Autoimmune hemolytic anemia (AIHA) is a class of disorders of antibody- mediated red blood cell destruction. In rare cases, AIHA presents with concurrent reticulocytopenia, resulting in severe anemia due to inability to replenish hemolyzed erythrocytes. In this case, a 24-year-old woman presented with IgG- mediated AIHA and marked reticulocytopenia. She required a rapid transfusion protocol and vasopressor support, immunosuppression with rituximab, vincristine, and intravenous immunoglobulin (IVIG), and stimulation of erythrocyte production with darbepoetin.

Due to her reticulocytopenia and her inability to replenish her red cells, she had persistent refractory anemia resulting in end-organ damage, underlining the importance of prompt identification and treatment of this condition.

• Autoimmune hemolytic anemia
• Hemolysis
• AIHA
• Reticulocytopenia
• IgG

Li1 K, Mehta R (2025) A Case of Autoimmune Hemolytic Anemia Exacerbated By Reticulocytopenia. JSM Clin Case Rep 13(1): 1253.

AIHA: Autoimmune Hemolytic Anemia, IVIG: Intravenous Immunoglobulin; DAT: Direct Antigen Test

Autoimmune hemolytic anemia (AIHA) is traditionally classified into warm IgG or cold IgM antibody mediated hemolysis [1]. A positive direct antigen test (DAT) for IgG or C3 is the primary diagnostic test; other characteristic findings include increased lactate dehydrogenase (LDH), increased indirect bilirubin, and decreased haptoglobin [2].

Rarely, AIHA presents with concurrent reticulo- cytopenia due to underlying vitamin deficiency, infection, or autoimmune targeting of red blood cell precursors [3,4]. AIHA with reticulocytopenia can result in severe anemia and medical emergency requiring rapid transfusion [4-6].

The current first line therapy for warm AIHA is corticosteroids, which are effective in approximately 80-95% of patients but may take weeks to take full effect [1]. Second-line therapies for warm AIHA include rituximab, azathioprine, cyclophosphamide, cyclosporin, splenectomy, and complement inhibitors. In contrast, the first-line therapy for symptomatic cold AIHA in adults is rituximab. To date, there has been no consensus on the optimal treatment algorithm for AIHA with reticulocytopenia.

A 24-year-old woman with a medical history of type 2 diabetes, Cushing syndrome, and ovarian teratoma presented to the emergency department with a 3-day history of weakness, nausea, vomiting, and jaundice. Upon presentation, her hemoglobin was 6 g/dl (12-16 g/dl), AST 69 U/L (10-40 U/L), ALT 51 U/L (10-40 U/L), total bilirubin 9.5 mg/dl (0.3-1.0 mg/dl), direct bilirubin 3.3 mg/dl (0.1-0.3 mg/dl), and blood glucose over 400 mg/dl.

The patient initially received IV fluids and transfusion of 2 units of packed red blood cells. She remained acutely anemic with repeat hemoglobin of 5 g/dl, absolute reticulocyte count of 2.9 k/cumm (21-115 k/cumm), and the reticulocyte percentage was 0.9% (0.5-2.5%). Further hematologic workup revealed a positive DAT for IgG and C3, folate of 11.2 ng/ml (1.8-9.0 ng/ml), and B12 of 607 pg/ml (200-800 pg/ml). A peripheral blood smear showed agglutination of red blood cells but no blasts or schistocytes. CT of her abdomen and pelvis and ultrasound of the right upper quadrant to rule out portal vein thrombosis showed patent vasculature and no acute findings. The patient was diagnosed with AIHA and began IV methylprednisolone and IVIG. The patient subsequently developed DKA.

She also spiked a fever, for which she received empiric antibiotics. A thorough infectious workup was ordered; she was weakly positive for Mycoplasma pneumoniae, but negative for bacteremia, parvovirus, CMV, EBV, VZV, SARS- COV-2, toxoplasmosis, RPR, and tick-borne illnesses. Due to the severity of her condition, she was transferred to an academic medical center for further management in the intensive care unit.

Upon arrival, the patient was hypertensive and tachycardic with hematocrit <15%. Her LDH was 643 units/L (80-225 units/L). Cold autoimmune antibody was minimally detected, with a cold agglutinin titer of 1:8. Donath-Landsteiner antibody was negative. Bilirubin was elevated at 13.1 mg/dl, of which 6.2 mg/dl was direct. Her absolute reticulocyte count was 9.4 k/cumm. She continued IV methylprednisolone and IVIG at a dose of 1g/ kg. Overnight, she continued to be anemic with hematocrit of 16% and icteric plasma despite administration of 3 units of packed RBCs. Evaluation of the patient’s labs was complicated by immediate marked agglutination upon blood draw.

The following night, the patient experienced progressive confusion and fevers to 40.6°C. She was intubated for airway protection, and a central line was placed. She became hypotensive, requiring vasopressor support and the initiation of a massive transfusion protocol. At this time, her hemoglobin was undetectable. She received 7 units of packed red blood cells through her central line before improvement of hematocrit to 8%. She was weaned from vasopressors that day. She started darbepoetin, rituximab, and vincristine dose-adjusted for her elevated bilirubin. No etiology was identified for the patient’s fever. The possibility of serotonin syndrome was considered, as the patient was previously on an SSRI and sedated with fentanyl; however, she never exhibited hyperreflexia and her fever did not improve when fentanyl was discontinued.

While she had no further need for massive transfusion protocol, the patient’s hospital course was further complicated by liver and renal failure. Her total bilirubin rose to 14.5 mg/dl, with 8.4 mg/dl direct bilirubin, suggesting a multifactorial cause beyond hemolysis. She also continued to experience fevers to 41.4°C, which improved after initiation of hemodialysis. Subsequent head CT showed no acute findings, and brain MRI showed bilateral globus pallidus ischemia. Four days after admission, her reticulocytes remained low at 7.8 k/cumm and 0.4%. A second dose of darbepoetin was administered. In the days following, she began to stabilize with transfusion requirement decreasing to 1-2 units of packed RBCs approximately every other day. Nine days after admission, her reticulocyte count increased to 16.9 k/cumm.

Further investigations to determine the cause of the patient’s AIHA were unrevealing. Serum protein electrophoresis indicated a slight nonspecific decrease in gamma globulin and nonspecific protein loss consistent with malnutrition. Flow cytometryshowedaheterogeneous cellular population with immunophenotypically normal T cells, polyclonal B cells, and a normal number of blasts. There was no evidence of lymphoproliferative disorders, lymphoma, or leukemia.

Ultimately, the patient experienced significant end organ damage with ischemic brain injury, renal failure, and shock liver. Due to her persistent reticulocytopenia, she underwent bone marrow biopsy, which revealed a full range of erythroid maturation and erythroid hyperplasia consistent with peripheral destruction. On continued immunosuppression, her reticulocyte count improved to 176.5 k/cumm (7.3%) two weeks after admission. After completing her four-week course of rituximab, she was stable for transfer from the ICU to the medical floor, where she improved until discharge to a rehabilitation facility.

This case describes a patient with severe refractory AIHA with reticulocytopenia. There was no apparent trigger to her hemolytic crisis, though she was weakly positive for Mycoplasma pneumoniae. She was initially presumed to have cold agglutinin disease due to significant erythrocyte agglutination noted on her peripheral blood smear and immediate agglutination of collected blood samples. However, the cold agglutinin titer was 1:8 and Donath-Landsteiner antibody was negative. Additionally, the DAT for IgG was positive, suggesting that the hemolysis was primarily IgG mediated. The patient’s presentation was notable for markedly decreased reticulocytes of only 2.9 k/cumm despite a hemoglobin of 5 g/dl. AIHA with reticulocytopenia is associated with severe anemia requiring multiple lines of therapy, due to inadequate compensation for hemolyzed erythrocytes [7].

In addition to corticosteroids, she also received IVIG. Though commonly a second-line treatment with lower efficacy than steroids, IVIG has shown benefit when administered with steroids, particularly in critically ill patients with hemoglobin <6-7 g/dl upon presentation [8- 11]. IVIG was favored due to its rapid response time of one to five days.

Despite initial treatment, the patient decompensated. Darbepoetin, vincristine and rituximab were added to her regimen. Darbepoetin was used to increase red blood cell production considering her marked reticulocytopenia. Vincristine was dose-adjusted to account for her hyperbilirubinemia, which was suspected to be multifactorial rather than secondary to hemolysis alone. Other second-line therapies, such as cyclophosphamide and azathioprine, were avoided due to concern for myelosuppression and exacerbation of reticulocytopenia. The patient subsequently received an additional dose of darbepoetin; her reticulocyte count was observed to slowly recover on this regimen. The initiation of complement inhibitors was considered, but ultimately withheld as she began to stabilize.

The patient’s bone marrow biopsy showed no abnormalities and appropriate erythroid bone marrow response. Coupled with her normal iron, folate, and vitamin B12 levels, this suggests that the patient’s reticulocytopenia was possibly caused by autoimmune destruction of red blood cell precursors. This is consistent with past case reports of reticulocytopenic AIHA patients with hypererythroid bone marrow [5,6]. Unfortunately, though the patient eventually stabilized hemodynamically, her prolonged anemia and hypoperfusion resulted in end organ damage requiring long-term care.

Autoimmune hemolytic anemia with reticulocytopenia presents unique treatment considerations due to its potentially severe, refractory presentation. Due to the inability to replenish hemolyzed red blood cells, reticulocytopenic AIHA patients are at especially high risk of anemia resulting in hypoxia and subsequent end organ damage. Prompt transfusion is imperative. In addition to corticosteroids and IVIG, physicians should consider erythroid stimulating agents such as darbepoetin as well as non- myelosuppressive immunosuppressantsA such as  rituximab,  vincristine  and  complement  inhibitors concurrently.

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