Discussion

wAIHA accounts for approximately 70-80% of all autoimmune hemolytic anemia cases and is characterized by IgG-mediated erythrocyte destruction occurring primarily through Fc receptor-mediated clearance by splenic macrophages [1,2]. While approximately one-half of cases are idiopathic, the remainder occur secondary to underlying conditions, including lymphoproliferative disorders, medications, infections, and systemic autoimmune diseases [1,3]. Among autoimmune disorders, SLE is one of the best-recognized causes of secondary wAIHA, whereas Sjögren syndrome represents a less common but increasingly recognized association [4-6].

Our patient presented with fulminant wAIHA in the setting of reported Sjögren's syndrome and multiple serologic and clinical findings concerning evolving SLE. Although she carried a prior diagnosis of Sjögren syndrome, hospitalization revealed a high-titer ANA (1:640), positive anti-SSA antibodies, antiphospholipid antibodies, thrombocytopenia, autoimmune hemolytic anemia, and a faint malar rash, prompting concern for an evolving lupus phenotype despite negative anti-double-stranded DNA antibodies and preserved complement levels. This case illustrates an important clinical principle: autoimmune cytopenias may precede fulfillment of formal SLE classification criteria and may represent one of the earliest manifestations of systemic autoimmunity [4,9]. Consequently, patients presenting with immune-mediated cytopenias should undergo a comprehensive rheumatologic evaluation, particularly when multiple autoimmune features coexist.

The coexistence of reported Sjögren syndrome, Hashimoto thyroiditis, and autoimmune hemolytic anemia in this patient also highlights the concept of polyautoimmunity, in which multiple autoimmune diseases coexist because of shared genetic susceptibility and common immunologic pathways. Chronic B-cell activation, impaired immune tolerance, autoreactive T-cell signaling, and production of pathogenic autoantibodies contribute to immune-mediated tissue injury across multiple organ systems [5,6]. Sjögren syndrome has traditionally been regarded as an exocrine gland disorder; however, it is increasingly recognized as a systemic autoimmune disease capable of producing hematologic manifestations including leukopenia, thrombocytopenia, hypergammaglobulinemia, lymphoma, and, less commonly, autoimmune hemolytic anemia [5]. Recognition of these overlapping autoimmune conditions is clinically important because hematologic abnormalities may be the initial or dominant manifestation of systemic disease.

The diagnosis of wAIHA requires demonstration of both hemolysis and immune-mediated erythrocyte destruction. Our patient exhibited nearly every characteristic diagnostic feature of the disease, including profound anemia, marked reticulocytosis, elevated lactate dehydrogenase, indirect hyperbilirubinemia, undetectable haptoglobin, spherocytes on peripheral blood smear, and a DAT positive for both IgG and complement (C3). Diagnostic findings supporting wAIHA are summarized in Table 3, while serial laboratory recovery following therapy is demonstrated in Table 1. Although most patients with wAIHA demonstrate IgG positivity alone, approximately 20-30% also exhibit complement deposition [1,2]. The updated 2024 classification of autoimmune hemolytic anemia emphasizes that positivity for both IgG and C3 on the DAT may occur in either classic wAIHA or mixed AIHA [10]. In this patient, blood bank antibody identification detected both warm and cold autoantibodies in addition to an anti-S alloantibody. However, IgM characterization and thermal amplitude studies were not available, precluding definitive classification as mixed AIHA. Nevertheless, the patient's predominant clinical presentation, absence of clinically significant cold-induced symptoms, and excellent response to corticosteroids and IVIG supported treatment as wAIHA with complement activation [10]. Complement-positive disease may be associated with more severe hemolysis because erythrocyte destruction occurs through both splenic macrophage-mediated clearance and complement activation, likely contributing to the profound hemolysis observed in this patient.

Diagnostic Finding | Patient Result | Interpretation
Hemoglobin | 3.2 g/dL nadir | Severe anemia
Reticulocytosis | Present | Supports hemolysis
LDH | Elevated | Supports hemolysis
Hyperbilirubinemia | Elevated (total bilirubin 4.g mg/dL; direct bilirubin 1.2 mg/dL) | Supports hemolysis
Haptoglobin | Undetectable | Supports hemolysis
DAT | IgG and C3 positive | Confirms immune-mediated hemolysis
Peripheral smear | Spherocytes present; schistocytes absent | Consistent with wAIHA
Response to corticosteroids and IVIG | Rapid clinical improvement | Supports diagnosis

One of the most remarkable aspects of this case was the severity of anemia. Despite transfusion of multiple PRBC units, the patient's hemoglobin continued to decline, reaching a nadir of 3.2 g/dL. Hemoglobin concentrations approaching 3 g/dL are rarely reported in adults with wAIHA and generally appear only in isolated case reports. At these levels, oxygen delivery becomes critically compromised, placing patients at risk for myocardial ischemia, high-output heart failure, cerebral hypoxia, arrhythmias, and death [7]. The favorable outcome observed in this case underscores the importance of early recognition and immediate initiation of immunosuppressive therapy before irreversible end-organ injury develops.

Management of severe wAIHA presents significant transfusion challenges because broadly reactive warm autoantibodies frequently interfere with serologic compatibility testing. Historically, concerns regarding transfusion-related hemolysis resulted in delays in blood product administration. Current evidence, however, emphasizes that transfusion should not be withheld in patients with life-threatening anemia solely because completely compatible blood cannot be identified [1,7]. Instead, collaboration with transfusion medicine specialists to provide the safest available or least-incompatible units is recommended while definitive immunosuppressive therapy is initiated. In our patient, transfusion was administered because of profound symptomatic anemia with ongoing hemolysis despite compatibility challenges. Following the transfer, the patient received four additional units of PRBCs to maintain a hemoglobin concentration above 7 g/dL while immunosuppressive therapy took effect. This approach is consistent with current recommendations that transfusion should not be delayed in patients with life-threatening anemia, even when completely compatible blood cannot be identified.

Current international guidelines recommend corticosteroids as first-line therapy for wAIHA, with initial response rates approaching 70-85% [1,2]. Corticosteroids decrease macrophage-mediated erythrophagocytosis and suppress autoantibody production, making them the cornerstone of treatment. Because our patient demonstrated rapidly progressive hemolysis with a critically low hemoglobin concentration, pulse-dose intravenous methylprednisolone (1 g daily) was selected rather than conventional oral corticosteroids. Although prospective data evaluating pulse-dose therapy remain limited, this strategy is widely employed in fulminant autoimmune disease because of its rapid immunosuppressive effects and extensive clinical experience in severe immune-mediated disorders.

IVIG was administered concurrently as adjunctive therapy. Unlike immune thrombocytopenia, IVIG has a less predictable role in wAIHA and is generally reserved for severe or refractory disease [11]. Proposed mechanisms include Fc receptor blockade, modulation of macrophage activity, and interference with pathogenic autoantibody function. Although responses are often transient, IVIG may provide sufficient disease control while corticosteroids achieve maximal therapeutic effect. In our patient, pulse-dose corticosteroids combined with IVIG resulted in rapid resolution of hemolysis, normalization of bilirubin, cessation of transfusion requirements, and sustained hematologic recovery.

Other rescue therapies have been described for refractory or fulminant AIHA. Therapeutic plasma exchange may provide temporary control of severe hemolysis while immunosuppressive therapy becomes effective, although supporting evidence remains limited. Complement-directed therapy with eculizumab has also been reported in selected cases with severe complement-mediated hemolysis, but it is not routinely recommended for classic wAIHA. Because our patient demonstrated rapid improvement following corticosteroids, IVIG, and transfusion support, neither therapeutic plasma exchange nor complement inhibition was required.

An important therapeutic consideration was whether escalation to rituximab would be necessary. Increasing evidence supports earlier incorporation of rituximab in patients with severe wAIHA because combination therapy with corticosteroids improves complete remission rates and reduces relapse compared with corticosteroids alone [2,8]. Nevertheless, rituximab is associated with prolonged B-cell depletion, hypogammaglobulinemia, infusion reactions, and infectious complications. Because our patient demonstrated prompt normalization of bilirubin, stabilization of hemoglobin, recovery of platelet count, and elimination of transfusion requirements following first-line therapy, escalation to rituximab was deferred. This case demonstrates that even patients presenting with profound anemia may achieve durable remission with aggressive first-line immunosuppressive therapy when treatment is initiated promptly.

The concurrent thrombocytopenia represented another important diagnostic challenge. The coexistence of autoimmune hemolytic anemia and thrombocytopenia raised concern for Evans syndrome, a rare autoimmune disorder characterized by simultaneous or sequential immune-mediated destruction of erythrocytes and platelets [12]. However, thrombocytopenia is also a well-recognized hematologic manifestation of systemic autoimmune diseases, particularly SLE. Because immune thrombocytopenia was never definitively established and platelet counts recovered rapidly with treatment directed at hemolysis, Evans syndrome remained a diagnostic consideration rather than a confirmed diagnosis. This distinction has important prognostic implications, as Evans syndrome generally follows a chronic relapsing course requiring prolonged immunosuppressive therapy.

Another notable feature of this case was the presence of moderate-to-severe splenomegaly demonstrated on abdominal ultrasonography (Figure 1). Although splenomegaly is not universally present in patients with wAIHA, when present, it reflects increased splenic macrophage activity and extravascular sequestration of IgG-coated erythrocytes and supports ongoing extravascular hemolysis. The enlarged spleen observed in our patient raises suspicion for active immune-mediated erythrocyte destruction and likely reflects the extraordinary burden of ongoing hemolysis that contributed to her profound anemia.

Bone marrow biopsy was initially considered because of profound anemia and thrombocytopenia. However, progressive normalization of both hemoglobin and platelet count following immunosuppressive therapy strongly supported peripheral immune-mediated destruction rather than intrinsic bone marrow pathology. Current consensus recommendations reserve bone marrow examination for patients with persistent unexplained cytopenias, atypical laboratory findings, suspected lymphoproliferative disease, or inadequate response to therapy [1]. Accordingly, the biopsy was deferred, with plans for outpatient evaluation only if recurrent cytopenias developed.

Although cases describing severe wAIHA associated with Sjögren syndrome have been reported, presentations involving a hemoglobin nadir of 3.2 g/dL remain exceedingly uncommon. Our case demonstrates that aggressive first-line therapy with pulse-dose corticosteroids and IVIG can successfully reverse fulminant immune-mediated hemolysis and avoid escalation to biologic therapy in carefully selected patients. Continued longitudinal follow-up will be important to monitor for recurrent cytopenias and further evolution of systemic autoimmune disease.