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Chapter 1

Normal ErythropoiesisThe oxygen required by tissues for aerobic metabolism is supplied by the circulating mass of mature erythrocytes (red blood cells). The circulating red blood cell population is continually

renewed by the erythroid precursor cells in the marrow, under the control of both humoraland cellular growth factors. This cycle of normal erythropoiesis is a carefully regulated process. Oxygen sensors within the kidney detect minute changes in the amount of oxygenavailable to tissue and by releasing erythropoietin are able to adjust erythropoiesis to matchtissue requirements. Thus, normal erythropoiesis is best described according to its major components, including red blood cell structure, function, and turnover; the capacity of the erythroid marrow to produce new red blood cells; and growth factor regulation .

STRUCTURE OF THE RED BLOOD CELLThe mature red blood cell is easily recognized because of its unique morphology . At rest,the red blood cell takes the shape of a biconcave disc with a mean diameter of 8 µm, athickness of 2 µm, and a volume of 90 fL. It lacks a nucleus or mitochondria, and 33% of 

its contents is made up of a single protein, hemoglobin. Intracellular energy requirements arelargely supplied by glucose metabolism, which is targeted at maintaining hemoglobin in asoluble, reduced state, providing appropriate amounts of 2,3-diphosphoglycerate (2,3-DPG), and generating adenosine triphosphate (ATP) to support membrane function. Without anucleus or protein metabolic pathway, the cell has a limited lifespan of 100-120 days .However, the unique structure of the adult red blood cell is perfect for its function, providingmaximum flexibility as the cell travels through the microvasculature (Figure 1-1).

A. INNER AND OUTER LAYERSThe shape(bentuk), pliability(lembek,lunak,lentur), and resiliency(kenyal) of the red bloodcell is largely determined by its membrane. The structure of this membrane is illustrated inFigure 1-2. It is a lipid sheath, just two molecules thick, that consists of closely packed

 phospholipid molecules. The external surface of the membrane is rich inphosphatidylcholine, sphingomyelin, and glycolipid , whereas the inner layer is largelyphosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol. Thisasymmetry is maintained by two transportersâ¼´flipase, an ATP-dependentaminophospholipid translocase that rapidly transports phosphatidylserine and ethanolaminefrom the outer to the inner membrane, and flopase, which moves phospholipids more slowlyin the opposite direction. The normal asymmetric distribution of membrane phospholipidscan also be rapidly disrupted by a calcium-activated â¼scramblaseâ¼ present in themembrane. Interference with these transporters results in a relocation of phosphatidylserine tothe cell surface with a resulting increase in the thrombogenic potential of the cell surface.Moreover, accumulation of excess phosphatidylserine on the red cell surface plays a role inmacrophage destruction.Approximately 50% of the red blood cell membrane is made up of cholesterol that is inequilibrium with the unesterified cholesterol in the plasma. Because of this, the cholesterolcontent of the membrane is influenced by plasma cholesterol levels, as well as by the activityof the enzyme lecithin cholesterol acyltransferase (LCAT) and bile acids. Patients withliver disease who have impaired LCAT activity accumulate excess cholesterol on the red

 blood cell membrane, which results in abnormal red blood cell morphology (targeting) andat times a shortened survival.

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B. RETICULAR PROTEIN NETWORK The outer lipid membrane layer is affixed to a reticular protein network consisting of spectrin and actin. As shown in Figure 1-2, the integral proteins glycophorin C and Band3, which function as anion exchangers , extend vertically from the spectrin lattice work through the lipid layer to make contact with the cell surface. Spectrin heterodimers interacthorizontally with protein 4.1 and complementary spectrin heterodimers to form a hexagonal

lattice framework under the lipid bilayer. Defects in the vertical structure of themembrane (deficiency of spectrin, ankyrin, or band 3, or loss of lipid) result inspherocyte formation. Damage to the horizontal spectrin framework results in severered cell fragmentation or mild elliptocytosis.The integral proteins and surface glycosphingolipids are also responsible for the cell'santigenic structure. More than 300 red blood cell antigens have now been classified with theABO and Rh blood group antigens being of primary importance in typing blood for transfusion (see Chapter 37). Autoantibodies against minor blood group antigens canresult in increased red blood cell destruction by the reticuloendothelial cells .

HemoglobinThe red blood cell is, basically, a container for hemoglobinâ ¼´a 64,500 dalton protein madeup of 4 polypeptide chains, each containing an active heme group. Each heme group iscapable of binding to an oxygen molecule. The respiratory motion of hemoglobin, that is, theuptake and release of oxygen to tissues, involves a specific change in molecular structure(Figure 1-3). As hemoglobin shuttles from its deoxyhemoglobin to its oxyhemoglobin form,carbon dioxide (CO2) and 2,3-DPG are expelled from their position between the β-globinchains, opening the molecule to receive oxygen. Furthermore, oxygen binding by one of theheme groups increases the affinity of the other groups to oxygen loading. This interaction isresponsible for the sigmoid shape of the oxygen dissociation curve.Inherited defects in hemoglobin structure can interfere with this respiratory motion. Mostdefects are substitutions of a single amino acid in either the α- or β-globin chains. Someinterfere with molecular movement, restricting the molecule to either a low- or high-affinity

state, whereas others either change the valency of heme iron from ferrous to ferric or reducethe solubility of the hemoglobin molecule . Hemoglobin S (sickle cell disease) is anexample of a single amino acid substitution that results in a profound effect onsolubility.The normal red blood cell contains approximately 32 pg of hemoglobin [mean cellhemoglobin (MCH) = 32 ± 2 pg]. Normal hemoglobin synthesis requires an adequatesupply of iron and normal production of both protoporphyrin and globin (Figure 1-4).Protoporphyrin synthesis is initiated in the mitochondria with the formation of deltaaminolevulinic acid from glycine and succinyl-CoA. Synthesis then moves to the cellcytoplasm for the formation of porphobilinogen, uroporphyrin, and coproporphyrin. The finalassembly of the protoporphyrin ring is carried out by the mitochondria, after which iron isincorporated under the control of the cytoplasmic enzyme, ferrochelatase, to form heme.

Globinchains are assembled by the cytoplasmic ribosomes under the control of two clustersof closely linked genes on chromosomes 11 and 16. The final globin molecule is a tetramer of two α-globin and two non⼳α-globin chains. In the adult, 96â¼³97% of thehemoglobin is made up of two α-globin and two β-globin chains (hemoglobin A) withminor components of hemoglobin F and A 2. The final assembly of the hemoglobinmolecule occurs in the cell cytoplasm. Small amounts of iron, protoporphyrin, and free globinchains remain after hemoglobin synthesis is complete. The iron is stored as ferritin, whereasthe excess porphyrin is complexed to zinc.

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This complex series of reactions is triggered by erythropoietin stimulation of red cell progenitors. With precursor differentiation, there is a coordinated transcriptional induction of heme biosynthesis, globin synthesis and transferrin receptor expression, which is required for iron transport (see Chapter 5). The rate of hemoglobin synthesis is determined by theavailability of transferrin iron and level of intracellular heme. Hemoglobin synthesis ismaximal in more mature marrow erythroblasts but persists to a lesser degree in the marrow

reticulocytes. The cessation of heme synthesis is heralded by a decrease in membranetransferrin receptor expression, followed by a downregulation of heme and globin synthesis.Cellular Metabolism. The stability of the red blood cell membrane and the solubility of intracellular hemoglobin depend on four glucose-supported metabolic pathways (Figure 1-5).

A. EMBDEN-MEYERHOFF PATHWAYThe Embden-Meyerhoff pathway (nonoxidative or anaerobic pathway ) isresponsible for the generation of the ATP necessary for membrane function and themaintenance of cell shape and pliability . Defects in anaerobic glycolysis are associatedwith increased cell rigidity and decreased survival, which produces a hemolytic anemia.The Embden-Meyerhoff pathway also plays a role in supporting the methemoglobinreductase, phosphogluconate, and Luebering-Rapaport pathways.

B. METHEMOGLOBIN REDUCTASE PATHWAYThe methemoglobin reductase pathway uses the pyridine nucleotide-NADH generated fromanaerobic glycolysis to maintain heme iron in its ferrous state. An inherited mutation of themethemoglobin reductase enzyme (also referred to as NADH-diaphorase or cytochrome

 b5 reductase) results in an inability to counteract oxidation of hemoglobin to methemoglobin,the ferric form of hemoglobin that will not transport oxygen. Patients with Type I NADH-diaphorase deficiency accumulate small amounts of methemoglobin in circulating red cells,whereas Type II patients have severe cyanosis and mental retardation.

C. PHOSPHOGLUCONATE PATHWAY

In a similar fashion, the phosphogluconate pathway couples oxidative metabolism with NADP and glutathione reduction. It counteracts environmental oxidants and prevents globindenaturation. When patients lack either of the two key enzymes, glucose 6 phosphatedehydrogenase (G6PD) or glutathione reductase (GSH), denatured hemoglobin precipitateson the inner surface of the red blood cell membrane, resulting in membrane damage andhemolysis.

D. LUEBERING-RAPAPORT PATHWAYFinally, the Luebering-Rapaport pathway is responsible for the production of 2,3-DPG. It istied to the rate of anaerobic glycolysis and the action of the pH-sensitive enzyme

 phosphofructokinase. The 2,3-DPG response is also influenced by the supply of phosphate tothe cell. Severe phosphate depletion in patients with diabetic ketoacidosis or nutritional

deficiency can result in a reduced 2,3-DPG production response.

REGULATION OF OXYGEN TRANSPORTRed blood cells play a central role in oxygen transport. At the cellular level, oxygen supply isa function of red blood cells perfusing the tissue and their hemoglobin oxygen-carryingcapacity. The unique physiology of the hemoglobin-oxygen dissociation curve allows anonsite adjustment of oxygen delivery to match tissue metabolism. At the same time,components such as pulmonary function, cardiac output, blood volume, blood viscosity,and adjustments of regional blood flow are also important contributors to oxygen transport.

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Hemoglobin-Oxygen Dissociation CurveUnder normal conditions, arterial blood enters tissues with an oxygen tension of 95 mm Hgand a hemoglobin saturation of better than 97%. Pooled venous blood returning from tissueshas an oxygen tension of 40 mm Hg and a saturation of 75 - 80%. Thus, only the top portionof the hemoglobin-oxygen dissociation curve is used in the basal state. This provides aconsiderable excess capacity for increased oxygen delivery to support increased oxygen

requirements. The sigmoid shape of the hemoglobin-oxygen dissociation curve also helps inthis regard by releasing oxygen more easily as the tissue PO2 falls below 40 mm Hg.

The affinity of hemoglobin for oxygen is also influenced by temperature, pH, CO2 concentration, and by the level of  red cell 2,3-DPG. As shown in Figure 1-6, the position of the hemoglobin-oxygen dissociation curve is affected by the rate of tissue metabolism, CO2 

 production, and blood pH (the Bohr effect). When a tissue generates increasing amounts of CO2 and acid metabolites, the resulting acidosis shifts the dissociation curve to the right.This shift permits the release of more oxygen for the level of tissue PO2. The reverse is alsotrue. With an increase in pH such as with an acute respiratory alkalosis, the hemoglobin-oxygen dissociation curve shifts to the left, reducing the amount of oxygen available at anytissue PO2.

The Bohr effect is instantaneous and can be highly localized to a specific site. For example,the blood perfusing an exercising muscle will be able to deliver 75% or more of its oxygen

 because of the low tissue PO2 and the acidosis-induced Bohr effect. Oxygen unloadingsimultaneously lowers the CO2 tension in the red cells (Haldane effect), thereby facilitatingits diffusion from metabolizing tissues. This reciprocal interaction promotes optimalexchange of oxygen and carbon dioxide during exercise.When the amount of oxygen removed by tissues continues at a high level (widened arterial-venous difference), the resulting increase in deoxyhemoglobin in the cell stimulates anincreased production of 2,3-DPG. This situation will be true regardless of whether the causeof the hemoglobin desaturation is hypoxia, cardiac failure, or anemia. The rise inintracellular 2,3-DPG sustains the shift of the dissociation curve to the right and providessignificant compensation for a chronic anemia or hypoxia.2,3-DPG metabolism also responds to systemic acidosis or alkalosis. The initial shift of thecurve to the right in a patient with acidosis will be corrected over the next 12-36 h by acompensatory reduction in the 2,3-DPG level. The Bohr effect is reversed by the lower 2,3-DPG and the curve shifts back to normal. Although this readjusts the level of oxygendelivery to match tissue requirements, it can create a problem if the acidosis is suddenlycorrected. Because it takes a number of hours to replace the intracellular 2,3-DPG, a suddenreturn to a normal pH will shift the oxygen dissociation curve to the left owing to the lower than normal 2,3-DPG level.

Hemodynamic FactorsThe self-regulating capacity of the oxygen dissociation curve takes care of most of the

variation in tissue oxygen requirements in the basal state. With maximal exercise, theuntrained subject will reach a limit determined not by oxygen loading but by a low maximalcardiac output resulting in poor oxygen delivery to tissues. In contrast, highly trained athleteshave a greatly increased cardiac output, so that pulmonary loading and peripheral transportdetermine their limits. To maximize performance, they must tolerate both arterial hypoxemiaand marked metabolic acidosis.

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A. ANEMIAThe oxygen dissociation curve will also compensate for an anemia of moderate severity. However, once the hemoglobin falls below 9 - 10 g/dL, components such as changes in bloodvolume, cardiac output, and regional blood flow come into play. Both the pulse rate andstroke volume increase in patients with severe anemia and there is a redirection of blood flowto vital organs. These hemodynamic changes are often appreciated by patients. As their 

anemia worsens, they are increasingly aware of the force of ventricular contraction and oftencomplain of pounding headaches, especially with physical exertion.

B. OXYGEN SUPPLYImpairments in lung function also affect oxygen supply. Although the sigmoid shape of thehemoglobin-oxygen dissociation curve does counterbalance reductions in alveolar PO2, thereis a limit to this compensation. Moreover, desaturation of hemoglobin results whenever unsaturated venous blood is shunted through areas of damaged lung tissue. The physiologicresponse to a decreased oxygen tension in ambient air, as for example the oxygen tension atmoderately high altitudes (3000-4000 m), is an increase in 2,3-diphosphoglycerate to raisethe P50, that is, shift the oxygen dissociation curve to the right. Moderate exercise will stillfurther elevate the P50 via the Bohr effect to maintain oxygen delivery to tissues. Under 

conditions of more marked hypoxia (altitudes > 4000 m), reflex hyperventilation results in areduced PCO2 and respiratory alkalosis. The latter shifts the oxygen dissociation curve to theleft with a reduction in oxygen delivery to tissues. Still, high hemoglobin affinity for oxygen

 provides a physiological advantage for acclimatization to high altitudes. Subjects born with ahigh-affinity hemoglobin such as hemoglobin Andrew-Minneapolis (P50 17 mm Hg)demonstrate normal arterial oxygen saturations at altitudes up to 4000 m, smaller increases inheart rate, and little or no increases in erythropoietin when compared with normalindividuals. Animals that normally live at high altitudes also have high-affinity hemoglobins.

C. BLOOD VISCOSITYSustained hypoxia usually results in a compensatory rise in the red blood cell mass andhematocrit. Although this increases the oxygen-carrying capacity of blood, it also increases

 blood viscosity. The interaction of the hematocrit level and blood viscosity is discussedextensively in Chapter 12. Tissue oxygen delivery theoretically is maximal at a hematocrit of 33â¼³36% (hemoglobin of 11â¼³12 g/dL), assuming no changes in cardiac output or regional

 blood flow. Above this level, an increase in viscosity will tend to slow blood flowand decrease oxygen delivery. This effect is relatively minor until thehematocrit exceeds 50%, at which time blood flow to key organs such asthe brain can be significantly reduced .

REGULATION OF ERYTHROPOIESISRed Blood Cell ProductionThe rate of new red blood cell (RBC) production varies according to the rate of red blood celldestruction and tissue oxygen requirements. Changes in the oxygen delivery to tissue aresensed by peritubular interstitial, fibroblast-like cells in the kidney. A decrease in the oxygencontent of hemoglobin (pulmonary dysfunction), the hemoglobin level (anemia), or thehemoglobin affinity for oxygen (shift in the oxygen dissociation curve) will stimulate anincreased production of erythropoietin by renal interstitial cells. This is accomplished byrecruitment of new cells to initiate transcription of erythropoietin messenger ribonucleic acid(mRNA) by a single gene on chromosome 7. The mechanism of regulation involves thesensing of oxygen tension by a flavo heme protein that controls the level of hypoxia

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inducible factor (HIF-1). The latter interacts with response elements in nuclear DNA toactivate erythropoietin gene expression.Erythropoietin then travels to the marrow, where it binds to a specific receptor (EPOR) onthe surface of committed erythroid precursors. This receptor is a 508â¼³amino acidglycoprotein coded by a gene on chromosome 19. Within hours, there is a detectable increasein deoxyribonucleic acid (DNA) synthesis. This is followed by proliferation and maturation

of committed stem cells to produce an increased number of new red blood cells. Erythroid progenitor apoptosis is also inhibited. The full marrow response takes several days. Given asustained increase in erythropoietin stimulation, a rise in the reticulocyte index will not occur for 4â¼³5 days and a detectable increase in hematocrit will take a week or more.Figure 1-7. Erythropoietin production and anemia. Once the hemoglobin level falls below12 g/dL, the plasma erythropoietin level increases logarithmically. Patients with renaldisease or the anemia associated with chronic inflammation show a lower than predictedresponse for their degree of anemia.

A. MEASURING THE ERYTHROPOIETIN RESPONSEThe erythropoietin response to anemia can be directly measured by assaying the serumerythropoietin level (Figure 1-7). Once the hemoglobin level falls below 12 g/dL, there is a

logarithmic increase in the serum erythropoietin level. At the same time, it is important tonote that with mild anemia (a hemoglobin level greater than 12 g/dL), the erythropoietin levelis not increased. This probably reflects the compensation of the 2,3-DPGâ¼³induced shift inthe hemoglobin-oxygen dissociation curve combined with the sensitivity level of the renalsensor. Physiologically, it may reflect that a hemoglobin level of 12 g/dL is best for maximum tissue oxygen delivery.

B. OTHER FACTORS INFLUENCING ERYTHROPOIETIN LEVELAlthough the erythropoietin response is primarily a function of the severity of anemia or hypoxia, other factors, such as the erythroid marrow mass and levels of inflammatorycytokines, will influence the serum erythropoietin level. Erythropoietin binds avidly toerythroid progenitors and is removed from circulation. Therefore, with aplastic anemia,extremely high levels of serum erythropoietin reflect both an increased production and adecreased clearance. In contrast, with chronic hemolytic anemias, the expansion of marrowerythroid precursors results in a more rapid clearance of erythropoietin from circulation and,therefore, a lower serum level.Inflammatory cytokines, including interleukin-1, tissue necrosis factor (TNF-α), andtransforming growth factor β, also play a role in regulating erythropoietin production anderythroid progenitor proliferation. They are responsible for the lower than normalerythropoietin response in patients with inflammatory disease states (see Chapter 4). Finally,direct suppression of the erythropoietin response is seen in patients receiving certain drugs(chemotherapeutic agents, cyclosporin A, and theophylline) or who are infected with humanimmunodeficiency virus (HIV).

Two other factors, angiotensin II and insulin-like growth factor-1 (IGF-1), may also play anerythropoietin-like role in certain settings. The erythropoietin-independent growth of erythroid progenitors in polycythemia vera may involve a hypersensitivity to IGF-1, whereashypoxia has been shown to induce IGF-1 binding protein. Evidence for a role for angiotensinII is indirect. Post renal transplant erythrocytosis can be reversed by the administration of angiotensin converting enzyme inhibitors, without changing the serum erythropoietin level.

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ERYTHROID MARROW PRODUCTIONErythroid marrow production can be defined for the basal state and in terms of its capacity toincrease in response to anemia. Patients who experience acute blood loss or suddenhemolysis of circulating red blood cells can show increases in new red blood cellproduction of 2 to 3 times normal ; that is, the release of 40â¼³60 mL of new red blood cells

 per day. With a chronic hemolytic anemia, even higher production levels can be attained.

This capacity to compensate for anemia is as much a normal characteristic of the erythroidmarrow as its steady-state characteristics.

MeasurementThe level of production can be assessed from several measurements of red blood cell

 production and destruction (Table 1-1). Clinically, the marrow E/G ratio and reticulocyteindex are of the greatest value. The marrow E/G ratio (the ratio of erythroid to granulocytic

 precursors) is determined by inspecting a stained smear of aspirated marrow particles. Aslong as the granulocyte production of the marrow is normal, it is possible to estimate the

 proliferation of erythroid precursors. In the basal state, there will be approximately oneerythroid precursor for every 3-4 granulocytic (myelocytic) precursors. With anemia andhigh levels of erythropoietin stimulation, the number of erythroid precursors increases

dramatically to give ratios of 1:1 or greater. The morphology of the precursors is alsoimportant. Normal proliferation shows a balanced increase in erythroid precursors at allstages of maturation. If the number is skewed toward a younger population, especially a

 population with abnormal morphology, this suggests a defect in DNA synthesis or cytoplasmic maturation. These defects can result in a failure of cells to mature and earlydeath in the marrow, so-called ineffective erythropoiesis.Effective red blood cell production is measured clinically by counting the number of reticulocytes (new red blood cells containing increased amounts of RNA) entering thecirculation. Although both the E/G ratio and reticulocyte count are at best semiquantitative,they do provide sufficient information for clinical diagnosis. A measurement of radioironincorporation into red blood cells (erythron iron turnover) can provide a more accuratemeasurement of red blood cell production. This technique was used originally to define andclassify red blood cell disorders as defects in either marrow proliferation (hypoproliferativeanemias), precursor maturation (ineffective erythropoiesis), or red blood cell destruction(hemorrhagic and hemolytic anemias).The performance of the erythroid marrow can also be extrapolated from studies of red

 blood cell destruction. Clinical indicators of red blood cell destruction include theserum lactic dehydrogenase level, the indirect bilirubin, and observation of the rate of rise or fall of the hematocrit over time. Research measurements that are more accurate indefining levels of red blood cell destruction include carbon monoxide (CO) excretion, stoolurobilinogen, and a direct measurement of radiolabeled red blood cell survival (51Cr red

 blood cell survival). The latter has been used clinically to define both the rate and the site of destruction, whether in spleen or liver. The other measurements are not as practical.

Table 1-1. Measurements of red blood cell production and destruction.Production Destruction

Marrow E/G ratio Change in hematocritReticulocyte index Indirect bilirubinErythron iron turnover Lactic dehydrogenase (LDH)

51Cr red blood cell survivalCO excretion/stoolurobilinogen

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Basal and Stimulated ErythropoiesisThe ability of the erythroid marrow to increase red blood cell production in response toanemia or hypoxia is a basic characteristic of the normal erythron. Thus, normalerythropoiesis is defined not only for the basal state but also for acute and chronic anemia

A normal 70-kg adult has a circulating red blood cell mass of approximately 2000 mL (300Ã 109 red blood cells per kg). Since red blood cells have a lifespan of 100-120 days, 1% of the red blood cell mass, approximately 20 mL of red blood cells, is destroyed daily andreplaced by new red blood cell production. This steady state is clinically appreciated fromthe E/G ratio of 1:3 and the reticulocyte index (the reticulocyte count corrected for hematocrit and reticulocyte shift; see Chapter 2). With an acute anemia secondary tohemorrhage or hemolysis, the marrow will respond with a threefold increase in cell

 production within 7-10 days. This can be detected from the increase in the E/G ratio to 1:1or higher and a rise in the reticulocyte index to three times normal. With a chronichemolytic anemia, red blood cell production can increase further, reaching levels of five toeight times normal. These patients show E/G ratios greater than 1:1 and reticulocyte indicesgreater than five times normal. The highest levels of red blood cell production in patients

with hemolytic anemias require an expansion of the erythroid marrow mass to new areasof the marrow cavity. This process takes time and is most prominent in patients whohave congenital, life long hemolytic anemias.Several factors play important roles in defining the marrow's response to anemia or hypoxia. Obviously, the severity of the anemia or hypoxia and the adequacy of theerythropoietin response are extremely important in setting a level of expectation. A chronichypoproliferative anemia develops, for example, when a patient cannot produce increasedamounts of erythropoietin because of renal damage.

Table 1-2. Normal response to anemia.Anemia (Hb 8 g/dL)

Basal (Hgb > 13 g/dL) Acute ChronicMarrow E/G ratio1:3 1:1 1:1Reticulocyte index 1.0 2-3 3-8

Factors that determine the marrow's responsiveness include its anatomical structure, the presence of a normal pool of stem cells, and the supply of essential nutrients. The anatomicalstructure of the marrow is organized to provide a nurturing environment for celldevelopment. Erythroid precursor cells are maintained in a network of reticular cells andfibers in close proximity to vascular sinusoids. The marrow syncytium is designed to sustainthe developing cells in a nutrient-rich environment while they proliferate and mature. Cellslining the sinusoids have the ability to regulate the exit of cells from the marrow intocirculation, allowing only those cells that have completed maturation to leave.

The importance of these marrow characteristics cannot be over emphasized. An abnormalityin marrow structure, as seen with radiation damage or myelofibrosis, significantly impairsnew red blood cell production. Overgrowth of other cellular components, as with myeloidleukemias or infiltrating tumors or lymphomas, will decrease red blood cell production byoccupying the space required for red blood cell precursor growth.The supply of nutrients to the marrow is also important. The most important nutrient is theiron required for hemoglobin formation. The level of the normal marrow's response to ahemorrhagic or hemolytic anemia is essentially a reflection of iron supply (Figure 1-8). Inresponse to a hemorrhagic anemia, a normal individual with normal iron stores will be able

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to maintain a serum iron level sufficient to support a production increase of up to 3 timesnormal. As shown in the figure, this level of production is attained as the hematocrit falls tolevels between 20% and 30%. More severe anemia with a greater erythropoietin responsedoes not result in a greater marrow production response. The cause of this plateau is thelimitation of iron delivery from normal stores.Figure 1-8 also shows the effect of variations in iron supply. With iron deficiency, the

erythroid marrow will be unable to respond despite a high level of erythropoietinstimulation. The patient with iron deficiency appears to have a hypoproliferative anemia eventhough the erythropoietin level is increased and the marrow morphology appears to benormal. In contrast, patients who have hemolytic anemias, in which the destruction of adultred cells provides a major source of iron for recycling to the marrow, can have marrow

 production that increases to levels well above three times normal. Chronically, these patientscan achieve production levels in excess of 5 times normal.

BIBLIOGRAPHYBeutler E et al: Hematology, 6th ed. McGraw-Hill, 2001.

Goodnough LT, Skikne B, Brugnara C: Erythropoietin, iron, and erythropoiesis. Blood2000;96:823.Hillman RS, Finch CA: Red Cell Manual, 7th ed. FA Davis, 1997.Hsia CCW: Respiratory function of hemoglobin. N Engl J Med 1998;338:239.Ponka P: Tissue-specific regulation of iron metabolism and heme synthesis: Distinct controlmechanisms in erythroid cells. Blood 1997;89:1.Zwaal RFA, Schroit AJ: Pathophysiologic implications of membrane phospholipidasymmetry in blood cells. Blood 1997; 89:1121.