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RBC Disorders: Basics to Clinicals

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1. Normal RBC Physiology - The Foundation

• Biconcave disc, ~7-8 µm diameter, no nucleus or organelles at maturity
• Lifespan: ~120 days; destroyed by splenic and hepatic macrophages (extravascular)
• Primary function: O2 transport via hemoglobin (Hb)

• Normal adult: 96% HbA (α₂β₂), 3% HbA2 (α₂δ₂), 1% HbF (α₂γ₂)
• O2 dissociation curve - shifted right by: ↑temperature, ↑CO2, ↑2,3-DPG, acidosis (Bohr effect)
• 2,3-DPG: stabilizes deoxygenated Hb → releases O2 to tissues

• Stem cell → BFU-E → CFU-E → proerythroblast → basophilic → polychromatophilic → orthochromic erythroblast → reticulocyte → mature RBC
• Regulated by erythropoietin (EPO) from peritubular cells of the kidney (released in response to hypoxia)
• Requires: iron (heme), B12 and folate (DNA synthesis), protein (globin chains)

• Harrison's Principles of Internal Medicine 22e, Table 66-1

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2. Anemia - Definition and Classification

• Men: Hb <13.5 g/dL
• Women: Hb <12 g/dL
• Pregnant women: Hb <11 g/dL

Classification by MCV (Wintrobe classification)

• Thalassemia
• Anemia of chronic disease (often normocytic)
• Iron deficiency
• Lead poisoning / sideroblastic
• Sideroblastic anemia

• Oval macrocytes (megaloblastic): B12 deficiency, folate deficiency, chemotherapy, myelodysplasia
• Round macrocytes (non-megaloblastic): Alcohol, liver disease, hypothyroidism, reticulocytosis

• Aplastic anemia, renal disease, anemia of chronic disease (early), hemolytic anemia, endocrinopathies, marrow invasion

Classification by Mechanism

• Blood loss (acute hemorrhage)
• Hemolytic anemia (intrinsic or extrinsic defect)

• Iron, B12, folate deficiency
• Aplastic anemia, myelophthisic anemia
• Anemia of chronic inflammation
• Renal failure (EPO deficiency)
• Harrison's 22e; Robbins & Kumar Basic Pathology

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3. Compensatory Mechanisms in Anemia

1. Increased cardiac output (minutes) - maintains O2 delivery when Hb falls
2. Increased 2,3-DPG (hours-days) - shifts O2 dissociation curve rightward, improves O2 offloading to tissues
3. Plasma volume expansion (weeks) - preserves cardiac output; can cause dilutional worsening if overactive → risk of high-output heart failure

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4. Anemias of Blood Loss

Acute Hemorrhage

• Loss >20% of intravascular volume → cardiovascular collapse/shock
• Initially: normal Hb (hemodilution not yet complete); full extent revealed in 2-3 days
• Morphology: normocytic, normochromic
• Recovery: EPO rises → reticulocytosis begins at 5-7 days lag

Chronic Blood Loss

• Gradual iron depletion → iron deficiency anemia (covered below)
• Common causes: GI bleeding (peptic ulcer, colorectal cancer), menorrhagia

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5. Hemolytic Anemias

Extravascular vs Intravascular Hemolysis

5a. Hereditary Spherocytosis (HS)

• Hemolytic anemia (severity varies from mild to severe)
• Jaundice (episodic, worsened by infection)
• Splenomegaly
• Pigment (bilirubin) gallstones
• Aplastic crisis triggered by parvovirus B19

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5b. Sickle Cell Anemia

• Deoxygenated HbS polymerizes into rigid fibers → RBC adopts sickle shape
• Reversible initially, but repeated sickling causes membrane damage → irreversible sickled cells
• Three key determinants of sickling:
  1. % HbS in the cell - heterozygotes (~40% HbS) rarely sickle in vivo
  2. HbF level - HbF inhibits polymerization; newborns protected until ~5-6 months
  3. Dehydration and hypoxia - increase sickling

1. Hemolytic anemia (chronic extravascular + intravascular)
2. Vaso-occlusion (sickled cells + neutrophil adhesion block microvasculature) → ischemia/infarction
3. Pain crises (vaso-occlusive crisis, VOC) - most common; precipitated by infection, cold, dehydration
4. Acute chest syndrome - fever, chest pain, new pulmonary infiltrate; most common cause of death
5. Stroke (particularly in children)
6. Dactylitis (hand-foot syndrome) - first manifestation in infants
7. Autosplenectomy - repeated splenic infarcts → functional asplenia → susceptibility to encapsulated organisms (Strep pneumoniae, H. influenzae, Salmonella)
8. Avascular necrosis of femoral/humeral head
9. Renal papillary necrosis, hyposthenuria
10. Priapism

• Hydroxyurea - increases HbF production; reduces crises by ~50%
• Voxelotor - inhibits HbS polymerization (FDA-approved 2019)
• Crizanlizumab - anti-P-selectin monoclonal antibody; reduces VOC
• L-glutamine - reduces oxidative damage
• Hematopoietic stem cell transplant - only curative option
• Gene therapy - lovotibeglogene autotemcel (Lyfgenia) approved by FDA 2023
• Prophylactic penicillin in children under 5; pneumococcal vaccines
• Transfusion for stroke prevention, acute chest syndrome

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5c. Thalassemias

Beta-Thalassemia

• Absent/reduced β-globin → excess α chains precipitate in erythroid precursors → ineffective erythropoiesis in marrow
• Bone marrow expansion → frontal bossing, maxillary prominence (chipmunk facies), "crew-cut" skull X-ray
• Extramedullary hematopoiesis in liver, spleen, lymph nodes
• Severe hemolysis + iron overload (from transfusions + increased GI absorption)

Alpha-Thalassemia

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5d. G6PD Deficiency

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5e. Paroxysmal Nocturnal Hemoglobinuria (PNH)

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5f. Immunohemolytic (Autoimmune Hemolytic) Anemia - AIHA

• IgG antibodies reactive at body temperature (37°C)
• Causes: Idiopathic, SLE, CLL, drugs (penicillin, methyldopa, cephalosporins)
• RBCs coated with IgG → splenic Fc-receptor binding → extravascular hemolysis
• Diagnosis: Direct Coombs/DAT positive (anti-IgG)
• Treatment: Steroids → rituximab → splenectomy

• IgM antibodies react in cold peripheral blood (0-4°C) → activate complement → intravascular hemolysis + agglutination
• Causes: Mycoplasma pneumoniae, EBV, lymphomas (cold agglutinin disease)
• DAT positive for complement (anti-C3)
• Treatment: Keep warm; rituximab; avoid cold exposure

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5g. Microangiopathic Hemolytic Anemia (MAHA)

• TTP (ADAMTS13 deficiency → ultra-large vWF multimers → platelet microthrombi)
• HUS (Shiga toxin from E. coli O157:H7 → endothelial damage in kidneys)
• DIC
• Malignant hypertension
• Prosthetic heart valves

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6. Anemias of Diminished Erythropoiesis

6a. Iron Deficiency Anemia (IDA)

• Increased demand: pregnancy, growth
• Decreased intake: poor diet (vegetarians, infants)
• Decreased absorption: celiac disease, post-gastrectomy
• Chronic blood loss: GI bleeding (most important in adults - always rule out colorectal cancer), menorrhagia

1. Pre-latent: Depleted iron stores (↓ferritin); normal Hb/MCV
2. Latent: ↓serum iron, ↑TIBC, ↓transferrin saturation; normal Hb
3. Iron deficiency anemia: ↓Hb, ↓MCV, ↓MCH, hypochromic microcytic cells

• Serum ferritin ↓ (most sensitive/specific) - <12 ng/mL diagnostic
• Serum iron ↓
• TIBC ↑ (transferrin up-regulated)
• Transferrin saturation <16%
• Peripheral smear: microcytic, hypochromic RBCs, pencil cells (elliptocytes), target cells

• Classic: fatigue, pallor, exertional dyspnea
• Pica (craving for ice = pagophagia, clay, dirt)
• Koilonychia (spoon nails)
• Angular cheilitis, glossitis
• Plummer-Vinson syndrome (dysphagia + esophageal web + IDA)

• Oral ferrous sulfate 325 mg TID (between meals for max absorption)
• IV iron (ferric carboxymaltose, ferumoxytol) for intolerance/malabsorption
• Treat underlying cause
• Reticulocytosis peaks at 7-10 days; Hb corrects in 4-8 weeks; stores replete in 3-6 months

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6b. Anemia of Chronic Inflammation (ACI) / Anemia of Chronic Disease

• Hepcidin (acute-phase protein from liver) is elevated by IL-6
• Hepcidin blocks: (1) ferroportin on enterocytes → ↓intestinal iron absorption; (2) ferroportin on macrophages → iron trapped inside macrophages (functional iron deficiency)
• EPO response is blunted by inflammatory cytokines
• RBC lifespan mildly shortened

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6c. Megaloblastic Anemias

• Oval macrocytes (MCV often >110 fL)
• Hypersegmented neutrophils (>5 lobes; ≥1 cell with 6 lobes = diagnostic)
• Pancytopenia in severe cases
• Megaloblastic bone marrow changes

Folate Deficiency

Vitamin B12 (Cobalamin) Deficiency

• B12 released from food by gastric acid + pepsin
• Binds haptocorrin in saliva
• In duodenum, released from haptocorrin by pancreatic proteases → binds intrinsic factor (IF) from gastric parietal cells
• IF-B12 complex absorbed in terminal ileum via cubilin receptor
• Stored in liver (5-20 years reserve)

• Pernicious anemia (most common): Autoimmune atrophic gastritis; anti-parietal cell and anti-IF antibodies; T-cell mediated destruction of parietal cells
• Gastrectomy, gastric bypass
• Terminal ileal disease/resection (Crohn's disease)
• Veganism (rare; eggs/dairy prevent deficiency)
• Metformin use (impairs B12 absorption)
• Fish tapeworm (Diphyllobothrium latum)

• Subacute combined degeneration (SCD) of spinal cord: degeneration of dorsal and lateral columns → loss of vibration/proprioception, spastic paraparesis
• Peripheral neuropathy
• Glossitis, angular cheilitis
• Neuropsychiatric symptoms (depression, dementia, psychosis)
• Anemia may be absent with prominent neurology

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6d. Aplastic Anemia

• Idiopathic (most common, ~70%) - autoimmune T-cell mediated HSC destruction
• Drugs (chloramphenicol, benzene, chemotherapy, NSAIDs)
• Viral (parvovirus B19, hepatitis, EBV, CMV)
• Radiation
• Paroxysmal nocturnal hemoglobinuria (PNH-AA overlap)
• Congenital: Fanconi anemia (chromosomal instability), Diamond-Blackfan

• Pancytopenia (all three cell lines low)
• Reticulocytes ↓↓ (hypoproliferative)
• Bone marrow biopsy: hypocellular with fat replacement (diagnostic)

• Severe: BM cellularity <25%; two of: ANC <500, platelets <20k, reticulocytes <60k
• Very severe: ANC <200

• Young patients with matched sibling donor: Allogenic HSCT (treatment of choice)
• No donor or older patients: IST - anti-thymocyte globulin (ATG) + cyclosporine + eltrombopag
• Supportive: transfusions, G-CSF, antimicrobials

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6e. Myelophthisic Anemia

• Bone marrow replacement by tumor (metastatic cancers, leukemia), fibrosis, granulomas
• Leukoerythroblastic picture on smear: nucleated RBCs, immature myeloid cells (left shift), teardrop cells (dacryocytes)
• Treat the underlying condition

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7. Polycythemia (Erythrocytosis)

Classification

• Polycythemia Vera (PV): JAK2 V617F mutation in >95% of cases; myeloproliferative neoplasm; all three cell lines elevated; low EPO; risk of thrombosis and transformation to myelofibrosis/AML
  • Classic symptom: Aquagenic pruritus (after hot bath/shower)
  • Splenomegaly; plethoric facies
  • Treatment: Phlebotomy, low-dose aspirin, hydroxyurea, ruxolitinib

• Appropriate: high altitude, chronic lung disease, sleep apnea, cyanotic heart disease
• Inappropriate: EPO-secreting tumors (RCC, hepatocellular carcinoma, cerebellar hemangioblastoma), exogenous EPO

• Dehydration, burns (Gaisböck syndrome / stress polycythemia)

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8. Sideroblastic Anemias

• Congenital: X-linked (ALAS2 mutation) - most common hereditary form
• Acquired: Alcoholism (#1 acquired cause), lead poisoning (inhibits ALAD and ferrochelatase), isoniazid, chloramphenicol, copper deficiency
• Myelodysplastic syndrome with ring sideroblasts (MDS-RS) - SF3B1 mutation

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9. Summary Flowchart

ANEMIA detected
       |
  Reticulocyte count
  /              \
HIGH              LOW
(loss/destruction) (underproduction)
   |                    |
Blood loss?         MCV?
Hemolysis?         /    \
  - HS          Micro  Macro   Normal
  - SCA         IDA    B12/Fol  Aplastic
  - Thal        Thal   Drugs    Renal
  - G6PD       Siderob MDS      ACI
  - PNH        ACI               
  - AIHA
  - MAHA

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10. High-Yield Clinical Pearls

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11. Drug-Induced Hemolytic Anemia - Quick Reference

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