Pregnancy loss and thrombosis with protein C deficiency Jennifer J. Trauscht-Van Horn, MD, Eleanor L. Capeless, MD, Thomas R. Easterling, MD, and Edwin G. Bovill, MD Seattle, Washington, and Burlington, Vermont OBJECTIVES: Protein C inhibits coagulation and promotes fibrinolysis. This study investigates the association between protein C deficiency and pregnancy loss, thrombosis in pregnancy, and thrombosis with oral contraception. STUDY DESIGN: Fifteen protein C-deficient patients and 37 controls from a single kindred were studied. An obstetric history was obtained by telephone. Data were analyzed by logistic regression, Fisher's exact test, and Student t test. RESULTS: Protein C-deficient women experienced a 33% pregnancy loss versus 19% in the controls (not significant). Thromboembolism during pregnancy in protein C-deficient women was 33% (45% in those not receiving prophylactic anticoagulation) versus 5% in controls (odds ratio 7.37, p = 0.026). Five of 12 protein C-deficient women using oral contraception developed thrombosis versus 0 of 33 controls. The risk of thrombosis for protein C-deficient women using oral contraception is increased (p < 0.001). CONCLUSIONS: Perinatal outcome is not statistically different with protein C deficiency. Protein C deficiency increases the risk of thrombosis during pregnancy and with oral contraception. Prophylactic heparin is suggested during pregnancy for protein C-deficient women with personal or family histories of thrombosis. Oral contraception is not advised. (AM J OasTET GVNECOL 1992;167:968-72.)
Key words: Protein deficiency, pregnancy, thrombosis, oral contraception, fetal loss
Protein C, a vitamin K-dependent plasma protein, circulates in the plasma as an inactive zymogen. It is activated by thrombin when bound to thrombomodulin, an endothelial membrane bound cofactor. I. 2 Protein C inhibits thrombosis through two mechanisms. It functions as an anticoagulant by degrading the active forms of V and VIII. Protein S, a vitamin K-dependent cofactor, aids in this inactivation.'·6 It also promotes fibrinolysis through the inhibition of tissue plasminogen activator inhibitor. 7•9 Protein C deficiency, inherited in an autosomal dominant pattern with variable expressivity, is associated with several clinical syndromes. The most common is thromboembolic disease. The increased risk of thrombosis has been well documented. 10·13 Coumarin-induced hemorrhagic skin necrosis has been described in heterozygotes. 14 Purpura fulminans occurs in infants homozygous for the gene. 15. 16 The effects of protein C deficiency in pregnancy are unknown. This study investigates the question of increased pregnancy loss in protein C-deficient women. It also examines thrombosis during pregnancy and oral contraception. We hypothesize that protein C defiFrom the Department of Obstetrics and Gynecology, University of Washington, and the Departments of Obstetrics and Gynecology and Pathology, University of Vermont College of Medicine. Presented at the Twelfth Annual Meeting of Society of Perinatal Obstetricians, Orlando, Florida, February 3-8, 1992. Reprint requests: Edwin G. Bovill, MD, Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405.
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ciency is associated with an increased risk of fetal loss and thrombosis during pregnancy and with oral contraception.
Material and methods The subjects for this investigation were drawn from a single New England kindred (n = 411) (Fig. 1).10 Of these, 184 members had previously been described in a thrombosis study at the Specialized Center of Research in Thrombosis, University of Vermont College of Medicine.1O In this group there were 114 living women. Eighty-five were of childbearing age (> 16 years). We were able to contact 75 of these women. Fifty-three had been pregnant. All 53 agreed to participate. One subject was excluded because she also had a lupus anticoagulant. Of the remaining 52, 15 were protein C deficient, and 37 were nondeficient controls. Protein C antigen levels were measured with murine monoclonal antibody HPC-2. 10 Protein C deficiency was defined as protein C antigen levels
Key words: Protein deficiency, pregnancy, thrombosis, oral contraception, fetal loss
Protein C, a vitamin K-dependent plasma protein, circulates in the plasma as an inactive zymogen. It is activated by thrombin when bound to thrombomodulin, an endothelial membrane bound cofactor. I. 2 Protein C inhibits thrombosis through two mechanisms. It functions as an anticoagulant by degrading the active forms of V and VIII. Protein S, a vitamin K-dependent cofactor, aids in this inactivation.'·6 It also promotes fibrinolysis through the inhibition of tissue plasminogen activator inhibitor. 7•9 Protein C deficiency, inherited in an autosomal dominant pattern with variable expressivity, is associated with several clinical syndromes. The most common is thromboembolic disease. The increased risk of thrombosis has been well documented. 10·13 Coumarin-induced hemorrhagic skin necrosis has been described in heterozygotes. 14 Purpura fulminans occurs in infants homozygous for the gene. 15. 16 The effects of protein C deficiency in pregnancy are unknown. This study investigates the question of increased pregnancy loss in protein C-deficient women. It also examines thrombosis during pregnancy and oral contraception. We hypothesize that protein C defiFrom the Department of Obstetrics and Gynecology, University of Washington, and the Departments of Obstetrics and Gynecology and Pathology, University of Vermont College of Medicine. Presented at the Twelfth Annual Meeting of Society of Perinatal Obstetricians, Orlando, Florida, February 3-8, 1992. Reprint requests: Edwin G. Bovill, MD, Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405.
616139604
ciency is associated with an increased risk of fetal loss and thrombosis during pregnancy and with oral contraception.
Material and methods The subjects for this investigation were drawn from a single New England kindred (n = 411) (Fig. 1).10 Of these, 184 members had previously been described in a thrombosis study at the Specialized Center of Research in Thrombosis, University of Vermont College of Medicine.1O In this group there were 114 living women. Eighty-five were of childbearing age (> 16 years). We were able to contact 75 of these women. Fifty-three had been pregnant. All 53 agreed to participate. One subject was excluded because she also had a lupus anticoagulant. Of the remaining 52, 15 were protein C deficient, and 37 were nondeficient controls. Protein C antigen levels were measured with murine monoclonal antibody HPC-2. 10 Protein C deficiency was defined as protein C antigen levels
