Eduovisual
Blood & Lymphoreticular
Hemolytic anemia: workup and Coombs-positive vs negative
— Intravascular: RBCs lyse in circulation → free hemoglobin → haptoglobin scavenges, then spills (hemoglobinemia, hemoglobinuria, hemosiderinuria). Causes: mechanical (TMA, prosthetic valve, march), complement-mediated (PNH, cold AIHA, ABO mismatch), severe G6PD crisis, Clostridium/malaria.
— Extravascular: RBCs opsonized/altered → cleared by splenic/hepatic macrophages. Causes: warm AIHA, hereditary spherocytosis, hemoglobinopathies, drug-induced.
— New normocytic (sometimes macrocytic from reticulocytosis) anemia with ↑ reticulocyte count, ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin.
— Jaundice + dark urine + anemia, especially after infection, new drug, transfusion, cold exposure, or fava beans.
— Splenomegaly, gallstones in a young patient, family history of anemia/splenectomy.
— Acute drop in Hb with no overt bleeding source; positive stool guaiac negative and no menstrual loss.
— Acute hemolysis (TTP, ABO transfusion reaction, severe AIHA, G6PD crisis) → hospitalize, type-and-screen, monitor for renal failure and DIC.
— Chronic compensated hemolysis (HS, sickle, thalassemia) → outpatient with folate, immunizations, transition-of-care planning.
Board pearl: The classic hemolysis tetrad — ↑ retics, ↑ LDH, ↑ indirect bili, ↓ haptoglobin — has the highest specificity when all four are present; haptoglobin <25 mg/dL with elevated LDH is ~90% specific for hemolysis. Step 3 framing: after confirming hemolysis biochemically, the very next step is the direct antiglobulin (Coombs) test — this single result bifurcates the entire differential and management pathway.
— Fatigue, dyspnea on exertion, pallor (anemia baseline).
— Scleral icterus, tea/cola-colored urine, back/flank pain (intravascular).
— Splenomegaly-related LUQ fullness, early satiety, pigment gallstones (chronic extravascular).
— Hyperacute (minutes–hours): ABO-incompatible transfusion → fever, hypotension, flank pain, oozing from IV sites (DIC).
— Days: new drug (cephalosporins, penicillins, dapsone, rifampin, NSAIDs), infection-triggered AIHA, G6PD oxidant exposure.
— Weeks–months: warm AIHA, lymphoproliferative-associated cold agglutinin, PNH.
— Lifelong/intermittent: hereditary spherocytosis, sickle cell, thalassemia, hereditary elliptocytosis.
— Medications: dapsone, sulfa, rasburicase, primaquine, ribavirin, methyldopa, fludarabine, ceftriaxone, piperacillin.
— Diet/exposures: fava beans, mothballs (naphthalene), henna in infants → G6PD.
— Travel/infection: malaria, babesiosis, Mycoplasma (cold agglutinin), EBV, HIV, hepatitis.
— Cold exposure: acrocyanosis of nose/ears/fingers → cold agglutinin disease or paroxysmal cold hemoglobinuria (Donath-Landsteiner, post-viral in kids).
— Family history: anemia, splenectomy, cholecystectomy in 20s/30s, ethnic background (Mediterranean, African, SE Asian).
— Mechanical: prosthetic valve, recent marathon, TAVR, LVAD, malignant hypertension.
— Obstetric: HELLP, preeclampsia, postpartum TMA.
— Autoimmune: SLE, RA, CLL, lymphoma symptoms (B symptoms, lymphadenopathy).
Key distinction: Warm AIHA worsens at body temperature (IgG, extravascular splenic clearance) and is often idiopathic or associated with CLL/SLE/drugs; cold AIHA worsens with cold exposure (IgM + complement, intravascular/hepatic Kupffer cell clearance) and is classically post-Mycoplasma, EBV, or Waldenström. Board pearl: Ask explicitly about timing relative to cold drinks, winter walks, and finger color change — this single history question often clinches cold agglutinin disease before any lab returns.
— Pallor of conjunctivae/palmar creases, scleral icterus (visible when total bili >2–3 mg/dL).
— Tachycardia, wide pulse pressure, flow murmur if Hb <8.
— Tachypnea, orthostasis, altered mentation → escalate to hospital.
— Acrocyanosis of nose, ears, fingertips that resolves with warming → cold agglutinin disease.
— Livedo reticularis, digital ischemia → cryoglobulinemia, APLS-associated TMA.
— Leg ulcers → sickle cell, hereditary spherocytosis (rare).
— Petechiae/purpura + neurologic signs + fever + AKI → TTP pentad (only ~5% have all five; treat on suspicion).
— Splenomegaly → chronic extravascular hemolysis (HS, thalassemia, AIHA, lymphoma).
— RUQ tenderness, Murphy sign → pigment gallstone cholecystitis.
— Hepatomegaly with cold AIHA (hepatic clearance dominant).
— New murmur of mechanical valve dysfunction → macroangiopathic hemolysis (paravalvular leak).
— Pulmonary hypertension findings in chronic intravascular hemolysis (sickle, PNH) — loud P2, RV heave.
— Focal deficits, confusion, seizure → TTP until proven otherwise.
— Peripheral neuropathy → B12 deficiency mimicking hemolysis (low retics distinguishes).
Step 3 management: A patient with anemia + thrombocytopenia + schistocytes + any neurologic or renal abnormality gets emergent plasma exchange (PLEX) for presumed TTP — do not wait for ADAMTS13 activity to return. Start caplacizumab + steroids alongside PLEX. CCS pearl: On CCS, order CBC, peripheral smear, retic count, LDH, haptoglobin, indirect bili, type & screen, DAT, BMP/Cr, UA, coags as your first cluster; advance the clock 1–2 hours and reassess — most hemolysis cases pivot on the smear + DAT.
— Retic count / reticulocyte production index (RPI): RPI >2 suggests appropriate marrow response to destruction. Absent reticulocytosis = consider aplastic crisis (parvovirus B19), marrow infiltration, or co-existing nutritional deficiency.
— LDH: elevated (intracellular enzyme released by RBC lysis); markedly high in intravascular hemolysis and TMA.
— Indirect (unconjugated) bilirubin: elevated; conjugated fraction usually normal unless hepatic dysfunction.
— Haptoglobin: <25 mg/dL strongly supports hemolysis; can be falsely normal in inflammation (acute phase).
— Plasma free hemoglobin, urine hemoglobin, urine hemosiderin (Prussian blue) → intravascular hemolysis (hemosiderin appears days later, useful for chronic).
— CBC with indices: MCV often normal or slightly elevated (reticulocytes are larger); microcytic suggests thalassemia or iron deficiency overlay.
— Peripheral smear — single most informative test:
— Schistocytes → MAHA (TTP, HUS, DIC, HELLP, malignant HTN, mechanical valve).
— Spherocytes → AIHA or hereditary spherocytosis (DAT differentiates).
— Bite/blister cells, Heinz bodies (supravital stain) → G6PD oxidative hemolysis.
— Sickle cells, target cells → hemoglobinopathy.
— Agglutination/rouleaux → cold agglutinin, multiple myeloma.
— Parasites within RBCs → malaria, babesiosis (Maltese cross).
— DAT positive → immune hemolytic anemia (AIHA, drug-induced, alloimmune, hemolytic transfusion reaction).
— DAT negative → non-immune (mechanical, membrane, enzyme, hemoglobinopathy, PNH, infection).
Board pearl: LDH:AST ratio >12:1 favors hemolysis over hepatocellular injury. Step 3 management: Always send type and screen + DAT + smear together at first encounter — repeat testing wastes 24–48 hours when the diagnosis hinges on smear morphology you can see in minutes.
— IgG positive ± C3: warm AIHA (optimal binding 37°C). Look for underlying CLL, lymphoma, SLE, common variable immunodeficiency, recent drugs.
— C3 only (IgG negative): cold agglutinin disease. Order cold agglutinin titer (significant if ≥1:64 at 4°C) and thermal amplitude. Screen for Mycoplasma IgM, EBV, hepatitis, SPEP/immunofixation (Waldenström, lymphoma).
— Mixed warm + cold features: evaluate for paroxysmal cold hemoglobinuria — Donath-Landsteiner test (biphasic IgG anti-P).
— Schistocytes present: check platelets, Cr, coags, fibrinogen, D-dimer.
— Low platelets + normal coags → TTP/HUS → send ADAMTS13 activity (TTP if <10%); stool studies for Shiga toxin (STEC-HUS).
— Abnormal coags + low fibrinogen → DIC.
— Spherocytes, family history: eosin-5-maleimide (EMA) flow cytometry (>90% sensitive for HS), osmotic fragility (older test).
— Bite cells, oxidant exposure: G6PD activity — but measure after the acute episode (young RBCs have higher enzyme levels, false-negative during crisis).
— Suspected PNH: flow cytometry for CD55/CD59 deficiency or FLAER assay on granulocytes (most sensitive); check for pancytopenia, thrombosis at unusual sites (hepatic, mesenteric).
— Hemoglobinopathy: hemoglobin electrophoresis or HPLC.
— Suspected microangiopathy from drug: quinine, calcineurin inhibitors, gemcitabine, VEGF inhibitors.
Key distinction: A negative DAT does not exclude AIHA — ~5–10% are DAT-negative due to low-affinity IgG or IgA antibodies; if clinical picture fits, send enhanced DAT or eluate testing at a reference lab. Board pearl: PNH triad = Coombs-negative intravascular hemolysis + cytopenias + thrombosis (especially Budd-Chiari).
— Hb <7 with symptoms, ongoing brisk hemolysis, hemodynamic instability, end-organ ischemia → admit, transfuse, treat empirically.
— Stable chronic hemolysis → outpatient workup with hematology referral within 1–2 weeks.
— Do not withhold blood from a bleeding or hypoxic patient even with AIHA — transfuse least incompatible units after extended phenotyping; involve blood bank early.
— In cold agglutinin disease: use blood warmer, keep patient warm, transfuse through warmed line.
— Avoid transfusion in stable TTP if possible (theoretical platelet worsening) — platelet transfusion contraindicated in TTP except for life-threatening bleeding or pre-procedure.
— DAT positive, warm pattern → prednisone 1 mg/kg/day immediately.
— Schistocytes + thrombocytopenia + no other explanation → PLEX + steroids for presumed TTP.
— G6PD suspected → stop offending agent, supportive care, hydration.
— Mechanical valve hemolysis → control HR, treat HF, consider valve re-intervention.
— Folic acid 1 mg daily (chronic hemolysis depletes folate stores).
— Monitor for hyperkalemia, AKI from pigment nephropathy.
— IV fluids and urine alkalinization considered in massive intravascular hemolysis.
— VTE prophylaxis especially in PNH and warm AIHA (both prothrombotic).
Step 3 management: When AIHA is suspected and the patient needs urgent transfusion, call the blood bank, document the clinical urgency, and accept "least incompatible" units — delaying transfusion to find perfectly matched blood causes preventable deaths. CCS pearl: Order folic acid on every chronic hemolysis patient — it's a high-yield "completeness" point.
— First-line: prednisone 1 mg/kg/day (max ~80 mg) for 2–4 weeks until Hb >10, then slow taper over 3–6 months. Response in 70–85%.
— Add rituximab early in severe disease or as steroid-sparing (now often co-first-line per recent guidelines, 375 mg/m² weekly × 4).
— Second-line: rituximab (if not used), splenectomy (consider after failure of medical therapy; immunize ≥2 weeks prior against encapsulated organisms).
— Third-line: azathioprine, cyclosporine, mycophenolate, cyclophosphamide, danazol, IVIG (transient).
— Supportive: folate, calcium/vitamin D + bisphosphonate consideration for prolonged steroids, PJP prophylaxis if prolonged high-dose immunosuppression.
— Avoid cold exposure — foundational; mild cases need only this.
— Steroids and splenectomy generally ineffective (hepatic clearance, IgM).
— Rituximab ± bendamustine is first-line for symptomatic disease.
— Sutimlimab (anti-C1s monoclonal) — FDA-approved, rapidly increases Hb by blocking classical complement.
— Stop the offending drug — the definitive treatment. Common culprits: cefotetan, ceftriaxone, piperacillin, NSAIDs, methyldopa, fludarabine, oxaliplatin.
— Short steroid course if severe.
— PLEX daily until platelets >150 × 2 days and LDH normalized.
— Steroids (methylprednisolone 1 g/day × 3 or prednisone 1 mg/kg).
— Caplacizumab (anti-vWF nanobody) reduces refractoriness and mortality.
— Rituximab for refractory/relapsing.
Board pearl: Before starting eculizumab/ravulizumab/sutimlimab, document meningococcal vaccination (MenACWY + MenB) — failure to vaccinate is a tested patient-safety lapse and an FDA black-box concern.
— Definitive for TTP — replaces ADAMTS13 and removes anti-ADAMTS13 IgG; initiate within 4–8 hours of suspicion.
— Requires large-bore central access (femoral or IJ); risks include line infection, citrate-induced hypocalcemia, hypotension, allergic reactions.
— Not effective for STEC-HUS in children; supportive care + dialysis as needed. Eculizumab is first-line for atypical HUS.
— Considered for refractory warm AIHA, hereditary spherocytosis (moderate-severe), and select thalassemia/hemoglobinopathy cases.
— Pre-op: vaccinate against pneumococcus (PCV20 or PCV15→PPSV23), Hib, meningococcus (ACWY + B), annual influenza ≥2 weeks before surgery.
— Post-splenectomy: lifelong awareness of overwhelming post-splenectomy infection (OPSI); standby antibiotic (amoxicillin-clavulanate) and immediate ED evaluation for any fever.
— Laparoscopic preferred; partial splenectomy in pediatric HS preserves immune function.
— Paravalvular leak → surgical or percutaneous repair; medical management with beta-blockers, iron, folate as bridge.
— Start when ferritin >1000 ng/mL or after ~20 units transfused: deferasirox (oral) or deferoxamine (parenteral).
Step 3 management: When admitting a patient for elective splenectomy, verify vaccination ≥14 days before surgery — if missed pre-op, vaccinate ≥14 days post-op. CCS pearl: On a TTP case, the order set is two large-bore lines → consent for central line → call apheresis → start steroids → PLEX within hours; advancing the clock without PLEX loses points.
— Higher prevalence of secondary AIHA from CLL, NHL, MDS, solid tumors. Always screen with peripheral smear, flow cytometry, SPEP/UPEP, and age-appropriate cancer screening in new AIHA >60.
— Drug-induced hemolysis is more common due to polypharmacy — review every medication including OTC NSAIDs and supplements.
— Steroid toxicity is amplified: hyperglycemia, osteoporosis, delirium, infection, GI bleed. Use lowest effective dose, add PPI cautiously (weigh fracture/CDI risk), bisphosphonate if >3 months expected, PJP prophylaxis if prednisone ≥20 mg/day for >4 weeks.
— Consider rituximab earlier as steroid-sparing strategy.
— Falls risk from anemia-related orthostasis — assess gait, deprescribe sedating meds.
— Pigment nephropathy from intravascular hemolysis (free heme is nephrotoxic) — aggressive IV fluids, monitor UOP, avoid additional nephrotoxins (NSAIDs, contrast when possible).
— TMA-driven AKI (HUS, aHUS, TTP, malignant HTN) — may require dialysis; eculizumab is renal-protective in aHUS.
— Dose-adjust: rituximab (no adjustment), cyclophosphamide (reduce in CrCl <30), MMF (caution), eculizumab (no adjustment but monitor).
— Avoid rasburicase in G6PD deficiency (causes severe hemolysis) — screen high-prevalence populations before tumor lysis prophylaxis.
— Worsens hyperbilirubinemia of hemolysis — may obscure cholestatic process; check GGT, alk phos, conjugated fraction.
— Azathioprine requires TPMT testing; dose-reduce in liver disease.
— Wilson disease can present with Coombs-negative hemolytic anemia + acute liver failure — check ceruloplasmin, urinary copper, slit-lamp in young patients with this combination.
Board pearl: G6PD screening before rasburicase, dapsone, or primaquine is mandatory in at-risk populations (African, Mediterranean, Middle Eastern, SE Asian ancestry) — missing this is a recurrent Step 3 patient-safety item.
— HELLP syndrome: hemolysis (schistocytes), elevated LFTs, low platelets — a TMA variant of preeclampsia. Definitive treatment: delivery if ≥34 weeks or maternal/fetal compromise; magnesium for seizure prophylaxis, antihypertensives, steroids for fetal lung maturity if <34 weeks.
— Pregnancy-associated TTP: ADAMTS13 falls physiologically; presents 2nd/3rd trimester or postpartum — PLEX + steroids, caplacizumab use under specialist guidance.
— Postpartum aHUS: consider eculizumab; differentiate from HELLP (resolves with delivery) and TTP (ADAMTS13 <10%).
— Autoimmune hemolytic anemia in pregnancy: prednisone is preferred (minimal placental transfer); rituximab can be used if needed but plan around B-cell depletion in neonate.
— Hemolytic disease of the fetus/newborn (HDFN): Rh(D)-negative mother with Rh-positive fetus — give anti-D immunoglobulin at 28 weeks and within 72 hours of delivery, miscarriage, amniocentesis, or trauma. Also monitor anti-Kell, which causes severe HDFN by suppressing erythropoiesis.
— STEC-HUS: classic triad after bloody diarrhea (E. coli O157:H7) in toddlers — supportive care, avoid antibiotics (may worsen toxin release) and avoid antimotility agents; dialysis as needed.
— Paroxysmal cold hemoglobinuria: post-viral in young children — IgG Donath-Landsteiner antibody; usually self-limited, keep warm.
— Hereditary spherocytosis: neonatal jaundice, splenomegaly; delay splenectomy until age >5–6 to preserve immune function.
— Sickle cell: newborn screening universal in US; penicillin prophylaxis from age 2 months to 5 years, pneumococcal vaccination, hydroxyurea by 9 months.
— G6PD: neonatal jaundice often the first presentation.
Key distinction: In a pregnant woman with anemia + thrombocytopenia + organ dysfunction, HELLP improves with delivery, TTP does not — if cytopenias persist >48–72 hours postpartum, escalate to TTP/aHUS workup with ADAMTS13 and complement studies.
— Hyperkalemia from massive RBC lysis → telemetry, calcium gluconate, insulin/dextrose, kayexalate or dialysis.
— Acute kidney injury from pigment nephropathy or TMA — fluid resuscitation, renal replacement therapy.
— DIC in severe intravascular hemolysis (ABO mismatch, Clostridium perfringens sepsis) — supportive product replacement.
— High-output heart failure in severe anemia, especially elderly.
— Aplastic crisis in chronic hemolysis + parvovirus B19 infection → transient red cell aplasia, reticulocytopenia, severe Hb drop; supportive transfusion + IVIG if immunocompromised.
— Hyperhemolytic crisis in sickle cell post-transfusion — paradoxical Hb drop with new alloantibodies; avoid further transfusion, give IVIG and steroids.
— Pigment gallstones → cholecystitis, choledocholithiasis, pancreatitis.
— Iron overload from chronic transfusions → cardiomyopathy, cirrhosis, endocrinopathy (diabetes, hypogonadism).
— Pulmonary hypertension in chronic intravascular hemolysis (PNH, sickle).
— Leg ulcers, priapism, stroke, avascular necrosis in sickle cell.
— Folate deficiency worsening anemia.
— Thrombosis in PNH (Budd-Chiari, cerebral venous sinus, mesenteric), warm AIHA, and TTP recovery phase.
— Splenic sequestration crisis in children with sickle cell — rapid splenic enlargement, profound anemia, hypovolemic shock.
— Steroid: osteoporosis, diabetes, infection, adrenal suppression.
— Rituximab: hepatitis B reactivation (screen HBsAg + anti-HBc before starting), PML (rare), infusion reactions.
— Eculizumab/ravulizumab: Neisseria meningitidis infection (vaccinate + consider penicillin prophylaxis).
— Splenectomy: OPSI, portal vein thrombosis, lifelong infection risk.
Step 3 management: Any post-splenectomy or eculizumab patient presenting with fever gets immediate empiric broad-spectrum antibiotics (ceftriaxone) before full workup — minutes matter in OPSI.
— Hemodynamic instability requiring vasopressors.
— Active intravascular hemolysis with DIC, AKI, hyperkalemia, or arrhythmia.
— TTP initiating PLEX — ICU-level monitoring for cardiac, neurologic deterioration.
— Severe AIHA with Hb <5 not responding to transfusion + steroids.
— Acute chest syndrome in sickle cell, splenic sequestration crisis.
— Acute hemolytic transfusion reaction with shock.
— Hb <7 with symptoms.
— New diagnosis of moderate-severe AIHA initiating immunosuppression.
— Pigment gallstone disease requiring intervention.
— Suspected drug-induced hemolysis requiring observation off the agent.
— Sickle cell vaso-occlusive crisis with pain control needs.
— Stable chronic hemolysis (HS, mild AIHA, compensated G6PD baseline).
— Hb stable >9 without symptoms, no organ dysfunction.
— Reliable follow-up, no transfusion need.
— Hematology: all new AIHA, suspected PNH, TTP, undiagnosed Coombs-negative hemolysis.
— Blood bank/transfusion medicine: difficult crossmatch, alloantibody workup, exchange transfusion needs.
— Nephrology: AKI, TMA with renal involvement, dialysis planning.
— Apheresis: PLEX setup for TTP, hyperviscosity, severe cold agglutinin.
— OB/MFM: pregnant patients with hemolysis.
— Genetics: hereditary spherocytosis family screening, sickle cell counseling.
— Cardiothoracic surgery: mechanical valve hemolysis from paravalvular leak.
CCS pearl: In a CCS case of suspected TTP, the high-yield action sequence is (1) order CBC/smear/LDH/retic/Cr/coags, (2) consult heme + apheresis, (3) place central line with consent, (4) start steroids, (5) initiate PLEX, (6) transfer to ICU/monitored bed. Skipping the apheresis consult or PLEX initiation loses major points.
— Warm AIHA (IgG±C3): body temperature antibodies, splenic clearance, spherocytes on smear, associated with CLL/lymphoma/SLE/drugs/CVID. Steroids first.
— Cold agglutinin disease (C3 only): IgM antibodies, hepatic clearance, agglutination on smear, associated with Mycoplasma, EBV, Waldenström. Cold avoidance + rituximab/sutimlimab.
— Paroxysmal cold hemoglobinuria: biphasic IgG anti-P, post-viral in children, intravascular hemolysis on cold exposure. Donath-Landsteiner positive.
— Drug-induced immune hemolysis: hapten (penicillin), immune complex (quinine), autoimmune (methyldopa, fludarabine), nonimmunologic adsorption (cephalosporins). Stop drug.
— Alloimmune (HDFN, hemolytic transfusion reactions): maternal anti-D/Kell, ABO mismatch.
— Membrane defects:
— Hereditary spherocytosis (ankyrin, spectrin, band 3) — EMA flow positive.
— Hereditary elliptocytosis, pyropoikilocytosis.
— Enzyme deficiencies:
— G6PD deficiency — oxidative hemolysis with bite cells, Heinz bodies; X-linked.
— Pyruvate kinase deficiency — autosomal recessive, no Heinz bodies.
— Hemoglobinopathies: sickle cell, thalassemia, unstable hemoglobins.
— PNH: acquired PIGA mutation, CD55/CD59 deficient cells, intravascular hemolysis + thrombosis + cytopenias.
— Mechanical/microangiopathic: TTP, HUS, DIC, HELLP, malignant HTN, prosthetic valve, march hemoglobinuria, TAVR/LVAD.
— Infectious: malaria, babesiosis, Clostridium perfringens, Bartonella.
— Toxic: snake/spider venom, copper (Wilson), arsine gas, lead.
Key distinction: The DAT alone bifurcates 80% of the differential — Coombs positive → immune, Coombs negative → mechanical/membrane/enzyme/hemoglobin/PNH. Board pearl: PNH is the only acquired Coombs-negative hemolytic anemia of adults that classically presents with thrombosis at unusual sites.
— Ineffective erythropoiesis: megaloblastic anemia (B12, folate deficiency) — high LDH, high indirect bili, but low retics (the giveaway).
— MDS: dysplastic marrow with intramedullary destruction; mimics hemolysis labs but retic count is low; smear shows dysplastic neutrophils, ring sideroblasts on iron stain.
— Tumor lysis syndrome: high LDH, hyperuricemia, hyperkalemia, hyperphosphatemia.
— Massive hematoma resorption: indirect bili and LDH up from extravasated blood breakdown.
— Gilbert syndrome: isolated indirect hyperbilirubinemia, normal LDH/haptoglobin/retic.
— Crigler-Najjar: severe unconjugated hyperbilirubinemia, no hemolysis labs.
— Hepatocellular dysfunction: mixed bili, transaminitis dominates.
— DIC: prolonged PT/PTT, low fibrinogen, elevated D-dimer — distinguish from TTP.
— Sepsis with bone marrow suppression.
— Evans syndrome: AIHA + ITP (DAT positive) — autoimmune both lines.
— Hypersplenism: sequestration; no schistocytes.
— HIT (heparin-induced thrombocytopenia): thrombocytopenia + thrombosis but no hemolysis typically.
— Catastrophic antiphospholipid syndrome: widespread thrombosis with TMA features.
— Rhabdomyolysis (myoglobinuria — heme-positive dipstick, no RBCs on micro, elevated CK).
— Beeturia, porphyria, certain drugs — dipstick negative for blood.
Key distinction: B12 deficiency vs hemolysis — both raise indirect bili and LDH and can show macro-ovalocytes that mimic spherocytes, but B12 deficiency has low/inappropriately normal reticulocyte count and hypersegmented neutrophils, while true hemolysis has reticulocytosis. Board pearl: Always check reticulocyte count; without it, you cannot distinguish hemolysis from ineffective erythropoiesis.
— Folic acid 1 mg PO daily — lifelong in ongoing hemolysis.
— Iron supplementation only if documented deficiency (chronic intravascular hemolysis can cause iron loss via hemosiderinuria — PNH classic example); avoid empiric iron in extravascular hemolysis (iron-overload risk).
— Pneumococcal, meningococcal, Hib, influenza, COVID-19 vaccinations per age and splenectomy status.
— Calcium 1000–1200 mg + vitamin D 800–1000 IU daily for patients on chronic steroids.
— Warm AIHA: prednisone taper over 3–6 months; monitor for relapse with monthly CBC, retic, LDH initially. Consider rituximab early to spare steroids. PJP prophylaxis (TMP-SMX) if prednisone ≥20 mg/day for >4 weeks.
— Cold agglutinin disease: avoid cold exposure, warm clothing, gloves; treat underlying lymphoproliferative disorder.
— PNH: eculizumab or ravulizumab indefinitely; lifelong anticoagulation if prior thrombosis; meningococcal vaccination and consider penicillin prophylaxis.
— Sickle cell: hydroxyurea for ≥3 VOC/year or acute chest history, L-glutamine, crizanlizumab, voxelotor; annual TCD in children for stroke risk; opioid stewardship.
— Hereditary spherocytosis: folate; splenectomy with cholecystectomy if indicated; pre-splenectomy vaccinations.
— G6PD: lifelong avoidance card listing oxidant drugs and fava beans; medical alert bracelet.
— Mechanical valve hemolysis: beta-blocker, ACEi for HF; refer surgery if hemolysis severe.
Step 3 management: Every patient discharged after splenectomy or starting eculizumab/ravulizumab needs written medical alert documentation, fever action plan with home antibiotic, and confirmed vaccination records — this is a recurring transition-of-care safety theme.
— Acute AIHA after discharge: clinic visit within 7–14 days with CBC, retic, LDH, haptoglobin, indirect bili to confirm response; then every 2–4 weeks during steroid taper.
— Stable chronic hemolysis: every 3–6 months with hematology; CBC, LDH, ferritin, folate, vitamin B12, RFT/LFT.
— Post-splenectomy: annual visit + immunization boosters (PCV20 once, meningococcal every 5 years, influenza yearly).
— PNH on eculizumab: every 2 weeks initially for LDH and breakthrough hemolysis; meningococcal booster every 3–5 years.
— Sickle cell: quarterly visits, annual TCD (ages 2–16), retinal exam, renal screening.
— Hemoglobin trend, reticulocyte count, LDH (response marker), haptoglobin recovery, DAT (may remain positive even after clinical remission).
— Ferritin trend for iron overload in transfused patients; MRI T2* of liver/heart if ferritin >1000.
— Echo with TR jet velocity for pulmonary hypertension screening in chronic intravascular hemolysis.
— DEXA scan baseline and every 1–2 years on chronic steroids.
— Bone marrow biopsy if cytopenias evolve to evaluate for MDS or lymphoproliferative transformation.
— G6PD: drug/food avoidance list; counsel female carriers about variable expression.
— Sickle cell trait: generally asymptomatic but counsel about exercise-related rhabdomyolysis, sudden death risk at altitude/dehydration; partner screening if family planning.
— Hereditary spherocytosis: family screening (autosomal dominant in 75%).
— Steroid education: taper adherence, infection awareness, no abrupt cessation.
Board pearl: A persistently positive DAT after clinical remission of AIHA is common and does not mandate continued therapy — clinical and biochemical hemolysis markers (Hb stability, normal LDH/haptoglobin, no reticulocytosis) drive treatment duration, not DAT alone.
— Two-person bedside verification of patient identity, blood product, and crossmatch before any transfusion — wrong-patient ABO mismatch is the leading cause of fatal acute hemolytic transfusion reactions.
— Document type, screen, and crossmatch in the chart before administration; report any acute reaction immediately to blood bank and stop the transfusion.
— Informed consent for transfusion: discuss risks (TRALI, TACO, infection, hemolysis, alloimmunization) and alternatives; document.
— Jehovah's Witness patients: explore acceptable alternatives (erythropoietin, IV iron, cell salvage, hyperbaric oxygen, expectant management) and document the specific products the patient refuses; respect autonomy even when life-threatening anemia exists in competent adults. Pediatric cases may require court order when refusal endangers a minor's life.
— Disclose to patient when a drug-induced hemolytic event occurs; document the offending agent prominently in the allergy/adverse reaction list with the specific reaction; cross-class alerts where relevant.
— G6PD status documentation in EHR for at-risk populations to prevent future oxidant exposure.
— A patient discharged on prednisone taper without explicit written instructions is at high risk of adrenal crisis from abrupt cessation; provide stress-dose education.
— Post-splenectomy patients leaving the hospital without vaccination documentation, standby antibiotics, and fever action plan represent a transition-of-care failure — common test item.
— Pregnant Rh-negative patients require anti-D administration tracked across providers.
— Acute hemolytic transfusion reactions are reportable to the FDA via MedWatch and the blood center; near-miss events should trigger root cause analysis.
— Suspected drug-induced hemolysis: report to FDA MedWatch.
Step 3 management: Always confirm and document informed consent for transfusion before the patient becomes too unstable to participate — emergency exceptions exist but proactive consent is the standard.
— Schistocytes + thrombocytopenia + neuro/renal → TTP (ADAMTS13 <10%).
— Schistocytes + AKI + bloody diarrhea in child → STEC-HUS.
— Schistocytes + pregnancy + ↑ LFTs + low platelets → HELLP.
— Spherocytes + positive DAT → warm AIHA.
— Spherocytes + negative DAT + family history → hereditary spherocytosis (EMA flow).
— Bite cells + Heinz bodies + male + oxidant trigger → G6PD.
— Sickle cells + target cells + African ancestry → sickle cell disease.
— Agglutination on smear + cold extremities + post-Mycoplasma → cold agglutinin disease.
— Intravascular hemolysis + pancytopenia + Budd-Chiari → PNH.
— Intracellular ring forms + recent travel → malaria; Maltese cross → babesiosis.
— Methyldopa → warm AIHA (classic).
— Cefotetan, ceftriaxone, piperacillin → drug-induced immune hemolysis.
— Dapsone, primaquine, rasburicase, sulfa, nitrofurantoin, methylene blue → G6PD hemolysis.
— Fludarabine → AIHA in CLL.
— Ribavirin → dose-dependent hemolysis.
— Quinine → drug-induced TMA.
— CLL → warm AIHA, ITP, pure red cell aplasia.
— SLE → AIHA + ITP (Evans), APLS-associated TMA.
— Mycoplasma, EBV → cold AIHA.
— Waldenström macroglobulinemia → cold agglutinin disease.
— Parvovirus B19 → aplastic crisis in chronic hemolysis.
— HIV → AIHA, TTP-like syndromes.
— Wilson disease → Coombs-negative hemolysis + liver failure in young patient.
Board pearl: "Pink plasma in the centrifuge tube" = visible hemoglobinemia = intravascular hemolysis until proven otherwise. Key distinction: Babesiosis in an asplenic patient is life-threatening — empirically treat with atovaquone + azithromycin or clindamycin + quinine for severe disease, consider exchange transfusion if parasitemia >10%.
— Stem: middle-aged woman with fatigue, jaundice, splenomegaly; Hb 7, retics 10%, LDH 600, haptoglobin <10, indirect bili 4.0; smear shows spherocytes.
— Next step: direct antiglobulin (Coombs) test. If IgG positive → prednisone. Always look for underlying CLL/SLE.
— Stem: young woman with confusion, fever, petechiae, AKI; Hb 8, platelets 15, schistocytes, normal PT/PTT/fibrinogen.
— Action: PLEX + steroids immediately, send ADAMTS13. Do not give platelets unless life-threatening bleed.
— Stem: African-American man started on dapsone for PCP or TMP-SMX for UTI, develops dark urine, jaundice, anemia.
— Smear: bite cells, Heinz bodies on supravital stain. Stop the drug, hydrate. G6PD level deferred until acute episode resolves.
— Stem: patient with recent Mycoplasma pneumonia or EBV develops anemia worsened by cold; agglutination on smear; DAT C3-positive, IgG-negative.
— Diagnosis: cold agglutinin disease. Treat underlying infection, avoid cold; rituximab if persistent.
— Stem: pancytopenia + dark morning urine + Budd-Chiari or mesenteric thrombosis; DAT negative.
— Test: flow cytometry for CD55/CD59 / FLAER. Treat: eculizumab (after meningococcal vaccination).
— Stem: patient with prior mechanical aortic valve develops fatigue, anemia, schistocytes, elevated LDH, low haptoglobin; new murmur of regurgitation.
— Diagnosis: paravalvular leak. Echo, consider surgical repair.
— Stem: Rh-negative pregnant woman at 28 weeks, unsensitized.
— Action: anti-D immunoglobulin at 28 weeks and within 72 hours of delivery.
Step 3 management: When a stem provides hemolysis labs + smear morphology + a single clear trigger or association, the answer is almost always the mechanism-specific therapy + remove the trigger — not generic transfusion alone.
Hemolytic anemia is destruction-driven anemia confirmed by elevated reticulocytes, LDH, and indirect bilirubin with low haptoglobin — and the direct Coombs test is the single pivotal study that splits the differential into immune (warm AIHA, cold agglutinin, drug-induced, alloimmune) versus non-immune (mechanical/MAHA, membrane, enzyme, hemoglobin, PNH, infection) causes, each with distinctive smear findings and mechanism-specific management.
Board pearl: When you don't know the next step in any hemolysis stem — order the peripheral smear and the direct Coombs. Those two results, plus the hemolysis tetrad, will answer >90% of Step 3 hemolytic anemia questions.