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Heparin Resistance due to an Acquired Antithrombin Deficiency in a Patient With Sickle Cell Disease During a Pregnancy Complicated by Bilateral Pulmonary Emboli: A Case Report

Wells, Ashley V. MD*; Zarkhin, Eli MD*; Weiner, Menachem M. MD; Katz, Daniel MD*

doi: 10.1213/XAA.0000000000000917
Case Reports
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We report a 31-year-old woman with sickle beta thalassemia zero who presented at 21 weeks gestational age with multiple bilateral pulmonary emboli and no hemodynamic instability. Acquired antithrombin deficiency was suspected due to a refractory response to therapeutic anticoagulation with enoxaparin, unfractionated heparin, and fondaparinux, and a reduced antithrombin antigen level. At 26 4/7 weeks, she developed signs concerning for increased pulmonary clot burden. To avoid the use of alternative anticoagulants that may cross the placenta and impact the fetus, a planned cesarean delivery was performed without complication at 27 weeks gestation. Both mother and child experienced successful long-term outcomes.

From the *Department of Anesthesiology, Perioperative & Pain Medicine

Division of Cardiothoracic Anesthesia, Icahn School of Medicine at Mount Sinai Hospital, New York, New York.

Accepted for publication September 17, 2018.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Ashley V. Wells, MD, Department of Anesthesiology, Perioperative & Pain Medicine, Icahn School of Medicine at Mt Sinai Hospital, Box 1010, One Gustave L Levy Pl, New York, NY 10029. Address e-mail to Awells2245@gmail.com.

Sickle cell diseases (SCDs) are characterized by sickled erythrocytes that result in chronic hemolytic anemia and painful vaso-occlusive crises (VOCs).1,2 Like pregnancy, SCDs are a hypercoagulable state.1,3 Consequently, the risk of a venous thromboembolism (VTE) is increased in pregnant women with SCD.1 Other factors that further increase the risk of VTE in patients with SCD include female sex, multiple hospitalizations, functional hyposplenism, the presence of an indwelling catheter, as well as the sickle beta thalassemia zero (Hb Sβ0) and homozygous hemoglobin S genotype.1

During pregnancy, unfractionated heparin (UFH) and low molecular weight heparin are preferred anticoagulants because they do not cross the placenta.4 When heparins bind to antithrombin (AT), they potentiate its ability to inactivate thrombin and activated factor Xa.4,5 AT deficiency is a common cause of heparin resistance during pregnancy.4,5 The management of VTE in the setting of heparin resistance during pregnancy is not well defined and treatment is guided by expert opinion.4,6 We report a patient with Hb Sβ0 whose pregnancy was complicated by pulmonary emboli refractory to anticoagulation.

Written consent was obtained from the patient for publication of this case report.

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CASE DESCRIPTION

A 31-year-old African American G5P0 woman with a history of Hb Sβ0 and deep vein thrombosis during a previous miscarriage presented to the hospital at 21 weeks gestation with chest pain and shortness of breath. The patient’s SCD was severe, complicated by frequent hospitalizations for anemia, acute chest syndrome, and VOCs. Prophylactic red blood cell (RBC) transfusions were infused every 4 weeks to limit complications of SCD during pregnancy.

On admission, computed tomography pulmonary angiogram revealed extensive bilateral acute pulmonary emboli. A deep vein thrombosis was detected in the upper extremity at the site of an indwelling peripherally inserted central catheter placed for transfusions. Electrocardiogram and cardiac enzymes were normal. Transthoracic echocardiogram showed no right ventricular strain. Fetal ultrasound revealed a complete placenta previa and breech presentation. The hematocrit was 29.2%, and a serum AT antigen level was low at 63%. Years before, an AT antigen and activity level were both normal.

Before presentation, aspirin 81 mg and enoxaparin 40 mg had been prescribed daily for preeclampsia and VTE prophylaxis, respectively. During this admission, the patient maintained a subtherapeutic response to anticoagulation with therapeutic doses of enoxaparin and an UFH infusion. Therapeutic anticoagulation was initially achieved on fondaparinux. While the patient remained hospitalized for recurrent VOCs, anticoagulation with fondaparinux was continued, but anti-Xa levels were mistakenly not monitored.

At 26 4/7 weeks, she developed hypoxia, tachycardia, and worsening pain in the setting of a VOC. Chest x-ray demonstrated an old area of scarring. Computed tomography pulmonary angiogram was not repeated to avoid further radiation exposure. Although recommended by the hematologists, the patient declined exchange transfusion. Anti-Xa levels demonstrated a subtherapeutic response to fondaparinux, and the dose was increased. The care team suspected that her clinical decline was more concerning for increasing pulmonary clot burden than for acute chest syndrome or other etiologies due to her lack of therapeutic anticoagulation.

A multidisciplinary team of anesthesiologists, obstetricians, neonatologists, pulmonologists, and hematologists was established. Potential treatment plans proposed included imminent cesarean delivery or continuing the pregnancy with an alternative anticoagulant. Although the hematologists suspected that an AT deficiency was contributing to the refractory response to anticoagulation, they declined to use recombinant AT with heparin due to the lack of guidelines to direct treatment. The decision on the timing of delivery required weighing the risks and benefits of delivering a fetus at 27 weeks gestation against continuing the pregnancy on anticoagulants like warfarin or argatroban that cross the placenta. Our neonatal intensivists justified delivery at 27 weeks given their history of favorable outcomes and concern for uncertain risk of anticoagulant exposure.

A cesarean delivery was planned with cardiac and obstetric anesthesia, cardiac surgery, and cardiopulmonary bypass (CPB) support immediately available. Before delivery, an inferior vena cava filter was placed and RBCs were transfused with the target hemoglobin S fraction of <30% and hematocrit of >30%. Recombinant AT was available to enable heparin anticoagulation in the event that the patient required CPB. Point-of-care (POC) coagulation testing with rotational thromboelastometry (ROTEM) demonstrated a hypercoagulable state despite anticoagulation with fondaparinux 24 hours before surgery (Figure). A radial arterial line was placed and general anesthesia was induced with propofol and succinylcholine without complication. Transesophageal echocardiogram demonstrated normal biventricular function. Anesthesia was maintained with a balanced anesthetic of isoflurane, opioid, and ketamine. The newborn had Apgar scores of 9 and 8 at 1 and 5 minutes, respectively. Blood loss was estimated at 1500 mL, 1 dose of intramuscular and intrauterine carboprost was administered, and 1 unit of RBCs was transfused to maintain a hematocrit >30%.

Figure.

Figure.

At the end of the surgery, the patient was extubated and transported to the intensive care unit. After the administration of fresh frozen plasma (FFP) as a source of AT, a therapeutic activated partial thromboplastin time was achieved on a heparin infusion while bridging to anticoagulation with warfarin. Warfarin was continued for 3 months postpartum.

For 1 month after delivery, the patient remained hospitalized for management of a VOC and surgical site infection. The infant was discharged at 12 weeks of age after an uncomplicated hospital course.

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DISCUSSION

In addition to the hypercoagulable state of pregnancy and SCD, AT deficiency placed our patient at further risk for a VTE.6 She was unable to achieve therapeutic anticoagulation on UFH, enoxaparin, and fondaparinux—all of which require AT for activity.4 The patient’s heparin resistance was likely due to an acquired AT deficiency from increased AT consumption after heparin exposure, VTE formation, SCD, and pregnancy. When exposed to heparins, AT levels decline due to the rapid clearance of the AT-thrombin complex after heparin’s dissociation.5 Likewise, the upregulated hemostatic system that occurs during VTE formation can also contribute to the accelerated consumption of AT.5 Furthermore, a significant reduction in AT levels in SCD patients has been reported.7 Last, a gradual decline in AT activity can occur during pregnancy.8

In the setting of heparin resistance, serum AT levels should be evaluated.5 The AT antigen level collected on admission supported a diagnosis of AT deficiency. POC ROTEM testing can rapidly detect changes in coagulation and its use confirmed that the patient was hypercoagulable before cesarean delivery despite treatment with fondaparinux. Although not obtained, a ROTEM after FFP administration may have helped monitor the effectiveness of the UFH infusion via comparison to the preoperative baseline.

Exogenous AT, via FFP or recombinant AT, can facilitate therapeutic anticoagulation. FFP is associated with transfusion-related complications and may take time to prepare—whereas AT products are well tolerated and readily available.9 During pregnancy, AT has been used to treat patients when adequate anticoagulation is not achieved with heparin due to hereditary AT deficiency.4,6 However, there are no reports of its use during the antepartum period for an acquired AT deficiency.6 In the event that the patient required CPB, our anesthesia team favored recombinant AT over FFP due to its superior tolerability and its ability to be rapidly administered in an emergency.9

Evidence is limited to support the safe use of anticoagulants other than heparins during pregnancy.4 The low molecular weight heparinoid, danaparoid, inhibits factor Xa and is an alternative in patients with severe heparin reactions due to its low cross-reactivity and lack of placental transfer. However, danaparoid remains unavailable in the US market.4,10 Fondaparinux is a synthetic factor that selectively inhibits factor Xa, but exhibits some transplacental transfer.4 In our patient, fondaparinux’s long half-life and lack of a reversal agent raised concerns for prolonged anticoagulation in the context of potential bleeding from placenta previa or urgent cesarean delivery. The hematologists recommended fondaparinux because it has been well tolerated without increased birth defects, bleeding, or allergic reactions in the limited studies available in pregnancy.11,12 Both danaparoid and fondaparinux rely on AT for activity rendering them less effective in the setting of AT deficiency.4 Argatroban is a direct thrombin inhibitor that is monitored using the activated partial thromboplastin time and has a short half-life that allows for rapid reversal of its anticoagulant effect. However, argatroban requires continuous intravenous administration, crosses the placenta, and data on its use during pregnancy are limited.4,11 The direct oral anticoagulants, including thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, are contraindicated because they cross the placenta and cause reproductive toxicity in animal studies; there are insufficient data in human pregnancy.10,13 Vitamin K antagonists cross the placenta and can result in birth defects, miscarriage, fetal hemorrhage, and neurodevelopmental abnormalities.10

Pregnancies complicated by SCD and AT deficiency are at an increased risk of morbidity, and management by a multidisciplinary team can lead to improvements in patient outcomes.2,6 This case highlights how an acquired AT deficiency can contribute to heparin resistance and the challenges it presents to providing adequate anticoagulation for a VTE. The identification of a hypercoagulable state with POC ROTEM testing and AT deficiency through laboratory testing confirmed that our patient had an acquired AT deficiency. Expeditious delivery of such patients can reduce the risk of fetal exposure to novel anticoagulants until further data on safety are available.

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DISCLOSURES

Name: Ashley V. Wells, MD.

Contribution: This author helped care for the patient and write the manuscript.

Name: Eli Zarkhin, MD.

Contribution: This author helped care for the patient and review the manuscript.

Name: Menachem M. Weiner, MD.

Contribution: This author helped care for the patient and review the manuscript.

Name: Daniel Katz, MD.

Contribution: This author helped care for the patient and review the manuscript.

This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.

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