Antiphospholipid antibodies and antithrombin deficiency: Double trouble for pregnancy
Authors: Jody Kujovich, Patrick A. Merrill
Journal: American Journal of Hematology (2011)

A 30-year-old G3P1 woman with a history of deep vein thrombosis (DVT) and recurrent pregnancy loss presented for hematology consultation in 2005. She developed a right lower extremity DVT at 13 weeks gestation during her first pregnancy in 2002, treated with enoxaparin. At 19 weeks, an obstetric ultrasound revealed a fetal demise. After a brief interruption of anticoagulation for a D&C, she developed new right leg thrombosis. A thrombophilia evaluation in 2002 included IgM anticardiolipin antibody (ACA) 64, IgG 27 (normal < 10 phospholipid [PL] units for both), normal protein C (133%) and protein S (115%) activity, and negative genetic testing for factor V Leiden. She completed a 6-month course of warfarin. Her antithrombin (AT) activity was 60% (normal 86–118%) 1 month after starting warfarin. She received enoxaparin and sporadic low-dose aspirin during her second pregnancy in 2003. Fetal growth restriction (FGR) was noted at 20 weeks. At 22 weeks, she was hospitalized with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome requiring delivery of a nonviable neonate. Additional testing revealed a strong lupus anticoagulant (LA), mildly elevated IgG and IgM ACA, and negative prothrombin 20210G>A mutation. Placental pathology showed numerous small gross and microscopic infarcts. She received a 6-week course of postpartum anticoagulation. Her third pregnancy in 2004 ended in a miscarriage at 8 weeks, 1 month after initiation of therapeutic-dose enoxaparin (1 mg/kg bid) and low-dose aspirin. A successful pregnancy requires the development and maintenance of an adequate placental circulation. Placental-mediated pregnancy complications including recurrent fetal loss, preeclampsia, and FGR each occur in 1–5% of pregnant women. A total of 1% of women experience three or more consecutive fetal losses [1]. Hematologists are frequently consulted by women with these complications, many of whom have already undergone thrombophilia testing. Her evaluation in 2005 showed: IgG ACA 44, IgM 111, IgM beta2glycoprotein1 (B2GP1) antibody 30 (normal < 20 PL units for all 3), and a strong LA with multiple assays; LA-sensitive partial thromboplastin time (PTT) 84 sec (26–37 sec); hexagonal PL PTT 53 sec (< 8 sec); DVV confirm 1.9 (<1.4). AT activity was 60% (86–118%), AT antigen 60% (82–136%). Her liver function tests and urinalysis were normal. She provided a well-documented family history of AT deficiency. Her mother and brother had AT antigen and activity levels of 44–51%, and a history of recurrent DVT and pulmonary embolism. Repeat thrombophilia testing several months later showed similar antiphospholipid (APLA) and AT levels. She was diagnosed with AT deficiency and APLA syndrome and started on long-term warfarin. Recurrent fetal loss is a well-established complication of the APLA syndrome. Inherited thrombophilias are also linked to adverse pregnancy outcomes, although the evidence is less compelling. Pregnant women with AT deficiency had a high incidence of fetal loss and other complications in several studies [2, 3]. Deficient women had a twofold higher risk of first and second trimester loss and a fivefold higher risk of late third trimester loss than women without thrombophilia [4]. Consensus guidelines recommend screening women with unexplained recurrent pregnancy loss for APLA [5, 6]. Testing for inherited thrombophilia is controversial and not routinely recommended unless the results will affect management. In this case, testing was justified by the patient's personal and family history of thromboembolism. AT deficiency is the most severe inherited thrombophilia with a lifetime risk of venous thromboembolism (VTE) risk exceeding 50% and a particularly high risk during pregnancy and postpartum [7]. Compared to other coagulation proteins, the reference range of AT is narrow, typically between 80% and 120% (100% equals the amount of AT that is present in normal plasma, or one unit per ml of normal plasma). There are two major types of AT deficiencies inherited as autosomal dominant traits. Type 1 is a quantitative deficiency reflected by a proportional decrease in AT activity and antigen levels less than 70% of normal. Type II deficiencies result from production of a variant protein with reduced activity, but the antigen level may be normal [8]. This patient's repeatedly low AT antigen and activity levels coupled with her well documented family history is diagnostic of type I deficiency. Diagnosis of the APLA syndrome requires a history of arterial thromboembolism or VTE or unexplained pregnancy morbidity and laboratory evidence of persistent APLA [9]. The patient's obstetric and thrombotic history with persistent moderate and high APLA levels satisfies these diagnostic criteria. The risk of fetal loss is likely much higher in AT-deficient women with APLA, although no studies have evaluated this particular combination of disorders. She received therapeutic dose enoxaparin and low dose aspirin throughout her fourth pregnancy in 2005. At 32 weeks, she presented with pre-eclampsia and FGR. She underwent a cesarean section delivery of a small for gestational age daughter who did well. She resumed anticoagulation with warfarin after delivery. Testing 4 months postpartum confirmed persistent APLA. Consensus guidelines recommend heparin or low-molecular weight heparin (LMWH) and low-dose aspirin for pregnant women with APLA syndrome and recurrent fetal loss [5]. Several randomized trials showed an improved pregnancy outcome with heparin and aspirin compared with aspirin alone [5]. Although an equivalent benefit of LMWH has not been confirmed, it is used more commonly because of its convenience and other advantages. A meta-analysis concluded that the combination of aspirin and heparin or LMWH achieved a significantly higher live birth rate than aspirin alone [10]. The benefit of antithrombotic therapy in women with inherited thrombophilia and fetal loss is unproven and strongly debated [11]. AT-deficient women who received anticoagulation during pregnancy had a lower incidence of fetal loss in several nonrandomized studies [2, 3]. Current guidelines suggest antepartum and postpartum prophylaxis for AT-deficient women to prevent VTE [5]. Because of her thrombotic history and multiple thrombophilic disorders, this patient required therapeutic dose enoxaparin. She transitioned from warfarin to therapeutic dose enoxaparin and low dose aspirin prior to confirmation of her fifth pregnancy in 2008. Her second trimester AT activity was 46%, lower than the level during her previous pregnancy. During the second trimester, she required a 50 mg increase in her enoxaparin dose to maintain therapeutic anti-Xa levels (target range 0.6–1.0 units/ml) despite a weight gain of only 3.6 kg. Acquired causes of a low AT level include disseminated intravascular coagulation, acute thrombosis, major surgery, liver disease, and nephrotic syndrome. Full dose heparin can lower AT levels by up to 30% due to accelerated consumption [8]. Interestingly, AT levels are much less affected by LMWH [12]. Although AT activity usually does not decrease during normal pregnancy, occasionally it does, and levels may fall late in twin and triplet gestations [7, 13]. Acquired AT deficiency is reported in pre-eclampsia and HELLP and may precede the clinical manifestations by several weeks [14]. Our patient's AT level below her prior baseline may have been a harbinger of developing placental insufficiency. Adequate AT levels are required for the anticoagulant activity of LMWH. Heparins induce a conformational change in AT that accelerates its activity 1,000-fold. AT-deficient individuals may have resistance to heparins and require higher doses. This patient required a substantial increase in enoxaparin dose disproportionate to her weight. Although the clinical utility of anti-Xa levels is unproven, monitoring AT-deficient women during pregnancy may avoid subtherapeutic dosing. An ultrasound at 19 weeks showed mild FGR with a normal anatomic survey. By 23 weeks, she had severe FGR with estimated fetal weight less than 10th percentile. Her enoxaparin dose was increased to maintain an anti-Xa level in the high therapeutic range (0.9–1.0 units/ml). A 25-week ultrasound showed persistent severe FGR and poor interval growth. She was hospitalized at 26.5 weeks with back pain, hypertension, thrombocytopenia, elevated liver enzymes, and proteinuria consistent with recurrent HELLP syndrome. After a preoperative loading dose of plasma-derived AT concentrate (pdAT), she delivered a 475 g male neonate (<3rd percentile) by cesarean section. He was successfully resuscitated but succumbed to an acute abdominal catastrophe 48 days later. This patient developed the complications which define the obstetric APLA syndrome including recurrent miscarriage, late fetal loss, severe pre-eclampsia, and FGR requiring delivery before 34 weeks [9]. HELLP syndrome is also associated with both APLA and AT deficiency, often developing in the second trimester and progressing rapidly as in this case [15, 16]. The specific profile of APLA is predictive of thrombotic and obstetric risk. Women with triple positive tests for a LA, ACA, and B2GP1 antibodies have the highest risk for obstetric complications, especially late fetal loss [17, 18]. In one study, triple positive women had a 23-fold higher rate of fetal loss than those with ACA and B2GP1 antibodies alone [18]. Triple positivity is also associated with low birth weight and is a strong predictor of neonatal death [19]. In our patient's case, enoxaparin and aspirin did not prevent fetal loss or other complications of placental insufficiency. A subset of women with APLA have unsuccessful pregnancies while receiving thromboprophylaxis. Women with triple positive APLA have a significantly higher incidence of pregnancy complications despite standard treatment [17-19]. Prior thromboembolism, triple positive APLA, and failure of standard therapy are predictive of fetal loss. Our patient had all three risk factors, indicating a high likelihood of a poor outcome. Her unusual combination of hereditary AT deficiency and APLA syndrome is the likely cause of her pregnancy complications. In 2009, thrombophilia testing prior to her sixth pregnancy showed persistent moderate to high ACA and B2GP1 antibody levels, a strong lupus inhibitor and AT activity 60%. She transitioned from warfarin to therapeutic dose enoxaparin and low dose aspirin. During her first trimester, her enoxaparin dose was increased by 30 mg to maintain therapeutic anti-Xa levels (0.6–1.0 units/ml). At 14 weeks, she started pdAT replacement (50 mg/kg) and continued it three times a week (Monday, Wednesday, and Friday) until delivery. An upper extremity peripherally inserted central catheter was removed 24 hr after insertion because of basilic vein thrombophlebitis. She received all infusions through peripheral veins without further problems. Peak AT levels 30 min after infusion were between 170% and 190%. Because her trough AT level remained within the target range (86–113%), her dose (3,700–4,100 units rounded off to the nearest vial) was not increased with her weight (Fig. 1). She tolerated AT infusions well without bleeding or other adverse effects. Her enoxaparin dose was reduced by 30 mg during the first month of AT replacement because of anti-Xa levels greater than 1.0 units/ml (therapeutic range 0.60–1.0 units/ml) (Fig. 1). Effect of AT replacement on AT activity, enoxaparin dose, and anti-Xa levels between 14 and 24 weeks gestation. AT replacement was initiated at 14 weeks. AT dose was rounded off to the nearest vial. Trough AT levels were drawn 30 min prior to Monday dose. Anti-Xa levels were drawn 4 hr after a subcutaneous enoxaparin dose. Blue shaded area indicates the normal range for AT activity. Green shaded area indicates the anti-Xa therapeutic range. Symbols: Blue filled diamonds, AT activity; red filled square, exoxaparin dose; green filled triangle, anti-Xa level. Abbreviations—AT: antithrombin, MWF: Monday, Wednesday, Friday. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] When standard thromboprophylaxis is ineffective, there are no evidence-based guidelines for treatment of obstetric APLA syndrome. The suspected contribution of AT deficiency to this patient's pregnancy complications provided a rationale for AT replacement. There are two major types of AT products: AT concentrate derived from the pooled plasma of healthy donors (pdAT) is approved for treatment and prophylaxis of VTE in hereditary AT deficiency. Recombinant AT, approved in 2009, is structurally identical to pdAT except for a different glycosylation pattern that increases affinity for heparin [7]. Because of its considerably shorter half-life (10.5 hr vs. 60 hr for pdAT), it is administered as a continuous infusion [7]. Pregnant women receiving recombinant AT during labor and delivery required more frequent dose adjustments to maintain target AT levels [20]. We did not use recombinant AT because the requirement for a continuous infusion and closer monitoring precluded outpatient therapy. The goal of AT replacement is to correct the deficiency and maintain peak and trough levels in the range of 120–80%, respectively [21]. AT-deficient individuals have biochemical evidence of activated coagulation [21]. Elevated plasma levels of prothrombin fragment 1+2 in pregnant women normalize promptly after AT replacement and remain in the normal range until AT levels decline to <70% [22]. Thus, maintaining trough AT levels >80% should effectively reduce thrombin generation and the prothrombotic state. Despite a shorter half-life in pregnant women, AT infusions three times a week maintained target trough AT levels above 80%, demonstrating the feasibility of extended outpatient treatment. AT replacement improved the anticoagulant activity of enoxaparin (Fig. 1). The substantial decrease in her enoxaparin requirement suggests that anti-Xa levels may guide dose adjustments during AT therapy. AT concentrate has an excellent safety profile [21]. There were no serious maternal or neonatal complications in studies of pdAT replacement during pregnancy [23]. Our patient tolerated AT infusions for 21 weeks without adverse effects. Importantly, concurrent treatment with AT, enoxaparin, and aspirin did not cause abnormal bleeding. Serial ultrasounds during the second and third trimesters showed normal interval growth with fetal weights in the 50th to 57th percentile. At 36 weeks, her blood pressure was mildly elevated without proteinuria or other evidence of pre-eclampsia. Because of her complicated obstetric history, she underwent an elective cesarean section the following day and delivered a vigorous 5 pound 6 ounce healthy son. She had a normal-weight placenta with a small focal infarct (<5%). AT replacement was continued perioperatively to maintain normal AT levels during the 36-hr interruption in anticoagulation. She resumed enoxaparin and warfarin after delivery and had an uneventful postpartum course. Accepted indications for AT replacement include refractory thrombosis, heparin resistance, and short-term thromboprophylaxis in high-risk circumstances when anticoagulation cannot be safely given, such as surgery and childbirth [6, 21]. Multiple case reports and small case series describe the use of pdAT for prophylaxis and treatment of VTE during pregnancy. AT alone or in combination with heparin was safe and effective during pregnancy, delivery, and postpartum [22, 23]. Treatment schedules ranged from infusions daily for several weeks to one to three times a week for several months [22, 23]. However, there are only a few reports of women who received AT replacement throughout pregnancy [13, 22]. Our patient had an uncomplicated term pregnancy with AT replacement throughout the second and third trimester. She delivered a healthy infant with a normal birth weight, in striking contrast to the severe growth restriction and other complications in previous pregnancies. We suspect that correction of AT deficiency contributed to her significantly improved course and successful outcome. In addition to anticoagulant activity, AT blocks thrombin-mediated activation of endothelial cells and cytokine release. AT binding to heparan sulfate on the endothelial cell surface also has direct anti-inflammatory effects, including production of prostacyclin, an anti-inflammatory cytokine and platelet inhibitor [7, 21]. Recent evidence suggests that the pathogenesis of APLA-induced pregnancy loss involves both thrombotic and inflammatory mechanisms [24]. APLA disrupt several natural anticoagulant pathways and have adverse effects on trophoblasts and other placental tissues unrelated to thrombosis. Thus, in addition to correcting this patient's deficiency, AT's anti-inflammatory effects may have prevented APLA-induced placental injury. We identified a single report of AT replacement in an AT-deficient woman with recurrent fetal loss despite thromboprophylaxis. She received LMWH and pdAT concentrate (2,000 units) twice a week during two subsequent pregnancies, both of which resulted in live births. Her trough AT levels fell to 52% between doses and she developed other obstetric complications [25]. There are no other studies evaluating AT replacement in women with recurrent fetal loss. AT concentrate improved maternal symptoms and fetal outcome in studies of preeclamptic women without a hereditary deficiency. Daily pdAT infusions for 7 days with or without heparin were more effective than heparin alone or placebo in several small randomized trials [14, 26]. Women who received AT had less severe hypertension, greater fetal weight gain, and longer gestations. Thrombin-induced endothelial dysfunction and activation of inflammatory pathways are implicated in preeclampsia. It is noteworthy that our patient did not develop preeclampsia or HELLP during AT replacement, in contrast to prior pregnancies. AT's combined antithrombotic and anti-inflammatory activity may improve uteroplacental circulation explaining the beneficial effects. Outpatient AT replacement throughout pregnancy is feasible and well tolerated. Because AT improved the anticoagulant response to LMWH, lower doses were required during replacement therapy in our patient. The combination of enoxaparin, aspirin, and AT concentrate prevented the complications of uteroplacental insufficiency in our high-risk patient with two severe thrombophilias. Her markedly improved pregnancy outcome suggests that AT replacement should be considered for deficient women with unexplained fetal loss who fail standard thromboprophylaxis.