INTRODUCTION Immune thrombocytopenic purpura (ITP) is a rare autoimmune disorder in which the body targets specific antibodies on platelets, resulting in platelet destruction by macrophages in the spleen and a sudden decrease in platelet count, defined as 160 U/mL (ref: <43.9 U/mL) consistent with acute EBV infection. Disseminated intravascular coagulation (DIC) labs were unremarkable except for mildly elevated D-dimer, likely secondary to inflammation from EBV. Additional workup of thrombocytopenia was completed, including human immunodeficiency virus (HIV), acute hepatitis panel, vitamin B12, folate, copper, and cytomegalovirus (CMV) serologies, all of which were unremarkable. Absolute lymphocyte count was increased overall, at 8490 cells/µL. Peripheral smear and flow cytometry revealed atypical lymphocytosis with increased subsets of T-cells with a 0.97/1.0 CD4:CD8 ratio, likely reflective of acute EBV infection with a significantly decreased platelet count. There was bright CD45 expression noted. There was no abnormal T-cell antigen deletion. Abdominal ultrasound revealed splenomegaly measuring 15.5 cm (Fig. 1). A working diagnosis of ITP was made, and the patient was started on prednisone 1 mg/kg/d. Intravenous immunoglobulin (IVIG) therapy was considered due to the severity of thrombocytopenia and the presence of mucosal bleeding. However, the patient remained hemodynamically stable without evidence of life-threatening hemorrhage and demonstrated an early platelet response within 48 to 72 hours of corticosteroid initiation; therefore, IVIG was deferred.Figure 1.: Abdominal ultrasound long axis, showing splenomegaly, with a measurement of 15.5 cm. In the setting of EBV, splenomegaly is a common finding but may have also contributed to this patient’s thrombocytopenia via sequestration mechanisms. EBV = Epstein-Barr virus.After 4 days of inpatient stay, the patient’s platelet count improved to 37K (cells/µL) and she was discharged home with close primary care and hematology follow-up as outpatient. Bone marrow biopsy was not performed given the presence of isolated thrombocytopenia, absence of additional cytopenias, normal peripheral smear without blasts or dysplasia, and rapid platelet recovery following corticosteroid therapy. Current ASH guidelines do not recommend routine bone marrow examination in patients with a typical presentation of ITP and appropriate treatment response.3 In subsequent follow-ups within a week of discharge, the patient’s platelet count improved to 67K (cells/µL) and 108K (cells/µL). The patient continued a slow oral prednisone taper with continued follow-ups and her platelet count returned to the normal range 167K (cells/µL) within 4 weeks of hospitalization. 3. DISCUSSION Although mild thrombocytopenia is frequently observed in acute EBV infection, the platelet nadir of 3000 to 4000/µL in this patient meets the ASH definition of severe ITP (<10,000/µL) and represents a markedly uncommon manifestation of EBV-associated thrombocytopenia. The severity of thrombocytopenia in this patient, combined with mucosal bleeding and splenomegaly, underscores the importance of early recognition and prompt immunomodulatory therapy to prevent hemorrhagic complications. Severe thrombocytopenia secondary to EBV is especially rare in the current literature review,5 where a review of 400 cases revealed platelet counts of (<50,000/µL) in only 6 cases. EBV-associated ITP is believed to result from molecular mimicry and immune dysregulation during viral infections.6 EBV can trigger an exaggerated immune response, producing autoantibodies against platelet glycoproteins such as GPIIb–IIIa.6 These autoantibodies mediate platelet destruction via macrophages, predominantly in the spleen, resulting in severe thrombocytopenia in some cases. This underscores the importance of considering EBV as a potential cause of ITP when evaluating patients with thrombocytopenia. Current guidelines, including those from the ASH,4 primarily define primary ITP as a diagnosis of exclusion but do not comprehensively address all secondary causes, such as EBV-associated ITP.7 While HIV- and Hepatitis C-associated ITP have established treatment guidelines targeting the underlying infection, other secondary ITPs remain underrepresented in clinical protocols. Identifying rarer secondary causes of ITP, including infections (EBV, CMV, HIV, hepatitis B and C), autoimmune disorders as well as malignancies, is essential for guiding management and may require targeted treatment.8 Despite differences in primary and secondary ITP pathophysiology, first-line treatment remains consistent as per ASH year guidelines, with corticosteroids as the cornerstone therapy.3,7 Prednisone is effective in suppressing immune-mediated platelet destruction.9 In refractory cases, second-line therapies such as IVIG or rituximab, an anti-CD20 monoclonal antibody, may be required.9 In our patient, early corticosteroid initiation led to a rapid platelet response, allowing deferral of IVIG, although clinicians should be aware that profound thrombocytopenia or significant mucosal bleeding may warrant earlier consideration of IVIG in EBV-associated secondary ITP. Antiviral therapy is not routinely indicated, as acute EBV infection is typically self-limited, but careful monitoring and individualized steroid tapering are essential to optimize platelet recovery and minimize the risk of relapse.2,3 The prognosis is generally favorable for EBV-induced ITP, as most cases resolve once the viral load decreases.10 Regular monitoring of platelet counts is essential during recovery to assess treatment response and detect potential bleeding risks.10 Patient education on recognizing signs of bleeding and when to seek medical attention is also crucial. If platelet counts fail to recover within 6 months of the acute illness, further investigation for chronic immune thrombocytopenia is essential.10 Hypersplenism can contribute to thrombocytopenia in viral infections such as EBV, which commonly presents with splenomegaly, in contrast to primary ITP, where spleen size is often normal. In this patient, the observed splenomegaly (15.5 cm) was secondary to acute EBV infection and may have contributed to platelet sequestration, a recognized mechanism in thrombocytopenia. The spleen is a major site for platelet removal, and in hypersplenism, its filtration capacity is increased.11 This results in excessive sequestration and destruction of platelets, further exacerbating thrombocytopenia.11,12 However, sequestration alone would be unlikely to explain the profound platelet nadir of 3000 to 4000/µL in this case, suggesting that immune-mediated platelet destruction remained the primary mechanism. In EBV infection, the virus induces an immune response that drives lymphoid proliferation and splenic enlargement,12 creating a hyperactive immune environment that enhances platelet destruction through autoimmune mechanisms and sequestration. The spleen’s macrophages, activated by EBV-induced immune dysregulation, target platelets marked by autoantibodies, accelerating platelet turnover and leading to severe thrombocytopenia.12 One of the limitations in this case was the absence of platelet-antibody testing (eg, GPIIb–IIIa), which limits definitive confirmation of immune-mediated platelet destruction. However, in cases where thrombocytopenia persists or recurs after initial treatment, further evaluation is warranted to distinguish relapsed ITP from other causes. If relapsed ITP is suspected, a comprehensive workup is essential to exclude non-autoimmune causes and identify secondary ITP. This includes a detailed history, physical exam, complete blood count (CBC), peripheral smear, and, if indicated, bone marrow evaluation.13 Additional testing should assess for infectious triggers (eg, HIV, hepatitis C, Helicobacter pylori), autoimmune conditions (eg, antinuclear antibodies), and drug-induced thrombocytopenia through a medication review.13 If relapsed ITP is confirmed, second-line treatments include rituximab, thrombopoietin receptor agonists (TPO-RAs), and splenectomy.13 Management should be individualized based on disease duration, bleeding severity, comorbidities, age, adherence, and patient preferences, with shared decision-making ensuring alignment with patient values and goals.13 4. CONCLUSION Immune thrombocytopenic purpura is an autoimmune disorder that can have dangerous consequences due to increased bleeding risk if unrecognized. Though most cases are idiopathic, this case highlights the interplay between ITP and different potential etiologies, such as EBV. Physicians and hematologists alike should be aware of this rare complication of EBV when working up differentials for severe thrombocytopenia.
Hanna et al. (Tue,) studied this question.