There is a paucity of literature surrounding the management of acute venous thromboembolism in the setting of clotting disorder and pregnancy. Historically, management of venous thromboembolism (VTE) in pregnancy has been extrapolated from data of the nonpregnant community and is limited to general principles which are applied to a diverse set of circumstances. Here we discuss and detail the decision-making in the management of a woman with a massive deep venous thrombosis (DVT) during pregnancy with an underlying antithrombin deficiency and May–Thurner syndrome (MTS).
Our patient is a G4P2103 female with a history of antithrombin deficiency and prior preterm birth. She was diagnosed with antithrombin deficiency in childhood due to a family history of venous thrombosis and antithrombin deficiency in multiple family members spanning three generations, some of which carry the heterozygous prothrombin gene mutation. Baseline antithrombin activity in adulthood was 53% with a proportional decrease in antithrombin antigen consistent with a type 1 (quantitative) deficiency. The pathogenic heterozygous SERPINC1 variant c.481C>T (p.Arg161∗) has been identified in her first cousin. She is a lifelong nonsmoker, with a normal BMI, no varicose veins or chronic venous insufficiency, and wild type for prothrombin gene mutation. She presented to the emergency department at 10w1d with left leg pain and was found to have a left lower extremity DVT involving the left common femoral, greater saphenous, superficial and deep femoral veins, and popliteal vein after halving her low molecular weight heparin (LMWH) dose to one injection/day due to inadequate insurance coverage. Therapeutic dose anticoagulation with enoxaparin 1 mg/kg twice daily had been initiated once pregnancy was confirmed, as had been done with prior pregnancies. Enoxaparin was restarted at therapeutic dosing (1 mg/kg twice daily) with confirmation of therapeutic anti-Xa levels of 0.66 IU/ml (0.6–1.0 IU/ml), and she was discharged home. At 13w6d, repeat ultrasound due to persistent swelling and worsened left leg pain showed an unimproved thrombus, and a pelvic MRI to evaluate the pelvic and abdominal venous system demonstrated MTS. Due to persistent intractable pain at 17w1d, she had angiogram that showed chronic occlusion of the left iliac vein with small, but patent, femoral vein, as well as a chronic, wall-adherent thrombus in the left external iliac vein. Her inferior vena cava (IVC) was found to be patent but there was mention of the right common iliac artery crossing over and compressing the left iliac vein, consistent with the MRI findings. Enoxaparin remains therapeutic with an anti-Xa of 0.68 IU/ml. She underwent thrombectomy with balloon dilation of iliofemoral veins from the IVC to lesser trochanter. Postdilation imaging showed luminal gain.
A multidisciplinary team, including hematology, maternal–fetal medicine, interventional radiology, and anesthesia, was involved to determine optimal management, which ultimately included therapeutic enoxaparin with twice daily dosing and close anti-Xa monitoring targeting the mid-therapeutic range with a brief anticoagulation hold for labor, with antithrombin concentrate given while anticoagulation was held for delivery.
She represented with worsening pain and edema at 27w5d, and ultrasound with Dopplers showed an extension of the known clot with probable occlusive thrombus in a single left posterior tibial vein. Recent anti-Xa activity was 0.88 IU/ml and hence the enoxaparin dose was increased by 30% achieving an anti-Xa level of 1.11 IU/ml (targeting to be at or slightly above the upper end of the reference range for twice daily dosing).
The patient presented at 33w4d with contractions and was admitted due to concern for preterm labor. She was admitted, given betamethasone for fetal lung maturity, and was started on intravenous unfractionated heparin (UFH) with a bolus of 80 U/kg followed by infusion at 18 U/kg/h adjusted through a nomogram using anti-Xa activity. Baseline antithrombin activity (prior to starting UFH) was 63%. Plasma-derived antithrombin concentrate (Thrombate) with weight-based dosing and targeting activity of 80% was administered to facilitate anticoagulation with UFH and anticipating the need to hold anticoagulation for delivery. Antithrombin activity was obtained every 12 h through delivery and a total of three doses of antithrombin concentrate were administered. She remained dilated at 4 cm and had several more episodes of threatened preterm labor. Following multidisciplinary discussion and shared decision-making with the patient, she underwent a planned induction of labor with oxytocin and amniotomy at 35 weeks gestation to have her delivery occur under planned circumstances. The patient desired a delivery without neuraxial anesthesia. Heparin drip was paused during active labor, and she had an uncomplicated vaginal delivery with minimal blood loss (75 ml).
As part of the multidisciplinary plan, the patient was taken from labor and delivery to an interventional radiology suite immediately postpartum, where a retrievable infrarenal IVC filter was placed, as it was felt that the involuting uterus might no longer provide a ‘filter-like effect’ on the IVC. Heparin drip was also restarted, limiting the total time without heparin to only 5 h. On postpartum day 2, she was transitioned from the heparin drip to LMWH. On postpartum day 3, LMWH levels were therapeutic, and she was discharged home.
The patient chose Depo-Provera injections for birth control. She underwent definitive treatment for MTS with iliac vein stenting (from the left common femoral vein to bifurcation) as well as thrombectomy and IVC filter removal 4 weeks postpartum. However, she rethrombosed 2 weeks later and required an additional two thrombectomies. At 7 weeks postpartum, she was bridged from LMWH to warfarin, and she remained on clopidogrel and aspirin.
Despite extensive investigation, there is a significant lack of literature regarding the management of massive VTEs in the peripartum period in the setting of thrombophilias. The absolute risk of VTE in the antepartum/postpartum in patients with antithrombin deficiency ranges from 3 to 47.7%, with one meta-analysis sitting at 16.6% as the absolute risk . However, antithrombin deficiency itself is rare, and as a result, data on the condition in pregnancy is sparse. Frequently the condition is combined with other high-risk thrombophilias, such as protein C & S deficiencies. In addition, a large portion of the literature on pregnancy surrounding antithrombin deficiency is from family studies that may confer a reporting bias.
The management of antithrombin deficiency and VTE in pregnancy is largely based on small patient cohorts and expert opinion and involves stratification of risks of treatment with anticoagulation, monitoring for bleeding, and fetal surveillance . For VTE, the most commonly used anticoagulant is low molecular weight heparin followed by UFH. Current recommendations do not offer many alternatives or address thrombosis refractory to first-line treatment, particularly in symptomatic patients. Direct thrombin inhibitors and direct factor Xa inhibitors have been considered reasonable alternatives to heparin in the nonpregnant population; however, the American College of Obstetricians and Gynecologists recommends against their use in pregnancy due to insufficient data regarding their safety. Further, transplacental passage of fondaparinux has been described, and safety of the drug is limited, therefore its use in the pregnant population is guarded [3,4]. The use of antithrombin concentrate concurrently with anticoagulation in patients with antithrombin deficiency and VTE in the setting of pregnancy has been discussed in several case reports, however more research is required to determine efficacy, appropriate doing, and safety of use [5,6].
For our patient, an IVC filter was chosen for several reasons. This is considered to mitigate the risk of clot migration or pulmonary embolism and has been described in the literature [7–9]. However, this is not an option without risks. Although the primary aim of an IVC filter is to prevent mortality from pulmonary embolism, in the nonpregnant patient population, no mortality benefit has been shown from IVC filter use, but rather a 63% reduction in the incidence of pulmonary embolism. Using this reduction in pulmonary embolisms, Du Plessis et al. assumed this extrapolates to a 63% reduction in maternal mortality as the ‘best-case scenario’, and thus the number needed to treat to prevent one pregnancy-associated VTE-related death would be 318. Given a procedural mortality rate of an IVC filter of 0.12%, In treating 318 individuals to prevent one maternal death, associated risks of IVC filter would include 26 iatrogenic lower limb DVTs, 2.9 IVC thromboses, 6.6 migrations of the filter, 19.9 IVC wall perforations, 4.4 filter strut fractures, 34.8 filter retrieval failures, 12.7 complications from filter insertion, and 15.9 episodes of postthrombotic syndrome. However, if the effectiveness of an IVC filter is found to reduce maternal mortality by 25% rather than 63%, then the number needed to treat increases to 800. Thus, procedure mortality approaches the VTE mortality rate, which would not justify its use . Given the limited data on pregnant people, determining the exact risks and benefits is challenging. In our patient, given the extensive size of her clot, our team felt that the risk for pulmonary embolism as the uterus was involuted was greater than the risk of the procedure.
Other management strategies considered included thrombolytic therapy and thrombectomy, both of which have been described in reviews of therapies nonspecific to a single thrombophilia or clot type. Thrombolytic therapy in pregnancy is generally reserved for instances of massive, life-threatening VTEs, stratifying the risk of VTE against the risk of therapy which includes maternal and fetal death, significant bleeding, preterm delivery, and spontaneous abortion [10,11]. Thrombectomy has been described in pregnancy for pulmonary embolism, stroke, and left lower extremity VTE, however, as in our patient, while the removal of part or all of the clot can allow for a resumption of blood flow and symptomatic improvement, it does not alter the definitive pathophysiology of clot formation, and thus must be considered in conjunction with other therapies.
Regarding iliac venous obstruction, as in MTS, iliac vein stenting has become the first-line treatment in nonpregnant populations. It is generally considered safe but has documented risks of stent thrombosis and occlusion and is technically difficult in the later stages of pregnancy. Accordingly, stenting, while definitive, is often reserved for the postpartum period. Most of the literature reports on patients receiving retrievable IVC filters during pregnancy followed by removal and subsequent IVC stenting postpartum. Delayed definitive treatment is described to allow for acute healing from delivery, the establishment of breastfeeding, and permitting uterine involution. Patients who enter pregnancy with iliac vein stent in place most often maintain stent patency regardless of the anticoagulation regimen . None of these case reports discuss the scenario of MTS in conjunction with antithrombin deficiency.
For patients with MTS who experience clot formation during pregnancy, as in other instances of VTE in pregnancy, therapeutic anticoagulation is the standard of care. One case series describes the favorable use of both therapeutic and prophylactic levels of LMWH in patients with MTS and a history of VTE without VTE during pregnancy. Most pregnancies resulted in term deliveries, although there was a slightly increased incidence of cesarian section noted .
With respect to our patient, the radiology team felt that compression from her gravid uterus was effectively providing an IVC ‘filter-like effect’ and the complication rate of the IVC filter in pregnancy was not worth the benefit, so she was managed medically. However, due to concern for the involuting uterus, a retrievable IVC filter was placed in the immediate postpartum period, and she was later taken for definitive stenting at 4 weeks postpartum.
In conclusion, the collaborative management by maternal fetal medicine, hematology, OB anesthesia, and ultrasonography was instrumental to this successful and safe pregnancy and delivery. Due to the limited available data of similar presentations, medical management of our patient with large VTE in the setting of antithrombin deficiency and MTS hinged on medically optimizing our patient with LMWH and thrombectomy followed by carefully and meticulously planned care in the peripartum period to allow for the safest possible delivery with immediate return to anticoagulation and long-term definitive treatments.
J.J.M. receives funding through the National Heart, Lung, and Blood Institute (HL150340-01) and the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR001436).
Conflicts of interest
The authors have no other disclosures to make.
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