Thrombotic storm with antiphospholipid syndrome in the setting of relapsing Evans syndrome and systemic lupus erythematosus: a case report

Introduction

Evans syndrome is a rare autoimmune disease with a poorly understood etiology. It is characterized by the concurrent presence of two or more immune-mediated cytopenias, such as autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) (1). Although a rare condition, the population of individuals diagnosed is growing, so further investigation of this disorder’s mechanisms is crucial as evidence has mainly been in the form of case reports or series, or smaller cohort studies (2). Additionally, the presence of thrombocytopenia and concurrent anemia is often seen in patients with systemic lupus erythematosus (SLE) (3), and few cases have reported an association between Evans syndrome and positive lupus anticoagulant and antiphospholipid antibodies (4-8) scenario discerning primary and secondary etiology is a complex approach. In this setting, the balance between immune-mediated thrombocytopenia and subsequent bleeding versus antiphospholipid antibody-mediated clot formation and hypercoagulability makes for a uniquely challenging clinical scenario presentation and approach to management in the inpatient setting. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-190/rc).

Case presentation

A 31-year-old female with a medical history of autism spectrum disorder, antiphospholipid syndrome (APS), complete SLE, and Evans syndrome in the setting of chronic idiopathic ITP and AIHA was admitted for cholecystitis requiring laparoscopic cholecystectomy complicated by aspiration pneumonia requiring antibiotic therapy.

Regarding her prior medical history, she has been followed throughout her life for her diagnosis of autism spectrum disorder. The patient was diagnosed with SLE 10 years prior after meeting at least 4 out of 11 of the diagnostic criteria established by the American College of Rheumatology: oral ulcers, discoid rash, thrombocytopenia, and iron deficiency anemia, and positive lupus anticoagulant (9). During this period, she developed deep venous thrombosis (DVT) of the distal right iliac, right common femoral, right superficial femoral, and right popliteal veins. She was also found to have a positive antiphospholipid antibody, thereby requiring lifelong anticoagulation with warfarin. Regarding her Evans syndrome, she was found to have positive direct Coombs antibodies and positive anti-nuclear antibody (ANA) with nuclear titer 1:320 6 months prior in the setting of relapsed ITP and concurrent AIHA, requiring multiple hospital admissions in the interim. She had been initially originally been trialed with Rituximab but reportedly had an adverse reaction following rituximab infusion in the form of fever (101 ℉), rigors, tachycardia, and lactic acidosis of 6.1. Coming into this current admission, she was receiving platelet stimulation therapy with eltrombopag 50 mg daily immunosuppression with mycophenolate mofetil 1,000 mg twice a day and an ongoing prednisone taper on hospital day 1.

During her hospital course on day 13, the patient demonstrated abdominal discomfort, and computed tomography (CT) demonstrated colonic dilatation concerning for ileus and a new 3.7 cm left adrenal hematoma (Figure 1). She was started on hydroxychloroquine 200 mg twice a day and mycophenolate mofetil 1,000 mg twice a day in the setting of repeat positive ANA, nuclear titer 1:80. She also reported one episode of hemoptysis, so anticoagulation was managed conservatively by being held for a day, and the hematoma was monitored with interval imaging. The patient demonstrated worsening thrombocytopenia (137,000 to 26,000 platelets/mcL) by hospital day 15, for which her Eltrombopag dosage was increased to 75 mg daily. Given the platelet count of 27,000/mcL, she subsequently underwent a platelet transfusion and was started on a 5-day course of intravenous immunoglobulin (IVIG). A venous Doppler ultrasound then revealed occlusive DVT in the right axillary and brachial veins and occlusive venous thrombosis in the left cephalic veins on hospital day 19. This led to the immediate restart of anticoagulation therapy with close monitoring of coagulation labs. Her platelets improved the following days of her hospital course up to 50,000 platelets/mcL (Figure 2). Regarding venous thrombosis, she was continued on therapeutic enoxaparin following discharge with close outpatient follow-up.

Figure 1 Axial computed tomography view demonstrating 3.7 cm left adrenal hematoma (crossmark).

Figure 2 Trend of platelet counts over hospital course and points in hospital course where Eltromopag and IVIG administered. IVIG, intravenous immunoglobulin.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case adds to the current literature on the nuanced approach toward diagnosing and managing thrombocytopenia in a patient with confounding SLE and Evans syndrome. This patient’s initial presentation led to an admission for cholecystitis, requiring surgical intervention. During this period, the patient’s thrombocytopenia in the context of Evans syndrome was in remission. However, it is possible that the patient undergoing this intervention exacerbated Evans syndrome, leading to progressive thrombocytopenia despite being on chronic platelet stimulation therapy. Given the administration of antibiotics for her aspiration pneumonia, it also remains possible that pharmacotherapy was responsible or contributory. Relapses in individuals with Evans syndrome are reported to be relatively frequent, with one cohort revealing that over 76% of its participants experienced at least one relapse event (10). To the best of our knowledge, no literature to date reports of a relapse event following cholecystectomy, such as in this case. Moreover, these relapses have been presented in the literature in the context of other inflammatory or stress physiology, including hepatitis (11), coronavirus (12), and mRNA vaccines (13,14). Furthermore, it is unlikely that the patient underwent a flare of her SLE, given her decreased ANA titer compared to her initial diagnosis 6 months ago. Regardless, the nature of this case presents as a relapse in thrombocytopenia in a patient with a history of Evans syndrome, so it is critical for clinicians managing patients with SLE hematologic manifestations (i.e., hemolytic anemia, thrombocytopenia) also to consider Evans syndrome in their approach.

Antiphospholipid antibodies and SLE have been estimated to co-occur at a frequency of 30–40% of patients (15). Although these disorders share clinical manifestations, including thrombocytopenia, the mechanisms behind these clinical associations are poorly understood. Autoantibodies in APS target either cell membrane phospholipids directly or proteins that bind to these phospholipids (15,16). These antibodies can contribute to various arterial and venous thrombosis, including myocardial infarction, splanchnic infarction, or venous thrombosis, as seen in this patient (17). This leads to close anticoagulation monitoring to reduce clotting risk. However, the approach for anticoagulation in this patient can be complex to discern given concomitant Evans syndrome, where bleeding is a prevailing cause of death in these individuals. This complexity has been reported in previous literature due to the concern of interfering with platelet aggregation (18). In this case, the presence of a new left adrenal hematoma contributed to the decision to temporarily hold anticoagulation during the patient’s hospitalization. Current literature reports that a 5-year survival rate of secondary Evans syndrome is approximately less than 40%. Clinicians must consider the mortality risk of bleeding in the setting of Evans syndrome, declining platelets count, and reported hemoptysis (2). However, this temporary hold in anticoagulation could increase the acute risk of thrombosis in this patient, leading to thrombotic storm as exhibited by this patient’s several upper extremity DVTs. There is literature that reports the concern of catastrophic APS among patients with SLE, which made it a key concern for this patient (17,19,20). However, this patient did not meet the diagnostic requirements of catastrophic APS, given the lack of evidence of multiple organ involvement. Instead, it was considered as a thrombotic storm given the short period of which these clots occurred (21).

The decision to increase Eltrombopag dosing in this patient and starting IVIG with concurrent corticosteroid administration led to a noticeable improvement in platelet count. Eltrombopag interacts with thrombopoietin receptors, activating JAK-STAT signaling and stimulating megakaryocyte differentiation, hence its role in the patient’s ITP (22,23). However, there remains a need to establish its role in Evans syndrome, especially considering that this patient is taking the maximum recommended dose of this medication. Rituximab is another agent that is used in Evans syndrome refractory to current treatment (24,25), but this patient had failed to tolerate it in the past, so the decision was made not to pursue this agent.

Conclusions

This patient’s case highlights the complex management of thrombocytopenia, bleeding, and concurrent thromboses in a patient with the triad of Evans syndrome, SLE, and APS. As exemplified by the thrombotic storm that ensued upon withholding anticoagulation, despite simultaneous bleeding, the road to coagulative stability is complex and can shift rapidly as demonstrated in this patient’s hospital course. However, this evidence does have its limitations as this reported single case, so there remains a need to observe these outcomes among a larger, similar cohort. There also remains an imperative need to observe long-term follow-up outcomes to understand the interaction of such complex disease states. Overall, this report emphasizes the need for increased awareness of Evans syndrome relapse triggered by potential stressors and the challenges of anticoagulation in this setting. Eltrombopag, prednisone, and IVIG offer a promising therapeutic management plan, but there remains a need for further investigation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-190/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-190/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-190/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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