Hematology & Oncology System
Hematology & Oncology
High-yield heme/onc for USMLE Step 1/2/3 — red cell morphology and hemoglobinopathies, iron physiology, platelet and coagulation disorders, leukemias and lymphomas, paraneoplastic syndromes, familial cancer genetics, and chemotherapy mechanisms. Each episode extracted, annotated, and organized for exam performance.
Red Cell Disorders
The unifying concept across all anemias: any defect in hemoglobin synthesis (heme or globin) forces microcytosis as a compensatory strategy to preserve MCHC. B12 and folate block DNA synthesis and cause macrocytosis; hemolytic anemias drive a reactive reticulocytosis and normocytosis. Master these axes and you can derive the type of anemia from first principles rather than pure memorization.
EP328
B12 Deficiency and the USMLEs
- Normal B12 physiology: Dietary B12 → stomach acid cleaves from salivary/dietary proteins → pancreatic enzymes cleave R-factor → B12 + intrinsic factor (IF) → absorbed via transcobalamin-2 receptors in terminal ileum. Liver stores 3–5 years
- Causes of deficiency: Pernicious anemia (anti-parietal cell / anti-IF antibodies), gastrectomy, Roux-en-Y bypass, Crohn's disease (terminal ileum), PPI/H2-blocker long-term, bacterial overgrowth (blind loop syndrome), Diphyllobothrium latum (fish tapeworm), metformin, chronic pancreatitis (R-factor not cleaved), transcobalamin-2 deficiency (genetic)
- Two key reactions need B12: (1) Homocysteine → methionine (methionine synthase) and (2) Methylmalonyl-CoA → succinyl-CoA (methylmalonyl-CoA mutase). Only #2 is unique to B12 — folate can substitute in #1
- Lab differentiation: Both B12 and folate deficiency → ↑ homocysteine. Only B12 deficiency → ↑ methylmalonic acid. Normal methylmalonic acid = folate deficiency
- Subacute combined degeneration: Methylmalonic acid damages myelin → dorsal columns (↓ vibration, proprioception, fine touch) + lateral corticospinal tract (hyperreflexia, Babinski, hypertonia). Positive Romberg (need 2 of 3: vision, dorsal columns, CN8)
- Schilling test logic: Give IM B12 (saturate stores) → oral radiolabeled B12 → check urine (expect ≥10%). No urine B12 → absorption defect. Add oral IF → urine B12 appears = pernicious anemia. Still absent → try antibiotics (bacterial overgrowth) or pancreatic enzymes (pancreatitis)
B12 Absorption Pathway — Complete Map
| Step | Location | What Happens | If Disrupted |
|---|---|---|---|
| Dietary B12 ingested | Mouth/esophagus | Binds salivary R-protein (haptocorrin) | Veganism → deficiency over years |
| Acid cleavage | Stomach | HCl frees B12 from dietary proteins; parietal cells secrete IF | PPI, gastrectomy, pernicious anemia |
| R-factor cleavage | Small intestine | Pancreatic enzymes free B12 from R-protein | Chronic pancreatitis |
| IF binding | Small intestine | B12 + IF complex formed | Anti-IF antibodies (pernicious anemia) |
| Absorption | Terminal ileum | TC2 receptors absorb B12-IF complex | Crohn's, ileal resection, TC2 deficiency |
| Storage | Liver | 3–5 years stored | Hemolytic anemia depletes faster (high cell turnover) |
Clinical Triad of B12 Deficiency
1. Megaloblastic anemia — hypersegmented neutrophils (≥5 lobes), macro-ovalocytes
2. Neuropsychiatric — depression, psychosis (↓ neurotransmitter synthesis from ↓ methionine)
3. Subacute combined degeneration — dorsal columns + lateral corticospinal tracts (NOT sensory-only)
Key distinguisher from folate: Folate deficiency does NOT cause neurologic disease (no methylmalonyl-CoA mutase involvement).
Schilling Test — Localize the Lesion
| Step | What's Added | Result if Positive | Diagnosis |
|---|---|---|---|
| 1 | IM B12 → saturate stores; oral radiolabeled B12 | <10% in urine | Absorption defect exists |
| 2 | Add oral intrinsic factor | ≥10% in urine now | Pernicious anemia (IF deficiency) |
| 3 | Add antibiotics | ≥10% in urine | Bacterial overgrowth |
| 4 | Add pancreatic enzymes | ≥10% in urine | Chronic pancreatitis |
Hemolytic Anemia → B12 Depletion
Sickle cell, autoimmune hemolytic anemia, hereditary spherocytosis → high cell turnover → depletes B12 stores faster. These patients also need daily folate supplementation (only 3 months stored vs 3–5 years of B12).
EP494
Thalassemia and the USMLEs
- Microcytic anemia mechanism: Any defect in heme or globin synthesis → ↓ hemoglobin mass → body shrinks cell volume to maintain MCHC (concentration = mass/volume). All thalassemias are autosomal recessive; target cells on blood smear
- Beta-thalassemia (chromosome 11, 2 genes): Minor (1 gene lost) = mild anemia, ↑ HbA2 (alpha-2 delta-2), ↑ HbF. Major (both genes lost) = no HbA, ↑↑ HbA2, ↑↑ HbF, transfusion-dependent, extramedullary hematopoiesis → chipmunk facies + hepatosplenomegaly
- Alpha-thalassemia (chromosome 16, 4 genes): 1 gene lost = silent carrier. 2 genes lost = mild anemia. 3 genes lost = Hemoglobin H disease (beta-4 = HbH; Heinz bodies; transfusion-dependent). 4 genes lost = Hemoglobin BART (gamma-4) → hydrops fetalis, die in utero
- Cis vs trans deletion: Cis (both deletions on same chromosome 16) = common in Asians; worse prognosis for offspring. Trans (one deletion per chromosome) = common in Africans
- Diagnosis: Beta-thalassemia → hemoglobin electrophoresis (↑HbA2 pathognomonic). Alpha-thalassemia → do NOT use hemoglobin electrophoresis (all hemoglobins proportionally decreased → normal-appearing). Use genetic testing or clinical context
- Treatment: Blood transfusions → iron overload → use iron chelators (deferoxamine, deferasirox, deferiprone). Hydroxyurea (↑ HbF). Daily folate supplementation. Parvovirus B19 → aplastic crisis (sudden drop in Hgb + low retic count)
Hemoglobin Types — Master Reference
| Hemoglobin | Chains | Normal % | When Elevated |
|---|---|---|---|
| HbA (adult) | α2β2 | 96–98% | — |
| HbA2 | α2δ2 | 2–3% | Beta-thalassemia (pathognomonic on USMLE) |
| HbF (fetal) | α2γ2 | <1% adults | Beta-thalassemia, sickle cell, hydroxyurea therapy |
| HbH | β4 | 0% | Alpha-thalassemia with 3-gene deletion |
| HbBart | γ4 | 0% | Alpha-thalassemia with 4-gene deletion (fatal in utero) |
| HbS | α2βS2 | 0% | Sickle cell disease |
Why Does Alpha-Thalassemia NOT Show on Hemoglobin Electrophoresis?
Alpha chains are present in every major hemoglobin (HbA, HbA2, HbF). If alpha chains are deficient, all hemoglobins decrease proportionally → no relative difference on electrophoresis → result looks normal. Beta chains are only in HbA → beta-thalassemia reduces HbA specifically while HbA2 and HbF rise comparatively.
Hydrops Fetalis — Two Mechanisms
1. High-output heart failure: HbBart (γ4) has extremely high O2 affinity → doesn't release O2 to fetal tissues → profound fetal hypoxia → compensatory ↑ cardiac output → eventual cardiac failure → ↑ hydrostatic pressure → fluid accumulation
2. ↓ Oncotic pressure: Extramedullary hematopoiesis overwhelms liver → liver prioritizes RBC production over albumin synthesis → ↓ albumin → ↓ oncotic pressure → further fluid extravasation
Extramedullary Hematopoiesis — Clinical Features
- Chipmunk facies / frontal bossing: skull bones expand as marrow invades cortex
- Hepatosplenomegaly: liver + spleen become sites of RBC production
- Osteoporosis / brittle bones: medullary space consumed by erythroid precursors
- Bilirubin gallstones + cholecystitis: chronic hemolysis → ↑ indirect bilirubin → supersaturated bile
Thalassemia — Geographic Associations
Found in: Greece, Italy, Middle East, South Asia (India, Pakistan), Southeast Asia, Africans. Mild forms (trait) confer protection against malaria — same selective advantage as sickle cell trait.
EP507
The Clutch Sickle Cell Disease Podcast — Part 1
- Molecular defect: Beta-globin gene point mutation → glutamic acid → valine at position 6 → HbS. Homozygous (SS) = sickle cell disease; heterozygous (SA) = sickle cell trait (normal life expectancy)
- Pathophysiology triad: (1) HbS polymerizes in hypoxia → sickling → (2) ↓ blood flow / stasis → hypercoagulability + (3) vascular occlusion → ischemia. Cells also hemolyze easily
- Anemia pattern: Normocytic, normochromic (Hgb 7–8 g/dL). High reticulocyte count (compensatory). If retic count LOW → Parvovirus B19 aplastic crisis. If MCV <80 in SCD patient → compound heterozygote (SCD + thalassemia)
- Hemoglobin electrophoresis in SCD: HbS present, NO HbA (confirms SS disease). HbF present (alpha-2-gamma-2 not affected). Sickle cell TRAIT: HbS + HbA + HbF all present
- Functional asplenia: Splenic infarction complete by age 4–5 → ↑ risk encapsulated organisms (S. pneumoniae > H. influenzae type B > N. meningitidis). Thrombocytosis from splenic sequestration loss
- Hydroxyurea — first-line treatment: ↑ HbF → inhibits HbS polymerization → reduces acute pain crises, acute chest syndrome, transfusion need, and mortality by ~40%
HbS Polymerization — What Triggers It
Deoxygenation is the primary trigger. Exacerbating factors tested on USMLE: hypoxia, dehydration, acidosis, fever, cold, high altitude, extreme exercise (important for sickle cell TRAIT counseling).
| Hemoglobin Electrophoresis Pattern | Diagnosis |
|---|---|
| SS only (+ HbF small amount) | Sickle cell disease (SCD) |
| HbS + HbA + HbF | Sickle cell trait (carrier) |
| HbS + ↑ HbA2 + small HbA | SCD + beta-thalassemia (compound heterozygote) |
| HbS + microcytic anemia | SCD + thalassemia (clinical clue) |
Newborn Screening and Prophylaxis
- Screening: hemoglobin electrophoresis (neonatal)
- Penicillin prophylaxis for at least 5 years (reduces mortality from pneumococcal infection)
- If penicillin allergy: amoxicillin or azithromycin
- Vaccines: pneumococcal (PCV13 + PPSV23), HiB, meningococcal, annual influenza
Prevention Medicine Question Framing
Preconception counseling for two sickle cell trait parents = primary prevention (preventing disease from developing). Prophylactic penicillin for a diagnosed infant = also primary prevention (preventing sepsis from developing). Secondary prevention = screening already affected individuals.
EP508
The Clutch Sickle Cell Disease Podcast — Part 2
- Exchange transfusion indications: Stroke (ischemic in kids = most common; hemorrhagic in adults = most common), fat embolism syndrome, acute chest syndrome (most common cause of death), extremity ulcers not healing. NOT for uncomplicated PE (manage PE directly)
- Iron overload from transfusions: Use iron chelators — deferoxamine or deferasirox. Fenton reaction: iron → free radicals → restrictive cardiomyopathy, liver failure, pituitary damage
- ACE inhibitors in SCD: Two indications: (1) hypertension and (2) proteinuria/early renal dysfunction. Mechanism: dilate efferent arteriole → ↓ intraglomerular pressure → ↓ hyperfiltration injury
- Acute chest syndrome: Most common cause of death in SCD. Diffuse interstitial infiltrates on CXR. Common triggers: mycoplasma, chlamydia pneumoniae infection. Treat with exchange transfusion + antibiotics
- Other SCD complications: Dactylitis (<5 years old, swelling of hands/feet), AVN of femoral/humeral head (unilateral joint pain), priapism/erectile dysfunction (microvasculature occlusion), osteomyelitis (Salmonella most common), cholecystitis (bilirubin gallstones from hemolysis), pulmonary hypertension → right heart failure
- Bone marrow transplant: Only cure; typically in patients <16 years old. Daily folate supplementation required (high cell turnover depletes folate rapidly)
SCD Complications — Complete Master Table
| Complication | Key Details | USMLE Pearl |
|---|---|---|
| Acute pain crisis | Vaso-occlusion; treat with opioids (NOT meperidine — seizures) | Do NOT use meperidine in SCD |
| Aplastic crisis | Parvovirus B19 → ↓ reticulocytes + ↓ Hgb (below SCD baseline of 7–8) | Low retic count = Parvo B19 |
| Acute chest syndrome | #1 cause of death; interstitial infiltrates; mycoplasma/chlamydia trigger | Exchange transfusion + empiric antibiotics |
| Stroke — kids | Ischemic stroke most common in children | Exchange transfusion |
| Stroke — adults | Hemorrhagic stroke most common in adults | Non-contrast CT head first |
| Dactylitis | Swollen hands/feet; typically <5 years old | Classic first presentation |
| AVN | Femoral or humeral head; unilateral joint pain | Also called osteonecrosis |
| Osteomyelitis | Bone pain + fever → Salmonella most common (not Staph) | MRI + bone culture |
| Cholecystitis | Bilirubin gallstones from chronic hemolysis | RUQ pain + fever + ↑ AST/ALT |
| Priapism/ED | Microvasculature occlusion | Erectile dysfunction = occlusion of microvasculature |
| Renal disease | Hyperfiltration injury → proteinuria → CKD | ACE inhibitor even without HTN if proteinuria present |
| Pulmonary HTN | Slow blood flow occludes pulmonary vessels → RV failure | Edema + JVD in SCD patient |
| Fat embolism | Bone infarction → fat in circulation; resembles acute chest syndrome | Chest pain + ↓ platelets + multi-organ failure |
Opioid Rule in SCD
Opioids are appropriate for acute pain crises. NEVER use meperidine (Demerol) — it accumulates as normeperidine and causes seizures. Use morphine or hydromorphone.
SCD and Supplemental Oxygen
Supplemental O2 indicated when: SpO2 <92% on room air OR PaO2 ≤70 mmHg. Does not need to be given prophylactically to all SCD patients.
EP605
The Extremely HY RBC Podcast (Step 1–3)
- Spherocytes: Always think membrane defect. Hereditary spherocytosis (spectrin/ankyrin/band proteins — autosomal dominant) = Coombs negative. Autoimmune hemolytic anemia = Coombs positive. ↑ MCHC because hemoglobin same mass, smaller volume
- Schistocytes (helmet/fragment cells): MAHA (microangiopathic hemolytic anemia) = TMA. Causes: TTP (ADAMTS-13 deficiency), HUS (Shiga toxin), DIC, HELLP syndrome, pre-eclampsia, malignant hypertension, prosthetic valve, vasculitis, glomerulonephritis
- Dacrocytes (teardrop cells): RBCs squeezed through fibrotic marrow → teardrop shape. Classic = primary myelofibrosis (megakaryocytes release PDGF → fibroblast activation → collagen)
- Rouleau formation: Positive proteins reduce negative charge on RBC surface → RBCs stack like coins. Most common cause = pregnancy (↑ fibrinogen). Also: multiple myeloma, Waldenstrom's, inflammation
- Acanthocytes (spur cells): Membrane lipid/protein defects. Causes: abetalipoproteinemia (MTP mutation → no chylomicrons → vitamin E deficiency), liver disease, severe anorexia
- Target cells (codocytes): Thalassemia, liver disease. Elliptocytes (ovalocytes) = hereditary elliptocytosis
Complete RBC Shape Guide
| Shape | Alternate Names | Mechanism | Key Associations |
|---|---|---|---|
| Spherocytes | — | ↓ membrane surface → spheroid shape | Hereditary spherocytosis (Coombs −), AIHA (Coombs +) |
| Schistocytes | Helmet cells, fragment cells | Traumatic shearing of RBC membrane | TTP, HUS, DIC, HELLP, prosthetic valve, malignant HTN |
| Dacrocytes | Teardrop cells | RBCs squeeze through fibrotic marrow | Primary myelofibrosis (most classic) |
| Target cells | Codocytes | ↑ surface-to-volume ratio | Thalassemia, liver disease, post-splenectomy |
| Acanthocytes | Spur cells | Membrane lipid/protein defect → spiny projections | Abetalipoproteinemia, liver disease, anorexia |
| Elliptocytes | Ovalocytes | Spectrin defect → elliptical shape | Hereditary elliptocytosis |
| Sickle cells | Drepanocytes | HbS polymerization in deoxygenated state | Sickle cell disease |
| Rouleau | Stacked coins | ↑ positive proteins reduce RBC surface charge | Pregnancy (#1), myeloma, Waldenstrom's, inflammation |
| Echinocytes | Burr cells | Uniform membrane spicules | Uremia, liver disease (vs acanthocytes — irregular spicules) |
RBC Inclusions — Full Reference
| Inclusion | Composition | Stain | Association |
|---|---|---|---|
| Howell-Jolly bodies | Nuclear remnant (DNA) | Regular H&E — single dark purple dot | Asplenia (sickle cell autosplenectomy, post-splenectomy, ITP treatment) |
| Heinz bodies | Denatured hemoglobin precipitate | Supravital stain required | G6PD deficiency (oxidative stress), alpha-thalassemia HbH disease |
| Bite cells | RBC after spleen removes Heinz body | Regular smear | G6PD deficiency post-splenic removal of Heinz bodies |
| Basophilic stippling | Ribosome aggregates | Multiple blue dots throughout cell | Lead poisoning, thalassemia, sideroblastic anemia |
| Pappenheimer bodies | Ferritin/iron deposits | 1–3 peripheral dots (eccentric) | Lead poisoning (iron accumulation because no protoporphyrin) |
| Ring sideroblast | Iron around mitochondria | Prussian blue stain — iron ring around nucleus | Lead poisoning, B6 deficiency, myelodysplastic syndrome, alcohol |
| Malaria parasites | Plasmodium | Banana-shaped forms | Malaria (P. falciparum = banana gametocytes) |
| Maltese cross | Babesia organisms | Tetrad form in RBC | Babesiosis (Ixodes tick, New England area) |
G6PD Deficiency — High-Yield Facts
X-linked recessive → only males affected on USMLE. Triggers: Dapsone, primaquine, fava beans, sulfonamides, nitrofurantoin. Heinz bodies → spleen removes → bite cells. G6PD is rate-limiting enzyme of oxidative phase of pentose phosphate pathway → makes NADPH → regenerates glutathione → handles oxidative stress.
EP550
The Iron Story and the USMLEs — Part 1
- Absorption site and form: Absorbed in duodenum (+ proximal jejunum). Only Fe2+ (ferrous) absorbed via DMT1 (divalent metal transporter 1). Fe3+ (ferric) must be reduced first by ferric reductase on microvilli. Absorb ~10% of dietary iron; can double in iron deficiency, pregnancy, or bleeding states
- Vitamin C enhances absorption: Ascorbate reduces Fe3+ → Fe2+ (increases bioavailability of oral iron). Same mechanism: methemoglobin (Fe3+) → treat with methylene blue (first line) or vitamin C as adjunct
- Heme vs non-heme iron: Heme iron (meat/fish/poultry) absorbed ~30%. Non-heme iron (vegetables/fruits) absorbed only 2–10%. Major clinical relevance for vegans and iron deficiency
- Ferroportin — the gatekeeper: Transports Fe2+ from enterocyte into bloodstream. Hepcidin (released by liver) binds ferroportin → blocks iron release → enterocytes eventually slough → iron lost in stool
- Hepcidin triggers: (1) Inflammation → IL-6 → ↑ hepcidin → anemia of chronic disease. (2) ↑ liver iron stores → ↑ hepcidin (protective). Low hepcidin = iron deficiency, hypoxia (↑ EPO → suppress hepcidin)
- Iron labs: Transferrin saturation = serum iron / TIBC × 100. Most sensitive test for iron stores. Ferritin = short-term storage (like checking account); hemosiderin = long-term storage. Ferritin is acute phase reactant (falsely elevated in inflammation, liver disease, malignancy)
Iron Lab Interpretation — Master Table
| Condition | Serum Iron | TIBC | Transferrin Sat | Ferritin |
|---|---|---|---|---|
| Iron deficiency anemia | ↓ | ↑ (hungry for iron) | ↓ (<20%) | ↓ (most specific) |
| Anemia of chronic disease | ↓ | ↓ | ↓ | ↑ or normal |
| Hereditary hemochromatosis | ↑ | ↓ | ↑ (>45%) | ↑↑ |
| Sideroblastic anemia | ↑ | ↓ or normal | ↑ | ↑ |
| Lead poisoning | ↑ (iron accumulates) | ↓ | ↑ | ↑ |
Transferrin Saturation vs Ferritin — Screening for Hemochromatosis
Both are acceptable. If both present as answer choices: transferrin saturation is more sensitive AND more specific. Ferritin is less specific because it is elevated by inflammation, liver disease, and malignancy. Use transferrin saturation when you must choose one.
Hemosiderin — Skin Hyperpigmentation Integration
- Iron-containing pigment → brown discoloration of skin
- Hereditary hemochromatosis → bronze skin (hemosiderosis of skin + diabetes = "bronze diabetes")
- Varicose veins → venous stasis → RBCs extravasate → hemosiderin deposits → stasis dermatitis (lower extremity hyperpigmentation + swelling)
- Any chronic bleeding condition → hemosiderin in surrounding tissue
Hepcidin — The Master Iron Regulator
Released by liver. Binds ferroportin on enterocytes AND macrophages → prevents iron release. Two triggers: inflammation (via IL-6) and high liver iron stores. Result: iron trapped in macrophages (unavailable to bacteria — evolutionary advantage) → ↓ serum iron despite adequate total body iron (anemia of chronic disease).
EP552
The Iron Story and the USMLEs — Part 2
- Hereditary hemochromatosis: HFE gene mutation (most commonly C282Y, chromosome 6). AR inheritance. Iron deposits in liver, pancreas, heart, pituitary, skin, joints. "Bronze diabetes" = skin + pancreas involvement. Screen with transferrin saturation (>45% is threshold)
- Hemochromatosis treatment: Phlebotomy (first line) — removes iron-containing RBCs. Chelation (deferoxamine) if phlebotomy not possible. Avoid iron supplements, vitamin C supplements, alcohol
- Conditions that improve with phlebotomy / iron loss: (1) Porphyria cutanea tarda (PCT) — mild iron deficiency ↑ UROD activity → symptom improvement; check for Hep C. (2) Polycythemia vera — reason women present later than men (menstruation is auto-phlebotomy). JAK2 mutation
- Restless legs syndrome and iron: Strong association with iron deficiency. Before prescribing dopamine agonists, check ferritin — if low, iron supplementation alone may resolve RLS
- Iron deficiency from gastric bypass: Bypasses duodenum → can't absorb iron → iron deficiency anemia → if patient has heavy menses compound risk. First step: check serum ferritin
- Lead poisoning — heme synthesis: Lead inhibits ALA dehydratase (upstream) + ferrochelatase (downstream) → can't make protoporphyrin → iron accumulates → ring sideroblasts + ↑ free erythrocyte protoporphyrin. Basophilic stippling = ribosome aggregates (lead inhibits RNA degradation)
Lead Poisoning — Heme Synthesis Block
| Lead Inhibits | Step in Pathway | Result | Lab Finding |
|---|---|---|---|
| ALA dehydratase | Early (upstream) | ↑ ALA (aminolevulinic acid) in urine | Elevated urine ALA |
| Ferrochelatase | Late (downstream) | Iron can't incorporate into protoporphyrin | Ring sideroblasts; ↑ free erythrocyte protoporphyrin; ↑ ferritin |
Clinical triad of lead poisoning: microcytic anemia + abdominal pain + peripheral neuropathy (lead demyelinates peripheral nerves — contrast with subacute combined degeneration of B12 which affects central nerves)
Polycythemia Vera — Sex Difference (Biostatistics Integration)
Men develop symptoms in their 40s; women develop symptoms in their 50s–60s. Mechanism: menstruation = monthly auto-phlebotomy → reduces RBC mass → delays symptom development. This can appear as a biostatistics question asking you to identify the pathophysiologic mechanism behind the different incidence curves by sex.
Hereditary Hemochromatosis — Organ-Based Complications
| Organ | Manifestation |
|---|---|
| Liver | Cirrhosis → hepatocellular carcinoma (even after treatment) |
| Pancreas | Bronze diabetes (exocrine + endocrine destruction) |
| Heart | Restrictive cardiomyopathy, conduction defects |
| Pituitary | Hypogonadism (↓ LH/FSH), loss of libido |
| Joints | Arthropathy (2nd and 3rd MCP joints — classic) |
| Skin | Bronze discoloration (hemosiderin deposition) |
RR 100EP476
Rapid Review 100 — Thalassemia, Anemia Types, and Iron Deficiency
- Microcytic anemia differential: Iron deficiency (↓ ferritin, ↑ TIBC, ↓ transferrin sat), beta-thalassemia (↑ HbA2 on electrophoresis), lead poisoning (microcytic + abdominal pain + peripheral neuropathy), anemia of chronic disease (sometimes microcytic; ↑ ferritin, ↓ TIBC)
- Macrocytic anemia: B12 or folate deficiency → impaired DNA synthesis → cell enlarges but can't divide → macrocytosis. B12 = ↑ methylmalonic acid (unique). Folate = only ↑ homocysteine
- Why hemoglobin electrophoresis diagnoses beta-thal but NOT alpha-thal: Beta chains only in HbA → beta deficiency changes proportions. Alpha chains in ALL hemoglobins → proportional decrease → normal-looking electrophoresis
- Normocytic anemias: Either hemolytic (hereditary spherocytosis, AIHA, G6PD, sickle cell) or renal disease (↓ EPO). High retic count = hemolysis. Low retic count = marrow failure or aplastic crisis
- Anemia of chronic disease mechanism: Hepcidin → (1) blocks DMT1 absorption in gut, (2) blocks ferroportin release from macrophages. Iron stored in macrophages but unavailable. Ferritin HIGH (sequestration), TIBC LOW (liver doesn't make transferrin when iron sufficient)
RR 104EP487
Rapid Review 104 — Hemoglobin Electrophoresis, Seminoma, Postpartum Hemorrhage
- ↑ HbA2 = beta-thalassemia: Almost pathognomonic on USMLE. HbA2 = alpha-2 delta-2. Beta genes are damaged → compensatory rise in delta chains pairing with alphas
- HbF elevated by hydroxyurea: Hydroxyurea is a ribonucleotide reductase inhibitor (anticancer) that also elevates HbF. Used in sickle cell disease and thalassemia
- HbBart = gamma-4: Alpha-thalassemia 4-gene deletion. Extremely high O2 affinity → fetal hypoxia → hydrops fetalis → die in utero
- HbH = beta-4: Alpha-thalassemia 3-gene deletion. Transfusion dependent. Heinz bodies (HbH precipitates). Can have target cells + Heinz bodies simultaneously
- Seminoma and beta-HCG: Testicular mass + markedly ↑ beta-HCG = seminoma. Very high beta-HCG (>100,000) in women = molar pregnancy or choriocarcinoma. AFP elevated = non-seminomatous germ cell tumor (yolk sac tumor)
Platelet & Coagulation Disorders
The key conceptual distinction: primary hemostasis defects (platelet plug) cause mucocutaneous bleeding (petechiae, epistaxis), while secondary hemostasis defects (coagulation cascade) cause deep bleeding (hemarthrosis, hematoma). TTP and HUS are classic microangiopathic hemolytic anemias with overlapping presentations but distinct pathophysiology and management. Drug-induced cytopenias are heavily tested — knowing mechanism predicts the drug.
EP433
Adverse Drug Reactions — Hematologic System (Step 1–3)
- Agranulocytosis / neutropenia: Clozapine (monitor WBC regularly), carbamazepine (trigeminal neuralgia), PTU/methimazole (antithyroid), trimethoprim-sulfamethoxazole, pyrimethamine-sulfadiazine, sulfasalazine, dapsone. All inhibit folate/DNA synthesis or direct marrow toxicity
- Febrile neutropenia from folate inhibitors: TMP-SMX (inhibits DHFR + dihydropteroate synthetase sequentially), pyrimethamine (inhibits DHFR), methotrexate. Rescue: leucovorin (folinic acid) — bypasses DHFR. Give leucovorin with pyrimethamine prophylactically
- Hemolytic anemia from drugs: G6PD-triggering drugs (primaquine, dapsone, sulfonamides, nitrofurantoin) → oxidative stress → Heinz bodies → hemolysis. Drug-induced AIHA (type II hypersensitivity): penicillin, cephalosporins, methyldopa (warm antibody)
- Thrombocytopenia from drugs: Heparin (HIT — white clot syndrome, antibodies against PF4-heparin), linezolid, valproate, vancomycin, quinidine, chloramphenicol (aplastic anemia)
- HIT management: Diagnose with platelet factor 4 antibody (serotonin release assay = gold standard). Stop heparin immediately. Switch to direct thrombin inhibitor: argatroban (hepatic failure safe), bivalirudin, fondaparinux. Do NOT give warfarin acutely (protein C/S depletion → limb gangrene)
Drugs Causing Agranulocytosis — Complete List
| Drug | Clinical Context | Mechanism |
|---|---|---|
| Clozapine | Refractory schizophrenia | Direct marrow toxicity; monitor WBC weekly → biweekly → monthly |
| Carbamazepine | Trigeminal neuralgia, epilepsy | Marrow suppression + aplastic anemia risk |
| PTU / Methimazole | Hyperthyroidism (pre-op or storm) | Immune-mediated marrow suppression |
| TMP-SMX | UTI, PCP prophylaxis, toxo prophylaxis | Sequential folate synthesis inhibition |
| Sulfasalazine | Inflammatory bowel disease | Folate antagonism + direct marrow toxicity |
| Pyrimethamine + sulfadiazine | Toxoplasmosis treatment (AIDS) | Sequential DHFR inhibition → add leucovorin |
| Chloramphenicol | Rare, resistant infections | Dose-independent aplastic anemia (idiosyncratic) |
HIT — The White Clot Paradox
Heparin-induced thrombocytopenia causes thrombosis despite low platelet count. Antibodies against PF4-heparin complex → activate platelets → white clot (fibrin-rich). Stop heparin; switch to direct thrombin inhibitor (argatroban preferred if hepatic failure, bivalirudin if renal failure). Never give warfarin acutely (Coumadin skin necrosis risk from protein C/S depletion).
Folate-Inhibitor Antibiotic ADR Chain
Thymidylate synthase converts dUMP → dTMP (requires folate). Block folate → block this step → block DNA synthesis → bone marrow suppression. 5-fluorouracil directly inhibits thymidylate synthase (chemotherapy). Leucovorin (folinic acid) bypasses DHFR → rescues marrow. Note: 5-fluocytosine (antifungal for cryptococcal meningitis) is converted to 5-FU by fungal cytosine deaminase.
RR 64EP336
Rapid Review 64 — HUS, TMA, Blood Smear, and Anemia
- Polycythemia vera → central retinal vein occlusion: Classic USMLE association. Hyperviscosity from ↑ hematocrit (JAK2 mutation) → sluggish venous flow → central retinal vein occlusion. Findings: flame-shaped hemorrhages throughout retina ("blood and thunder" fundus), dilated tortuous veins, disc edema
- TTP (thrombotic thrombocytopenic purpura): ADAMTS-13 deficiency (hereditary or acquired antibody) → cannot cleave ultra-large vWF multimers → platelet-fibrin microthrombi → schistocytes + thrombocytopenia + microangiopathic hemolytic anemia (MAHA). Pentad: MAHA, thrombocytopenia, fever, renal failure, neurologic symptoms
- HUS (hemolytic uremic syndrome): Shiga toxin (E. coli O157:H7 most common, also Shigella) damages endothelium → MAHA + thrombocytopenia + acute kidney injury (kidney most affected, unlike TTP where CNS predominates). No fever typically. Do NOT give antibiotics (↑ toxin release)
- TTP vs HUS: TTP = neurologic predominance + ADAMTS-13 antibody. HUS = renal predominance + Shiga toxin + no CNS. Treatment: TTP → plasma exchange (plasmapheresis) ± rituximab. HUS → supportive (dialysis if needed)
TTP vs HUS vs DIC vs HELLP — Comparison Table
| Feature | TTP | HUS | DIC | HELLP |
|---|---|---|---|---|
| Mechanism | ↓ ADAMTS-13 → ↑ vWF multimers | Shiga toxin → endothelial damage | Systemic coagulation activation | Preeclampsia → endothelial dysfunction |
| Schistocytes | Yes | Yes | Yes | Yes |
| Platelets | ↓↓ | ↓ | ↓↓ | ↓ |
| PT/PTT | Normal | Normal | ↑↑ (both prolonged) | Normal or mildly ↑ |
| D-dimers | Normal | Normal | ↑↑↑ | ↑ |
| Dominant organ | CNS (altered mental status) | Kidney (AKI) | Multi-organ (bleeding) | Liver (↑ LFTs) + kidney |
| Treatment | Plasma exchange ± rituximab | Supportive; NO antibiotics | Treat underlying cause + FFP/cryoprecipitate | Deliver fetus |
HUS — Do NOT Give Antibiotics
E. coli O157:H7 HUS: antibiotics cause bacterial lysis → release of Shiga toxin surge → worsens renal injury. Treatment is entirely supportive — hydration, dialysis if needed, RBC transfusion for severe anemia.
EP341
Lupus and the USMLEs — Hematologic Manifestations
- Primary pathogenesis: Type III hypersensitivity (immune complex deposition → complement activation → inflammation). Anticardiolipin antibodies → antiphospholipid syndrome → recurrent pregnancy loss (thrombosis of uteroplacental artery)
- Cytopenias are Type II hypersensitivity: Autoantibodies against red cells (AIHA — Coombs positive), platelets (ITP — anti-GP2B3A), white cells (leukopenia). These are NOT immune complex mediated
- Key antibodies: ANA (screening — very sensitive, not specific). Confirmatory: anti-dsDNA (tracks disease activity) or anti-Smith (both ~100% specific). Drug-induced lupus: anti-histone antibodies, no anti-dsDNA, no low complement, no renal/CNS involvement
- Drug-induced lupus drugs: Hydralazine, procainamide, isoniazid, sulfonamides, etanercept (TNF inhibitor). Stop drug → symptoms resolve. No treatment needed
- Lupus nephritis: Low complement (C3/C4) from immune complex consumption. Type IV (diffuse proliferative) = most common on USMLE. Diagnosis by renal biopsy (required before treatment). Most common cause of death = cardiovascular disease (not nephritis)
- Libman-Sachs endocarditis: Sterile vegetations on mitral valve → mitral regurgitation murmur. Type III hypersensitivity at cardiac valves. Also pericarditis and pleuritis (serosal surface inflammation responsive to NSAIDs)
Lupus Arthritis vs Rheumatoid Arthritis — Critical Distinction
| Feature | Lupus Arthritis | Rheumatoid Arthritis |
|---|---|---|
| Distribution | Symmetric | Can be symmetric or asymmetric |
| Erosion | Non-erosive (joints spared) | Erosive (joint destruction) |
| Deformity | Non-deforming | Deforming (ulnar deviation, etc.) |
| Joints affected | Hands (MCP, PIP distribution) | Hands, knees, hips — polyarticular |
Anti-Ro/SSA Antibodies in Lupus — Fetal Risk
Anti-Ro (SSA) and anti-La (SSB) antibodies are IgG → cross placenta → damage fetal cardiac conduction system → complete (3rd degree) heart block in newborn. Not second degree — complete. Screen pregnant lupus patients for these antibodies.
Lupus Treatment Ladder
- Hydroxychloroquine: first-line maintenance. Annual eye exam required (retinopathy risk — damages RPE)
- NSAIDs: acute pleuritis/pericarditis (serosal inflammation)
- Steroids: acute flares (especially nephritis or severe manifestations)
- Belimumab (anti-BLyS): biologic for refractory lupus
- Do NOT use etanercept (TNF inhibitor) → triggers drug-induced lupus
ANA Positive — Does NOT Mean Lupus
ANA positive in: scleroderma (anti-Scl-70), Sjögren's (anti-Ro/La), drug-induced lupus, and ~70% of normal people at low titer. Confirmatory tests for lupus: anti-dsDNA (tracks disease activity) or anti-Smith (more specific). Low complement (C3/C4) in active lupus nephritis.