10.1 Immune & Nonimmune Anemia

Classifying Anemia by Mechanism

The SBB Content Guideline (III.B) tests anemia through the lens of the immunohematology reference laboratory: what antibody class is involved, what serologic pattern it produces, and what workup resolves it. Anemia splits first into immune-mediated hemolysis (an antibody drives red cell destruction) and nonimmune hemolysis (mechanical, enzymatic, membrane, or hereditary red cell defects with a negative direct antiglobulin test (DAT)). Making the DAT result and the smear morphology agree with the clinical story is the core skill tested here.

Autoimmune hemolytic anemia (AIHA) occurs when a patient makes autoantibody against their own red cell antigens. AIHA is classified by the thermal range of the autoantibody: warm (reactive best at 37C), cold (reactive best at 0-4C, pathologic when the thermal amplitude extends toward body temperature), or mixed (both patterns in the same patient).

Warm Autoimmune Hemolytic Anemia

Warm AIHA is the most common form of AIHA (roughly 70-80% of cases). The autoantibody is almost always IgG, frequently with a broad Rh-related specificity that appears panreactive because Rh antigens sit on essentially every red cell. IgG does not fix complement efficiently on its own, so hemolysis is primarily extravascular: splenic macrophages bearing Fc receptors bind IgG-coated cells and remove membrane fragments, producing spherocytes on the peripheral smear rather than intravascular lysis.

Serologic pattern: DAT positive for IgG alone or IgG plus C3d; eluate reactive with all reagent cells, reflecting a broadly cross-reactive autoantibody rather than a true alloantibody. Warm AIHA is often secondary to systemic lupus erythematosus, chronic lymphocytic leukemia, other lymphoproliferative disease, or drugs, though a primary/idiopathic form exists. Workup priority is to rule out an underlying alloantibody hiding under the autoantibody using autologous and allogeneic adsorption techniques, because transfusion decisions cannot rely on a panreactive panel alone. Treatment is corticosteroids first-line, then rituximab, IVIG, or splenectomy for refractory disease.

Cold Agglutinin Disease and Paroxysmal Cold Hemoglobinuria

Cold agglutinin disease (CAD) is driven by IgM autoantibody, classically with anti-I specificity, that agglutinates red cells at low temperature and fixes complement efficiently because IgM's pentameric structure is highly effective at activating C1q. Because complement fixation happens at the red cell surface even though the IgM itself elutes off at 37C, the DAT is typically positive for C3d only - IgG and IgM wash off, while C3d remains covalently bound. Clinically significant CAD requires a high thermal amplitude, meaning reactivity that extends up toward 30-37C rather than only at 4C, which is why a cold agglutinin titer is performed at multiple temperatures instead of at 4C alone. CAD is often secondary to Mycoplasma pneumoniae infection (classic anti-I) or lymphoproliferative disorders; anti-i is the classic specificity associated with infectious mononucleosis (Epstein-Barr virus). Management centers on keeping the patient warm and avoiding cold IV fluids; rituximab is used for significant disease. Warmed blood administration and prewarmed testing technique reduce interference from a benign, low-thermal-amplitude cold autoantibody.

Paroxysmal cold hemoglobinuria (PCH) is a distinct, often pediatric, postviral entity caused by the Donath-Landsteiner antibody, a biphasic IgG hemolysin, classically with anti-P specificity. The antibody binds red cells in the cold and fixes complement, but hemolysis - intravascular, unlike warm AIHA - only completes when the cells rewarm to 37C, which is why the reaction is called biphasic. The Donath-Landsteiner test demonstrates this cold-sensitize, warm-lyse pattern directly and is the confirmatory assay the exam expects you to name.

Mixed-Type AIHA and Drug-Induced Immune Hemolytic Anemia

Mixed-type AIHA shows both a warm-reactive IgG autoantibody and a cold-reactive, usually high-titer, high-thermal-amplitude IgM autoantibody in the same patient, producing a DAT positive for both IgG and C3d with a more severe, chronic hemolytic course than either type alone; it is frequently associated with SLE.

Drug-induced immune hemolytic anemia (DIIHA) has three classic serologic mechanisms the exam expects you to separate:

A fourth pattern, nonimmunologic protein adsorption (NIPA) - classically linked to cefotetan and other cephalosporins - causes a positive DAT from nonspecific plasma protein coating without true antibody-mediated hemolysis. It is a serologic mimic, not true DIIHA. Stopping the offending drug is the definitive treatment for true DIIHA, and the DAT typically reverts to negative over the following weeks.

Nonimmune Hemolytic and Other Anemias

Nonimmune causes give a negative DAT and point away from immunohematology and toward mechanical or intrinsic red cell disease. Microangiopathic hemolytic anemia (MAHA) from TTP, HUS, or DIC produces schistocytes from red cells shearing on fibrin strands or mechanical heart valves. Hereditary spherocytosis (a membrane cytoskeleton defect) and G6PD deficiency (oxidative hemolysis, Heinz bodies, bite cells) are inherited. Iron deficiency and anemia of chronic disease are non-hemolytic and reflect a production problem rather than red cell destruction.

Exam Traps

The DAT-negative versus DAT-positive split is the fastest exam filter: a hemolytic anemia with a negative DAT and schistocytes is never AIHA - think TTP, HUS, DIC, or a mechanical valve instead. A DAT positive for C3d only should trigger the cold-antibody or immune-complex drug pathway, not an automatic warm AIHA diagnosis. Remember that an eluate is only informative when the DAT is positive; running an eluate on a DAT-negative sample is a technique error the exam will flag.