Understand erythropoiesis, EPO regulation, and RBC destruction mechanisms as tested on ASCP BOC hematology exam.

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Chapter 2 โ€” ERYTHROCYTE PRODUCTION & DESTRUCTION

ASCP Board Exam ยท Lab-Focused Study Guide
Normoblast Maturation ยท Reticulocytes ยท Erythropoietin ยท Membrane & Metabolism ยท Extravascular vs Intravascular Hemolysis ยท Practice Questions

1 ยท Priority Table & Quick Foundation

Topic Priority Why It’s Tested
Normoblast sequence & stage identification (N:C, chromatin, nucleoli, cytoplasm color) HIGH Cell-ID items: ‘which stage is described?’, last stage that divides, first stage with visible Hb
Reticulocyte: stain, count, reference range, polychromasia, shift retics HIGH Every anemia work-up; NMB vs Wright confusion; absolute count math
Erythropoietin: source, stimulus, target cell, three actions, levels in anemia vs CKD HIGH ‘Most EPO-sensitive cell’, ‘EPO in renal anemia’, hypoxia as the real stimulus
Extravascular vs intravascular hemolysis & lab markers (Hp, hemoglobinuria, hemosiderinuria, bilirubin) HIGH Classic pattern-recognition questions with a hemolysis panel
RBC metabolic pathways (EMP, HMP/G6PD, MetHb reductase, Rapoport-Luebering) HIGH ‘Which pathwayโ€ฆ?’ questions; G6PD/Heinz bodies; 2,3-BPG and Oโ‚‚ release
Membrane skeleton: spectrin, ankyrin, band 3, 4.1, 4.2 (vertical vs horizontal) HIGH Basis for spherocytosis/elliptocytosis questions later in the course
Deformability & cation balance (Naโบ/Kโบ-ATPase, Caยฒโบ, ATP loss โ†’ spherocyte) MEDIUM Explains senescence and why ATP failure โ†’ hemolysis
Membrane lipids: asymmetry, cholesterol exchange, LCAT, echinocyte vs stomatocyte MEDIUM Target cells/acanthocytes in liver disease; shape-change questions
Apoptosis in erythropoiesis (Fas/FasL, Bcl-XL, JAK2-STAT5) MEDIUM Mechanism item: ‘the main way EPO increases RBC mass’
Erythroblastic islands & marrow egress (fibronectin, sinus pores) MEDIUM Location questions; ‘what determines timing of egress?’
Erythrokinetics numbers (18โ€“21 days, 3โ€“5 divisions, 120-day life span) MEDIUM Quick recall numbers
Physiologic anemia of newborn, sex and altitude differences MEDIUM Reference-interval interpretation questions
Nomenclature systems (rubriblast vs erythroblast vs normoblast) LOW Matching names only
Membrane electrophoresis band numbers beyond the major proteins LOW Rarely tested beyond spectrin, ankyrin (2.1), band 3, 4.1, 4.2
๐ŸŽฏ KEY POINT โ€” Where to spend your time

Focus: the 6 maturation stages with their key features, the reticulocyte, EPO (kidney, hypoxia, CFU-E, blocks apoptosis), the 4 metabolic pathways and what each protects, and the extravascular vs intravascular hemolysis panels. Skim: individual phospholipid names, minor skeletal proteins (adducin, tropomodulin, dematin), and history.

Quick Foundation โ€” from zero

  • The red cell has one real job: carry oxygen from the lungs to the tissues. Everything in this chapter protects that job.
  • RBCs are made in the marrow from committed progenitors (BFU-E โ†’ CFU-E), then pass through six visible stages, getting smaller, making hemoglobin, and finally throwing out the nucleus.
  • The young, nucleus-free cell still has some RNA โ€” the reticulocyte. It tells you how hard the marrow is working.
  • The kidney senses low oxygen and releases erythropoietin (EPO), which rescues young erythroid cells from programmed death, so more of them survive to become RBCs.
  • A mature RBC has no nucleus and no mitochondria โ€” it cannot repair itself and gets all its energy from glucose by glycolysis.
  • Its flexible membrane and skeleton let a 7โ€“8 ยตm cell squeeze through 3 ยตm gaps in the spleen for about 120 days.
  • Old cells are eaten by macrophages (extravascular, ~90%). A small share burst inside vessels (intravascular, ~10%); plasma proteins (haptoglobin, hemopexin) salvage what spills out.
๐Ÿ’ก Analogy

The RBC is a delivery van with no mechanic. It is built in a factory (marrow) that removes the engine shop (nucleus) to make room for cargo (hemoglobin). It runs on one fuel line (glycolysis). When parts wear out, it can’t be repaired โ€” so the city’s tow service (splenic macrophages) scraps it at ~120 days and recycles the metal (iron) and tires (globin), sending the trash (bilirubin) to the liver.

๐Ÿฅ Why this matters clinically

Every anemia is either too little production (low retic, check EPO/iron/marrow) or too much destruction/loss (high retic + hemolysis markers). This chapter gives you the tools to tell them apart.

Concept Plain-English Explanation
Erythron vs RBC mass Erythron = ALL erythroid cells in the body (marrow precursors + circulating + splenic). RBC mass = only circulating cells
Normoblast / erythroblast Nucleated RBC precursor with normal appearance; ‘megaloblast’ = the abnormal large version in B12/folate deficiency
N:C ratio How much of the cell is nucleus vs cytoplasm; falls as the RBC matures (8:1 โ†’ 1:2)
Polychromasia Bluish-gray young RBCs on Wright stain = reticulocytes seen without a supravital stain
Shift (stress) reticulocyte Retic pushed out of the marrow early by high EPO โ€” large, very blue, no central pallor
Apoptosis Planned cell suicide without inflammation โ€” the brake that sets how many RBCs are produced
Senescence Aging of the RBC as its enzymes run down; ends in removal by macrophages
Hemolysis RBC destruction โ€” extravascular (in macrophages) or intravascular (inside vessels)

2 ยท Core Content Tables

2.1 Erythroid Progenitors (BFU-E โ†’ CFU-E)

Feature Details
Definition Committed (unipotent) erythroid progenitors โ€” not morphologically recognizable; defined by colonies in culture
BFU-E CD34+, high proliferative potential, low cycling; few EPO receptors (EPO-insensitive except at high levels); driven by ‘burst-promoting activity’ = IL-3 / GM-CSF; forms large multifocal ‘burst’ colonies (10โ€“14 days)
CFU-E Loses CD34, gains glycophorin A, Rh, ABH/Ii antigens; most EPO receptors โ†’ most EPO-sensitive; 3โ€“5 divisions; cannot survive without EPO
Timing ~1 week BFU-E โ†’ CFU-E; ~1 week CFU-E โ†’ pronormoblast; ~6 days pronormoblast โ†’ circulating retic; total 18โ€“21 days BFU-E โ†’ RBC
Other positive cytokines SCF, TPO, IL-11 (plus IL-3, GM-CSF, EPO)
Negative regulators TNF-ฮฑ, TGF-ฮฒ, IFN-ฮณ

Progenitors are defined by behavior, precursors by appearance. The first cell you can see and name is the pronormoblast.

2.2 Normoblast Maturation โ€” Stage Table

Stage (normoblastic / rubriblastic) Size N:C Nucleus Cytoplasm Divides? % BM nucleated / Time
Pronormoblast (rubriblast) 12โ€“20 ยตm* 8:1 Round, fine open chromatin, 1โ€“2 nucleoli Dark blue (ribosomes); Golgi halo; may have tufts Yes ~1% ยท ~24 h
Basophilic normoblast (prorubricyte) 10โ€“15 ยตm* 6:1 Chromatin begins to condense (‘wheel-spoke’); nucleoli 0โ€“1, disappear Deeper, richer blue than pronormoblast; Hb made but masked Yes 1โ€“4% ยท ~24 h
Polychromatic normoblast (rubricyte) 10โ€“12 ยตm* 4:1 โ†’ ~1:1 Coarse clumped chromatin; no nucleoli Murky gray-blue โ€” first stage with visible Hb Last stage that divides (early) 10โ€“20% ยท ~30 h
Orthochromic normoblast (metarubricyte) 8โ€“10 ยตm* 1:2 Pyknotic, eccentric, extruded late in stage Salmon-pink with slight blue tinge No 5โ€“10% ยท ~48 h
Polychromatic erythrocyte / Reticulocyte 8โ€“10 ยตm No nucleus None Wright: diffusely bluish; NMB: blue reticulum No ~1% ยท 1โ€“2 d marrow + ~1 d blood
Erythrocyte 7โ€“8 ยตm; 1.5โ€“2.5 ยตm thick; MCV 80โ€“100 fL No nucleus None Salmon pink; central pallor โ‰ˆ โ…“ of diameter No Circulates ~120 days

*Sizes and marrow percentages from Rodak; McKenzie lists larger sizes (pronormoblast 20โ€“25, basophilic 16โ€“18, polychromatic 12โ€“15, orthochromic 10โ€“15 ยตm) and polychromatic normoblasts at 13โ€“30%. Learn the trend (steady shrinkage, N:C falling) rather than exact micrometers.

Maturation Trend Immature โ†’ Mature Why
Cell and nuclear diameter โ†“ (nucleus shrinks faster than cell) Nuclear condensation โ†’ N:C falls
Chromatin Fine โ†’ coarse, clumped โ†’ pyknotic Transcription shuts down
Nucleoli Present โ†’ gone Ribosome production stops
Cytoplasm color Blue โ†’ gray-blue โ†’ salmon pink RNA (basophilic) falls, Hb (acidophilic/eosinophilic) rises
Division Yes until polychromatic normoblast Condensed chromatin can’t divide

One pronormoblast undergoes 3โ€“5 divisions โ†’ 8โ€“32 RBCs. The extruded nucleus wrapped in membrane is a pyrenocyte; macrophages eat it by recognizing phosphatidylserine (‘eat me’). Nuclear fragments left behind = Howell-Jolly bodies, normally pitted by the spleen. About 80% of the cell’s hemoglobin is made in the normoblast stages and 20% in the reticulocyte.

2.3 Reticulocyte

Feature Details
Definition Anucleate young RBC containing residual ribosomal RNA (and mitochondria); called polychromatic erythrocyte on Wright stain, reticulocyte with a supravital stain
Reference range 0.5โ€“2.5% of RBCs in adults; absolute โ‰ˆ 18โ€“158 ร— 10โน/L (lab-specific). Newborn: 4โ€“7%, falling to <1% within a week
Stain Supravital โ€” new methylene blue (NMB) or brilliant cresyl blue precipitate RNA as a blue mesh/dots. Not visible as a reticulum on Wright stain
Mechanism of increase Blood loss or hemolysis โ†’ hypoxia โ†’ โ†‘ EPO โ†’ more precursors survive + early release of shift (stress) retics
Mechanism of decrease Marrow failure, EPO deficiency (CKD), nutrient lack (iron, B12, folate) โ€” inadequate production
Life cycle ~3 days total: first 1โ€“2 days in marrow, then ~1 day in blood (longer for shift retics); spleen pits inclusions and ‘polishes’ excess membrane โ†’ biconcave disc
Egress Loses adhesion receptors (fibronectin receptor) โ†’ leaves island โ†’ squeezes through pores in sinus endothelial cells
Absolute count Absolute retic = retic % ร— RBC count (e.g., 2% ร— 4.0 ร— 10ยนยฒ/L = 80 ร— 10โน/L)
Beyond these two chapters (highly tested) Corrected retic = retic % ร— (patient Hct รท 45); Reticulocyte Production Index = corrected retic รท maturation time (1.0 d at Hct 45, 1.5 at 35, 2.0 at 25, 2.5 at 15). RPI > 2โ€“3 = adequate marrow response
Key pitfalls Polychromasia on Wright โ‰ˆ increased retics. Punctate basophilia (basophilic stippling) is degenerate RNA in distinct dots on Wright stain โ€” not the same thing
๐Ÿงช PRE-ANALYTICAL โ€” Reticulocyte count
  • Specimen: EDTA whole blood; follow your analyzer’s validated stability (retic RNA degrades with time โ€” analyze promptly)
  • Manual: equal volumes blood + NMB incubated ~10โ€“15 min before smearing; count โ‰ฅ1,000 RBCs (Miller disc reduces imprecision)
  • False โ†‘ (manual): Heinz bodies, Howell-Jolly bodies, Pappenheimer bodies, HbH inclusions, stain precipitate โ€” reticulum is a mesh of two or more blue particles
  • False โ†‘ (automated): WBC fragments, large platelets, malaria parasites, nucleated RBCs, Howell-Jolly bodies
  • Always convert to an absolute count or corrected value in anemia โ€” the % alone overstates response when the RBC count is low

2.4 Erythropoietin (EPO)

Feature Details
Definition Thermostable glycoprotein hormone, ~34 kD; true hormone (endocrine). Terminal sialic acid required for in-vivo activity
Tissue source Peritubular interstitial (fibroblast) cells of the kidney โ€” 80โ€“90%; liver <15% in adults (liver is main source in the fetus); small amount from marrow macrophages
Stimulus Tissue hypoxia, not RBC count. Kidney gets ~20% of cardiac output, so it detects falling Oโ‚‚ delivery early
Mechanism of elevation Hypoxia โ†’ HIF-1 (hypoxia-inducible factor) is no longer degraded โ†’ binds the EPO gene enhancer โ†’ โ†‘ transcription. Rise is new synthesis, not release of stores
Receptor & signaling EPO-R homodimer (no intrinsic kinase) โ†’ JAK2 โ†’ STAT5 โ†’ anti-apoptotic Bcl-XL; GATA-1 needed for red cell survival
Action 1 โ€” rescue from apoptosis (MAJOR) Keeps CFU-E alive; reduces Fas expression on young normoblasts so FasL on older normoblasts can’t kill them
Action 2 โ€” faster maturation Shortens cell cycle; fewer mitoses; increases RNA/Hb synthesis; marrow transit ~6 days โ†’ <4 days
Action 3 โ€” early release Widens sinus wall pores and downregulates adhesion receptors โ†’ shift retics (even nRBCs in severe anemia)
Normal range Plasma ~4โ€“27 mU/mL (Rodak) / 2โ€“25 IU/L (McKenzie) โ€” method-specific. Stays constant until Hb falls below ~12 g/dL, then rises steeply
Levels in disease โ†‘ in most anemias (highest in pure red cell aplasia) ยท โ†“ in anemia of renal disease ยท โ†“ in hypothyroidism (low Oโ‚‚ demand) ยท โ†‘ with some tumors (renal, cerebellar) โ†’ polycythemia
Other stimuli Testosterone (explains higher adult male Hb โ€” ~1โ€“2 g/dL), thyroid, pituitary/growth hormone, adrenal hormones
Therapeutic use / abuse rHuEPO for CKD, chemotherapy, HIV (zidovudine) anemia, pre-autologous donation; illicit ‘blood doping’ โ†’ high viscosity, thrombosis
Limits of response Marrow can raise output 5โ€“10ร— only if iron is available: ~6ร— in hemolysis (iron recycled) but usually โ‰ค2.5ร— in blood loss (iron lost)
๐Ÿงช PRE-ANALYTICAL โ€” Serum/plasma EPO
  • Immunoassay (e.g., chemiluminescence) on serum or plasma; collect before transfusion or ESA therapy
  • Interpret against the hemoglobin โ€” a ‘normal’ EPO in a severely anemic patient is inappropriately low (think renal disease)
  • Urine EPO parallels plasma but is rarely used clinically

2.5 Apoptosis & Erythropoiesis

Feature Details
Why it exists It takes 18โ€“21 days to make an RBC. Instead of storing RBCs, the body overproduces CFU-E and lets extras die โ€” giving an 8โ€“10 day head start when demand rises
Death signal Fas (death receptor) on young precursors (pronormoblast, basophilic) + FasL on older normoblasts (polychromatic). Many old cells in marrow โ†’ young cells die โ†’ erythropoiesis slows
EPO rescue EPO โ†“ Fas on young cells and โ†‘ Bcl-XL, which stops mitochondrial release of cytochrome c
Morphology of apoptosis Condensed nucleus, nucleolar breakdown, cell shrinkage, membrane blebbing, apoptotic bodies; DNA ladder (multiples of 180โ€“185 bp); no inflammation (vs necrosis)

2.6 Bone Marrow Microenvironment for Erythropoiesis

Feature Details
Erythroblastic island Central macrophage surrounded by rings of erythroblasts at different stages โ€” macrophage supplies cytokines, eats extruded nuclei and defective cells (ineffective erythropoiesis)
Iron Delivered by transferrin, not by direct macrophage contact (old ‘suckling pig’ theory abandoned)
Anchoring Stromal cells + adhesive molecules (fibronectin, thrombospondin) + receptors on the erythroblast
Egress timing Determined by maturing cells losing their adhesion receptors โ€” not by stromal cells or pore timing
Route out Between adventitial cells โ†’ through basement membrane โ†’ through pores in (not between) endothelial cells of the venous sinus
Lab note Islands are fragile and usually disrupted by aspiration; seen intact mainly in core biopsies

2.7 Erythrocyte Membrane โ€” Composition & Structure

Feature Details
Composition ~52% protein, ~40% lipid, ~8% carbohydrate
Lipids โ‰ˆ equal unesterified cholesterol + phospholipids. Outer leaflet: PC, SM (choline). Inner leaflet: PE, PS, PI (amino). Asymmetry kept by ATP-dependent flippase. Glycolipids (outer) carry ABH, Lewis, P antigens
Lipid renewal Mature RBCs can’t make lipid; exchange with plasma lipoproteins. LCAT deficiency/liver disease โ†’ excess membrane cholesterol โ†’ target cells (proportional โ†‘) or acanthocytes (cholesterol-only โ†‘)
Shape and leaflets Outer leaflet expansion โ†’ echinocytes (crenation) ยท inner leaflet expansion โ†’ stomatocytes
Integral proteins Span the bilayer: band 3 (anion exchanger AE1, >1 million copies, Clโป/HCOโ‚ƒโป exchange, Ii antigens, binds glycolytic enzymes and Heinz bodies), glycophorins (GPA = MN, GPB = Ss/U, GPC = Gerbich; negative charge/zeta potential), Rh, Kell, glucose transporter, pumps, DAF
Peripheral (skeleton) proteins Inner face: spectrin (ฮฑ/ฮฒ heterodimers โ†’ tetramers; ‘spring’), ankyrin (band 2.1), band 4.2, band 4.1, actin, adducin, band 4.9 (dematin), tropomyosin, tropomodulin
Vertical attachments Major: spectrin โ†’ ankyrin โ†’ band 3 (stabilized by 4.2). Secondary: spectrinโ€“actinโ€“4.1 junctional complex โ†’ glycophorin C
Horizontal interactions Spectrin dimerโ€“dimer (head-to-head tetramers) and spectrinโ€“actinโ€“4.1 junctions, parallel to the membrane. More dimers = more fragile; more tetramers = more stable
Clinical significance Vertical defects โ†’ lost membrane (microvesicles) โ†’ spherocytes; horizontal defects โ†’ elliptocytes/fragmentation (covered in the membrane-disorders chapter)

2.8 Deformability & Permeability

Feature Details
Why deformability matters A 7โ€“8 ยตm cell must pass ~3 ยตm splenic slits and marrow sinus pores for 120 days
Three determinants โ‘  Biconcave shape (high surface-to-volume ratio) โ‘ก Low cytoplasmic viscosity (Hb ‘solution’, MCHC) โ‘ข Membrane viscoelasticity (skeleton)
Permeability Freely permeable to water (aquaporin) and anions (band 3); nearly impermeable to Naโบ, Kโบ, Caยฒโบ. Glucose enters by transporter, no ATP and no insulin needed
Cation gradients RBC Naโบ 5.4โ€“7 vs plasma 135โ€“145 mmol/L; RBC Kโบ 98โ€“106 vs plasma 3.6โ€“5.0 mmol/L (Kโบ โ‰ˆ 25ร— higher inside)
Pumps (ATP-dependent) Naโบ/Kโบ-ATPase: 3 Naโบ out, 2 Kโบ in per ATP. Caยฒโบ-ATPase keeps Caยฒโบ very low; needs Mgยฒโบ
Mechanism of failure โ†“ ATP or โ†‘ leak โ†’ Naโบ and water enter faster than Kโบ leaves โ†’ swelling โ†’ sphere โ†’ osmotic lysis or splenic trapping. โ†‘ Caยฒโบ โ†’ cross-linked rigid skeleton (irreversibly sickled cells) and Gรกrdos channel Kโบ loss โ†’ dehydration

2.9 Erythrocyte Metabolism โ€” Four Pathways

Pathway Share / Key Enzyme Product & Job What Fails When Deficient
Embden-Meyerhof (glycolysis) 90โ€“95% of glucose; hexokinase, PFK, pyruvate kinase (PK) Net 2 ATP/glucose (anaerobic only โ€” no mitochondria) โ†’ powers pumps, shape, flippase PK deficiency โ†’ โ†“ ATP โ†’ rigid cells โ†’ hemolytic anemia (most common glycolytic enzyme defect)
Hexose monophosphate shunt 5โ€“10%; G6PD (first step), glutathione reductase NADPH โ†’ keeps glutathione reduced (GSH) โ†’ neutralizes oxidants (Hโ‚‚Oโ‚‚) G6PD deficiency โ†’ oxidant stress (drugs e.g. primaquine, infection, fava beans) โ†’ Hb denatures โ†’ Heinz bodies โ†’ spleen bites them out โ†’ hemolysis
Methemoglobin reductase Off glycolysis; MetHb reductase (NADH-cytochrome b5 reductase / diaphorase) Uses NADH to reduce Feยณโบ (MetHb) โ†’ Feยฒโบ (functional Hb) ~2% MetHb forms daily; without the enzyme it builds to 20โ€“40% โ†’ โ†“ Oโ‚‚ capacity โ†’ cyanosis
Rapoport-Luebering shunt BPG mutase / synthase (sacrifices 1 ATP step) 2,3-BPG โ†’ lowers Hbโ€“Oโ‚‚ affinity โ†’ โ†‘ Oโ‚‚ release to tissues Deficiency โ†’ โ†‘ Oโ‚‚ affinity โ†’ tissue hypoxia (compensatory erythrocytosis); โ†‘ activity at altitude and in anemia
๐ŸŽฏ KEY POINT โ€” One sentence each

Energy = glycolysis (ATP) ยท Protection from oxidants = HMP (NADPH/GSH) ยท Keeping iron ferrous = MetHb reductase (NADH) ยท Oxygen release = Rapoport-Luebering (2,3-BPG).

๐Ÿงช PRE-ANALYTICAL โ€” Enzyme & Heinz body testing
  • G6PD / PK assays: EDTA or heparin whole blood. Test when the patient is not in active hemolysis and not recently transfused โ€” young cells and retics have higher enzyme activity and can give a falsely normal result
  • Heinz bodies: supravital stain (crystal violet, brilliant cresyl blue); not visible on Wright stain
  • Methemoglobin: co-oximetry on fresh arterial or venous blood; MetHb continues to change on standing

2.10 Senescence โ€” Why RBCs Die at ~120 Days

Feature Details
Root cause No nucleus โ†’ no new protein. Glycolytic and antioxidant enzymes decline and can’t be replaced
Mechanism โ†“ ATP โ†’ pumps fail โ†’ Naโบ/water in โ†’ cell becomes spherical and rigid; oxidized membrane lipids/proteins; membrane lost โ†’ โ†“ surface-to-volume
Where trapped Spleen red pulp: sluggish flow, low glucose, low pH, hypoxic โ†’ the ‘splenic sieve’ of sinus endothelium + basement membrane
‘Eat me’ signals Phosphatidylserine flipped to the outer leaflet, IgG binding to clustered band 3, loss of cation balance, CD47 change (binds thrombospondin-1). Aging is called eryptosis (‘apoptosis in slow motion’)
Daily turnover ~1% of RBCs replaced per day

2.11 Extravascular vs Intravascular Hemolysis

Feature Extravascular (macrophage-mediated) Intravascular (fragmentation)
Share of normal destruction ~90% โ€” the normal, preferred route ~10%
Where Macrophages of spleen, liver, bone marrow Inside blood vessels (turbulence, bifurcations, clots, heart chambers)
What happens to Hb Inside macrophage: Hb โ†’ heme + globin. Globin โ†’ amino acid pool. Heme โ†’ iron (ferritin/hemosiderin or transferrin โ†’ marrow) + CO (exhaled) + biliverdin โ†’ bilirubin Free Hb in plasma โ†’ ฮฑฮฒ dimers โ†’ bound by haptoglobin (1:1) โ†’ liver. Excess โ†’ kidney โ†’ hemoglobinuria; tubular iron โ†’ hemosiderinuria. Oxidized heme โ†’ hemopexin โ†’ then methemalbumin
Bilirubin โ†‘ unconjugated (indirect) โ†‘ unconjugated (liver still processes Hp-Hb)
Haptoglobin Normal to โ†“ (โ†“ in brisk extravascular hemolysis too) Markedly โ†“ / absent
Plasma free Hb Normal โ†‘ (pink/red plasma)
Urine โ†‘ urobilinogen; no Hb Hemoglobinuria (acute) ยท hemosiderinuria (days later) ยท โ†‘ urobilinogen
Smear Spherocytes common Schistocytes common (mechanical)

2.12 Hemoglobin Scavenging Proteins

Feature Details
Haptoglobin (Hp) ฮฑ2-globulin from liver; binds Hb ฮฑฮฒ dimers 1:1; Hp-Hb too big to filter; cleared in 10โ€“30 min (Tยฝ). Ref โ‰ˆ 35โ€“165 mg/dL (lab-specific). Depleted fast because liver can’t keep up
Haptoglobin pitfall Acute-phase reactant โ€” inflammation, infection, cancer can keep it normal despite hemolysis; liver disease lowers it without hemolysis
Hemopexin ฮฒ-globulin from liver; binds free heme 1:1; Tยฝ 7โ€“8 hours; used after Hp is depleted
Methemalbumin Oxidized heme + albumin when hemopexin is exhausted โ€” temporary heme carrier; brown plasma; detected by Schumm’s test
Hemosiderinuria Iron-laden tubular cells shed into urine; Prussian blue stain; sign of recent/chronic intravascular hemolysis
Bilirubin pathway Unconjugated bilirubin + albumin โ†’ liver (UDP-glucuronyltransferase) โ†’ conjugated (direct) โ†’ bile โ†’ gut bacteria โ†’ urobilinogen โ†’ stool (stercobilin); 10โ€“20% reabsorbed โ†’ urine urobilinogen
๐Ÿงช PRE-ANALYTICAL โ€” Hemolysis panel
  • In-vitro hemolysis (traumatic draw, small needle, forceful transfer) raises plasma free Hb and potassium and interferes with bilirubin โ€” recollect before calling intravascular hemolysis
  • Haptoglobin: serum; interpret with CRP (acute phase) and liver function in mind
  • Bilirubin: protect from light (photodegradation falsely lowers results); hemolyzed specimens interfere with many methods
  • Urine hemosiderin: urine sediment stained with Prussian blue; appears several days after the hemolytic event and persists โ€” a negative test the day of an acute event does not exclude it

2.13 Erythrocyte Concentration โ€” Normal Variation

Feature Details
At birth RBC ~5.2 ร— 10ยนยฒ/L, Hb ~19 g/dL; retic 4โ€“7% (high fetal EPO from the hypoxic uterine environment + high-affinity Hb F)
Physiologic anemia of the newborn After birth Oโ‚‚ saturation rises 45% โ†’ 95% โ†’ EPO becomes undetectable โ†’ marrow pauses โ†’ Hb falls to ~10โ€“11 g/dL (RBC ~3.5) by 2โ€“3 months, then EPO restarts
Sex Adult males higher after puberty โ€” testosterone stimulates EPO and progenitors; no sex difference in children
Altitude Lower atmospheric Oโ‚‚ โ†’ โ†‘ EPO โ†’ higher RBC count (physiologic erythrocytosis); also โ†‘ 2,3-BPG

3 ยท Visual Memory Hooks

๐Ÿง  Maturation order
โ€œPro Baseball Players Often Run Everywhereโ€ โ†’ Pronormoblast ยท Basophilic ยท Polychromatic ยท Orthochromic ยท Reticulocyte ยท Erythrocyte.
๐Ÿง  N:C ratios
8 โ€“ 6 โ€“ 4 โ€“ ยฝ โ†’ pronormoblast 8:1, basophilic 6:1, polychromatic 4:1 (โ†’1:1), orthochromic 1:2.
๐Ÿง  Cytoplasm color
โ€œBlue โ†’ Bluer โ†’ Muddy โ†’ Pinkโ€ โ†’ pronormoblast blue, basophilic deeper blue, polychromatic muddy gray-blue, orthochromic salmon.
๐Ÿง  Last dividing stage
โ€œPoly is the last to multiplyโ€ โ†’ polychromatic normoblast = last mitosis AND first visible Hb.
๐Ÿง  Retic stains
โ€œNMB sees the Net; Wright sees the Tintโ€ โ†’ new methylene blue shows the reticulum; Wright shows only a bluish tint (polychromasia).
๐Ÿง  EPO’s three actions
โ€œSAFE Releaseโ€ โ†’ Survival (anti-apoptosis โ€” major) ยท Accelerated maturation ยท Fewer divisions ยท Early Release of shift retics.
๐Ÿง  EPO source & stimulus
โ€œKidneys Hate Hypoxiaโ€ โ†’ Kidney peritubular cells respond to Hypoxia via HIF-1.
๐Ÿง  Fas / FasL
โ€œOld cells hold the Lighter (FasL), young cells are the Fuse (Fas)โ€ โ†’ older normoblasts kill younger ones unless EPO removes the fuse.
๐Ÿง  Metabolic pathways
โ€œEnergy, Protection, Iron, Oxygenโ€ = EMP, HMP, MetHb reductase, R-L shunt โ†’ ATP ยท NADPH ยท NADH ยท 2,3-BPG.
๐Ÿง  Membrane leaflets
โ€œCholine on the Outside, Amino on the Insideโ€ โ†’ PC, SM outer; PE, PS, PI inner. PS out = ‘eat me’.
๐Ÿง  Shape changes
โ€œEcho goes Out, Stoma goes Inโ€ โ†’ outer leaflet expansion = echinocyte; inner leaflet expansion = stomatocyte.
๐Ÿง  Vertical anchor
โ€œSpectrin Asks Band 3 For a hugโ€ โ†’ Spectrinโ€“Ankyrinโ€“Band 3 (+4.2) = vertical; loss โ†’ spherocytes.
๐Ÿง  Hemolysis sites
โ€œEXTRA = EATEN, INTRA = IN the vesselโ€ โ†’ extravascular = macrophages (90%); intravascular = burst in vessels (10%).
๐Ÿง  Scavenger order
โ€œHp Hurries, Hemopexin Holds, Albumin is Lastโ€ โ†’ haptoglobin first (minutes), hemopexin (hours), methemalbumin when both are used up.

Pattern Triggers

If you seeโ€ฆ Thinkโ€ฆ Becauseโ€ฆ
โ†‘ retic + โ†“ haptoglobin + โ†‘ indirect bilirubin Hemolysis Marrow compensates for cells being destroyed; Hp mops up Hb; heme โ†’ bilirubin
Above + hemoglobinuria / pink plasma / hemosiderinuria Intravascular hemolysis Hb exceeded haptoglobin and was filtered by the kidney
Spherocytes + โ†‘ retic + normal-to-low Hp, no hemoglobinuria Extravascular hemolysis Macrophages destroy cells; free Hb never reaches plasma
Anemia + low retic + low EPO + โ†‘ creatinine Anemia of chronic kidney disease Peritubular EPO-producing cells lost
Hemolysis after primaquine, sulfa or fava beans; Heinz bodies, bite cells G6PD deficiency No NADPH โ†’ GSH can’t protect Hb from oxidants
Cyanosis with normal PaOโ‚‚, chocolate-brown blood Methemoglobinemia (โ†“ MetHb reductase or oxidant drug) Feยณโบ Hb can’t carry Oโ‚‚
Large, very blue RBCs without central pallor in a bleeding patient Shift (stress) reticulocytes High EPO released retics 1โ€“2 days early
Nucleated RBCs in blood of a severely anemic adult Extreme EPO drive or marrow infiltration EPO can push even normoblasts out early
Target cells / acanthocytes in liver disease Membrane cholesterol excess (โ†“ LCAT) Free cholesterol loads into the RBC membrane
Hemolysis with normal haptoglobin in a febrile, infected patient Hp raised as acute-phase reactant False reassurance โ€” look at other markers
Infant Hb 16 โ†’ 11 g/dL at 2 months, well baby Physiologic anemia of newborn EPO switched off after birth

Commonly Confused Pairs

Feature A B
Erythron vs RBC mass All erythroid cells (marrow + blood + spleen) Circulating RBCs only โ€” a pronormoblast is in the erythron but NOT the RBC mass
Polychromasia vs basophilic stippling Diffuse bluish tint (retics) on Wright Distinct blue dots of degenerate RNA on Wright (lead poisoning, thalassemia)
Reticulocyte vs Heinz body (on NMB) Blue mesh/network of RNA Round denatured-Hb inclusions near the membrane
BFU-E vs CFU-E CD34+, few EPO-R, IL-3/GM-CSF driven CD34โˆ’, many EPO-R, EPO-dependent
Apoptosis vs necrosis Planned, shrinkage, no inflammation Injury, swelling, lysis, inflammation
Haptoglobin vs hemopexin Binds Hb dimers; ฮฑ2-globulin; Tยฝ minutes Binds heme; ฮฒ-globulin; Tยฝ 7โ€“8 h
Hemoglobinuria vs hemosiderinuria Acute โ€” free Hb spills into urine Days later โ€” iron in shed tubular cells (Prussian blue)
Integral vs peripheral proteins Span bilayer (band 3, glycophorins); carry antigens Inner surface skeleton (spectrin, ankyrin, 4.1, 4.2)
NADPH vs NADH HMP shunt โ†’ glutathione โ†’ oxidant protection Glycolysis โ†’ MetHb reductase โ†’ iron stays Feยฒโบ
Hypoxia vs low RBC count The actual EPO stimulus Only one of many causes of hypoxia (lung/heart disease, abnormal Hb also)

Diagnostic Window / Timeline Table

Marker / Event Onset Peak Duration Best Clinical Use
EPO rise after hypoxia Hours (new transcription via HIF-1) Proportional to hypoxia While hypoxia lasts Separates renal (low) from other anemias (high)
Reticulocyte response to bleed/hemolysis ~3โ€“5 days* ~7โ€“10 days* Until Hb recovers Proof of adequate marrow response
Shift reticulocytes 1โ€“2 days after strong EPO stimulus โ€” Circulate ~2โ€“3 days as retics Explains polychromasia and RPI correction
Plasma free Hb / hemoglobinuria Immediately Hours Clears once Hp/renal handling catches up Acute intravascular hemolysis
Haptoglobin fall Hours (Hp-Hb Tยฝ 10โ€“30 min) Absent in brisk hemolysis Recovers over days after hemolysis stops* Most sensitive hemolysis marker (watch acute phase)
Hemopexin-heme clearance Hours โ€” Tยฝ 7โ€“8 h Supports Hp depletion
Hemosiderinuria ~3โ€“4 days after onset* โ€” Persists weeks Chronic or recent intravascular hemolysis
Indirect bilirubin Hoursโ€“1 day Days While hemolysis continues Increased heme catabolism
BFU-E โ†’ RBC production โ€” โ€” 18โ€“21 days total; precursors ~6 days (โ†“ to <4 days with EPO) Why anemia response lags
RBC life span โ€” โ€” ~120 days (100โ€“120) ~1% replaced daily
Newborn retic 4โ€“7% at birth โ€” <1% by ~1 week until month 2 Physiologic anemia of newborn

*Typical values from general hematology practice, not stated in these two chapters.

4 ยท Diagnostic Flowcharts

Flowchart 1 โ€” Anemia: production problem or destruction/loss?

Adult with โ†“ Hb โ†’ Order reticulocyte count; convert to absolute/corrected (RPI)
Retic low / inappropriate (RPI < 2) โ†’ Hypoproliferative โ†’ check EPO, iron, B12/folate, creatinine, marrow
Low retic + low EPO + โ†‘ creatinine โ†’ Anemia of CKD (EPO deficiency)
Retic high (RPI > 2โ€“3), no bleeding history โ†’ Hemolysis โ†’ go to Flowchart 2
Retic high + recent bleeding โ†’ Acute blood loss with appropriate marrow response
โš ๏ธ Common mistake: reading a ‘high’ retic % in a severely anemic patient as a strong response. When the RBC count is low, the % inflates โ€” correct it first.

Flowchart 2 โ€” Hemolysis: extravascular or intravascular?

โ†‘ Retic, โ†‘ indirect bilirubin, โ†“ haptoglobin โ†’ Hemolysis confirmed โ€” now check plasma and urine
Pink/red plasma, โ†‘ plasma free Hb, hemoglobinuria โ†’ Acute intravascular hemolysis
Hemosiderinuria (Prussian blue urine sediment) โ†’ Recent or chronic intravascular hemolysis
No free Hb, no hemoglobinuria, spherocytes on smear โ†’ Extravascular (macrophage-mediated)
Haptoglobin normal but other markers positive + fever/CRP high โ†’ Hemolysis likely โ€” Hp raised by acute phase
โš ๏ธ Common mistake: assuming a low haptoglobin always means intravascular hemolysis. Brisk extravascular hemolysis and liver disease also lower it; the urine and plasma separate them.

Flowchart 3 โ€” Timing: what will the lab show after a bleed?

Healthy patient loses 1,500 mL at surgery, no transfusion โ†’ Day 0: Hb may look near normal (plasma not yet re-expanded)
Hours โ†’ day 1โ€“3 โ†’ Hypoxia โ†’ โ†‘ EPO (first and most predictable change); Hb falls as plasma volume restores
Days 3โ€“5 โ†’ Reticulocytes rising; polychromasia on smear
Days 7โ€“10 โ†’ Retic peak; iron supply limits output (~2.5ร— normal) because iron was lost
Bilirubin / haptoglobin โ†’ Expected to stay normal โ€” no RBC destruction
โš ๏ธ Common mistake: expecting โ†‘ bilirubin or โ†“ haptoglobin after blood loss. Those are destruction markers; bleeding removes cells without breaking them down in the body.

Flowchart 4 โ€” Method selection for a young RBC or inclusion

Need to count reticulocytes โ†’ Supravital NMB smear (manual, Miller disc) or automated RNA-dye flow cytometry
Only a Wright smear available โ†’ Report polychromasia (semi-quantitative), not a retic count
Suspect Heinz bodies (oxidant hemolysis) โ†’ Supravital crystal violet / brilliant cresyl blue โ€” not Wright
Suspect iron granules (Pappenheimer) โ†’ Prussian blue stain โ†’ siderocytes / sideroblasts
Suspect methemoglobin โ†’ Co-oximetry on fresh blood
โš ๏ธ Common mistake: calling bluish cells on a Wright smear ‘reticulocytes’ and giving a %, or trying to find Heinz bodies on a Wright stain.

Flowchart 5 โ€” Oxidant hemolysis work-up (G6PD pattern)

Young man, fever and dark urine days after starting primaquine/sulfa or eating fava beans โ†’ Suspect oxidant hemolysis
Smear: bite cells, blister cells; supravital: Heinz bodies โ†’ Hb denatured by oxidants (HMP failure)
Labs: โ†“ Hp, โ†‘ indirect bilirubin, hemoglobinuria โ†’ Intravascular + extravascular components
G6PD fluorescent spot test positive (no fluorescence) โ†’ G6PD deficiency
G6PD normal during the crisis but strong clinical suspicion โ†’ Repeat 2โ€“3 months after recovery
โš ๏ธ Common mistake: testing G6PD during acute hemolysis. The old, deficient cells were destroyed; retics have more enzyme, so the result can be falsely normal.

5 ยท 25 High-Yield Facts

# Fact
1 BFU-E and CFU-E are committed erythroid progenitors that cannot be identified morphologically.
2 The CFU-E has the most EPO receptors and cannot survive without EPO.
3 It takes 18โ€“21 days to produce an RBC from a BFU-E, including about 6 days as recognizable precursors.
4 The maturation order is pronormoblast, basophilic, polychromatic, orthochromic normoblast, reticulocyte, erythrocyte.
5 The pronormoblast has an N:C ratio of about 8:1, dark blue cytoplasm, and 1โ€“2 nucleoli.
6 The basophilic normoblast has a deeper blue cytoplasm than the pronormoblast.
7 The polychromatic normoblast is the last stage capable of mitosis and the first with visible hemoglobin.
8 The orthochromic normoblast has a pyknotic nucleus, an N:C ratio of about 1:2, and cannot divide.
9 One pronormoblast produces 8โ€“32 RBCs through 3โ€“5 divisions.
10 The extruded nucleus (pyrenocyte) is ingested by marrow macrophages that recognize phosphatidylserine.
11 The adult reticulocyte reference range is about 0.5โ€“2.5%; newborns have 4โ€“7%.
12 Reticulocytes are identified with supravital stains such as new methylene blue.
13 Reticulocytes spend 1โ€“2 days in the marrow and about 1 day in the peripheral blood.
14 EPO is made mainly by peritubular interstitial cells of the kidney in response to hypoxia via HIF-1.
15 The main way EPO increases RBC production is by preventing apoptosis of erythroid progenitors.
16 EPO signals through JAK2 and STAT5 to induce the anti-apoptotic protein Bcl-XL.
17 EPO is increased in most anemias but decreased in the anemia of renal disease.
18 Erythroblastic islands consist of a central macrophage surrounded by developing erythroblasts.
19 RBCs leave the marrow when they lose adhesion receptors, such as for fibronectin, and pass through pores in sinus endothelial cells.
20 The mature RBC is a 7โ€“8 ยตm biconcave disc with a life span of about 120 days.
21 Glycolysis supplies 90โ€“95% of RBC energy, with a net of 2 ATP per glucose.
22 The HMP shunt, starting with G6PD, generates NADPH to keep glutathione reduced.
23 The Rapoport-Luebering shunt produces 2,3-BPG, which increases oxygen release to tissues.
24 About 90% of normal RBC destruction is extravascular in splenic macrophages; about 10% is intravascular.
25 In intravascular hemolysis, haptoglobin falls, and hemoglobinuria and later hemosiderinuria appear.
โญ EXAM TIP โ€” The single most testable pattern

Retic + hemolysis panel: โ†‘ retic, โ†‘ indirect bilirubin, โ†“ haptoglobin = hemolysis. Add hemoglobinuria / hemosiderinuria / โ†‘ plasma Hb = intravascular. Missing those with spherocytes = extravascular. Low retic with low EPO = kidney.

Quick Interpretation Table

Lab Finding Clinical Interpretation
โ†‘ Retic, โ†‘ indirect bilirubin, โ†“ Hp, hemoglobinuria Acute intravascular hemolysis
โ†‘ Retic, โ†‘ indirect bilirubin, spherocytes, no hemoglobinuria Extravascular hemolysis
Hemosiderinuria with mild anemia Chronic intravascular hemolysis
Anemia, โ†“ retic, โ†“ EPO, โ†‘ creatinine Anemia of chronic kidney disease
Anemia, โ†‘โ†‘ EPO, absent retics Pure red cell aplasia / marrow failure
Heinz bodies after oxidant drug G6PD deficiency (HMP shunt failure)
Cyanosis + โ†‘ MetHb MetHb reductase deficiency or oxidant exposure
Polychromasia 3+ on Wright smear Increased (shift) reticulocytes โ€” marrow responding

๐ŸŽด Flashcards โ€” Active Recall Practice

How it works: tap the card to flip it. Then mark it โœ“ Knew It or โœ— Review Again (buttons unlock after flipping). Use ๐Ÿ”€ Shuffle to randomize and ๐Ÿ Finish anytime โ€” your summary appears at the end, and you can drill only the cards you missed.

๐Ÿ“ Practice Quiz โ€” Test Your Knowledge

How it works: tap an answer for each case. You’ll get instant feedback with the full explanation and the examiner’s trap. Your final score appears once all 10 are answered.

๐Ÿชค Trap Questions โ€” Beat the Examiner

Harder on purpose. Each question targets a real misconception. After answering you’ll see the correct reasoning, the trap explained, why the examiner wrote it, and the wrong answer most students choose.

8 ยท Rapid Revision Sheet

๐Ÿ“– READ THIS 2 HOURS BEFORE YOUR EXAM

Stage Numbers

  • Pro 8:1 ยท Baso 6:1 ยท Poly 4:1โ†’1:1 ยท Ortho 1:2
  • Nucleoli: pro 1โ€“2 only
  • Last division + first Hb: POLY
  • Nucleus out: ORTHO
  • 1 pro โ†’ 8โ€“32 RBCs (3โ€“5 divisions)

Time Numbers

  • BFU-E โ†’ RBC 18โ€“21 d
  • Precursors ~6 d (<4 d on EPO)
  • Retic 1โ€“2 d marrow + ~1 d blood
  • RBC life 120 d ยท ~1%/day
  • Hp-Hb Tยฝ 10โ€“30 min ยท Hemopexin 7โ€“8 h

Reticulocyte

  • Adult 0.5โ€“2.5% ยท newborn 4โ€“7%
  • NMB = reticulum ยท Wright = polychromasia
  • Absolute = % ร— RBC
  • Shift retic = big, blue, no pallor
  • Heinz/HJ/Pappenheimer โ†’ false โ†‘

EPO

  • Kidney peritubular 80โ€“90% ยท liver <15%
  • Hypoxia โ†’ HIF-1 โ†’ EPO gene
  • Target: CFU-E (max EPO-R)
  • JAK2 โ†’ STAT5 โ†’ Bcl-XL
  • โ†‘ most anemias ยท โ†“ renal anemia
  • Rises when Hb < ~12 g/dL

Metabolism

  • EMP 90โ€“95% ยท 2 ATP ยท PK
  • HMP 5โ€“10% ยท G6PD ยท NADPH/GSH
  • MetHb reductase ยท NADH ยท Feยฒโบ
  • R-L shunt ยท 2,3-BPG ยท โ†“ Oโ‚‚ affinity
  • G6PD โ†’ Heinz ยท MetHb โ†’ cyanosis

Membrane

  • 52% protein ยท 40% lipid ยท 8% CHO
  • Outer PC/SM ยท inner PE/PS/PI
  • Vertical: spectrinโ€“ankyrinโ€“band 3 (+4.2)
  • Horizontal: spectrinโ€“actinโ€“4.1
  • GPA = MN ยท GPB = Ss ยท GPC = Gerbich
  • Naโบ/Kโบ pump: 3 out / 2 in

Extravascular vs Intravascular

  • Extra 90% ยท Intra 10%
  • Extra: spherocytes, no Hb in urine
  • Intra: โ†‘ plasma Hb, hemoglobinuria, hemosiderinuria
  • Both: โ†‘ indirect bili, โ†“ Hp
  • Intra: schistocytes

Opposites

  • Outer leaflet โ†‘ โ†’ echinocyte ยท inner โ†‘ โ†’ stomatocyte
  • Blood loss: โ†‘ EPO, bili normal ยท hemolysis: โ†‘ bili
  • Hp โ†“ hemolysis/liver dz ยท โ†‘ acute phase
  • EPO โ†“ renal/hypothyroid ยท โ†‘ PRCA/tumors

Confusing Pairs

  • Erythron โ‰  RBC mass
  • Polychromasia โ‰  basophilic stippling
  • Hp (Hb dimers, ฮฑ2) โ‰  hemopexin (heme, ฮฒ)
  • Hemoglobinuria (acute) โ‰  hemosiderinuria (delayed)
  • BFU-E (CD34+) โ‰  CFU-E (CD34โˆ’)

Normal Variation

  • Birth: Hb ~19, RBC 5.2
  • 2โ€“3 months: Hb 10โ€“11 (physiologic)
  • Men > women after puberty (testosterone)
  • Altitude โ†’ โ†‘ RBC, โ†‘ 2,3-BPG
  • Egress: loss of fibronectin receptor

9 ยท Final Memory Map

  • ๐Ÿ”ด ERYTHROCYTE PRODUCTION & DESTRUCTION
    • Progenitors
      • BFU-E: CD34+, IL-3/GM-CSF, few EPO-R
      • CFU-E: max EPO-R, EPO-dependent
      • 18โ€“21 days to RBC
    • Precursors
      • Pro (8:1, nucleoli) โ†’ Baso (deeper blue) โ†’ Poly (last mitosis, first Hb) โ†’ Ortho (pyknotic, extrudes)
      • Pyrenocyte eaten via PS ยท Howell-Jolly = fragments
      • Erythroblastic island: central macrophage, fibronectin
    • Reticulocyte
      • 0.5โ€“2.5% ยท NMB stain ยท polychromasia on Wright
      • Absolute = % ร— RBC ยท shift retics under EPO
      • Leaves marrow after losing adhesion receptors
    • Erythropoietin
      • Kidney peritubular cells ยท hypoxia ยท HIF-1
      • Anti-apoptosis (Fas/FasL, Bcl-XL) = main action
      • Faster maturation ยท early release
      • โ†“ in renal anemia
    • Membrane
      • Lipid asymmetry (flippase) ยท cholesterol exchange/LCAT
      • Integral: band 3, glycophorins ยท Peripheral: spectrin, ankyrin, 4.1, 4.2
      • Deformability: shape, viscosity, skeleton ยท Naโบ/Kโบ pump
    • Metabolism
      • EMP โ†’ ATP (PK)
      • HMP โ†’ NADPH (G6PD) โ†’ Heinz bodies if deficient
      • MetHb reductase โ†’ NADH โ†’ Feยฒโบ
      • R-L shunt โ†’ 2,3-BPG โ†’ Oโ‚‚ release
    • Destruction
      • Senescence: enzymes decay โ†’ sphere โ†’ splenic trap
      • Extravascular 90%: heme โ†’ bilirubin, iron recycled
      • Intravascular 10%: Hp โ†’ hemopexin โ†’ methemalbumin; hemoglobinuria, hemosiderinuria



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