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You Make the Call: Would you start a patient who presented with a left cerebrovascular accident likely due to oral contraceptive use on warfarin?

November 30, 2023

December 2023

Shruti Chaturvedi, MBBS, MS

Shruti Chaturvedi, MBBS, MS
Associate Professor of Medicine
Johns Hopkins University
Baltimore, Maryland

 

 


CLINICAL DILEMMA

I have a 27-year-old female patient who presented with a left cerebrovascular accident (CVA). A CT scan of the head did not show any evidence of acute intracranial abnormality. A cerebral perfusion CT scan did not show any evidence of abnormal perfusion; however, an MRI of the brain with and without contrast revealed a 7 mm focus of restricted diffusion in the left side of the medulla, likely representing acute infarct. Upon admission, the patient was started on aspirin, clopidogrel, and a statin. Although she had no prior history of elevated blood pressure, she was hypertensive during hospitalization and started on losartan. A transthoracic echocardiogram with a bubble study was normal. The patient was on an oral contraceptive (norethindrone and ethinyl estradiol tablets, 0.4 mg/0.035 mg) before her CVA, which was discontinued as this was felt to be a potential cause.

Three months later, neurology performed a partial hypercoagulable workup to further evaluate her CVA. The workup found her homozygous for MTHFR C677T polymorphism but with a normal homocysteine level. Her anti-β2 glycoprotein-1 antibody (β2GP1) IgG was elevated at 66 SGU U/mL and on repeat testing one month later (63 SGU U/mL). Other components of the hypercoagulable workup, including anticardiolipin and lupus anticoagulant studies, were normal. She has no other personal history of thrombosis and no significant personal or family history of strokes or myocardial infarctions at an early age.

I will repeat β2GP1 testing in three months but suspect it will be elevated again. Would you start her on anticoagulation given the homozygous MTHFR C677T polymorphism and elevation in β2GP1, and if so, would the anticoagulant of choice be warfarin? Would you also empirically start folic acid, cyanocobalamin, and pyridoxine? She is concerned about the risks associated with lifelong anticoagulation, and though it could have been provoked by her oral contraceptive, I am most concerned about her stroke risk going forward.


EXPERT OPINION

This young patient has two risk factors for stroke – likely antiphospholipid syndrome (APS) if β2GP1 IgG remains positive at 12 weeks, as well as combined oral contraceptive pills. Arterial events such as stroke are the presenting manifestation in about 13% of APS cases,1 and it has been suggested that more than 20% of strokes in patients under the age of 45 may be associated with APS. Oral contraceptive use is also associated with stroke, though the risk is lower with newer low-estrogen preparations.2

Data to guide treatment of arterial thrombosis (stroke or myocardial infarction) in APS are limited. If APS is confirmed, I would treat this patient with standard-​intensity warfarin (target internalized normal ratio [INR] of 2.0-3.0) plus low-dose aspirin. The European Alliance of Associations for Rheumatology recommendations support either standard-intensity warfarin with aspirin or high-intensity warfarin (INR of 3.0-4.0).3 However, I rarely target an INR greater than 3 because of a randomized trial that found that high-intensity warfarin (INR of 3.0-4.0) was not superior to standard-intensity warfarin (INR of 2.0-3.0) in preventing recurrent thrombosis in APS (though patients with arterial thrombosis were underrepresented in this study).4

Warfarin remains the anticoagulant of choice for high-risk APS (including arterial thrombosis), and I would not recommend a direct oral anticoagulant (DOAC) for this patient. Recent trials in APS have demonstrated increased rates of recurrent thrombosis on rivaroxaban or apixaban compared to warfarin.5,6 All recurrent thromboses in the DOAC arms of these trials were arterial thromboses, mostly stroke.5,6

The MTHFR C677T polymorphism is very common in white and Hispanic individuals and may be associated with elevated homocysteine levels. Hyperhomocystinemia has been associated with increased risk of cardiovascular events, but the increase in risk is small and a causal relationship with cardiovascular events is not certain.7 Homocysteine-lowering treatment with folic acid, vitamin B6, and vitamin B12 does not reduce the risk of venous thrombosis or myocardial infarction, though it may have a modest effect on reducing stroke.8 In this patient who does not have elevated serum homocysteine levels, I would not supplement with folic acid, vitamin B12, or vitamin B6.

Finally, contraception must be addressed in all patients of childbearing age. Pregnancy is a risk factor for thrombosis, and this risk is compounded in patients with APS. My first choice would be a levonorgestrel-​containing intrauterine device (IUD), which provides effective contraception without increasing the risk of thrombosis.8 This may have the added benefit of reducing excessive menstrual bleeding due to anticoagulation. If an IUD is not acceptable to the patient, other progestin-only (pill or subcutaneous depot injections) contraceptives may be considered. I avoid combined estrogen-​progesterone-containing preparations in patients with APS as much as possible.

References

  1. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):1019-1027.
  2. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA. 2000;284(1):72-78.
  3. Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78(10):1296-1304.
  4. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349(12):1133-1138.
  5. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365-1371.
  6. Woller SC, Stevens SM, Kaplan D, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv. 2022;6(6):1661-1670.
  7. Moll S, Varga EA. Homocysteine and MTHFR mutations. Circulation. 2015;132(1):e6-9.
  8. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Homocysteine-​lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8(8):CD006612.

NEXT MONTH'S CLINICAL DILEMMA

I have a 23-year-old male patient who presented with lymphadenopathy, underwent an excisional lymph node biopsy, and was diagnosed with classic (nodal) Rosai-Dorfman disease (RDD). He has bulky lymphadenopathy, and high-dose prednisone (1-1.5 mg/kg for six weeks) has only resulted in a modest partial response. He continues to have bulky cervical lymphadenopathy and a lymphedema in his left leg due to enlarged inguinal lymph nodes. Given the rarity of his disease, what second-line therapies are available?

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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