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You Make the Call: How would you treat a female patient with a history of upper extremity DVT taking enoxaparin?

April 25, 2023

May 2023

Barbara Lam, MD

Barbara Lam, MD
Hematology/Oncology Fellow
Clinical Informatics Fellow
Beth Israel Deaconess Medical Center

 

 

Kenneth A. Bauer, MD

Kenneth A. Bauer, MD
Professor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School

 

 


CLINICAL DILEMMA

A 45-year-old female patient who is pregnant has a history of catheter-related upper extremity deep vein thrombosis (DVT) during a hospitalization for COVID-19 in 2021. As of note, she was taking estrogen at the time. She also has a history of three first-trimester miscarriages, as well as a miscarriage of twin sons. She has a family history that is positive for venous thromboembolism (VTE), with a maternal aunt who experienced a DVT in her 50s. She is heterozygous for prothrombin gene mutation. Hereditary thrombophilia testing and testing for antiphospholipid syndrome (APS) have been done, both of which were negative.

The patient is currently 11 weeks pregnant after in vitro fertilization (IVF) and implantation. She has been on estrogen supplementation for pregnancy support, but this will be ending within a few weeks. She has also been taking enoxaparin 40 mg SQ daily. Once she is off estrogen, would you recommend that she continue enoxaparin up to the time of delivery and then for six weeks postpartum, or discontinue it at that time and restart it after delivery through six weeks postpartum?


EXPERT OPINION

The patient’s history does not place her at a sufficiently high enough risk for pregnancy-associated venous thrombo­embolism to warrant continued prophylactic anticoagulation either antepartum or postpartum. While heter­o­zygosity for the prothrombin G20210A mutation increases the risk of pregnancy-associated VTE, the absolute risk is small in women without a history of VTE (0.6% for age ≥35).1 Though she had an upper extremity deep vein thrombosis in association with multiple risk factors (the most significant being the PICC line while hospi­talized for COVID-19), she was also on estrogen at the time. While women with DVT or pulmonary embolism in association with oral contraceptives are generally placed on prophylaxis with low-molecular-weight heparin (LMWH) during pregnancy, this patient’s history does not require this. With respect to her family history, no first-degree relatives had VTE. Thus, her absolute risk of pregnancy associated VTE remains low at under 1-2%, which is used as a threshold for recommending antepartum thromboprophylaxis with LMWH.2

Early reports suggested an association between hereditary thrombophilia and pregnancy loss, but these were primarily in the second and third trimesters.3 One of the clinical criteria for antiphospholipid syndrome is three or more first trimester pregnancy losses, but this patient tested negative for markers of the syndrome. In contrast to APS, hereditary thrombophilia has not clearly been shown to be associated with recurrent first trimester losses, and there is considerable evidence that LMWH does not improve fetal outcomes in these women. The TIPPS trial, in which 20% of women had the prothrombin G20210A mutation, found that LMWH (dalteparin) did not reduce rates of pregnancy loss, placenta-mediated pregnancy complications, or VTE.4 In addition, the ALIFE2 trial randomized women with two or more pregnancy losses and hereditary thrombophilia (25% of whom had the prothrombin G20210 mutation) to LMWH once daily versus standard surveillance; no improvement was found in the live birth rate, which was around 70%.5 

We acknowledge that the specifics of this patient’s case may not be fully captured in clinical trials; for example, the average age of participants was 31 years in the TIPPS trial and 33 years in the ALIFE2 trial, with few likely to have conceived with IVF. She should be followed by an obstetrician who cares for high-risk pregnancies, who will likely recommend low-dose aspirin daily to reduce the risk of preeclampsia. A plan needs to be developed by this patient’s obstetrician and hematologist that best addresses her medical situation and concerns.

References

  1. Gerhardt A, Scharf RE, Greer IA, et al. Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood. 2016;128(19):2343-2349.
  2. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2(22):3317-3359.
  3. Robertson L, Wu O, Langhore P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;​132(2):171-196.
  4. Rodger MA, Hague WM, Kingdom J, et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet. 2014;384(9955):1673-1683.
  5. Quenby S, Booth K, Hiller L, et al. Low-molecular-weight heparin versus standard pregnancy care for women with recurrent miscarriage and inherited thrombophilia: an open-label, phase III randomized controlled trial (ALIFE2). Blood. 2022;140(Supplement 2):LBA-5.

NEXT MONTH'S CLINICAL DILEMMA

A 52-year-old male was diagnosed with chronic myeloid leukemia (CML) in chronic phase. At diagnosis, his white blood cell (WBC) count was 2.82 × 109/L with 5% blasts, his hemoglobin was 10.6 g/dL, and his platelet count was 761 × 109/L. The spleen tip was palpable 5 cm below the left costal margin at the midclavicular line. In the bone marrow, the cellularity was 100% and there were 1% blasts. BCR::ABL1 fusion gene p210 type (e13/14a2) transcripts were detected, and the ratio was quantified at 58.4505% on the International Scale (IS). He was started on nilotinib and received only 12 days of treatment, as he was not able to tolerate it and was then lost to follow-up.

After returning to clinic three months later (still in chronic phase), his treatment was changed to dasatinib 100 mg daily, and he has not missed any doses since. After three months of treatment, BCR::ABL1 fusion gene to ABL1 ratio was 34.4846% on the IS. Two months later, the ratio was 30.3079%. With little change despite five months of treatment, there was a concern for inherent resistance, but tyrosine kinase mutation analysis was performed and was negative.

After seven months of treatment with dasatinib, a repeat bone marrow biopsy was completed. At the time, the patient’s WBC count was 3.2 × 109/L, hemoglobin was 11.8 g/dL, and platelet count was 272 × 109/L. The bone marrow was hypocellular (20%) with maturing trilineage hematopoiesis biopsy and did not have any morphologic evidence of CML. Cytogenetics were positive for t(9;22), as BCR::ABL1 fusion was detected in 64.5% of interphase cells.

He is currently asymptomatic and in complete hematologic remission but has persistent positive cytogenetic and molecular tests. In terms of management, should this patient switch to another tyrosine kinase inhibitor? No mutations were detected on the tyrosine kinase mutation analysis, so how should another line of therapy be chosen? Should he be referred for allogeneic hematopoietic cell transplantation instead and proceed if a well-matched donor can be found?

How would you respond? Email us at ashclinicalnews@hematology.org.


Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.

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