Autoimmune hemolytic anemia (AIHA)

Classification by Coombs (DAT) Pattern

• AIHA is subclassified by the DAT pattern and the thermal reactivity of the autoantibody. The DAT pattern (IgG vs C3 only vs both) is the single most useful discriminator.
• DAT IgG = warm AIHA; DAT C3 only = cold agglutinin disease (or PCH); both IgG and C3 = usually warm AIHA; mixed AIHA requires a warm autoantibody plus a clinically significant cold agglutinin.

Warm AIHA

• Epidemiology: most common type of AIHA. Incidence 1 to 3 per 100,000 per year. Median age 52, slight female predominance.
• Pathophysiology: IgG panagglutinating autoantibody directed against a public epitope (Rh system, glycophorin) present on all RBCs; optimally binds RBCs at 37°C (warm). May or may not fix complement. Antibodies do not cause agglutination because of their small size. Fc-receptor-bearing splenic macrophages phagocytose antibody-coated RBCs; partial phagocytosis produces spherocytes, giving extravascular hemolysis.
• Etiologies:
  • Primary (idiopathic), roughly 50%.
  • Secondary: lymphoproliferative disorders (lymphoma, CLL; consider flow cytometry, CT, and bone marrow biopsy), rheumatologic disease (SLE; send autoimmune panels), non-lymphoid neoplasms (ovarian teratoma/tumors), chronic inflammatory disease (ulcerative colitis), HIV, and drugs (a-methyldopa, fludarabine, cephalosporins, checkpoint inhibitors). Evans syndrome if concurrent ITP.
• Clinical features: anemia of variable severity, often jaundice and splenomegaly. May present with severe acute hemolysis.
• Workup: CBC, retic, smear (spherocytes), LDH, haptoglobin, indirect bili, DAT (IgG ± C3 positive), ANA, HIV, hepatitis serologies, peripheral flow if lymphoproliferative disease suspected, age-appropriate cancer screening, drug review.
• Treatment of warm AIHA:
  • 1L, corticosteroids (prednisone 1 mg/kg/d for 3 to 4 weeks, then taper). Good initial response (~80%) but remission rate is low; initial response usually within 1 to 2 weeks; little improvement by about 3 weeks suggests failure and prompts escalation and many relapse on taper.
  • 2L, rituximab (preferred, especially earlier in younger patients), given weekly for 4 doses. Response is delayed but better; combining rituximab with steroids roughly doubles the 12-month response vs steroids alone (75% vs 36%, phase 3, first-line). Splenectomy is effective but reserved (vaccinate first for encapsulated organisms).
  • Nipocalimab (Imaavy): FcRn blocker; FDA Aug 2026 as the first approved drug for warm AIHA (age ≥12 years, currently or previously treated with corticosteroids), 30 mg/kg IV every 4 weeks. Phase 2/3 ENERGY: durable Hb response 24% vs 8% placebo.
  • 3L and beyond: azathioprine, mycophenolate mofetil, cyclophosphamide, danazol, cyclosporine, IVIG (less effective than in ITP).
  • Refractory: fostamatinib (off-label, SYK inhibitor), bortezomib, daratumumab (case series). Rilzabrutinib (BTK inhibitor; FDA-approved for ITP Aug 2025 based on LUNA 3): FDA breakthrough designation in warm AIHA (Feb 2026) on phase 2b LUMINA 2 data; phase 3 LUMINA 3 ongoing. Sutimlimab in warm AIHA: case series only.
• Transfusion in warm AIHA:
  • Identify the patient's ABO type to give ABO-identical or ABO-compatible blood and avoid a concurrent hemolytic transfusion reaction.
  • Risk of a transfusion reaction with ABO- and RhD-matched blood is nearly zero in patients never previously transfused or pregnant, and remains low (<10%) in those with prior pregnancy or transfusion.
  • Do not withhold blood over incompatibility: a dropping hemoglobin with reticulocytopenia is life-threatening. Reticulocytopenia occurs in a substantial minority early (autoantibody outpaces marrow, or reticulocytes are destroyed) and is an emergency. It is acceptable to transfuse crossmatch-incompatible ("least incompatible") blood in a transfusion-naive patient; communicate with the blood bank.
  • Panagglutinating autoantibodies cause multiple incompatible crossmatches. In previously transfused or pregnant patients, the blood bank must test for concurrent alloantibodies. Autoadsorption (patient's own RBCs) removes autoantibody to unmask alloantibody, but only if not transfused within about 3 months; after recent transfusion use allogeneic (differential) adsorption; it is time-intensive. Extended RBC typing (DNA-based, since a positive DAT interferes with serologic typing) helps identify new alloantibodies after transfusion.

Cold Agglutinin Disease (CAD)

• Pathophysiology: a low-grade clonal lymphoproliferative disorder producing complement-dependent hemolysis. Cold-reactive IgM autoantibody binds RBCs optimally at <37°C (especially peripherally where blood cools); the pentameric IgM directly agglutinates RBCs and fixes complement. Extravascular clearance of C3b-coated RBCs, mainly by hepatic Kupffer cells, predominates; direct intravascular lysis by the terminal complement (MAC) sequence occurs if severe.
• Antibody target: most often (~90%) the Ii blood group. Neonatal RBCs express i antigen; after about 18 months RBCs express I antigen. Mycoplasma yields anti-I (capital), EBV/mononucleosis yields anti-i (lowercase).
• Titer and thermal amplitude: titers ≥ 1:64 (at 4 C) are supportive, not alone diagnostic; thermal amplitude matters more than titer Thermal amplitude (the highest temperature at which the cold agglutinin reacts) is more clinically significant than the titer. Cooling of blood in acral parts allows binding, complement fixation, and hemolysis; the process abates with warming.
• Two classes:
  • Primary (chronic) CAD: clonal B-cell lymphoproliferative disorder; MYD88 L265P typically absent (distinguishes CAD-associated LPD from lymphoplasmacytic lymphoma/Waldenstrom); its presence suggests LPL/WM; "cold agglutinin-associated lymphoproliferative disorder."
  • Secondary cold agglutinin syndrome (distinct from primary clonal CAD): infection-associated (Mycoplasma anti-I, EBV anti-i) is usually transient; lymphoma- or autoimmune-associated cases may persist and track the underlying disease.
• Clinical: hemolysis worsens in cold (Raynaud-like acrocyanosis of fingers, ears, nose), livedo reticularis, hemoglobinuria.
• Workup: CBC, retic, LDH, haptoglobin, indirect bili, DAT (C3 only positive), cold agglutinin titer (≥1:64 supportive), thermal amplitude, peripheral flow (clonal B cells found even when marrow morphology does not support lymphoma), SPEP (IgM kappa monoclonal band in >90%), MYD88, bone marrow biopsy if clonal LPD suspected. Note spurious elevation of MCHC and MCV from RBC agglutination.
• Treatment of CAD:
  • Avoid cold exposure (warm clothing, warm IV fluids, warm OR; caution with bypass/hypothermic surgery). Anemia is often mild and needs no treatment. If transfusion is needed, use a blood warmer.
  • Steroids and splenectomy are NOT generally effective (C3b-opsonized RBCs are cleared by hepatic Kupffer cells, not the spleen (cold IgM dissociates on rewarming, leaving C3b), so splenectomy is ineffective).
  • Treat the underlying disorder: rituximab monotherapy, or rituximab combinations (R-bendamustine or R-fludarabine); bortezomib is an option.
  • Sutimlimab (Enjaymo): anti-C1s monoclonal antibody; rapidly controls complement-mediated hemolysis without addressing the clone. CARDINAL trial showed transfusion avoidance and Hb improvement; FDA Feb 2022. Riliprubart (next-generation anti-C1s) is in trials.
  • Plasmapheresis (TPE) for severe acute exacerbation (removes intravascular IgM fraction). Eculizumab (anti-C5) has limited efficacy because hemolysis is C3-mediated upstream.

Paroxysmal Cold Hemoglobinuria (PCH)

• Pathophysiology: rare form of AIHA caused by the biphasic Donath-Landsteiner antibody, a complement-fixing IgG directed against the P antigen (distinct from cold agglutinin disease; note rare p (P-null) phenotype cells lack P antigen and are not lysed). It binds RBCs and fixes complement at <37°C, then activates complement as the temperature reaches 37°C, giving intravascular hemolysis.
• Clinical: previously associated with syphilis; now more often in children after a viral infection (measles, mumps, parainfluenza, EBV). Sudden chills, back and leg pain, abdominal cramps, fever, and dark urine (hemoglobinuria). The antibody appears 7 to 10 days after the febrile illness and may persist 6 to 12 weeks (2 to 3 months).
• Labs: findings of hemolysis; decreased serum complement; DAT positive for C3d and negative for IgG during the hemolytic episode; smear with agglutination, spherocytes, and erythrophagocytosis by neutrophils during an acute attack.
• Donath-Landsteiner test: incubating the sample at 37°C alone shows nothing; incubating in the cold (0 to 4°C) for 30 minutes and then warming to 37°C produces hemolysis (antibody binds RBCs in the cold, then complement activates on warming).
• Treatment: usually self-limited. Supportive, treat symptoms, keep the patient warm, and use a blood warmer if transfusion is needed. Splenectomy is not useful; steroids are of questionable benefit. For chronic symptomatic disease not controlled by cold avoidance, steroids or immunosuppression (cyclophosphamide, azathioprine, rituximab) may be tried; data with anti-complement therapy are limited.

Drug-Induced Immune Hemolytic Anemia (DIIHA)

• Epidemiology: over 70 drugs implicated. By class, roughly 42% antimicrobials, 16% NSAIDs, 13% antineoplastics, and 6% antihypertensives.
• Course: most cases resolve within 1 to 2 weeks of stopping the drug; cefotetan-induced hemolysis may last longer.
• Treatment: cornerstone is discontinuing the offending drug; recovery is typically days to weeks. Symptomatic or severe disease can be treated with glucocorticoids and/or IVIG, especially when it is not yet clear whether the cause is drug-induced or a drug-independent autoimmune process, or when anemia is severe and there is no time to observe for a response to drug withdrawal.

• Cefotetan and ceftriaxone: classic causes of severe drug-induced immune hemolytic anemia.

Evans Syndrome

• Definition: AIHA plus ITP (and/or autoimmune neutropenia) in the same patient, synchronous or sequential.
• Workup: underlying lymphoproliferative disorder, autoimmune disease, or primary immunodeficiency (ALPS with FAS mutations; CVID).
• Treatment: steroids plus rituximab; mycophenolate or sirolimus for refractory disease; HSCT in severe cases.

Cold-Related Special Considerations

• CAD vs PCH: CAD = IgM, monophasic, chronic. PCH = IgG biphasic Donath-Landsteiner, post-viral in children, self-limited.
• Mycoplasma yields anti-I (capital); EBV yields anti-i (lowercase).

High Yield (AIHA)

• DAT IgG = warm AIHA; DAT C3 only = CAD (or PCH); both IgG and C3 = usually warm AIHA (consider mixed AIHA or drug-induced).
• Warm AIHA: prednisone 1L; rituximab 2L preferred over splenectomy (rituximab plus steroids ~75% vs steroids alone ~36% at 12 months).
• CAD: avoid cold; steroids/splenectomy NOT effective; rituximab ± bendamustine; sutimlimab (anti-C1s, FDA Feb 2022).
• Mycoplasma yields anti-I yields cold AIHA; usually transient.
• Methyldopa yields a warm-AIHA-pattern autoantibody.
• Cefotetan/ceftriaxone yield severe immune-complex DIIHA (intravascular hemolysis).
• Reticulocytopenia with brisk AIHA is an emergency; do not withhold transfusion over incompatibility in a transfusion-naive patient.
• Checkpoint-inhibitor-induced AIHA is increasingly common; manage as warm AIHA.
• Evans syndrome = AIHA plus ITP; work up ALPS, lymphoma, SLE.
• IVIG is less effective in AIHA than in ITP.