Kalappa SB*, Shende D**, Chauhan AR***.
(*Second Year Resident, ** Assistant Professor, *** Professor, Department of Obstetrics and Gynecology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai India.)
Thrombophilias refer to inherited or acquired deficiencies of one or more inhibitory proteins of the coagulation cascade which can lead to hypercoagulabilty and recurrent venous thromboembolism. Normal pregnancy itself increases the thrombogenic potential of inherited disorders as it is associated with increased stasis and alterations in the levels of various coagulation factors that promote thrombosis. These combined thrombophilias complicating pregnancy frequently pose a challenge to obstetricians. Here we present a case of inherited antithrombin III and protein S deficiency in a pregnant patient, associated with various maternal and fetal complications, managed successfully through a multi-disciplinary approach.
Antithrombin III is an important inhibitor of thrombin in clot formation. Protein S is a natural circulating anticoagulant, which is activated by protein C and inactivates factors Va and VIIIa of the coagulation cascade. The prevalence of antithrombin III deficiency is estimated to be 1 in 2000 to 5000 individuals and the prevalence of protein S deficiency is 2 per 1000. More than 100 autosomal dominant mutations can lead to the deficiency of either of these factors. Inherited thrombophilias have been linked with various pregnancy complications such as recurrent pregnancy loss, preeclampsia, placental abruption and fetal growth restriction.
A 30 year old gravida 4, para 3, with no living issue, 26 weeks of gestation, a known case of antithrombin III and protein S deficiency, was referred from hematologist in view of bad obstetric history and recently diagnosed preeclampsia for obstetric management. Her first pregnancy had resulted in an intrauterine fetal death at seven months of gestation with abruptio placentae. This was followed by a second intrauterine fetal death at 6 months of gestation, with intrauterine growth restriction and oligohydramnios. Her third pregnancy resulted in a term still birth with abruptio placentae. Inherited thrombophilia was diagnosed four years ago during the course of her evaluation for bad obstetric history; she was not on any medication for the same.
She was admitted in the antenatal ward. On examination, her general condition was fair, her pulse was 86 beats /minute, and blood pressure was in the range of 150/ 90 to 160/ 100 mm Hg. No abnormalities were detected in the respiratory and cardiovascular systems. Grade 3 pitting edema was present in both lower limbs. Abdominal wall edema and facial puffiness was also present. On per abdominal examination, uterus size corresponded to 26 weeks of gestation and fetal heart sounds were regular. On per vaginal examination the cervical os was closed and uneffaced.
She was thoroughly investigated: her routine biochemical, hematological and serological investigations including hemoglobin, platelet count, lipid profile and serum electrolytes were normal. Prothrombin time was 10.3 (control 9.9), international normalized ratio (INR) was 1.04 and partial thromboplastin time was 33.1 (control 28.0); all in the normal range. Her serum TSH had previously not been done and was elevated. It was 6.27 µIU/ ml. Alkaline phosphatase was also raised to 255.30 IU/L (normal range 15 - 112 IU/L) while rest of the liver function tests were normal. Renal function tests were deranged with serum uric acid 7.5 mg % (normal range 2.4 – 4.9 mg %); blood urea nitrogen 20 mg % (normal range 3 – 13 mg %) and serum creatinine was 1.4 mg % (normal range 0.4 – 0.8 mg %). Her 24 hours urine protein was also high at 2860 mg/ day (normal range 47 – 186 mg/ day). Renal ultrasound was normal. Her urine culture showed insignificant bacteruria.
Anti nuclear antibody, double stranded DNA antibody, anti cardiolipin antibody and anti phospholipid antibody tests were negative. Lupus anticoagulant was absent. Her antithrombin III levels were 10 % (normal range 70 – 130 %), protein S was 94 % (normal range 70- 140 %) and protein S activity was 4 % (normal range 65 – 140 %).
She was started on low molecular weight heparin (enoxaparin) 0.6 ml subcutaneously twice a day along with tablet aspirin 150 mg daily when the pregnancy was diagnosed. Preeclampsia was detected at 26 weeks of gestation and she was started on antihypertensives; tablet labetalol 200 mg twice daily, tablet alpha methyldopa 500 mg four times a day and capsule nifedipine 10 mg four times a day were added to control the progressively increasing blood pressure. Routine examination of the fundus revealed no evidence of papilledema. Hypothyroidism detected during routine evaluation was treated with tablet thyroxine 25 µg daily. 2D echocardiography was done as patient complained of breathlessness; it revealed moderate mitral regurgitation secondary to minor chordal rupture. Hence, patient was started on tablet digoxin 0.25 mg daily and tablet furesemide 40 mg twice daily as per cardiologist’s advice.
Hematology, nephrology, cardiology and ophthalmology consultants were involved periodically for comprehensive management of all pregnancy related complications. Fetal well being was monitored by bi-weekly non stress test and weekly obstetric Doppler studies. Two doses of injection betamethasone 12 mg were given intramuscularly 24 hours apart at 28 weeks of gestation. Obstetric Doppler revealed severe utero-placental and feto-placental insufficiency which progressed to absent diastolic flow in the umbilical artery followed by reversal of flow in the umbilical artery at 29 weeks of gestation. In consultation with neonatologist, decision to terminate the pregnancy was taken and emergency lower segment cesarean section was done. Outcome was a female baby with birth weight of 720 grams and an Apgar score of 4/10 and 9/10 at 1 and 5 minutes respectively. Baby was intubated and shifted to the neonatal intensive care unit where it was intensively managed for three months and discharged. The patient was monitored in the intensive care unit in the immediate post operative period. Injection low molecular weight heparin was continued for the entire puerperal period. All other medications were tapered or changed to meet post partum requirements and patient was discharged on day 10 post operatively.
Numerous pregnancy related complications have been linked with various thrombophilias, both acquired and inherited. Pregnancy associated changes in various coagulation factors that increase the risk of thrombogenic events are: a) increased resistance to activated protein C from the second trimester b) decreased protein S activity c) increase in fibrinogen and factors II, VII, VIII, X d) levels and activity of some fibrinolytic inhibitors like thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 increase. In particular, antithrombin III deficiency has been associated with increased risk of early pregnancy loss, preeclampsia and placental abruption, while protein S deficiency is more likely to cause late pregnancy loss.
Pathological changes in the placental vasculature have been suspected to be one of the main causes of pregnancy related complications in patients with thrombophilias. These changes are characterized by superficial invasion of cytotrophoblast in the myometrial spiral arteries, acute atherosis and thrombi in the spiral arteries and the inter-villous space. The thrombotic nature of these lesions and the increased thrombotic risk associated with thrombophilias suggests a direct cause-and-effect relationship between inherited thrombophilias and the above mentioned severe obstetric complications.
A recently conducted meta-analysis has suggested that severe preeclampsia is associated with thrombophilias, mainly Factor V Leiden mutation, deficiencies of antithrombin III, protein C and protein S and hyperhomocysteinemia.
There is circumstantial eveidence that treatment with low molecular weight heparin may improve the pregnancy outcome in patients with inherited thrombophilias. But, the use of anticoagulant therapy in pregnancy is challenging in view of the potential fetal and maternal complications. In asymptomatic women who have never experienced an episode of venous thromboembolism, the recommendation is either clinical surveillance or prophylactic therapy during the third trimester of pregnancy and for two to six weeks postpartum. Either unfractionated heparin 5000 IU twice daily or a low molecular weight heparin 40 mg once daily is used. In women with antithrombin III deficiency, this therapy is probably indicated throughout pregnancy in view of the substantially greater risk associated with the condition.
There is insufficient evidence to draw any conclusions regarding the strength of association between inherited thrombophilia and adverse pregnancy outcomes. The guidelines for the prophylaxis and treatment of these conditions with anticoagulants are also in need of large scale randomized controlled trials to confirm the advantage and risk reduction for pregnancy complications. The best strategy at present is to conduct individual based risk assessment and provide treatment with a multi-disciplinary approach for successful pregnancy outcomes.
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Kalappa SB, Shende D, Chauhan AR. Inherited Thrombophilia In Pregnancy: Management And Outcome. JPGO 2017. Volume 4 No. 2. Available from: http://www.jpgo.org/2017/02/inherited-thrombophilia-in-pregnancy.html