A 28-year-old man presents with progressive jaundice, dark urine, and dyspnea for 1 week. He has no prior medical history and denies drug use or transfusions. On examination: temperature 38.2°C, icterus, no lymphadenopathy, mild splenomegaly. Labs: Hb 7.8 g/dL, reticulocyte count 12%, indirect bilirubin 5.1 mg/dL, LDH 920 U/L, haptoglobin <5 mg/dL. Direct antiglobulin test (DAT/Coombs) is strongly positive (3+) with IgG and complement coating. Peripheral blood smear shows spherocytes and polychromasia. What is the most likely diagnosis?

Explanation

## Diagnosis: Warm Autoimmune Hemolytic Anemia (Warm AIHA) **Key Point:** Warm AIHA is caused by IgG autoantibodies binding to RBC surface antigens, leading to complement activation and splenic sequestration. It is the most common form of autoimmune hemolytic anemia (~70% of AIHA cases). ### Clinical Features Pointing to Warm AIHA | Feature | Warm AIHA | Cold Agglutinin Disease | MAHA | TRAHR | |---------|-----------|------------------------|------|-------| | **Temperature of antibody binding** | 37°C (body temp) | 4°C (cold) | N/A (mechanical) | Alloimmunization | | **Antibody type** | IgG (+ complement) | IgM (+ C3) | None | IgG alloantibody | | **DAT result** | Positive IgG ± C3 | Positive C3 only | Negative | Positive (alloantibody) | | **RBC morphology** | Spherocytes | Agglutination | Schistocytes | Spherocytes | | **Splenomegaly** | Common | Rare | No | Rare | | **Onset** | Insidious, any age | Acute, post-viral, elderly | Acute (DIC, TTP, HUS) | Immediate post-transfusion | | **Trigger** | Idiopathic, SLE, CLL | Viral infection, Mycoplasma | Sepsis, malignancy, drugs | ABO/Rh incompatibility | ### Pathophysiology of Warm AIHA ```mermaid flowchart TD A[Autoimmune trigger]:::outcome --> B[IgG autoantibodies produced]:::outcome B --> C[Bind RBC surface antigens]:::outcome C --> D[Complement activation C1q → C3]:::outcome D --> E[Opsonized RBCs]:::outcome E --> F{Site of destruction?}:::decision F -->|Spleen| G[Splenic macrophages remove RBCs]:::action F -->|Intravascular| H[Complement-mediated lysis]:::action G --> I[Spherocytes in circulation]:::outcome H --> J[Hemoglobinuria, dark urine]:::outcome I --> K[Hemolytic anemia]:::urgent ``` ### Why This Case is Warm AIHA 1. **Positive DAT with IgG:** Diagnostic hallmark of warm AIHA 2. **Spherocytes on smear:** Result of partial splenic destruction and membrane loss 3. **Splenomegaly:** Site of RBC sequestration and destruction 4. **Fever:** Suggests immune activation (not typical of cold agglutinin disease) 5. **No transfusion history:** Rules out transfusion-related acute hemolytic reaction 6. **Insidious onset:** Warm AIHA develops over days to weeks; cold agglutinin disease is typically acute post-viral **High-Yield:** The **DAT is the gold standard** for diagnosing AIHA. Warm AIHA = IgG ± C3; Cold agglutinin disease = C3 only (IgM does not fix complement well in vivo). **Clinical Pearl:** In warm AIHA, spherocytes form because splenic macrophages bite off membrane while leaving the hemoglobin intact. This reduces surface-area-to-volume ratio, making cells osmotically fragile. ### Management 1. **First-line:** Corticosteroids (prednisolone 1 mg/kg/day) 2. **Second-line:** Splenectomy (if steroid-dependent or refractory) 3. **Third-line:** Rituximab, azathioprine, or IVIG 4. **Transfusion:** Only if Hb <5 g/dL; use least incompatible blood [cite:Robbins 10e Ch 13; Harrison 21e Ch 135]