A Rare Case of Hereditary Antithrombin III Deficiency with Recurrent Thrombosis in Pregnancy: Challenges in Management and Review of Literature

Pregnancy is associated with a hypercoagulable state due to increased levels of procoagulant factors, decreased natural anticoagulants, and impaired fibrinolysis. While these physiological adaptations help minimize hemorrhage during childbirth, they also predispose women to thrombotic complications. Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), remains a leading cause of maternal morbidity and mortality.

Hereditary thrombophilias, including ATIII deficiency, significantly heighten the risk of thromboembolic events. Antithrombin III is a natural anticoagulant that inactivates thrombin and factors Xa and IXa. Its deficiency, either quantitative or qualitative, is a rare but severe thrombophilia, affecting 0.02–0.2% of the population. During pregnancy, women with ATIII deficiency have a 10–20 times higher risk of thrombosis compared to the general population. This case illustrates the challenges of managing ATIII deficiency during pregnancy and highlights the role of multidisciplinary care in achieving favorable outcomes.

A 32-year-old primigravida presented for her booking visit at 8 weeks of gestation. She was a known case of hereditary ATIII deficiency diagnosed after experiencing mesenteric vein thrombosis six years prior, which required jejunal resection and anastomosis. She also had a history of deep vein thrombosis (DVT) in her right leg while on Warfarin therapy, prompting a switch to Rivaroxaban for long-term anticoagulation. Upon confirmation of her pregnancy, Rivaroxaban was discontinued due to its teratogenic potential. The patient was started on low-dose aspirin (75 mg daily) and prophylactic low molecular weight heparin (LMWH) (40 mg once daily). Antithrombin activity at the time was 42% (reference range >80%), confirming ongoing deficiency. At 10 weeks of gestation, the patient presented with left leg swelling and pain. Doppler ultrasonography confirmed acute DVT and associated superficial thrombophlebitis. LMWH was escalated to therapeutic doses (1 mg/kg twice daily). Despite therapeutic anticoagulation, the patient remained at high risk for further thrombotic events due to persistently low antithrombin levels and the hypercoagulable state of pregnancy.

At 19 weeks of gestation, the patient experienced sudden-onset severe headache and generalized tonic-clonic seizures. Neurological evaluation and imaging revealed acute superior sagittal sinus thrombosis (SSST) with associated venous infarction in the left frontal cortex. The infarct had hemorrhagic transformation, precluding the use of thrombolytic therapy. Therapeutic anticoagulation with LMWH was continued, and the patient was closely monitored in a multidisciplinary setting involving neurologists, hematologists, intensivists, and obstetricians. During the second trimester, the patient was also diagnosed with gestational diabetes, which was managed with oral hypoglycemics. Despite these complications, her pregnancy progressed without further thrombotic events. At 37 weeks of gestation, the patient was admitted for induction of labor. She delivered a live male infant weighing 2720 grams via vaginal delivery. Postpartum, she was continued on therapeutic LMWH for six weeks to mitigate the heightened risk of thrombotic events during the puerperium. Subsequently, she was transitioned back to Rivaroxaban for long-term anticoagulation.

Pathophysiology of Antithrombin III Deficiency

Antithrombin III is a serine protease inhibitor that regulates coagulation by inactivating thrombin and factors Xa and IXa. Inherited ATIII deficiency is an autosomal dominant disorder caused by mutations in the SERPINC1 gene. The condition can be quantitative (type I) or qualitative (type II), with both forms leading to a hypercoagulable state. The physiological changes of pregnancy, including increased levels of coagulation factors and decreased antithrombin activity, exacerbate the risk of thrombosis in affected individuals.

Thrombotic Risks in Pregnancy

Pregnancy increases the risk of VTE fivefold, and this risk is further amplified in women with ATIII deficiency. Studies have shown that approximately 50–70% of pregnancies in women with ATIII deficiency are complicated by thrombotic events. Thrombosis can occur at unusual sites, as seen in this case with superior sagittal sinus thrombosis. Other complications include recurrent pregnancy loss, preeclampsia, fetal growth restriction, and stillbirth.

Management Strategies

Managing ATIII deficiency during pregnancy requires a multidisciplinary approach, with the goals of preventing thrombotic events and optimizing maternal and fetal outcomes. Key strategies include:

Anticoagulation Therapy

LMWH is the cornerstone of anticoagulation in pregnancy due to its safety profile and efficacy. Prophylactic or therapeutic doses are determined based on thrombotic history and antithrombin levels. Postpartum anticoagulation is essential due to the heightened risk of thrombotic events during the puerperium.

Adjunctive Therapies

Antithrombin concentrates may be required in cases of severe deficiency or recurrent thrombosis despite anticoagulation. These concentrates can be administered during high-risk periods, such as delivery.

Monitoring

Close monitoring of antithrombin activity, coagulation parameters, and clinical signs of thrombosis is crucial. Doppler studies are used to assess for DVT, while imaging is essential for evaluating cerebral or visceral thrombosis.

Multidisciplinary Care

Collaboration among obstetricians, hematologists, neurologists, and intensivists is critical, particularly in managing complex cases with multiple complications.

The prevalence of ATIII deficiency in the general population is low; however, its association with pregnancy complications is well-documented. A systematic review by Pabinger et al. (2010) highlighted the high incidence of VTE in pregnant women with ATIII deficiency, emphasizing the need for prophylactic anticoagulation. Similarly, studies by Brenner and Kuperman (2005) have demonstrated the efficacy of LMWH in preventing thrombotic events in this population. Recent guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetricians and Gynaecologists (RCOG) recommend risk-based thromboprophylaxis in women with hereditary thrombophilias. The use of antithrombin concentrates during delivery has been supported in severe cases to reduce maternal morbidity.

Prognosis

With appropriate management, the prognosis for both mother and fetus is favorable. However, the risk of recurrence remains high, necessitating long-term anticoagulation.

Antithrombin III deficiency is a rare but serious thrombophilia that poses significant challenges during pregnancy. This case highlights the importance of individualized anticoagulation therapy, vigilant monitoring, and a multidisciplinary approach in managing such high-risk pregnancies. Early diagnosis and adherence to evidence-based guidelines are critical in achieving successful maternal and fetal outcomes.