Treatment of Pregnant Female with Mesenteric Vein Thrombosis and History of Spontaneous Fetal Losses

In 2011, the question was posed concerning treatment of heparin-induced thrombocytopenia (HIT) during pregnancy. While there are no new treatment options for this patient, a couple of points are worth making. In terms of treatment, options are actually more limited for the acute setting, as the intravenous direct thrombin inhibitor lepirudin is no longer available. More data on the use of fondaparinux in treatment of HIT have been reported, and this remains a good option for treatment of outpatients and stable inpatients with HIT.¹  The major caveats remain its renal clearance and long half-life without a reversal agent.

The patient present had a history of both pregnancy loss and mesenteric vein thrombosis (MVT) during her prior pregnancy. The indication for anticoagulation in this pregnancy was the history of MVT. Since 2011, more data have been published showing that anticoagulation does not prevent pregnancy loss.^2,3  The evidence is strong in women without documented thrombophilia. In women with thrombophilia, we await the results of an ongoing clinical trial; however, based on current data, if there is an effect on pregnancy loss, it is small.

While we have more oral anticoagulant options than in 2011, they remain without indication in pregnancy and, depending on the drug, animal data have demonstrated pregnancy loss and fetal harm.⁴  Dabigatran crosses the placenta, and given that the other drugs are small molecules, they also would be expected to cross the placenta. Excretion in breast milk is unknown. There are accumulating data reported in women with some exposure during pregnancy,⁴  but they are not sufficient to assess safety, and thus these drugs (dabigatran, rivaroxaban, apixaban, edoxaban) should not be initiated during pregnancy.

Updated Conflict of InterestDr. Konkle's spouse has equity ownership in GlaxoSmithKline and Johnson and Johnson.

A 34-year-old woman had mesenteric vein thrombosis during her last pregnancy in 2007 and two prior second trimester spontaneous fetal losses. She now presents at 13 weeks of pregnancy after being started on low-molecular-weight heparin (LMWH) by another hematologist 14 days prior. Her baseline platelet count was 160,000, but today it is 80,000. A PF4 antibody assay sent to rule out heparin-induced thrombocytopenia (HIT) was positive. Is it reasonable to stop the LMWH and put her on warfarin, since she has completed the first trimester? Danaparoid is not available, and fondaparanux is not on the American College of Chest Physicians’ list for HIT treatment.

HIT is uncommon during pregnancy. In a retrospective cohort study of 488 heparin-treated women (244 pregnant), there were no cases of HIT in the 10 pregnant women who became thrombocytopenic, but 10 cases in the 26 thrombocytopenic non-pregnant women.¹  A study of 31 pregnant women receiving LMWH found that none were positive for anti-heparin/PF4 antibodies or developed antibodies when followed prospectively throughout their pregnancies.²  However, case reports and clinical experience document the occurrence of HIT with and without thrombosis during pregnancy. Although HIT may be less common in patients treated with LMWH versus unfractionated heparin (UFH), it can occur and must be considered in pregnant women receiving LMWH who have a > 50 percent decrease in platelet count.

In choosing an anticoagulant for a pregnant woman with HIT, one has to consider the effects on both the woman and the fetus. Concerns with anticoagulants that cross the placenta include teratogenicity and bleeding. Data are limited and mostly reflect predictions based on drug characteristics and/or animal studies. Danaparoid, the drug with which there is the most experience in pregnancy, is unavailable in the United States. Fondaparinux, argatroban, and lepirudin have been reported in treatment of pregnant women with HIT.^3,4  All are FDA Class B, indicating that animal studies have not shown harm in pregnancy, but there are no data from human studies. Outside the setting of pregnancy, fondaparinux, unlike argatroban and lepirudin, is not FDA-approved for HIT, but there are reports of its use in this setting.⁵  Patients who receive this drug may develop anti-heparin/PF4 antibodies, but it is not clear that these are associated with the development of HIT.

Fondaparinux is a pentasaccharide that, with antithrombin, inhibits factor Xa. An advantage of this drug is its long half-life (~17 hrs.) allowing once-daily dosing. Disadvantages include managing a drug with a long half-life around delivery. Also, the drug has been detected in cord blood but at concentrations unlikely to cause bleeding,⁶ and no adverse outcomes have been reported in infants. The short-acting direct thrombin inhibitors (DTI) argatroban, lepirudin, and bivalirudin require intravenous administration. Successful short-term use of argatroban and lepirudin has been reported in pregnant women with HIT.⁴  Based on their pharmacokinetic properties, little or no drug would be expected to cross the placenta, although one study showed minor transplacental passage of lepirudin.⁶ 

The patient presented above has a history of mesenteric thrombosis in her prior pregnancy. Pregnancy is a known risk factor for splanchnic bed thrombosis, and, in women with such a history, it is appropriate to provide at least prophylactic anticoagulation during subsequent pregnancies. The decision to test for additional conditions should be based on clinical and laboratory indicators of underlying disease. We would check a platelet count remote from pregnancy, because essential thrombocythemia is associated with both pregnancy loss and splanchnic bed thrombosis. It is unknown whether the Jak2 V617F mutation is associated with thrombosis in the setting of pregnancy.

When a pregnant woman develops HIT, the heparin should be discontinued; she should be evaluated for thrombosis by vascular ultrasound studies, and, unless contraindicated, alternative anticoagulation should be initiated. This patient needs continued anticoagulation because of the history of mesenteric vein thrombosis and her increased risk of thrombosis in the setting of HIT. As in non-pregnant patients, warfarin should not be started in the setting of acute HIT. The patient could be transitioned to warfarin later after the acute HIT resolves. Teratogenic effects have not been demonstrated when warfarin is ingested after 12 weeks gestation; however, it does cross the placenta and complications related to fetal hemorrhage have been reported. Two new oral anticoagulants, dabigatran and rivaroxiban, will not be useful alternatives, as both demonstrated reproductive toxicity and excretion in breast milk in animals.⁷ 

Given the need for continued outpatient anticoagulation, it is reasonable to switch her to fondaparinux, recognizing the need to discontinue the drug in anticipation of labor given its long half-life. In a patient on prophylactic therapy without a recent thrombotic event, it may be possible to stop the drug three days prior to scheduled induction or cesarean section. Epidural or spinal anesthesia could be given if an anti-Xa measurement demonstrates drug clearance. A woman at higher risk for thrombosis could be transitioned to an intravenous short-acting DTI, but since there will be anticoagulant effects in the mother and possibly the fetus, it should be discontinued in anticipation of a scheduled delivery to prevent bleeding complications. The best approach to delivery should be carefully considered in collaboration with maternal fetal medicine specialists.

After delivery, anticoagulation should be re-initiated with either fondaparinux or a DTI with transition to warfarin. Fondaparinux is excreted in breast milk in animals, while argatroban, bivalirudin, and lepirudin are not predicted to be excreted in breast milk. Data from one lactating woman on therapeutic doses of lepirudin demonstrated no measureable drug in her breast milk. Thus, if the patient plans to breast feed, lepirudin with transition to warfarin, which also is not excreted in breast milk, may be the best postpartum option.

While HIT in pregnancy is rare, it does occur and management requires knowledge of disease and drug effects on the mother and developing fetus, although data to inform these decisions are limited. Potential risks and benefits of different approaches should be discussed with the patient and her other health-care providers.