Family Medicine Board Review · Hematology · Source: AAFP 2018
Hemolytic Anemia: High-Yield Board Summary
Acute vs. chronic presentation, direct/indirect Coombs testing, the ITP/TTP/DIC comparison, extravascular vs. intravascular hemolysis, and the six classic hemolytic entities side-by-side.
Clinical Features
Acute Hemolysis
Jaundice or hematuria in the presence of anemia
Chronic Hemolysis
Lymphadenopathy, hepatosplenomegaly, cholestasis, and choledocholithiasis
Other nonspecific symptoms: fatigue, dyspnea, hypotension, and tachycardia.
Investigations — Direct vs. Indirect Coombs
The direct antiglobulin test (DAT) further differentiates immune causes of hemolytic anemia from nonimmune causes.
Direct Antiglobulin Test (Direct Coombs)
Detects antibodies
on the surface of RBCs
Binds patient's RBCs with donor antibodies
Mainly done in
AIHA
Indirect Antiglobulin Test (Indirect Coombs)
Detects antibodies in
serum that recognize antigens on RBCs
Mix patient's serum + donor RBCs + Coombs serum (anti-human Ig); positive if agglutination
Done for
hemolytic disease of the newborn
Board trap: direct Coombs = antibodies already on the patient's own RBCs (used to diagnose AIHA); indirect Coombs = antibodies in the serum (used for prenatal/newborn compatibility screening). Don't mix up which one diagnoses AIHA.
ITP vs. TTP vs. DIC
| Parameter | ITP | TTP | DIC |
|---|
| Pathogenesis | Antiplatelet antibodies | Endothelial defect (ADAMTS13 deficiency) | Thrombin excess |
| Clinical condition | Not ill | Ill-appearing | Ill-appearing |
| Red cells | Normal | Schistocytes | Schistocytes |
| PT (INR) | Normal | Normal | Increased |
| PTT | Normal | Normal | Increased (slight) |
| Fibrinogen | Normal | Normal (slight increase) | Decreased |
| Fibrinogen degradation products | Normal | Increased | Increased |
| D-dimer | Normal | Increased (slight) | Increased |
| Management | Supportive, steroids, IVIG | Supportive, plasma exchange | Supportive |
Board trap: ITP patients are classically "not ill"-appearing with entirely normal coagulation studies — a well-appearing patient with isolated thrombocytopenia and normal PT/PTT/fibrinogen points away from TTP/DIC. TTP and DIC both show schistocytes and are ill-appearing, but DIC has deranged PT/PTT/fibrinogen while TTP's coagulation panel stays essentially normal — this is the single best discriminator between the two.
| Extravascular | Intravascular |
|---|
| Etiologies |
Warm autoimmune hemolytic anemia, hypersplenism, delayed hemolytic transfusion reaction, hemoglobinopathies |
Cold autoimmune hemolytic anemia, acute hemolytic transfusion reaction, microangiopathic hemolytic anemia, G6PD deficiency, paroxysmal nocturnal hemoglobinuria, hemoglobinopathies |
| Site of RBC destruction | Macrophages (spleen) | Blood vessels |
| Haptoglobin | Low | Very low |
| LDH | High | Very high |
| Urine hemosiderin | Negative | Positive |
| Peripheral smear | Spherocytes | Schistocytes |
Board trap: spherocytes → extravascular (macrophage/splenic destruction, classic in warm AIHA); schistocytes → intravascular (mechanical/complement-mediated destruction within vessels, classic in MAHA/TMAs). Both processes drop haptoglobin and raise LDH, but intravascular hemolysis is more severe on both fronts and specifically causes positive urine hemosiderin.
Autoimmune Hemolytic Anemia (AIHA)
Causes
Idiopathic (majority), viral and bacterial infections, autoimmune conditions, connective tissue disorders, lymphoproliferative malignancies, blood transfusions, and transplantation.
Classification
- Cold agglutinins — IgM-mediated
- Warm agglutinins — more common, IgG-mediated
Labs
Positive DAT (direct Coombs) result.
Treatment
| Warm AIHA | Cold AIHA |
|---|
| Glucocorticoids; management of underlying condition; blood transfusion if necessary; supportive care |
Supportive measures; avoidance of triggers (cold exposure); management of underlying disease |
Exam pearl: warm AIHA responds to steroids, but cold AIHA does not — cold agglutinin disease is managed with supportive care and trigger avoidance instead. Don't reach for glucocorticoids as the answer for cold AIHA.
Drug-Induced Immune Hemolytic Anemia
- Progression of the condition is typically gradual
- Treatment involves removal of the offending agent
- Will have a positive DAT test
Microangiopathic Hemolytic Anemia (MAHA)
- Can be caused by trauma from an endovascular device or microthrombotic microangiopathies (TMAs)
- Causes schistocytes
Thrombotic Thrombocytopenic Purpura (TTP)
Symptoms
Thrombocytopenia, fever, renal injury, MAHA, and neurologic dysfunction.
Fever
Thrombocytopenia
Microangiopathic hemolytic anemia
Neurologic dysfunction
Renal injury
"Classic pentad" of TTP — though not all 5 features need be present simultaneously to make the diagnosis.
Investigations
Schistocytes, negative DAT, normal coagulation studies.
Treatment
Plasma exchange and glucocorticoids should begin immediately.
Board trap: TTP is a DAT-negative hemolytic process (nonimmune, mechanical) despite showing hemolysis — don't expect a positive Coombs test here, unlike AIHA. Treatment (plasma exchange) should never be delayed once suspected — this is a hematologic emergency.
Hemolytic Uremic Syndrome (HUS)
- Characterized by MAHA and acute kidney injury, commonly with thrombocytopenia and neurologic dysfunction
- Shiga toxin–producing Escherichia coli (STEC) is a classic cause; inadequately cooked ground beef is the primary source of STEC infection
- Mainly affects children
- Classic prodrome: abdominal pain with diarrhea, often preceding MAHA, AKI, and thrombocytopenia by 5–10 days
Treatment
- Supportive care and continued evaluation of renal function
- Antibiotics are NOT recommended
Board trap: antibiotics are specifically avoided in STEC-associated HUS — treating the underlying E. coli infection with antibiotics can increase toxin release and paradoxically worsen HUS risk/severity. This is a frequently tested "don't treat" exception.
G6PD Deficiency
Evaluation
Diagnosed by G6PD enzyme activity testing — but false-negative results may occur in patients tested during acute hemolysis, because the most severely G6PD-deficient (oldest) cells have already been destroyed, leaving behind younger cells with relatively higher residual enzyme activity that can mask the deficiency.
Exam pearl: if G6PD testing is falsely reassuring during an acute hemolytic episode, repeat testing 3 months after the hemolytic episode has resolved to get an accurate result.
Dietary Trigger
The only food specifically recommended to avoid is fava beans (favism).