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Protein S deficiency in pregnancy: A case report
Protein S deficiency in pregnancy: A case report Tessie Tharakan, MD, Laxmi V. Baxi, MD, and David Diuguid, MD New York, New York Protein S deficiency is uncommon, may cause recurrent thrombosis, and may complicate pregnancy. A patient with protein S deficiency presented with a stillbirth followed by postpartum pulmonary embolism. She then had a successful pregnancy managed by anticoagulation and close fetal monitoring. (AM J OasTET GVNECOL 1993;168:141-2.)
Key words: Protein S deficiency, pregnancy, stillbirth, thrombosis
Thromboembolism is an important complication of pregnancy, and pulmonary embolism is a leading cause of maternal death. Pregnancy is a hypercoagulable state because of increased coagulation factors, venous stasis, and release of tissue thromboplastins. Normally, the plasma anticoagulant system of protein S, protein C, and antithrombin III counters this tendency, but in congenital or acquired deficiencies this protection is lost. Protein S deficiency may be a cause of stillbirth, as a result of a hypercoagulable state associated with thrombosis of major vessels. We present a case of a patient with such a history, who was successfully treated in her next pregnancy. Case report A 41-year-old woman, gravida 3, para 2, was seen for prepregnancy consultation. She had one term normal delivery and an early spontaneous abortion. Her last pregnancy ended in an intrauterine death at 34 weeks' gestation complicated by a postpartum pulmonary embolism for which she received long-term warfarin therapy. The autopsy examination of the fetus was nonsignificant and placental examination revealed intravascular thrombosis. Intrauterine fetal death was possibly attributable to protein S deficiency, because she had a low level of free protein S (17%, normal value 20% to 40%). Other significant medical history in this patient included the presence of ulcerative colitis, which was being treated with sulfasalazine. The patient was next seen for her antepartum checkup at 13 weeks' gestation. At that time her free protein S level was 44%. The subsequent level of functional protein S at 20 weeks of gestation was 61 % (normal 65% to 140%). (Functional protein S was mea-
From the Department of Obstetncs and Gynecology, College of Physicians and Surgeons, Columbia University, and Sloane Hospital for Women at Columbia PresiJyterian Med!cal Center. Recezved for publicatIOn July 14, 1992; accepted July 22, 1992. Reprint requests: Laxml V. Baxl, MD, Department of Obstetrics and Gynecology, Columbia PresiJyteTUIn Medical Center, 622 West 168th St., New York, NY 10032. 6/1/41195 0002-9378/93 $1.00
+ 0.20
sured in our institution by the coagulation method. Free protein S was measured by the Laurell rocket immunoelectrophoresis technique.) Her pregnancy was uneventful with normal fetal karyotype and appropriate fetal growth. In view of repeated episodes of rectal bleeding caused by ulcerative colitis, she was treated with cortisone enemas. The protein S level at 30 weeks was 10%. She was started on a regimen of heparin, which was titrated to keep the activated partial thromboplastin time (APTf) within one and a half times normal levels. At a gestation of 31 weeks 5 days, the patient presented with decreased fetal movement. The nons tress test was reactive with severe variable and repeated late decelerations. A primary cesarean section was performed, and a female infant, weighing 1440 gm with Apgar scores of 5, 6, and 8, was delivered. The patient had received 9000 units of heparin 3 hours before the cesarean section, and APTf was normal. Fresh-frozen plasma was available but no replacement therapy was required. At delivery, the maternal functional protein S level was 55% (normal 65% to 140%) and the free protein S level was 17% (normal 20% to 40%). Cord blood had a functional protein S value of 37% and a free protein S value of 12%. Heparin was administered postoperatively to keep APTf within one and a half times normal levels. Subsequently, she received warfarin therapy. The infant did well and was discharged home at the age of 14 days. Placental pathologic examination revealed no evidence of thrombosis. Comment Protein S is a vitamin K-dependent, naturally occurring inhibitor of hemostasis. It is a cofactor for protein C in the neutralization of activated factor V and in fibrinolysis. It is synthesized and released from the endothelium. Congenital deficiency is known to occur, as are acquired deficiencies, which may result from decreased production caused by chronic liver disease or increased consumption, as in disseminated intravascular coagulation. About 40% of protein S is in the free, active form, whereas the remainder is bound to C4b binding protein, an inhibitor of the complement system, and is 141
142 Tharakan, Baxi, and Diuguid
inactive. A decrease in total and free protein S is seen in pregnancy and the postpartum period. The free protein S level was reported to fall significantly and progressively during pregnancy although in only one third of patients did the level fall below the normal range. I Protein S is an inhibitor of hemostasis, and its deficiency leads to recurrent venous thrombosis. Rose et al. 2 reported a case of pregnancy complicated by this condition, which was managed with prophylactic heparin therapy and elective pregnancy termination. Thrombosis in the placental vessels could result in stillbirth, but a review of the literature revealed no previous reports of this complication resulting from protein S deficiency.
January 1993 Am J Obstet Gynecol
In summary, protein S deficiency is an interesting but uncommon disorder. Stillbirth caused by this disorder has not been previously reported. We present such a case, successfully managed in the patient's next pregnancy, and suggest heparin anticoagulation and close monitoring for these patients. REFERENCES 1. Warwick R, Hutton RA, Goff L, Letsky E, Heard M. Changes in protein C and free protein S during pregnancy and following hysterectomy. J R Soc Med 1989;82:591. 2. Rose PG, Essy GF, Vaccaro PS, Brandt JT. Protein S deficiency in pregnancy. AM J OBSTET GYNECOL 1986;155:140.
Key words: Protein S deficiency, pregnancy, stillbirth, thrombosis
Thromboembolism is an important complication of pregnancy, and pulmonary embolism is a leading cause of maternal death. Pregnancy is a hypercoagulable state because of increased coagulation factors, venous stasis, and release of tissue thromboplastins. Normally, the plasma anticoagulant system of protein S, protein C, and antithrombin III counters this tendency, but in congenital or acquired deficiencies this protection is lost. Protein S deficiency may be a cause of stillbirth, as a result of a hypercoagulable state associated with thrombosis of major vessels. We present a case of a patient with such a history, who was successfully treated in her next pregnancy. Case report A 41-year-old woman, gravida 3, para 2, was seen for prepregnancy consultation. She had one term normal delivery and an early spontaneous abortion. Her last pregnancy ended in an intrauterine death at 34 weeks' gestation complicated by a postpartum pulmonary embolism for which she received long-term warfarin therapy. The autopsy examination of the fetus was nonsignificant and placental examination revealed intravascular thrombosis. Intrauterine fetal death was possibly attributable to protein S deficiency, because she had a low level of free protein S (17%, normal value 20% to 40%). Other significant medical history in this patient included the presence of ulcerative colitis, which was being treated with sulfasalazine. The patient was next seen for her antepartum checkup at 13 weeks' gestation. At that time her free protein S level was 44%. The subsequent level of functional protein S at 20 weeks of gestation was 61 % (normal 65% to 140%). (Functional protein S was mea-
From the Department of Obstetncs and Gynecology, College of Physicians and Surgeons, Columbia University, and Sloane Hospital for Women at Columbia PresiJyterian Med!cal Center. Recezved for publicatIOn July 14, 1992; accepted July 22, 1992. Reprint requests: Laxml V. Baxl, MD, Department of Obstetrics and Gynecology, Columbia PresiJyteTUIn Medical Center, 622 West 168th St., New York, NY 10032. 6/1/41195 0002-9378/93 $1.00
+ 0.20
sured in our institution by the coagulation method. Free protein S was measured by the Laurell rocket immunoelectrophoresis technique.) Her pregnancy was uneventful with normal fetal karyotype and appropriate fetal growth. In view of repeated episodes of rectal bleeding caused by ulcerative colitis, she was treated with cortisone enemas. The protein S level at 30 weeks was 10%. She was started on a regimen of heparin, which was titrated to keep the activated partial thromboplastin time (APTf) within one and a half times normal levels. At a gestation of 31 weeks 5 days, the patient presented with decreased fetal movement. The nons tress test was reactive with severe variable and repeated late decelerations. A primary cesarean section was performed, and a female infant, weighing 1440 gm with Apgar scores of 5, 6, and 8, was delivered. The patient had received 9000 units of heparin 3 hours before the cesarean section, and APTf was normal. Fresh-frozen plasma was available but no replacement therapy was required. At delivery, the maternal functional protein S level was 55% (normal 65% to 140%) and the free protein S level was 17% (normal 20% to 40%). Cord blood had a functional protein S value of 37% and a free protein S value of 12%. Heparin was administered postoperatively to keep APTf within one and a half times normal levels. Subsequently, she received warfarin therapy. The infant did well and was discharged home at the age of 14 days. Placental pathologic examination revealed no evidence of thrombosis. Comment Protein S is a vitamin K-dependent, naturally occurring inhibitor of hemostasis. It is a cofactor for protein C in the neutralization of activated factor V and in fibrinolysis. It is synthesized and released from the endothelium. Congenital deficiency is known to occur, as are acquired deficiencies, which may result from decreased production caused by chronic liver disease or increased consumption, as in disseminated intravascular coagulation. About 40% of protein S is in the free, active form, whereas the remainder is bound to C4b binding protein, an inhibitor of the complement system, and is 141
142 Tharakan, Baxi, and Diuguid
inactive. A decrease in total and free protein S is seen in pregnancy and the postpartum period. The free protein S level was reported to fall significantly and progressively during pregnancy although in only one third of patients did the level fall below the normal range. I Protein S is an inhibitor of hemostasis, and its deficiency leads to recurrent venous thrombosis. Rose et al. 2 reported a case of pregnancy complicated by this condition, which was managed with prophylactic heparin therapy and elective pregnancy termination. Thrombosis in the placental vessels could result in stillbirth, but a review of the literature revealed no previous reports of this complication resulting from protein S deficiency.
January 1993 Am J Obstet Gynecol
In summary, protein S deficiency is an interesting but uncommon disorder. Stillbirth caused by this disorder has not been previously reported. We present such a case, successfully managed in the patient's next pregnancy, and suggest heparin anticoagulation and close monitoring for these patients. REFERENCES 1. Warwick R, Hutton RA, Goff L, Letsky E, Heard M. Changes in protein C and free protein S during pregnancy and following hysterectomy. J R Soc Med 1989;82:591. 2. Rose PG, Essy GF, Vaccaro PS, Brandt JT. Protein S deficiency in pregnancy. AM J OBSTET GYNECOL 1986;155:140.