withdrawn postpartum when satisfactory anti-coagulation with warfarin was achieved. Warfarin was continued for 3 months postpartum and she had an uneventful peurperium. Antithrombin III level was normal 6 weeks after delivery. Genetic analysis confirmed the presence of a FV Leiden mutation.
3. Discussion This is the first confirmed case of a Factor V Leiden mutation in our unit and this case highlights the difficulties and potential complications of management of a patient with this condition. The heparin resistance can be due to the increase in FVIII level commonly found during preg-
nancy. There is also an acquired APCR during pregnancy. These factors could act as additional risk factors for the development of thrombosis in patients with hereditary thrombophilia. Activated protein C resistance due to the factor V Leiden mutation is the most common inherited risk factor for thrombo-embolic disease during pregnancy and for patients on oral contraceptive use [3]. It is unsure whether screening of the general population is justified, but genetic testing on this individual patient’s offspring and immediate family would be advisable. For her next pregnancy she was advised to attend a pre-conception clinic and to receive subcutaneous heparin therapy through the pregnancy. The prevalence of factor V Leiden among South African population groups should be addressed in a future study. This should also be of particular value in South Africa, with its high incidence of pre-eclampsia and intra-uterine growth retardation, as activated protein C resistance was found to be significantly higher among these groups of patients [4].
References [1] Bertina RM, Koeleman BPC, Koster T et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–6. [2] Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 1997;127((10)):895–903. [3] Hallak M, Senderowicz J, Cassel A et al. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obstet Gynecol 1997;176((4)):889–93. [4] Kupferminc MJ, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. New Engl J Med 1999;340:9–13.
www.elsevier.com / locate / ejogrb
Case Report
Factor V Leiden mutation and the risk of thrombo-embolic disease in pregnancy: a case report Danie J. Schneider, Petrus S. Steyn*, Erna P.G. Mansvelt Department of Obstetrics and Gynaecology and Department of Haematology, University of Stellenbosch Medical School, Tygerberg Hospital, Parow, South Africa Received 23 March 1999; received in revised form 1 October 1999; accepted 27 October 1999
Abstract Factor V Leiden mutation is a risk factor for the development of thrombo-embolic episodes in pregnancy. A case is presented of a pregnant woman with repeated episodes of venous thrombosis with a complicated clinical course. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Leiden mutation; Pregnancy; Thrombotic episodes
1. Introduction A single-point mutation in the gene coding for factor V, known as Factor V Leiden, modifies the normal cleavage site at arginine 506 for activated protein C. This renders activated factor V resistant to inactivation by protein C and leads to a three- to six-fold increased risk for the development of venous thrombo-embolism [1]. In a selected population of pregnant women with venous thrombo-embolism, the incidence of activated protein C resistance (APCR) is as high as 46% [2]. There is a relatively low incidence of venous thrombo-embolism during pregnancy in South Africa and the prevalence of the FV Leiden mutation is still unknown in this country. A case of recurrent venous thrombo-embolism and subsequent management difficulties in a young primiparous woman is presented. 2. Case report Mrs EB, a 20-year-old primigravida, booked in a rural *Corresponding author. Tel.: 127-21-938-4432; fax: 127-21-9333084. E-mail address: [email protected] (P.S. Steyn)
town at 13 weeks pregnancy, confirmed with an early ultrasound. There was no previous or family history of thrombosis, intra-uterine growth restriction or pre-eclampsia. She presented at 20 weeks gestation to the rural practitioner with swelling of the left leg and an ultrasound evaluation of the leg confirmed the presence of a thrombus in the left femoral vein. The patient was managed on intravenous heparin for 1 week and was discharged on the oral anticoagulant warfarin, 7.5 mg daily. She subsequently moved to a coastal town and at 30 weeks gestation presented to another hospital with another deep vein thrombosis on the left side. The diagnosis was again confirmed ultrasonically in the left femoral vein. She also had a drug-induced hepatitis from paracetamol overuse. The prothrombin time, expressed as the international normalised ratio (INR), was prolonged beyond the highest detectable level. Paradoxically to the thrombosis, she had a severe bleeding tendency and developed a hematoma of the parotid gland. Her warfarin was discontinued, she was treated with fresh frozen plasma and parenteral vitamin K and was subsequently placed on subcutaneous low molecular weight heparin, 40 mg twice daily. She was then referred to our tertiary care unit, where she first presented at 34 weeks of gestation. At that stage there was no residual sequela of the thrombosis. Her liver function tests
0301-2115 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00265-1
198
D. J. Schneider et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 197 – 198
had normalised. She continued on subcutaneous low molecular weight heparin. She was admitted to hospital at 36 weeks for intravenous heparinisation. In spite of increasing dosage, therapeutic levels as monitored by the activated partial thromboplastin time (APTT) could not be attained. A factor VIII assay revealed a FVIII activity of 303% (303 mg / ml), a probable explanation for her heparin resistance. She also had a persistently low platelet count of around 100 000 / ml. Collagen screening and anticardiolipin antibodies were negative. Heparin induced thrombotic thrombocytopaenia was regarded as an unlikely cause because her platelet count remained constant. Protein S assay was within normal limits and protein C was decreased. Antithrombin III level and APCR could not be determined at this stage due to heparin therapy. At 38 weeks she developed a fever of unknown origin and labour was induced at term. She was eventually delivered by caesarean section due to poor progress of labour. A healthy baby boy of 3189 g was delivered with good Apgar scores. Heparin was withdrawn postpartum when satisfactory anti-coagulation with warfarin was achieved. Warfarin was continued for 3 months postpartum and she had an uneventful peurperium. Antithrombin III level was normal 6 weeks after delivery. Genetic analysis confirmed the presence of a FV Leiden mutation.
3. Discussion This is the first confirmed case of a Factor V Leiden mutation in our unit and this case highlights the difficulties and potential complications of management of a patient with this condition. The heparin resistance can be due to the increase in FVIII level commonly found during preg-
nancy. There is also an acquired APCR during pregnancy. These factors could act as additional risk factors for the development of thrombosis in patients with hereditary thrombophilia. Activated protein C resistance due to the factor V Leiden mutation is the most common inherited risk factor for thrombo-embolic disease during pregnancy and for patients on oral contraceptive use [3]. It is unsure whether screening of the general population is justified, but genetic testing on this individual patient’s offspring and immediate family would be advisable. For her next pregnancy she was advised to attend a pre-conception clinic and to receive subcutaneous heparin therapy through the pregnancy. The prevalence of factor V Leiden among South African population groups should be addressed in a future study. This should also be of particular value in South Africa, with its high incidence of pre-eclampsia and intra-uterine growth retardation, as activated protein C resistance was found to be significantly higher among these groups of patients [4].
References [1] Bertina RM, Koeleman BPC, Koster T et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–6. [2] Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 1997;127((10)):895–903. [3] Hallak M, Senderowicz J, Cassel A et al. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obstet Gynecol 1997;176((4)):889–93. [4] Kupferminc MJ, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. New Engl J Med 1999;340:9–13.