Measurement (units) Men Women

Hemoglobin (gm/dL) 13.6–17.2 12.0–15.0

Hematocrit (%) 39–49 33–43

Red cell count (106 /μL) 4.3–5.9 3.5–5.0

Reticulocyte count (%) 0.5–1.5

Mean cell volume (μm3 ) 82–96

Mean corpuscular hemoglobin (pg) 27–33

Mean corpuscular hemoglobin concentration (gm/dL) 33–37

RBC distribution width 11.5–14.5

RBC, red blood cell.

*Reference ranges vary among laboratories. The reference ranges for the laboratory providing the result should always be used in interpreting the test result.

is external or internal. The effects of acute blood loss are mainly due to the loss of intravascular volume, which can lead to cardiovascular collapse, shock, and death. If the patient survives,

the blood volume is rapidly restored by shift of water from the interstitial fluid compartment. The resulting hemodilution lowers the hematocrit. Reduction in the oxygenation of renal

juxtaglomerular cells triggers increased production of erythropoietin, which stimulates the proliferation of committed erythroid stem cells (CFU-E) in the marrow. It takes about 5 days for

the progeny of these CFU-Es to fully differentiate, an event marked by the appearance of increased numbers of newly released red cells (reticulocytes) in the peripheral blood. The iron in

hemoglobin is recaptured if red cells are lost internally, as into the peritoneal cavity, but external bleeding leads to iron loss and possible iron deficiency, which can hamper restoration of

normal red cell counts.

The earliest change in the peripheral blood immediately after acute blood loss is leukocytosis, due to the mobilization of granulocytes from marginal pools. Initially, red cells appear normal

in size and color (normocytic, normochromic). However, as marrow production increases, there is a striking increase in the reticulocyte count, reaching 10% to 15% after 7 days.

Reticulocytes are recognizable as polychromatophilic macrocytes in the usual blood smear. Early recovery from blood loss is often accompanied by thrombocytosis, which is caused by

increased platelet production.

Chronic Blood Loss

Chronic blood loss induces anemia only when the rate of loss exceeds the regenerative capacity of the marrow or when iron reserves are depleted. Iron deficiency anemia, which has

identical features regardless of underlying cause (e.g., bleeding, malnutrition, malabsorption states), will be discussed later.

HEMOLYTIC ANEMIAS

Hemolytic anemias share the following features:

• A shortened red cell life span (normal = 120 days); that is, premature destruction of red cells

• Elevated erythropoietin levels and increased erythropoiesis in the marrow and other sites, to compensate for the loss of red cells

• Accumulation of the products of hemoglobin catabolism, due to an increased rate of red cell destruction

The physiologic destruction of senescent red cells takes place within the mononuclear phagocytic cells of the spleen. In the great majority of hemolytic anemias, the premature destruction

of red cells also occurs within the mononuclear phagocyte system (extravascular hemolysis), which undergoes a form of work-related hyperplasia marked by splenomegaly. Much less

commonly, lysis of red cells within the vascular compartment (intravascular hemolysis) predominates.

Intravascular hemolysis of red cells is caused by mechanical injury, complement fixation, infection by intracellular parasites such as falciparum malaria ( Chapter 8 ), or exogenous toxic

factors. Mechanical injury caused by defective cardiac valves, thrombi within the microcirculation, or repetitive physical trauma (marathon running, bongo drum beating) can physically

lyse red cells. Complement fixation can occur on antibody-coated cells during transfusion of mismatched blood. Toxic injury is exemplified by clostridial sepsis, which releases toxins that

attack the red cell membrane.

Whatever the mechanism, intravascular hemolysis is manifested by (1) hemoglobinemia, (2) hemoglobinuria, (3) jaundice, and (4) hemosiderinuria. Free hemoglobin in plasma is promptly

bound by an a2 -globulin (haptoglobin), producing a complex that is rapidly cleared by the mononuclear phagocyte system, thus preventing excretion into the urine. Decreased serum

haptoglobin is characteristic of intravascular hemolysis. When the haptoglobin is depleted, free hemoglobin is prone to oxidation to methemoglobin, which is brown in color. The renal

proximal tubular cells reabsorb and catabolize much of the filtered hemoglobin and methemoglobin, but some passes out with the urine, imparting a red-brown color. Iron released from

hemoglobin can accumulate within tubular cells, giving rise to renal hemosiderosis. Concomitantly, heme groups derived from the complexes are catabolized to bilirubin within the

mononuclear phagocyte system, leading to jaundice. In hemolytic anemias, the serum bilirubin is unconjugated and the level of hyperbilirubinemia depends on the functional capacity of

the liver and the rate of hemolysis. When the liver is normal, jaundice is rarely severe. Excessive bilirubin excreted by the liver into the gastrointestinal tract leads to increased formation

and fecal excretion of urobilin ( Chapter 18 ).

Extravascular hemolysis takes place whenever red cells are rendered "foreign" or become less deformable. Since extreme alterations in shape are required for red cells to navigate the

splenic sinusoids successfully, reduced deformability makes the passage difficult and leads to sequestration within the cords, followed by phagocytosis ( Fig. 13-2 ). This is an important

pathogenetic mechanism of extravascular hemolysis in a variety of hemolytic anemias. With extravascular hemolysis,

Figure 13-2Schematic of splenic sinus (electron micrograph). A red cell is in the process of squeezing from the red pulp cords into the sinus lumen. Note the degree of deformability

required for red cells to pass through the wall of the sinus.

Figure 13-3Marrow smear from a patient with hemolytic anemia. The marrow reveals greatly increased numbers of maturing erythroid progenitors (normoblasts). (Courtesy of Dr. Steven

Kroft, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 13-4Schematic representation of the red cell membrane cytoskeleton and alterations leading to spherocytosis and hemolysis. Mutations weakening interactions involving a-

spectrin, b-spectrin, ankyrin, band 4.2, or band 3 all cause the normal biconcave red cell to lose membrane fragments and adopt a spherical shape. Such spherocytic cells are less

deformable than normal and therefore become trapped in the splenic cords, where they are phagocytosed by macrophages.

Figure 13-5Model of the pathophysiology of hereditary spherocytosis. (Adapted from Wyngaarden JB, et al [eds]: Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992,

p. 859.)

Figure 13-6Hereditary spherocytosis (peripheral smear). Note the anisocytosis and several dark-appearing spherocytes with no central pallor. Howell-Jolly bodies (small dark nuclear

remnants) are also present in red cells of this asplenic patient. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,

TX.)

Figure 13-7Role of glucose-6-phosphate dehydrogenase (G6PD) in defense against oxidant injury. The disposal of H2 O2 , a potential oxidant, is dependent on the adequacy of reduced

glutathione (GSH), which is generated by the action of NADPH. The synthesis of NADPH is dependent on the activity of G6PD. GSSG, oxidized glutathione.

Figure 13-8G6PD deficiency: effects of oxidant drug exposure (peripheral blood smear). Inset, Red cells with precipitates of denatured globin (Heinz bodies) revealed by supravital

staining. As the splenic macrophages pluck out these inclusions, "bite cells" like the one in this smear are produced. (Courtesy of Dr. Robert W. McKenna, Department of Pathology,

University of Texas Southwestern Medical School, Dallas, TX.)

Figure 13-9Sickle cell anemia (peripheral blood smear). A, Low magnification show sickle cells, anisocytosis, and poikilocytosis. B, Higher magnification shows an irreversibly sickled

cell in the center. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 13-10Pathophysiology of sickle cell anemia.

Figure 13-11A, Spleen in sickle cell anemia (low power). Red pulp cords and sinusoids are markedly congested; between the congested areas, pale areas of fibrosis resulting from

ischemic damage are evident. B, Under high power, splenic sinusoids are dilated and filled with sickled red cells. (Courtesy of Dr. Darren Wirthwein, Department of Pathology, University

of Texas Southwestern Medical School, Dallas, TX.)

Figure 13-12Splenic remnant in sickle cell anemia. (Courtesy of Drs. Dennis Burns and Darren Wirthwein, Department of Pathology, University of Texas Southwestern Medical School,

Dallas, TX.)

Figure 13-13Diagrammatic representation of the b-globin gene. Arrows denote sites where point mutations giving rise to thalassemia have been identified.

Figure 13-14Pathogenesis of b-thalassemia major. Note that aggregates of unpaired a-globin chains are not visible in routinely stained blood smears. Blood transfusions are a doubleedged

sword, correcting the anemia and thereby reducing the stimulus for marrow expansion, but also adding to systemic iron overload.

TABLE 13-3-- Clinical and Genetic Classification of Thalassemias

Date: 2016-04-22; view: 829