A rare case of catastrophic antiphospholipid syndrome triggered by estrogen‐containing oral contraceptives in a patient with double heterozygous factor V Leiden and prothrombin <scp>G20210A</scp> mutations
Authors: Hannah L. McRae, Annie H. Yang, Karen Kruzer, Glynis A. Scott, Majed A. Refaai
Journal: American Journal of Hematology (2021)

A 25-year-old white female presented to urgent care with severe right lateral neck and shoulder pain that radiated to the right upper arm and worsened with movement. She denied smoking, alcohol, and illicit drug use. Her medical history included untreated hypothyroidism and gravida 2 para 2. She had started desogestrel and ethinyl estradiol oral contraceptive pills (OCP) 6 months prior to presentation. The maternal family history included a “possible clotting disorder.” She was given ketorolac for presumed muscle strain and prescribed cyclobenzaprine. The following day, she presented with dyspnea and pleuritic chest pain. Chest computed tomography (CT) revealed acute submassive pulmonary embolism (PE) and small pericardial effusion with associated axillary lymphadenopathy and enlarged subcarinal lymph nodes. She was given enoxaparin and thrombolytics and transferred to our center for specialized care. The patient was found to be hypotensive, tachycardic, tachypneic, and hypoxic (Table S1). She endorsed a one-month history of fatigue, weakness, nausea, chills, night sweats, and acute pleuritic chest pain and dyspnea. COVID-19 was ruled out. Bedside ultrasound revealed a clot in transit in the inferior vena cava (IVC); CT revealed nonspecific inflammatory changes throughout the right breast, axilla, and right body wall believed to be related to infection or venous obstruction, without IVC thrombus or PE. Repeat ultrasound on day 1 in the ICU revealed nonocclusive thromboses of the right subclavian/axillary veins and complete thrombosis of the left axillary vein. She was a poor candidate for thrombolytics and thrombectomy given her current shock state and hemodynamic instability. She received unfractionated heparin, norepinephrine, and vasopressin. She also received synthroid (200mcg-IV) and stress-dose steroids for profound hypothyroidism. Examination revealed right hand phlegmasia and she disclosed a three-year history of spontaneous hand swelling and pain, which had never been evaluated. Her large clot burden and thrombocytopenia prompted concern for thrombotic microangiopathy (TMA)/possible malignancy. She was intubated due to worsening respiratory and hemodynamic status. On day 2, lupus anticoagulant (LA, HemosIL® dRVVT, Instrumentation Laboratory) was positive at 1.74 (cut-off ≤1.16). The heparin administration prompted initial concern for false positivity, although dRVVT neutralizes heparin up to 1 U/mL.1 On day 4, the patient started 2 g/kg intravenous immunoglobulin (IVIG) and a two-hour activated partial thromboplastin time (aPTT) mixing study was performed along with the repeat LA. The baseline aPTT was 58.9 seconds, which remained slightly prolonged at 39.8 seconds following heparinase (heparin-neutralizing enzyme). The aPTT mixing study revealed increasingly prolonged aPTT, supporting the presence of aPL (Table S1). Factor VIII was not performed as bleeding was not clinically suspected. The confirmatory LA test using the heparinased sample was weakly positive (1.21) due to IVIG interference. By day 3 she had developed cerebral edema with two areas of subacute infarct. Her platelets fell to 15 × 109/L by day 4; negative ADAMTS13 activity and PF4 antibody (HemosIL® HIT-Ab[PF4-H], Instrumentation Laboratory) ruled out thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT), respectively. Genetic testing revealed double heterozygous factor V Leiden (FVL) (G1691A, Arg506Gln) and prothrombin G20210A mutation (PTGM). Anticardiolipin (aCL) and beta-2-glycoprotein (B2GP1) (IgG and IgM) were consistently negative. The patient underwent five rounds of plasmapheresis for presumed antiphospholipid syndrome (APS) on days 5, 7, 8, 12, and 13, and received pulse dose steroids and continued weight based (1 mg/kg) methylprednisone until day 19. She also continued to receive heparin, which was frequently monitored via aPTT and anti-Xa. She developed acute renal failure, acute hypoxemic respiratory failure, and consumptive coagulopathy. She exhibited diffuse, reticular, erythematous skin lesions and areas of ischemia within 3 days of admission. A skin biopsy revealed epidermal and pandermal necrosis and intravascular organizing thrombi in small caliber vessels (Image 1). This progressed to bilateral upper and lower extremity necrosis necessitating amputation of the right hand from the radiocarpal joint, all left-hand digits, and all bilateral toes (Image 2). Unfractionated heparin was eventually discontinued, and she transitioned to warfarin bridged with enoxaparin. LA performed on day 102 was positive (1.60), confirming the diagnosis of APS with catastrophic presentation. She was discharged home on day 133. Catastrophic antiphospholipid syndrome (CAPS) is a severe form of APS involving diffuse thrombosis, ischemia, and multi-organ failure.2 CAPS occurs in <1% of patients with APS, has a mortality rate of approximately 50%, and is treated with anticoagulation, IVIG, plasmapheresis, and corticosteroids.3-5 Diagnostic criteria include (a) involvement of ≥3 organs; (b) positive aPL; (c) small vessel occlusion(s) in ≥1 organ; and (d) rapid development of clinical phenomena (<1 week).6 The pathophysiology is poorly understood, and the low incidence is not conducive to widespread research. Therefore, the CAPS Registry was created, and to date includes the clinical, laboratory, and therapeutic data of at least 500 CAPS patients.7 The relative risk of thrombosis in women taking combined OCP is 3- to 5-fold.8 This is amplified further in women with thrombophilia (eg. 35-fold in FVL),9 and APS is a strict contraindication for use.10 Heterozygous carriers of FVL and PTGM have respective risks of 5- and 3-fold for first-time thrombosis; however, the risk is 20-fold higher in individuals with double heterozygous mutations (occurring in 0.1% of the Caucasian population).11, 12 One study reported a significantly increased risk during OCP use in patients with combined FVL and PTGM (0.86 [95% CI, 0.10–3.11] per 100 pill-years), which increased further during the peripartum period (7.65 [95% CI, 3.08–15.76] per 100 pregnancy-years).13 Pregnancy complications and OCP have been previously reported as precipitating factors in CAPS.5, 14 In the absence of other known risk factors, we presume that our patient's CAPS was provoked by OCP. To our knowledge, this is the first report of CAPS precipitated by OCP in a double carrier of FVL and PTGM. We thank Anna Israel, MD for her assistance with obtaining the photo of the dermatopathology slide used in this report. We also thank the staff of the special coagulation laboratory for their assistance. There is no source of funding to report. Dr. Majed Refaai has received personal fees from CSL Behring, Octapharma, Bayer, Instrumentation Laboratory, Diagnostica Stago, and iLine microsystems. All other authors have no conflicts of interest to report. This case report did not require approval by the University of Rochester Research Subjects Review Board. The patient and her family provided their signed informed consent for release of medical information including photographs, histology slides, and laboratory results, for the purpose of publication of a case report as contribution to medical literature. Consent was obtained by one of the co-authors of this manuscript (a member of the primary treating team) and performed according to Strong Memorial Hospital/University of Rochester Medical Center guidelines. A copy of the signed informed consent may be provided to the Journal upon request. Hannah L. McRae: Case report conception, compiled images and laboratory data, co-wrote manuscript, approved final version. Annie H. Yang: Case report conception, compiled images and laboratory data, co-wrote manuscript, approved final version. Karen Kruzer: Case report conception, obtained patient consent for case report publication, compiled images and laboratory data, final manuscript review, approved final version. Glynis A. Scott: Case report conception, interpretation of histopathology and analysis of clinical data, final manuscript review, approved final version. Majed A. Refaai: Case report conception, analysis of clinical and laboratory data, oversaw manuscript preparation, final manuscript review, approved final version. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Table S1 Vitals and laboratory values from days 0 to 3 of admission. *The patient tested negative for COVID-19 PCR (polymerase chain reaction) on the first day of admission and on multiple subsequent occasions throughout the duration of hospitalization. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.