Red Blood Cell

Biconcave shape maximizes surface-to-volume ratio for gas exchange and gives RBCs deformability to squeeze through capillaries (3 μm) smaller than the cell itself (8 μm). The cytoskeleton (spectrin, ankyrin, band 3, protein 4.1) maintains the shape under shear stress; defects cause spherocytosis (small spheres lyse in spleen) or elliptocytosis. Loss of nucleus during late erythroblast maturation makes room for hemoglobin and prevents nuclear damage from O2 free radicals. The cost: no protein synthesis, fixed lifespan ~120 days.

Hypoxia in renal interstitial fibroblasts stabilizes HIF-2α, transcribing EPO. EPO travels to bone marrow, binds JAK2-coupled receptors on erythroid progenitors, prevents apoptosis, and promotes proliferation/differentiation. Erythroblasts mature: proerythroblast → basophilic → polychromatophilic → orthochromatophilic → reticulocyte (extrudes nucleus, still has RNA, ~1% of circulation) → mature RBC. Process takes ~7 days. Iron, B12, folate, and EPO are required. Recombinant EPO treats CKD anemia and chemotherapy-induced anemia.

Most common anemia globally. Causes: blood loss (menstruation, GI bleeding from ulcers, malignancy, hookworm), inadequate intake (vegetarian, infants on cow's milk), malabsorption (celiac, gastric bypass, achlorhydria), increased demand (pregnancy, growth). Labs: low MCV (microcytic), low MCH (hypochromic), low ferritin, low transferrin saturation, high TIBC. Treatment: oral iron (ferrous sulfate 325 mg, 65 mg elemental, every other day better absorbed than daily), IV iron if intolerance or malabsorption. Always investigate cause — especially in older adults (rule out colon cancer).

Sickle cell disease (HbSS): point mutation Glu→Val at β6 causes deoxy-HbS to polymerize, distorting RBCs into sickle shapes that occlude vessels and lyse prematurely (lifespan ~10-20 days). Pain crises, acute chest syndrome, stroke, splenic autoinfarction. Thalassemias: reduced production of α (alpha thalassemia, deletions) or β (beta thalassemia, point mutations) globin chains. Imbalanced globin precipitates, damaging RBCs. Severe forms (β-thal major) need lifelong transfusions or stem cell transplant. New treatments: hydroxyurea (HbF induction), voxelotor, crizanlizumab, gene therapy (Casgevy, FDA-approved 2023).

Premature RBC destruction. Intravascular: TTP, DIC, mechanical (prosthetic valves), severe burns, paroxysmal nocturnal hemoglobinuria, ABO mismatch transfusion. Extravascular: hereditary spherocytosis, autoimmune (warm — IgG, cold — IgM agglutinins), G6PD deficiency, sickle cell. Labs: low haptoglobin, high indirect bilirubin, high LDH, high reticulocytes, schistocytes on smear (microangiopathic), spherocytes. Coombs (DAT) test distinguishes immune-mediated. Treatment depends on cause — steroids for AIHA, transfusion, splenectomy in selected cases.

Senescent RBCs are phagocytosed by splenic and hepatic macrophages. Heme is broken into iron (recycled to transferrin then back to bone marrow), CO (excreted by lungs), and biliverdin (reduced to bilirubin). Bilirubin binds albumin (unconjugated/indirect), is conjugated in liver with glucuronic acid, secreted in bile, becomes urobilinogen in gut (some reabsorbed, most excreted as stercobilin in stool). Iron homeostasis: hepcidin (liver hormone) regulates intestinal absorption and macrophage release. Hemochromatosis: HFE mutation causes iron overload.

Mean corpuscular volume guides anemia workup. Microcytic (< 80 fL): iron deficiency, thalassemia, anemia of chronic disease (sometimes), sideroblastic (lead, B6 deficiency). Normocytic (80-100): acute blood loss, hemolysis, CKD, marrow failure, anemia of chronic disease. Macrocytic (> 100): B12/folate deficiency (megaloblastic — hypersegmented neutrophils, oval macrocytes), liver disease, hypothyroidism, alcohol, drugs (hydroxyurea, methotrexate), reticulocytosis. Reticulocyte index helps distinguish production vs destruction issues.