Physiologic Classification

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The physiologic classification of anemia is based on response of the bone marrow. The three major categories are hypop-roliferative anemia, maturation disorders (ineffective eryth-ropoiesis), and hemolytic-hemorrhagic anemia (Box 39-2).

Hypoproliferative Anemia

In hypoproliferative anemias the response of the bone marrow is impaired by one of three general mechanisms. The first is marrow damage, which results from an injury to the bone marrow and makes it impossible for the marrow to respond to adequate EPO stimulation. Aplastic anemia is a classic example, but chemotherapy-induced marrow aplasia is more common (Box 39-3). The physiologic hallmark of marrow damage is a low RPI (<2 at Hb >10 g/dL; <2.5 at Hb of 7-10 g/dL). EPO is typically elevated, with evidence of premature release of reticulocytes from the bone marrow (shift reticulocytes, including nucleated RBCs in some cases). Despite EPO stimulation, however, the bone marrow is unable to proliferate. Bone marrow examination may reveal an empty or hypocellular marrow or one replaced by tumor cells or fibrosis. Treating these patients with recombinant human EPO is rarely useful.

A second mechanism of hypoproliferation is inflammation, which is the most common form of anemia seen in hospitalized patients. Often referred to as the "anemia of chronic disease" (ACD), it has more recently been termed the anemia of inflammation (AI) (Weiss and Goodnough, 2005). The anemia associated with inflammatory states is complex and involves altered iron homeostasis as well as decreased EPO production and an impaired response of erythroid progenitor cells in the marrow to EPO. Inflammation comes in many forms in addition to acute and chronic infection. Also

Box 39-2 Classification of Anemias

Hypoproliferative anemias

Aplastic anemia Anemia of inflammation Chronic renal insufficiency Hypothyroidism Mild iron deficiency associated with changes consistent with AI is tissue damage, as caused by necrosis, surgery, myocardial infarction, and other tissue injury.

The major effect of AI is on iron metabolism. With inflammation, iron absorption from the gut is blocked, as is iron release to transferrin from reticuloendothelial stores. The net effect is a decrease in the serum iron level and in transferrin saturation. This results in an inadequate supply of iron to the erythroid marrow for hemoglobin synthesis. Over time, the clinical picture (e.g., microcytic, hypochromic RBCs) may come to resemble true iron deficiency anemia, despite the fact that iron stores in the body are normal or increased. The mediator of these alterations in iron metabolism is hepcidin, a small molecule made in the liver that is critical to iron homeostasis and that is upregulated in the presence of inflammation. Hepcidin interferes with the cellular iron export protein ferroportin. The ferroportin pathway is the mechanism by which iron absorbed from the diet is shunted through the gut and reticuloendothelial cells and released to circulating transferrin. Iron regulatory proteins (IRP-1 and IRP-2) also play a role in balancing iron storage as well as circulating iron. Although there are many similarities to iron deficiency, providing iron in this setting is generally ineffective. Recombinant human EPO (epoetin) may stimulate RBC production, but the approach to treatment is primarily to identify and reverse, if possible, the inflammatory trigger.

In addition to changes in iron homeostasis, inflammation results in the release of proinflammatory cytokines such as IL-1, tumor necrosis factor alpha (TNF-a) and interferon y (IFN-y). These cytokines have many effects on erythropoi-esis, such as decreasing EPO production and blunting the response of erythroid progenitors in the marrow to EPO. All these changes result in marrow hypoproliferation and an inadequate marrow response to anemia.

The third major category of hypoproliferative anemia is that associated with inadequate EPO production, which results in understimulation of the marrow. Typically, this is seen in patients with chronic renal insufficiency whose diseased kidney cannot produce EPO despite often profound anemia. The advent of successful renal replacement therapy (peritoneal or hemodialysis) has resulted in an increasingly large population of severely and chronically anemic patients. For these patients, epoetin therapy has been lifesaving in terms of quality of life and overall health.

Box 39-3 Mechanisms of Marrow Damage


Drug-induced (immunologic)



Autoimmune (idiopathic aplastic anemia) Chemotherapy

Congenital anemia (Fanconi's, Blackfan-Diamond)

Marrow replacement

Metastatic malignancy



Maturation disorders

Megaloblastic anemias Myelodysplasia Severe iron deficiency Thalassemia syndromes

Hemolytic-Hemorrhagic anemia

Autoimmune hemolysis Drug- or chemical-induced hemolysis Acute or chronic blood loss Sickle cell anemia

In the family physician's office, the question often is how much anemia can be ascribed to mild or moderate renal insufficiency. There is no easy answer, but generally, if the creatinine level is higher than 2 mg/dL with no other obvious or reversible cause for the anemia (blood loss, hemolysis after appropriate testing), it is reasonable to ascribe the anemia to renal insufficiency.

Another pathologic process resulting in inadequate EPO stimulation is hypometabolism, particularly hypothyroidism. The anemia may reflect a reduced need for oxygen-carrying capacity because of the reduced metabolic load resulting from the thyroid hormone deficiency.

Mild iron deficiency anemia also is associated with a hypo-proliferative marrow response. Iron deficiency, with mild to moderate anemia, impairs the erythroid marrow response. If the anemia is mild, circulating RBCs are normocytic or slightly microcytic, and the red cell distribution width (RDW) index is normal (Fig. 39-3). The serum iron is usually low, transferrin saturation less than 15%, and serum ferritin less than 15 ng/mL.

Table 39-3 compares anemia of inflammation and classic iron deficiency anemia. The major difference is the serum

Figure 39-3 Hypochromic, microcytic red blood cells, with anisocytosis.

(From the American Society of Hematology image Bank image #1214. Copyright 1996 American Society of Hematology, used with permission.)

Figure 39-3 Hypochromic, microcytic red blood cells, with anisocytosis.

(From the American Society of Hematology image Bank image #1214. Copyright 1996 American Society of Hematology, used with permission.)

ferritin level, which is typically normal or increased with AI and characteristically low with true iron deficiency. Making this distinction is important because the mechanisms that lead to inflammation or iron deficiency are generally distinct, as is the approach to treatment.

Maturation Disorders

Maturation disorders are characterized by adequate EPO stimulation and erythroid marrow hyperplasia, but in the absence of a sufficiently increased reticulocyte production index. Under these conditions, premature cell death (apop-tosis) takes place in the marrow, and a mismatch occurs between degree of erythroid hyperplasia on bone marrow aspiration or biopsy and the reticulocyte (effective) production index. Consequently, RBC production in such patients is considered ineffective and can involve nuclear or cytoplasmic maturation defects.

Nuclear maturation defects result in a megaloblastic bone marrow and are typical in patients with severe folate or vitamin B12 deficiency. The RBCs are macrocytic, and the reticulocyte production index is normal or slightly above normal (Fig. 39-4). Examining the bone marrow of patients with vitamin B12 or folate deficiency reveals increased erythroid marrow precursors and loosening of nuclear chromatin, as well as more cells with nuclear degeneration (karyorrhexis and karyolysis). These are the features of apoptosis.

Because of the degree of RBC destruction in the bone marrow, serum bilirubin may be elevated and haptoglobin decreased. It is important to distinguish between vitamin B12 and folate deficiency because the pathogenesis is different and the treatment must be specific. Patients who present with folate deficiency and alcoholic neuropathy pose a particularly difficult diagnostic challenge; the neuropathy of vitamin B12 deficiency should not be treated inappropriately with folic acid, because the anemia may be partly corrected with folic acid, but the neuropathy associated with vitamin B12 deficiency will progress. This is rarely seen at present. The neurologic symptoms may precede the anemia, so it is important to screen older adults with unexplained memory loss for vitamin B12 deficiency.

Table 39-3 Comparison of Anemia of Inflammation and Iron Deficiency Anemia

Iron Deficiency

Anemia of Inflammation

Low serum iron level

Low serum iron level

Elevated TIBC

TIBC normal or reduced

Transferrin saturation low (<15%)

Transferrin saturation low (15%-20%)

Serum ferritin level low (<15 ng/mL)

Serum ferritin level normal or elevated

Microcytic, hypochromic RBCs

Normocytic to microcytic RBCs

RBC protoporphyrin level elevated

RBC protoporphyrin level elevated

TIBC, Total iron-binding capacity; RBCs, red blood cells.

Figure 39-4 Megaloblastic changes of macrocytosis and hypersegmented neutrophils. (From the American Society of Hematology image Bank image #2611. Copyright 1996 American Society of Hematology, used with permission.)

The diagnosis of these disorders is relatively straightforward and can be made with laboratory testing for serum vitamin B12 and folate levels. RBC levels of folate may also be useful, particularly in a folate-deficient patient receiving diet therapy or an undernourished alcoholic patient being fed. Alcohol inhibits the entry of folic acid, decreasing serum folic acid levels. Thus, folic acid deficiency may result from both dietary insufficiency and inhibition of folic acid release in patients with chronic alcohol intake. Folic acid deficiency has greatly decreased since 1998, when most grains began to be fortified with folic acid in the United States.

Treatment of vitamin B12 or folic acid deficiency is simply replacement with the appropriate vitamin. In patients who appear with severe megaloblastic anemia and who need treatment immediately, it is prudent to obtain blood samples, both whole blood and serum, for later diagnostic tests and then to treat the patient with both vitamins. This ensures that the anemia and central nervous system (CNS) manifestations of potential vitamin B12 deficiency are adequately treated.

The Schilling test is useful to specify the defect leading to B12 deficiency. This involves a small, oral dose of radiolabeled vitamin B12 along with a large, parenteral flushing dose of B12. The B12 absorbed from the diet is excreted in the urine because there are no transport binding sites in the circulation. This first stage of the absorption test indicates if the patient can absorb vitamin B12. The second stage is similar to the first, except the oral dose of B12 is given with intrinsic factor (IF). Theoretically, the addition of IF should correct the absorption defect associated with pernicious anemia. If the absorption defect is caused by disease of the terminal ileum, both stages of the Schilling test will be positive. A host of surrogate markers for pernicious anemia include measurement of IF or anti-parietal cell antibodies. However, these markers are positive in an increasing percentage of patients as they grow older, and consequently cannot be considered definitive for the diagnosis.

Another cause of a macrocytic anemia associated with ineffective erythropoiesis is myelodysplasia. The myelodysplastic syndromes are primary bone marrow neoplasms, and the macrocytosis does not respond to vitamin replacement therapy. This is now an increasingly frequent diagnosis, particularly because it is a more common diagnosis in older adults and the population is aging.

Transient megaloblastic and macrocytic anemia may be seen with certain types of anticancer drugs that interfere directly with DNA synthesis and cell division. Common drugs in this category include hydroxyurea and thymidine inhibitors. Family physicians also see patients with mild anemia and macrocytosis who have a history of excessive alcoholic intake, with or without a mild to moderate degree of liver disease. The macrocytosis in these cases has two probable causes: spurious macrocytosis caused by lipid loading of the RBC membrane, and macrocytosis caused by intermittent folate deficiency associated with bouts of high alcohol consumption in the absence of other caloric intake.

Iron Deficiency

In addition to nuclear maturation defects that result in macrocytic anemia, cytoplasmic maturation defects such as severe iron deficiency occur. Extreme iron deficiency and severe anemia may result in a pattern of ineffective RBC production. With mild anemia, iron deficiency limits erythroid proliferation, and the anemia appears to be hypoprolifera-tive. However, as anemia becomes more profound and EPO stimulation of the marrow increases, the marrow becomes more ineffective in appearance. In either case, laboratory test results indicating low serum iron, low transferrin saturation, and extremely low ferritin are diagnostic.

Once the diagnosis of iron deficiency is definitive, the family physician needs to consider the cause. Women in their childbearing years typically have marginal iron stores, and even being an occasional blood donor may result in mild anemia, with iron deficiency. The case is different in an adult male or postmenopausal woman. Unless there is a clear explanation, gastrointestinal (GI) blood loss should be the prime suspect and must carefully be ruled out.

Treatment of iron deficiency is not always straightforward. The goal is to remedy the hemoglobin deficit and replace iron stores. Many oral iron preparations are available, but ferrous sulfate and ferrous gluconate are most often used and inexpensive. The best regimen is to give 3 iron tablets daily; this provides about 150 mg of elemental iron daily. If the patient is compliant and absorption normal, reticulocytosis will occur in a week and Hb level will increase at least 1 g/ dL within 2 weeks. Microcytosis may take up to 4 months to resolve. The iron is best taken on an empty stomach because certain foods interfere with iron absorption. However, 15% to 20% of patients will have significant gastric upset with oral iron and may not be compliant. If poor absorption or noncompliance is of concern, parenteral iron may be given. Several preparations are available, including iron sucrose and iron gluconate intravenously (IV) at 125 to 250 mg/day, and have a good safety profile compared with iron dextran. In treating iron deficiency, the target for therapy is not just to correct the anemia, but also to provide some degree of iron stores, so it is recommended that iron treatment be continued for 2 to 3 months after a normal Hb level is reached.

Various preparations of ferrous salts are equally tolerated and effective for the treatment of iron deficiency anemia. Controlled-release (CR) iron formulations cause fewer GI side effects than non-CR salt preparations, but discontinuation rates are similar. Ferrous salts are the treatment of choice for iron deficiency anemia (McDiarmid and Johnson, 2002).

Hemochromatosis in hereditary form has a homozygous incidence of 0.44% and a 10% heterozygous incidence, all in populations of white European descent. Elevated transferrin saturation levels (>45%-50%) and elevated ferritin levels (>300 mg/L) are markers of increased iron stores that may indicate the need for further evaluation.


Severe cytoplasmic maturation defects are usually inherited and are characteristic of the thalassemic syndromes or defects in heme synthesis. The inherited thalassemias represent a large number of mutations in the globin genes themselves or in the regulation of globin gene expression. When either the alpha or the beta globin chains are produced in unequal amounts, the excess chains aggregate and the ery-throid precursor cells die, leading to ineffective erythropoi-esis. p-Thalassemia produces decreased numbers of beta chains and a-thalassemia decreased alpha chains. Homo-zygous p-thalassemia is one of the most severe forms of human anemia; more than 200 million people worldwide carry the p-thalassemia gene. Because of the large number of mutations that can result in thalassemia, most patients who have the clinical phenotype of homozygous thalassemia are compound heterozygotes. Homozygous a-thalassemia is not seen in adults because it results in hydrops fetalis in the newborn. p-Thalassemia trait and a-thalassemia trait, however, are common but are usually associated with only mild anemia.

With increasing numbers of immigrants from Southeast Asia, there are more people with a complex thalassemia syndrome, known as hemoglobin Constant Spring, who might be seen in practice. Obtaining a definitive diagnosis is important so as not to prescribe iron or other therapies inappropriately.

Hemolytic-Hemorrhagic Anemia

Hemolytic-hemorrhagic anemia (HHA) is diagnosed in patients with persistent anemia or decreasing Hb and Hct levels despite what appears to be an adequate bone marrow erythropoietic response. For patients with chronic hemo-lytic disease, this means a marrow production index of 3. In patients with hemorrhagic disease, this level of production may not be reached quickly because of the ongoing iron loss, and production indices about 2 to 2.5 times normal are more common. In the latter case, however, blood loss dominates the clinical picture unless the loss is internal.

In a discussion of the hemolytic anemias, which can be complex to diagnose, it is helpful to consider the patho-physiology of disease and how to categorize the hemolytic process. One should first consider whether the hemolysis appears to be intravascular or extravascular.

Intravascular Hemolysis

Intravascular hemolysis is associated with the rupture of erythrocytes and dispersion of their contents into the plasma. This results in free hemoglobin in the plasma and, if sufficient RBC destruction takes place, there is Hb spillover into the urine (hemoglobinuria). The primary Hb-binding protein in the plasma is haptoglobin, but in the presence of intravascular hemolysis, free haptoglobin becomes unde-tectable. This is a useful test only if the results are negative because ineffective RBC production, associated with substantial destruction of RBCs in the bone marrow (or even primarily extravascular hemolysis), will result in the release of sufficient Hb to reduce circulating haptoglobin levels.

Intravascular hemolysis can be life threatening if acute and can have several causes. For example, RBC membrane damage and intravascular hemolysis can result from burns or exposure to certain toxins that target the RBC membrane, such as Clostridium perfringens. Hypotonic lysis is rarely seen but could occur because of the IV infusion of free water. Immune-mediated lysis of RBCs can occur when mismatched transfusions are given. With ABO incompatibility, the operative mechanism is immunoglobulin M (IgM) antibodies that fix complement to the RBC surface and cause rapid lysis.

Mechanical fragmentation is probably the most common form of intravascular hemolysis seen in North America and is associated with microvascular diseases such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome (HUS; Fig. 39-5), defective mechanical heart valves, and disseminated intravascular coagulation. Acute attacks of malaria

Krossad Spagris
Figure 39-5 Schistocytes and helmet cells characteristic of a hemolytic process (hemolytic uremic syndrome). (From the American Society of Hematology image Bank image #4678. Copyright 1996 American Society of Hematology, used with permission.)

are also associated with intravascular hemolysis. Paroxysmal nocturnal hemoglobinuria (PNH) is an unusual form of intravascular hemolysis caused by an acquired X-linked defect in the hematopoietic stem cell. Patients with PNH have varying degrees of hemolysis throughout the day, and in crisis, this can be severe.

An inherited condition that predisposes patients to intra-vascular hemolysis is the Mediterranean form of glucoses-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is the most common inborn error of RBC metabolism worldwide, affecting almost 0.5 billion people. Because it is an X-linked genetic disorder, it is most severe in men. G6PD protects RBCs from oxidative stressors such as superoxide anions and hydrogen peroxide. Oxidative products in RBCs are normally neutralized by reduced glutathione, which is generated by glutathione reductase. This pathway is part of the hex-ose monophosphate shunt pathway and requires G6PD for proper functioning. The Mediterranean abnormality of G6PD deficiency is associated with moderate chronic hemolysis, but this may become overwhelming and even fatal when the RBCs are exposed to oxidative stress. Any oxidative stress in these patients may have severe clinical consequences that could require transfusion or exchange transfusion as part of therapy.

The more common variety of G6PD deficiency in North America is G6PDA-, which affects approximately 10% of the African American population. G6PDA- is an enzyme with reduced stability and catalytic activity that become more prominent as the red cell ages. In these people, hemolytic events typically involve older RBCs and are therefore benign and relatively self-limited. The accumulation of oxidized glutathione reacts with hemoglobin and causes precipitation of Hb into Heinz bodies, resulting in hemolytic disease. The hemolytic process can be enhanced by infection, surgical stress, diabetic acidosis, and certain medications, such as the antimalarials primaquine and quinacrine.

Extravascular Hemolysis

Contrasted with intravascular hemolysis is the destruction of RBCs that occurs primarily in the reticuloendothelial system (RES), so-called extravascular hemolysis. The primary site of destruction is outside the vascular compartment, in the liver, spleen, and bone marrow. A form of extravascular hemoly-sis is the ineffective RBC production seen with nuclear or severe cytoplasmic maturation defects. More common sites for extravascular destruction are the liver and particularly the spleen. Again, it is useful to determine whether the hemo-lysis is congenital or acquired. Congenital forms include inherited hemoglobinopathies (thalassemias, sickle cell disease), inherited membrane defects (hereditary spherocytosis or elliptocytosis), and enzyme defects. Defective RBC metabolism usually causes hemolysis by creating unstable Hb or by failing to generate adequate adenosine triphosphatase (ATP) to maintain RBC membrane plasticity, as occurs in pyruvate kinase deficiency; this autosomal recessive disorder is the most common enzyme deficiency of the glycolytic pathway. Most patients with pyruvate kinase deficiency have a mild anemia and generally do not require transfusions.

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