Homozygous Antithrombin Deficient Type II (99Leu to Phe mutation): Description of a Successful Outcome during Pregnancy
Authors: Novas C. Muñoz , Pascual C. , Sanchez J. , Rodriguez A. , Pérez G. , Kwon M. , Gomez-Pineda A. , Corral J. , Diez-Martín J. 
Published: April 2020

INTRODUCTION: inherited antithrombin (AT) deficiency is the thrombophilia with the highest incidence of thrombotic events (TE). Homozygous AT deficiency is extremely rare. A variant of Budapest 3 (99Leu to Phe mutation) a subtype (type II deficiency), it is a defect at the heparin-binding site and carries an increased risk of severe venous and arterial thromboembolism from an early age. AT deficiency is also associated with a higher risk of adverse outcome during pregnancy (fetal loss, preeclampsia, intrauterine growth restriction) and its the mechanism is unclear. We describe the second case of a successful pregnancy in a woman who was homozygous for AT deficiency.

PATIENT: A 32-year-old woman developed a spontaneous deep vein thrombosis in both femoral arteries, the iliac artery and inferior vena cava, at the age of 27 years. A severe AT deficiency was detected due to AT activity of 20% (normal 80–120%). The patient was put on long-term oral anticoagulation (OAC) with vitamin-K antagonists. Molecular analysis revealed homozygous for the 99Leu to Phe mutation, which was compatible with a type II defect at the heparin-binding site and, consequently, reduced affinity for heparin. When the patient was diagnosed to be pregnant in the 5th week of gestation, OAC was stopped due to the risk of embriopathy, low molecular weight heparin (LMWH) (enoxaparin) 1mg/kg/12h was started and 2,000 U per week of AT concentrates was administered. Anti-Xa activity was below the detection limit at all time and the AT level was below 40%. Therefore, the dose of enoxaparin was increased to 1.7mg/kg/12h without reaching anti-Xa therapeutic levels, despite a switch to others LMWH. The patient was hospitalized at week 12 of gestation to monitor anticoagulation and AT levels; 3,000 U/48h of AT concentrates was administered and AT levels of over 50% were achieved. Intravenous heparin (IH) was started and an acceptable anticoagulation range was reached. In the 14th week of gestation, OAC was introduced and LMWH and AT replacement were discontinued after an international normalized ratio (INR) of 2 to 3 had been reached. Around week 36, the patient was hospitalized to prepare for the birth, the dose of AT concentrate was increased to 3,000 U/d, and OAC was stopped and replaced by IH. Caesarean section was performed at week 38 with a successful outcome; the patient gave birth to a perfectly healthy boy, weighins 2,460g (Apgar score 8/9), and tubal ligation was performed at the patient’s request. On the 3rd day postpartum, OAC treatment was started. Therapeutic INR was reached on day 10, when AT replacement and IH were discontinued, and the patient and her baby were discharged in good health. Checkups during puerperium did not reveal evidence of acute thrombosis.

CONCLUSIONS: There have only been six reports of homozygous AT deficiency (99Leu to Phe mutation) that led to severe, and in some cases, fatal TE during childhood. Interestingly, our patient developed TE in early adulthood. There have only been two reports (including the present case) of a successful pregnancy in patients with this deficiency. Only heparin is ineffective as an anticoagulant therapy and an AT replacement is needed. An efficient anticoagulant therapy with OAC during pregnancy has a positive impact on intrauterine growth and fetal outcome.