Case presentation

A 25-year-old woman with a past medical history of reported Sjögren syndrome, Hashimoto thyroiditis status post hemithyroidectomy, chronic migraines, and depression was transferred to our tertiary care center for evaluation and management of severe autoimmune hemolytic anemia after requiring multiple blood transfusions at an outside hospital.

Five days prior to her initial presentation, she developed a severe left-sided migraine associated with nausea, vomiting, and photophobia. She denied fever, recent illness, medication changes, travel, toxic exposures, recent infections, significant cold exposure (including occupational or environmental exposure), or cold-induced symptoms. Evaluation at the outside hospital revealed profound anemia with a hemoglobin concentration of 5.6 g/dL and persistent sinus tachycardia. She received two units of PRBCs; however, her hemoglobin demonstrated only transient improvement and continued to decline despite transfusion support. During her hospitalization, she ultimately required a total of five units of PRBCs. Initial laboratory evaluation demonstrated a positive DAT, elevated total bilirubin (4.6 mg/dL), reticulocytosis (15%), and folate deficiency, raising concern for autoimmune hemolytic anemia. Iron studies demonstrated a serum iron concentration of 184 µg/dL, total iron-binding capacity of 273 µg/dL, transferrin saturation of 67%, and a ferritin concentration of 1,739 ng/mL. These findings were not consistent with iron deficiency, and intravenous iron supplementation was therefore not indicated. She received prednisone 60 mg before transfer to our institution for higher-level hematologic care.

Upon arrival, the patient reported a six-month history of progressively worsening fatigue, exertional dyspnea, palpitations, tinnitus, and generalized weakness. She also described a one-week history of dark-colored urine and jaundice. She denied any prior history of anemia, blood transfusions, thromboembolic disease, or known hematologic disorders. Family history was negative for inherited blood disorders or autoimmune hemolytic anemia.

On examination, she appeared ill, fatigued, and markedly pale with scleral icterus and persistent tachycardia. Cardiovascular examination revealed a regular rhythm without murmurs. Pulmonary examination was unremarkable. Abdominal examination demonstrated mild right upper quadrant tenderness without rebound or guarding. No palpable lymphadenopathy or hepatosplenomegaly was appreciated on physical examination.

Initial laboratory studies demonstrated a hemoglobin concentration of 6.1 g/dL, which rapidly declined despite transfusion support, reaching a nadir of 3.2 g/dL during hospitalization. The platelet count decreased from 140 × 10⁹/L to 70 × 10⁹/L, while the reticulocyte count increased to 31.4%, reflecting an appropriate marrow response to severe hemolysis. Lactate dehydrogenase exceeded 1,000 U/L, total bilirubin peaked at 4.6 mg/dL with a direct bilirubin of 1.2 mg/dL (calculated indirect bilirubin approximately 3.4 mg/dL), and haptoglobin was undetectable. Peripheral blood smear demonstrated spherocytes without schistocytes or other features of microangiopathic hemolysis. The DAT was positive for both IgG and C3, confirming immune-mediated hemolysis. The laboratory report documented DAT positivity for both IgG and C3; however, the specific testing methodology (polyspecific versus monospecific sequence) was not available. Blood bank antibody identification demonstrated an anti-S alloantibody together with warm and cold autoantibodies, and compatible S-negative red blood cell units were recommended for transfusion. Because IgM characterization and thermal amplitude studies were unavailable, a definitive distinction between complement-positive wAIHA and mixed AIHA could not be established. Coagulation studies demonstrated an isolated prolonged activated partial thromboplastin time (50.9 seconds) with normal prothrombin time and international normalized ratio. Serial laboratory trends throughout hospitalization are summarized in Table 1.

Laboratory Parameter | Units | Reference Range | Presentation | Peak/Nadir | Discharge
Hemoglobin | g/dL | 12.0–16.0 | 6.1 | 3.2 | 11
Platelet count | ×10⁹/L | 150–400 | 140 | 70 | 223
Reticulocyte count | % | 0.5–2.5 | 15 | 31.4 | Not Recorded
Lactate dehydrogenase (LDH) | U/L | 140–280 | >1000 | >1000 | Improved
Total bilirubin | mg/dL | 0.2–1.2 | 4.6 | 4.6 | 0.9
Haptoglobin | mg/dL | 30–200 | Undetectable | Undetectable | Not Recorded
Direct antiglobulin test (DAT) | — | Negative | IgG+C3 positive |  | 

Because of rapidly progressive hemolysis and critical anemia, the hematology service was consulted immediately. Pulse-dose intravenous methylprednisolone (1 g daily) was initiated along with IVIG (1 g/kg/day) for three consecutive days (hospital days 1-3). Following the transfer, the patient required four additional units of PRBCs. Transfusion was administered to maintain hemoglobin above 7 g/dL while definitive immunosuppressive therapy took effect despite anticipated compatibility challenges. Folic acid supplementation (5 mg daily) was also initiated. Given the severity of the disease, rituximab was considered as second-line therapy should she fail to demonstrate an adequate response to corticosteroids and IVIG.

The concurrent development of thrombocytopenia prompted concern for an underlying systemic autoimmune disorder and possible Evans syndrome. Rheumatology was consulted for further evaluation. Autoimmune testing demonstrated a positive antinuclear antibody (ANA) at 1:640 with a homogeneous nuclear pattern, positive anti-SSA antibodies, positive anticardiolipin antibodies, positive anti-thyroid peroxidase antibodies, and positive antiphosphatidylserine IgG antibodies. Anti-double-stranded DNA antibodies were negative, complement levels (C3 and C4) remained within normal limits, and paroxysmal nocturnal hemoglobinuria (PNH) flow cytometry was negative. The prolonged activated partial thromboplastin time, together with positive anticardiolipin antibodies, raised concern for lupus anticoagulant; however, confirmatory lupus anticoagulant testing was not available. A summary of the autoimmune and hematologic evaluation is provided in Table 2. In conjunction with her reported history of Sjögren syndrome, thrombocytopenia, autoimmune hemolytic anemia, and a faint malar rash observed during hospitalization, these findings raised concern for evolving SLE. Hydroxychloroquine 200 mg daily was initiated.

Test | Result | Reference/Interpretation
Antinuclear antibody (ANA) | Positive (1:640, homogeneous nuclear pattern) | Negative
Anti-SSA (anti-Sjögren syndrome-related antigen A) | Positive | Negative
Anticardiolipin antibody | Positive | Negative
Antiphosphatidylserine IgG | Positive | Negative
Anti-thyroid peroxidase (Anti-TPO) | Positive | Negative
Anti-double-stranded DNA (dsDNA) | Negative | Negative
Complement component 3 (C3) | Normal | Normal
Complement component 4 (C4) | Normal | Normal
Direct antiglobulin test (DAT) | IgG and C3 positive | Negative
Paroxysmal nocturnal hemoglobinuria (PNH) flow cytometry | Negative | Negative

During hospitalization, the patient developed diffuse abdominal pain, most pronounced in the right upper quadrant. Abdominal ultrasonography demonstrated moderate-to-severe splenomegaly and diffuse gallbladder wall thickening without cholelithiasis (Figure 1). Subsequent hepatobiliary iminodiacetic acid (HIDA) scanning demonstrated no evidence of acute cholecystitis. She also experienced persistent severe headaches with photophobia following IVIG administration. Computed tomography of the head demonstrated no acute intracranial hemorrhage or other intracranial abnormality, and her symptoms were attributed to IVIG-associated headache.

Figure 1: Longitudinal abdominal ultrasonography demonstrating moderate-to-severe splenomegaly.The red arrow indicates the enlarged spleen, which measured 15.8 cm in maximal longitudinal dimension, consistent with increased extravascular hemolysis and splenic sequestration of immunoglobulin G (IgG)-coated erythrocytes in warm autoimmune hemolytic anemia.

Given the severity of anemia and associated thrombocytopenia, bone marrow biopsy was considered to exclude an underlying marrow disorder or lymphoproliferative process. However, as the patient's hematologic parameters improved rapidly with immunosuppressive therapy, the procedure was deferred, with plans for outpatient evaluation only if recurrent or persistent cytopenias developed.

Following completion of pulse-dose corticosteroids and IVIG, laboratory improvement paralleled the patient's clinical recovery. Hemoglobin increased from 3.2 g/dL to 6.1 g/dL, then 8.9 g/dL, and ultimately 11.0 g/dL by discharge. Concurrently, platelet count recovered from a nadir of 70 × 10⁹/L to 223 × 10⁹/L, while total bilirubin normalized from 4.6 mg/dL to 0.9 mg/dL without additional transfusion requirements (Table 1), demonstrating rapid resolution of hemolysis. Because of this sustained clinical response, rituximab was ultimately deferred. Intravenous methylprednisolone was transitioned to an oral prednisone taper beginning on hospital day 10, while hydroxychloroquine and folic acid were continued.

By hospital day 13, the patient remained hemodynamically stable with no evidence of ongoing hemolysis or additional transfusion requirements. She reported significant improvement in fatigue, dyspnea, and jaundice, and was discharged home on an oral prednisone taper, hydroxychloroquine, and folic acid with close outpatient follow-up by hematology and rheumatology.