Disorders of Red Cells

James R. Eckman, M.D.

Regulation of Erythropoiesis

Erythropoiesis is regulated to maintain sufficient oxygen delivery to tissues. Oxygen delivery is proportional to the concentration of oxyhemoglobin (the hemoglobin level oxygen saturation) and cardiac output. Cells in the kidney "sense" tissue oxygenation and control bone marrow erythropoiesis by producing erythropoietin (EP). This hormone increases red cell production and release.

Table 1.
Normal Values (Mean Range 2 SD)
Sex Hemoglobin Hematocrit Red Cell Mass
Male 15.5
(13.3 - 17.7)
46.0
(39.8 - 52.2)
29
(26 - 32)
Female 13.7
(11.7 - 15.7)
40.9
(34.9 - 46.9)
26
(23 - 29)

 

Figure 1.
Approach to Anemia

The normal red cell life span is 100 to 120 days; thus, approximately 1% of red cells must be replaced each day to maintain homeostasis. Anemia results if the loss of red cells from the circulation exceeds the rate of their replacement. The reticulocyte count is an estimate of red cell survival and marrow production. Thus, the causes of most anemias can be divided into (a) decreased production (hypoproliferative) or (b) increased destruction (hemolytic or bleeding) of erythrocytes.

If the hemoglobin is decreased, the reticulocyte count must be corrected for the decrease in total red cells either by calculating a corrected percentage or the absolute reticulocyte count.

Approach to Anemia

The classification shown in Figure 1 is of value in approaching the patient with anemia in a logical manner. The mean corpuscular volume (MCV) of red cells is most useful in evaluating a hypoproliferative anemia. A search for blood loss, examination of a peripheral blood smear, and direct Coombs' test are used to evaluate an anemia caused by increased loss. Some anemias will have the characteristics of both decreased production and increased loss.

Anemia Secondary to Decreased Production

These anemias are characterized by an erythrocyte production index of <2%. The absence of appropriate reticulocytosis reflects the bone marrow's inability to compensate for the decrease in hemoglobin. Although not essential in all cases, the bone marrow may need to be evaluated to find the cause of the underproduction.

Microcytic Hypochromic Anemia

A mean corpuscular volume of <80 and hypochromic microcytic red cells in the blood smear characterize this group of anemias. All result from deficient hemoglobin synthesis. Causes of hypochromic microcytic anemias are (a) iron deficiency, (b) anemia of chronic inflammation, (c) sideroblastic anemia, and (d) thalassemia.

Hemoglobin production requires iron, protoporphyrin, and globin chains. Protoporphyrin is produced from succinyl coenzyme A and glycine. The first reaction requires pyridox phosphate, and a number of critical steps occur in the mitochondria of erythroid precursors. Insertion of iron into the porphyrin ring results in heme formation. Alpha- and beta-globin chains are produced as amino acids assemble on polyribosomes. Microcytic anemia can result if a reduced amount of iron is delivered to the marrow erythroid precursors, as occurs in iron deficiency or inflammatory block. Heme synthesis may be defective, as in sideroblastic anemias. Thalassemia syndromes result from inherited defects in globin-chain synthesis.

Iron requirements: Normally, iron is efficiently recycled, so losses are minimal. A precise balance is maintained between losses and absorption. Males and nonmenstruating females lose 1.0 mg of iron per day; menstruating females lose an average of 2.0 mg/d. During pregnancy, the average loss of 3 to 4 mg/d are obligatory losses to fetal demands, an increased blood volume, and in blood and lochia lost at delivery. Bleeding results in a loss of 50 mg of iron per 100 mL of whole blood.

Body stores of iron can be estimated by a variety of methods: (a) serum iron, TIBC, and percent transferrin saturation; (b) serum ferritin; and (c) iron stains of bone marrow for sideroblasts and storage (RE) iron.

Iron Deficiency Anemia

Iron deficiency anemia results when body stores of iron are depleted by a prolonged loss in excess of absorption. Iron deficiency is a symptom of a process that is causing a prolonged negative iron balance, the causes of which must be determined as soon as the diagnosis of iron deficiency has been established (Table 2).

Table 2.
Etiologies of Iron Deficiency in 371 British Subjects
Factor (Frequency)

Increased Iron Loss

  • Gastrointestinal bleeding (56%)
    • Unknown site (16%)
    • Hemorrhoids (10%)
    • Salicylates (8%)
    • Peptic ulcer (7%)
    • Hiatal hernia (7%)
    • Diverticulitis (4%)
    • Neoplasia (2%)
  • Increased menstruation (29%)

Increased Requirements

  • Pregnancy (6%)

Decreased Intake

  • Inadequate diet (19%)
  • Decreased absorption
    • Achlorhydria (41%)
    • Gastric surgery (10%)
    • Celiac disease (6%)
    • Pica (<1%)

Cause Unknown (17%)

Note: Percentages total >100 because many patients had more than 1 cause.

Abstracted from Beveridge BR, Bannerman RM, Evanson JM, Witts LJ. Hypochromic anemia: a retrospective and follow-up of 378 in-patients. Q J Med. 1965;34:145-161 by permission of Oxford University Press.
Clinical Findings

There is a history of weakness, fatigue, tachycardia, dyspnea, and pallor from anemia and tissue iron depletion. Physical findings include pallor, tachycardia, glossitis, koilonychia (spoon nails), and angular stomatitis. Signs and symptoms of an underlying disease may be present. Laboratory studies reveal (a) decreased reticulocyte count and MCV, (b) hypochromic microcytic cells on blood smears, (c) low serum ferritin, and (d) hypercellular marrow with absent sideroblasts and storage iron.

Therapy

Determine and correct the underlying etiologic factors. Administer ferrous sulfate, 300 mg tid, for 4 to 6 months to replete body stores. Monitor treatment for reticulocyte response, increase in hemoglobin, and resolution of anemia to confirm the diagnosis.

Anemia of Chronic Inflammation

These disorders appear to be caused by release of tumor necrosis factor and interleukin 1 by activated monocytes and macrophages. Red cell survival is slightly reduced, and iron reutilization is defective. Iron, liberated during the degradation of hemoglobin, accumulates in the reticuloendothelial system and is not returned to erythroid precursors for the production of new red cells.

This anemia is associated with certain long-standing diseases: (a) chronic infections, (b) neoplastic diseases, and (c) chronic, noninfectious inflammation (ie, rheumatoid arthritis, systemic lupus erythematosus).

Clinical Findings

Manifestations of anemia and underlying disease. Laboratory findings include (a) anemia (hemoglobin 9 to 11 g/dL); (b) decreased reticulocytes; (c) MCV normal (two thirds of patients) or low (one third of patients); (d) serum iron and TIBC are decreased, and transferrin saturation of 10% to 20%; (e) serum ferritin is high; and (f) marrow is normocellular with increased storage iron and decreased or absent sideroblasts. Occasionally, bone marrow is required for accurate diagnosis.

Treatment

Anemia responds to control of underlying disease.

Sideroblastic Anemias-Defective Heme Synthesis

A heterogeneous group of diseases in which heme synthesis is abnormal. A unifying characteristic is the presence of "ringed" sideroblasts in marrow smears stained for iron. Ringed sideroblasts result from the accumulation of iron in the mitochondria of erythroid precursors.

Etiology

Primary sideroblastic anemias occur as hereditary disorders that may be X-linked or autosomal. Acquired primary anemias are either pyridoxine responsive or pyridoxine refractory.

Secondary sideroblastic anemias are caused by drugs, other marrow toxins, and as primary marrow disorders. Drugs implicated are isoniazid, pyrazinamide and chloramphenicol. Other substances and etiologies include alcohol, lead poisoning, neoplastic and chronic inflammatory states, preleukemia, and myeloid leukemia.

Clinical Findings

Signs and symptoms of anemia and underlying disease are often present. Laboratory findings include anemia with a decreased reticulocyte count. Mean corpuscular volume may be normal, increased, or decreased. The blood smear frequently appears dimorphic with a population of hypochromic microcytic cells and a population of normal or macrocytic cells. Ferritin, iron, and transferrin saturation are increased. Bone marrow shows hypercellularity with increased iron stores, increased sideroblasts, and ring sideroblasts.

Treatment

Primary forms occasionally respond to pyridoxine, 200 mg/d, alone or in combination with folic acid. The secondary forms respond when the offending drug is withdrawn or the underlying disease is treated. If transfusions are required, iron overload will be a serious problem. Administration of iron is contraindicated.

Thalassemia Syndromes

Normal Hemoglobin in Adults

Hemoglobin is a heterogeneous group of proteins consisting of four globin chains and four heme groups. In adults, the hemoglobins are A, A2, and F.

Pathophysiology

Thalassemias are autosomally dominant inherited disorders in which either alpha- or beta-globin chains are synthesized at a reduced rate, thereby reducing the production of hemoglobin A. The absence of, decrease in, or defective translation of specific messenger RNA (mRNA), coding for either the alpha or the beta chains is responsible for the decreased production of these globins. This can occur either by gene deletion, defective mRNA production, or production of defective mRNA. Alpha thalassemia results from the decreased synthesis of alpha chains and beta thalassemia from the decreased production of beta chains.

Features

Decreased ability to produce hemoglobin A results in a hypochromic microcytic anemia. In beta thalassemia, a relative increase in delta and gamma chains is associated with increased levels of hemoglobin A2 and F. In alpha thalassemia, there is no compensatory mechanism for the loss in alpha-chain production, so tetramers of the beta and gamma chains may combine to form hemoglobin H and Barts, respectively. Both hemoglobin H and Barts are ineffective oxygen carriers. Unbalanced chain synthesis leads to the precipitation of globin chains, thereby shortening red-cell survival and causing ineffective erythropoiesis in both alpha and beta thalassemia.

Table 3.
Hemoglobins in Adults
  Hemoglobin A Hemoglobin A2 Hemoglobin F
Formula f2 g2 f2 i2 f2 h2
% in adults 95 - 98 2 - 3 <1

The clinical manifestations of thalassemias are due to a decreased rate of hemoglobin synthesis, shortened red-cell survival induced by the unbalanced chain synthesis, and ineffective erythropoiesis.

Table 4.
Hemoglobins in Alpha Thalassemia
  Hemoglobin A Hemoglobin H Hemoglobin Barts
Formula f2 g2 g4 h4
Beta Thalassemia

An autosomal genetic mutation that causes thalassemia major in the homozygous state and thalassemia minor in the heterozygous state. Beta thalassemia occurs in high frequency in populations from Greece, Italy, Southeast Asia, and Africa. DNA coding for beta globin is present in beta thalassemia, but messenger RNA is either not produced, is made in reduced amounts, or has a defective function.

An intermediate clinical state also exists. It is termed thalassemia intermedia and is defined by severe anemia that does not require transfusion also exist. Genotypes are variable and complicated.

Beta Thalassemia Major Clinical Findings

Patients have severe anemia in the first year of life, accompanied by jaundice and hepatosplenomegaly. Symptoms and signs are growth retardation, frequent infections, and skeletal changes secondary to an expanded marrow space. Iron overload with skin pigmentation, cardiac decompensation, and endocrinopathies is a universal problem.

Laboratory findings include: (a) Severe hypochromic microcytic anemia with target cells, basophilic stippling, normoblasts, and an increased reticulocyte count; (b) serum iron, percent transferrin saturation, serum ferritin, and marrow iron are increased; and (c) hemoglobin electrophoresis shows decreased A (0% to 30%), increased F (30% to 90%), and normal to increased A2.

Beta Thalassemia Minor Clinical Findings

The patient's history reveals no symptoms. Splenomegaly is present in many patients.

Laboratory findings include: (a) Anemia with more microcytosis than anemia (MCV reduced more than hemoglobin on Coulter indices); (b) red cell count is frequently increased, and the reticulocyte count may be increased; (c) a blood smear reveals target cells and basophilic stippling; and (d) hemoglobin electrophoresis shows hemoglobin A, increased A2, and normal or increased F.

Alpha Thalassemia

The highest incidence is found in peoples from Southeast Asia, Africa, and the Mediterranean area. As two loci exist for the alpha gene, four genes control alpha globin synthesis. The inheritance or absence of one to all four of these genes explains the observed clinical syndromes.

In homozygous alpha thalassemia-hydrops fetalis, there are no alpha globin chains produced and only hemoglobin Barts (h4) is made. It results from absence of all 4 alpha genes, is fatal in utero at 34 to 40 weeks, and is extremely rare in African Americans. In hemoglobin H disease there is elevated hemoglobin Barts (h4) at birth and hemoglobin H (g4) in later life. The clinical pattern is variable and severe cases resemble beta thalassemia major. Laboratory data reveal microcytic hypochromic anemia with increased reticulocytes. The hemoglobin electrophoresis shows 4% to 30% hemoglobin H, 70% to 90% hemoglobin A, and variable small amounts of hemoglobin Barts. It represents deletion of three of the four alpha genes and is very rare in African Americans. In alpha thalassemia minor, the anemia is mild or absent, but microcytosis is usual. This disorder may be diagnosed by small amounts of hemoglobin H in adults or by 4% to 15% hemoglobin Barts in a newborn. It results from the loss of two of the four genes. It occurs in 2% of African Americans and has a higher incidence in Southeast Asian Americans. Silent carriers (one gene deletion) are hematologically normal and only detected by family studies or by the presence of 1% to 4% hemoglobin Barts at birth.

Clinical Management

The accurate diagnosis and family studies are important to prevent numerous unnecessary diagnostic and therapeutic manipulations. Chronic iron administration is contraindicated because iron absorption is increased and iron overload usually is a problem. In patients with beta thalassemia major and severe alpha thalassemias, splenectomy may be helpful in decreasing transfusion frequency in transfusion dependent patients. Hypertransfusion accompanied by iron chelation with deferoxamine improves the prognosis in beta thalassemia major. Bone marrow transplantation has been established as curative therapy in children.

Normocytic Anemia

In normocytic anemias the mean corpuscular volume ranges between 80 and 94 and normochromic-normocytic cells are seen in the peripheral blood smear.

Causes

Acute Blood Loss

Acute bleeding may present with a decreased hemoglobin without an increased reticulocyte count. The initial evaluation of any anemia excludes blood loss as its etiology.

Expanded Plasma Volume

Increased plasma volume and a normal red cell mass may cause "factitious" anemia. The physiologic anemia of pregnancy is caused by a 40% expansion of plasma volume, beginning after week 6 to 8 of pregnancy, reaching a maximum by 24 weeks. It is also seen with cardiac or renal failure, overhydration, and after prolonged bedrest, especially if edema is present.

Aplastic Anemia

Pancytopenia with a marked decrease in the cellularity of bone marrow is characteristic. In pure red cell aplasia (and aplastic crisis in patients with hemolytic anemia), erythroid precursors alone may be absent from the marrow. The etiologies of aplastic anemia are idiopathic, secondary to drugs, chemicals, radiation, viral infections (eg, hepatitis), or the immune destruction or suppression of stem cells. Diagnosis is based on a bone marrow biopsy that shows marked reduction found in erythroid, myeloid, and megakaryocytic elements in a patient with pancytopenia. Aplastic anemia following hepatitis and severe aplasia presenting with a reticulocyte count of <0.6, a granulocyte count <500/mm3, platelets <20,000/mm3, and hypocellular marrow with more than 70% nonmyeloid cells, is associated with a median survival of <6 months from the time of diagnosis.

Therapy includes looking for and withdrawing drugs that may be incriminated. Early bone marrow transplantation with HLA-compatible, related donors is recommended for young patients in the poor prognostic group. Best results are obtained if patients have had no prior transfusions. Antithymocyte globulin with or without cyclosporin is effective in older patients and in those without marrow donors.

Pure red cell aplasia can present as a congenital problem (Diamond Blackfan syndrome) or as an acquired disorder (associated with a thymoma in 30% to 50%). Only anemia is present and the bone marrow shows severe erythroid hypoplasia. Red cell aplasia in patients with hemolytic anemia or immunodeficiency is caused by parvovirus B19.

 

Table 5.
Summary of Findings in Hypochromic, Microcytic Anemias
 

Iron Deficiency

Chronic Inflammation

Sideroblastic Anemia

Thalassemia

Red cells

Microcytic hypochromic

Normocytic microcytic

Dimorphic, basophilic stippling

Microcytic hypochromic target cells, basophilic, stippling

Serum iron

Decreased

Decreased

Increased

Normal or increased

TIBC

Increased

Decreased

Normal

Normal

Transferrin saturation (%)

<16

10-20

50-100

30-100

Serum ferritin

Decreased

Increased

Increased

Increased

Bone marrow storage iron

Absent

Increased

Increased

Normal or increased

Bone marrow sideroblasts

Absent

Decreased or absent

Increased with "ring" sideroblasts

Increased

Myelophthisic Anemia

Myelophthisic anemia is caused by infiltration and replacement of the marrow by tumor, granulomatous process, or fibrosis. Blood smears reveal a leukoerythroblastotic reaction and teardrop-shaped red cells. Diagnosis requires a bone marrow biopsy. Treatment involves controlling the infiltrating process and supportive measures.

Endocrine Disorders

Hypothyroidism causes a mild normochromic, normocytic anemia and is probably caused by decreased tissue oxygen requirements and is corrected by administering thyroid hormone. Adrenal corticosteroid deficiency causes a mild anemia that responds to replacement therapy. Gonadal dysfunction in males causes anemia. Androgens increase the production of erythropoietin and enhance its effect on bone marrow. In males, gonadal dysfunction may result in hemoglobin levels equal to female normal values.

Chronic Renal Disease

Progressive anemia occurs in proportion to the degree of renal insufficiency. Etiologic factors in the anemia are relative erythropoietin deficiency from kidney dysfunction, shortened red cell survival by unknown mechanisms, increased blood loss secondary to platelet dysfunction, iron deficiency from increased bleeding, and folic acid deficiency in dialyzed patients. The anemia is relatively well tolerated because tissue oxygen delivery is increased by metabolic acidosis and increased erythrocyte 2,3-DPG secondary to a high plasma phosphate. Transfusion support may be necessary but administration of erythropoietin usually controls the anemia. Iron or folic acid may benefit selected patients.

Anemia in AIDS

AIDS is commonly associated with anemia. The anemia is most commonly normocytic unless there is deficiency of iron, folic acid, B12, or complications of therapy. Severe, persistent red cell aplasia is seen secondary to infection by parvovirus. The etiology of the anemia is complex and factors may include toxicity from therapy, relative erythropoietin deficiency, anemia of chronic inflammation, effects of the virus on stem cell function, and marrow infiltration by infectious or neoplastic disease.

Chronic Inflammation

The anemia is normochromic-normocytic in two-thirds of patients and microcytic in the rest. (See Microcytic Anemias.)

Macrocytic Anemias

Macrocytosis without megaloblastic changes (impaired nuclear maturation) may occur with high reticulocyte counts, liver disease, obstructive jaundice, and after splenectomy. True megaloblastic anemia results from impaired DNA synthesis, causing abnormal nuclear maturation in erythrocyte precursors, white cells, and megakaryocytes.

Causes of megaloblastic anemia include vitamin B12 deficiency, folic acid deficiency, drug-induced inhibition of DNA synthesis, inherited disorders of DNA synthesis, erythroleukemia.

Hematologic Manifestations

Peripheral blood changes include reticulocytopenia with increased MCV and macro-ovalocytes, neutropenia with hypersegmented PMNs, and thrombocytopenia with large platelets. In the bone marrow, red cell precursors are large, with immature nuclei when compared to cytoplasm. In myeloid precursors, the nuclear-cytoplasmic asynergy is reflected by giant bands, giant metamyelocytes, and hypersegmentation. The bone marrow is hypercellular, without adequate production of mature cells (ineffective erythropoiesis). Other manifestations of ineffective erythropoiesis include elevated serum LDH, increased indirect bilirubin, high serum iron, increased disappearance of radiolabeled iron from plasma, but decreased incorporation into circulating red cells, increased urobilinogen excretion, and high serum and urine lysozyme secondary to the death of white cell precursors in the marrow.

Biochemical Roles and Interactions of Folate and Vitamin B12

Folic acid is required for purine synthesis, pyrimidine synthesis, conversion of homocystine to methionine, conversion of serine and glycine, and degradation of histidine. Vitamin B12 is required for oxidation of propionate to succinyl CoA and conversion of homocystine to methionine. In folate deficiency, the abnormal synthesis of DNA may be the result of depressed pyrimidine synthesis. Increased excretion of formiminoglutamate (FIGLu) in urine results from the abnormal degradation of histidine.

In B12 deficiency, the excretion of methylmalonate is increased because the production of succinyl CoA is inhibited. Abnormal DNA synthesis may be due to the decreased synthesis of methionine because N-methyl tetrahydrofolate is trapped in a storage form and unavailable for pyrimidine synthesis and also because the cellular uptake of folate requires B12.

Clinical Syndromes-Vitamin B12 Deficiency

Symptoms and Signs

These include weakness, fatigue, dyspnea, edema, pallor, jaundice (indirect hyperbilirubinemia), paresthesias, numbness, and decreased vibratory and position sense. A neurologic syndrome of subacute combined degeneration caused by B12 deficiency may be seen without anemia and may progress (occasionally acutely) if the B12 deficiency is treated with folate.

Causes

Causes include inadequate ingestion, malabsorption, and impaired transport.

Clinical Syndromes-Folate Deficiency

Signs and Symptoms

Folate deficiency is usually found in individuals with poor dietary habits and is frequently associated with chronic alcohol abuse. Thus many patients show signs of chronic liver disease. Atrophic tongue is frequent. Subacute combined degeneration is not seen; however, neurologic syndromes, secondary to associated alcoholism may be present.

Causes

Causes of folic acid deficiency included inadequate diet, increased vitamin requirements, impaired absorption or defective folate metabolism.

Inadequate diet with a diet deficient in folic acid is a frequent cause of folate deficiency. The minimum daily requirement for folate is 50 qg; the average diet contains 700 qg, of which only 10% is absorbed. The diet must contain fresh vegetables, fruits, or meats. Cooking style may contribute because prolonged heating destroys folate. Body stores comprise only 5 to 10 mg of the vitamin, one third of which is found in the liver. Consequently, folate deficiency is most frequently caused by dietary deficiency.

Increased requirements for folate are also a common cause. Requirements for folate may be increased three- to five-fold in patients with chronic hemolytic anemia, pregnancy, chronic exfoliative dermatitis, chronic infections, or peritoneal dialysis.

Impaired absorption may cause folate deficiency. Folate absorption may be impaired in patients with small bowel disease or resection, who lack the enzymes required to deconjugate (ie, reduce) the plant and animal form of folic acid (ie, pteroglutamic acid) to the dihydro- and tetrahydrofolates required for transport and absorption. Drugs such as diphenylhydantoins, estrogens, and oral contraceptives, may inhibit the deconjugation of pteroglutamic acid. Congenital absence of the enzymes required for deconjugation is a rare cause.

Defective folate metabolism results in deficient interconversion: The activity of folic acid depends on its conversion to tetrahydrofolic acid and to certain one-carbon methylated derivatives. This conversion is inhibited by liver disease, vitamin B12 deficiency, and drugs such as methotrexate, ethanol, and diphenylhydantoin.

Other Clinical Syndromes

Inherited disorders of DNA synthesis are rare causes of megaloblastic anemias that are unresponsive to B12 or folate. In addition, many drugs used in cancer chemotherapy induce megaloblastic anemia secondary to inhibition of DNA synthesis.

Clinical Approach

An accurate differentiation between B12 deficiency and folate deficiency is required because treatment with the wrong vitamin may mask the true deficiency. Measurements of serum B12, serum folate, and red cell folate are indicated. Interpretation of levels may not be easy. Serum folate levels return to normal very rapidly, if a folate deficient patient begins eating a normal diet; however, folate levels in red cells will continue to be depressed for 7 to 10 days. In B12 deficiency, red cell folate levels may be low and serum folate levels high because cellular uptake of folate required B12.

Gastric analysis documenting histamine-fast achlorhydria will help support the diagnosis of pernicious anemia. Gastrin levels may be high because of the atrophic gastritis. Studies of B12 absorption, with and without intrinsic factor, will document pernicious anemia and detect other forms of malabsorption. Autoantibodies (such as antiparietal cell, antithyroid, and others) are common in pernicious anemia, but are not specific. Anti-intrinsic factor antibodies are specific, but only occur in about half of the patients with pernicious anemia. Therapeutic trials in which physiologic amounts of vitamin B12, 1 to 5 qg IM QD, are administered and patients observed for a reticulocyte response after five to seven days of treatment can confirm B12 deficiency.

Treatment

Once the diagnosis has been established, treatment should be started and a complete hematologic remission documented. For folate deficiency, 1 mg PO QD of folic acid is sufficient if malabsorption is not present. Repletion of B12 requires frequent initial doses of cyanocobalamin, 100 qg IM QD for 2 weeks, to replace exhausted stores, then 100 qg every month for life.

Hemolytic Anemias

General Considerations

Hemolytic anemias result from the increased destruction of circulating erythrocytes. Normal red cell survival in the circulation is 120 days. Therefore, 1% of the circulating red cell mass must be replaced every day. When red cell survival is shortened, bone marrow can compensate by increasing its red cell production six- to tenfold. Tests useful in determining if hemolysis is present are shown in Table 6.  

Table 6.
Laboratory Tests Useful in Establishing the Presence of a Hemolytic Anemia
  • Sustained, elevated reticulocyte count without an increase in hemoglobin.
  • Erythroid hyperplasia in bone marrow.
  • Elevated levels of indirect bilirubin secondary to the increased catabolism of hemoglobin.
  • Elevated lactate dehydrogenase levels are due to the increased destruction of red cells.
  • Hemoglobinuria and hemoglobinemia are specific, but uncommon.
  • Decrease in, or absence of serum haptoglobins.
  • With chronic intravascular hemolysis, hemosiderin may appear in urine.
  • Red cell survival with 51Cr-labeled erythrocytes is reduced.

General Classification of Hemolytic Anemias

Once hemolysis is established, the cause is determined using the clinical history, Coombs' test and red cell morphology on blood smear. The history determines whether the hemolytic anemia is congenital or acquired. Acquired hemolytic anemias usually result from an abnormal erythrocyte environment that shortens the cell's survival. These anemias can also be considered extrinsic because the erythrocyte is normal, unless acted on by its environment. One of several exceptions is paroxysmal nocturnal hemoglobinuria, an acquired disorder in which the erythrocyte is intrinsically abnormal. Congenital hemolytic anemias result from inherited abnormalities of erythrocyte hemoglobin, membrane, or enzymes.

Acquired Hemolytic Anemias

Acquired hemolytic anemias result from acquired abnormalities of the erythrocyte environment that shorten the red cell's survival by non-immunologic mechanisms or by immune hemolysis (Coombs'-positive hemolytic anemias).

Non-immune Environmental Abnormalities

Hypersplenism

Diseases that cause splenomegaly, such as portal hypertension, infection, infiltration, or collagen vascular disorders, accelerate red cell destruction. Hypersplenism usually causes pancytopenia with a hypercellular bone marrow. Diagnosis is based on the demonstrated presence of an enlarged spleen, red cell sequestration in the spleen, and the absence of other conditions that shorten red-cell survival. Treatment is directed at the underlying disease. Splenectomy, if medically warranted, is curative.

Microangiopathic Hemolytic Anemias

These anemias are caused by mechanical disruption of erythrocytes within abnormal small or large blood vessels. The abnormality could be prosthetic heart valves, severe valvular disease, arterial and cardiac patches, or severe coarctation of the aorta; disseminated intravascular coagulation; hemolytic uremic syndrome or thrombotic thrombocytopenic purpura; small vessel vasculitides (eg, graft rejection, immune complex disease); malignant hypertension and eclampsia; hemangiomas; and disseminated carcinoma. A blood smear shows fragmented red cells. Hemolysis is intravascular, so hemosiderin may be present in urine. Chronic iron loss through the kidneys may cause iron deficiency. Folic acid and iron may be required for chronic cases.  

Table 7.
Causes of Acquired Hemolytic Anemias Secondary to Nonimmune Environmental Abnormalities
  • Hypersplenism
  • Microangiopathic
  • Chemical agents
  • Physical agents
  • Lipid abnormalities
  • Infectious agents
Chemical Agents

An infusion of intravenous water or drowning in fresh water results in the osmotic hemolysis of erythrocytes. Exposure to arsine gas results in acute hemolysis.

Physical Agents

Damage to the red-cell membrane occurs with extensive third-degree burns. Radiation may cause hemolysis in rare cases.

Lipid Abnormalities

Abetalipoproteinemia is associated with changes in membrane lipids, which result in the formation of acanthocytes and hemolysis. Spur-cell hemolytic anemia of severe liver disease also results from similar lipid changes in the erythrocyte membrane.

Infectious Agents

Intraerythrocytic parasites, such as malaria and babesiosis, lyse erythrocytes as they emerge from them. Clostridium welchii septicemia is associated with severe hemolysis, induced by the liberation of lecithinase, which attacks membrane lipids.

Paroxysmal Nocturnal Hemoglobinuria

This is an acquired disorder where the erythrocyte is intrinsically abnormal. Acquired complete or partial deficiency of glycosyl-phosphatidylinositol linked proteins causes the erythrocyte to be exquisitely sensitive to hemolysis by complement. White cells and platelets share the deficiency. Clinical manifestations include episodic intravascular hemolysis with hemoglobinuria frequently occurring at night, increased susceptibility to infection, and recurrent thrombotic episodes. The diagnosis is based on the presence of a positive sucrose and acid hemolysis test. Iron deficiency may be present secondary to the chronic loss of iron in the urine.

Immune Hemolytic Anemias

Immune hemolytic anemias result when antibodies are directed against a component of the erythrocyte membrane, or when drugs interact with the red cell. The direct Coombs' (antiglobulin) reaction is used to detect the presence of immunoglobulin or complement on the red-cell membrane and to determine the specific class of immunoglobulin or complement present. For this test, red cells are washed to remove nonspecific adherent globulins. Rabbit antiserum to human gamma globulin and complement are then added to the washed cells. The rabbit antibody causes agglutination results when antibody or complement is bound to the red cell. Specific antisera to IgG or complement can be used to determine which of these substances is present on the red cell. The antibody can also be eluted from the patient's red cells and used to determine the antigenic specificity of the immunoglobulin.

The immune hemolytic anemias can be divided into isoimmune, autoimmune, and drug-induced anemias.

Immune Hemolysis Due to Alloantibodies

Transfusion reactions are caused when antibodies formed in the patient's plasma are formed against antigens that are not present on the patient's red cells (eg, ABO, Rh, and other blood groups). Acute hemolysis results when erythrocytes are administered to an individual whose plasma contains antibodies against antigens present on the transfused cells. Delayed transfusion reactions occur when antibody is formed 7 to 14 days after exposure to antigens on the transfused cells. Infusion of large amounts of plasma may cause hemolysis if transfused plasma contains antibody to antigens on the recipient's erythrocytes. Antibodies to the major blood group antigens (A and B) develop naturally. Rh and other minor blood group antigens generally require prior exposure to antigen-containing red cells before antibodies develop. The indirect Coombs' is often positive, and the eluate antibody shows blood group specificity.

Erythroblastosis fetalis occurs when IgG antibody from the mother crosses the placenta. The antibody formed by the mother is directed against Rh-positive fetal cells. This occurs when the mother is Rh-negative and has been sensitized by previous exposure to Rh-positive blood, either by a previous pregnancy or a transfusion. Most (93%) are related to Rh(D) antibodies. Erythroblastosis fetalis can be prevented by administering RhoGam (IgM anti-Rh gamma globulin) to nonimmunized Rh-negative women who are at risk, whether the pregnancy terminates by abortion or delivery. Rh-negative women of childbearing age should not be transfused with Rh-positive blood.

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemias are caused by autoantibodies directed against components of the red cell membrane. The pattern of red cell destruction in autoimmune hemolytic anemia is determined by the characteristics and quantity of autoantibody produced. Immunoglobulin G (IgG) autoantibodies are generally inefficient at fixing complement to the erythrocyte (usually only to C3 or C4) and are warm reacting. Immune hemolysis, caused by this class of immunoglobulins, usually results from phagocytosis in reticuloendothelial organs, primarily spleen, liver, and bone marrow. Immunoglobulin M (IgM) autoantibodies efficiently bind complement, agglutinate red cells, and react in the cold. Hemolysis caused by IgM antibodies occurs primarily in the liver. Efficient complement binding and agglutination may also cause intravascular hemolysis with hemoglobinemia and hemoglobinuria. The IgM antibody attaches in the peripheral circulation (fingers, toes, nose, and ears) and binds early complement components. It dissociates when it returns to the central circulation and later complement components may be bound.

Table 8.
Pathophysiology in Immune Hemolysis
Type Immunoglobulin Properties Coombs' Test Mechanism Of Red Cell Destruction
Warm antibody IgG Active at 37C; nonagglutinating; fix complement Positive for IgG or IgG and complement Destroyed primarily in the spleen; intravascular hemolysis is rare
Cold antibody IgM Active at 4C; agglutinating; fix complement Positive for complement only Hemolysis mainly in the liver; may cause intravascular hemolysis
Diagnosis of Immune Hemolysis Due to IgG Warm Antibodies

Laboratory findings of hemolysis are present. The blood smear may show spherocytes and polychromatophilic erythrocytes. Diagnosis is based on a positive direct Coombs' (antiglobulin) reaction for IgG or IgG and complement. The eluate usually reacts with all red cells in the panel (nonspecific).

Treatment of Immune Hemolysis Due to IgG Warm Antibodies

High-dose steroids are an effective initial treatment in most patients. Complete remission occurs in 20% and persists after steroids are withdrawn. Continued low doses of steroids are required by 50% of the patients. Of the remaining, 15% to 20% require high-dose steroids, or will not respond. If steroids prove ineffective or high doses are required to maintain remission, splenectomy should be undertaken if the patient is a candidate for surgery. Complete or partial remission occurs in approximately 50% of these patients after splenectomy. Treatment with immunosuppressive therapy, vincristine, Danazol, or IV gamma globulin may be considered for those in whom splenectomy was unsuccessful or who are not surgical candidates. Treatment of the underlying disease may induce a remission in the hemolysis.  

Table 9.
Diseases Associated with Warm Antibody Hemolytic Anemia
Associated Diseases

Idiopathic (18%)

Secondary (83%)

  • CLL (21%)
  • Lymphoma (11%)
  • Myeloma (4%)
  • Other malignancy (9%)
  • Collagen vascular (15%)
  • Infectious disease (33%)
  • Thyroid disease (11%)
  • GI diseases (12%)
  • Benign cysts and tumors (7%)
Modified after Pirofsky B: Clinical aspects of autoimmune hemolytic anemia. Semin Hematol 1976;13:251-265. Reprinted with permission.
Etiology of Immune Hemolysis Due to IgM, Cold-Reacting Antibodies

The causes of immune hemolysis due to IgM are: (a) Mycoplasma infections and viral infections; (b) lymphoproliferative disease; (c) paroxysmal cold hemoglobinuria (IgG cold antibody, eg, Donath-Landsteiner antibody), syphilis, and viral infections; or (d) chronic-idiopathic.

Immune hemolysis due to IgM, cold-reacting antibodies has the signs and symptoms of hemolytic anemia. Hemoglobinuria and hemoglobinemia are common. The patient may exhibit Raynaud's phenomenon secondary to occlusion of small vessels by aggregates of erythrocytes. The Coombs' test is positive for complement. High-titer cold agglutinins usually are present.

Acute immune hemolysis due to IgM, cold-reacting antibodies is self-limited if the underlying disease can be cured and requires support only. Steroids and splenectomy are of little or no benefit. Support includes keeping the patient warm, forcing fluids, and transfusion only if absolutely necessary. The underlying disease should be treated when possible. Cytotoxic therapy may benefit cases of chronic idiopathic disease.

Drug-Induced Immune Hemolysis

These anemias occur by one of three mechanisms: hapten type, innocent bystander mechanism, and the induction of autoimmune hemolysis (Aldomet type). All respond to stopping the drug. With the Aldomet (methyldopa) type, responses may be delayed.

In the hapten or penicillin type, the drug inserts into the erythrocyte membrane and antibody against the drug attaches (IgG). This is seen when high doses of penicillins or cephalosporins are administered intravenously.

The innocent bystander mechanism occurs when antibody in plasma forms an immune complex with the drug and the complex passively adheres to the erythrocyte membrane. The immune complex causes complement to bind to the red cell. The complement Coombs' is positive. Sulfonamides, quinidine, chlorpromazine, isonicotine hydrazide, and a long list of other drugs cause immune hemolysis through this mechanism.

Aldomet (methyldopa) causes antibody to be formed that is directed against the red cell membrane and not the drug. A positive direct Coombs' test occurs in 15% of patients on long-term, high dosage Aldomet therapy, but only 1% develop hemolytic anemia. Other drugs that cause hemolysis by this mechanism include L-Dopa, mefenamic acid, ibuprofen, procainamide, and thioridazine. The hemolysis may persist for weeks to months after the drug is withdrawn. Treatment with steroids may occasionally be required.

Congenital Hemolytic Anemias-Intrinsic Erythrocyte Abnormalities

This group of disorders is caused by an inherited abnormality in the red-cell membrane, hemoglobin, or metabolism that shortens the life span of red cells (Table 10).

Table 10.
Congenital Hemolytic Anemias

Secondary to Membrane Abnormalities

  • Hereditary spherocytosis
  • Hereditary elliptocytosis

Secondary to Abnormal Hemoglobin (Hemoglobinopathies)

  • Sickle cell anemia
  • Hemoglobin C and SC disease
  • Congenital Heinz body hemolytic anemias
  • Thalassemia

Secondary to Disturbed Metabolism (Enzymopathies)

  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Glycolytic pathway enzyme deficiency (pyruvate kinase, hexokinase)

Hemolysis, in general, results when erythrocytes are trapped in the spleen, liver, and microvasculature because volume-surface relationships (sphere formation) or when red cells have altered and decreased deformability. Damage to the red cell membrane surface may also lead to phagocytosis in the reticuloendothelial system. The decreased deformability of the red cells may also lead to their entrapment in the capillaries of many tissues, causing obstruction with ischemic symptoms (ie, pain crisis in sickle cell anemia, skin ulcers in sickle cell anemia, and hereditary spherocytosis). Intravascular hemolysis may also occur.

Membrane Abnormalities

Hereditary Spherocytosis
Genetics and Pathophysiology

Inheritance is usually autosomal dominant but may be recessive. Hereditary spherocytosis is the most common congenital hemolytic anemia in whites. A membrane protein abnormality causes quantitative reduction in spectrin leading to the spherical shape, membrane budding, and increased permeability to sodium. Hemolysis occurs almost exclusively in the spleen.  

Clinical Findings

Symptoms and signs suggest compensated hemolytic anemia with mildly to severely decreased hemoglobin and sustained reticulocytosis. Intermittent jaundice and premature pigment gallstones are common. Splenomegaly is characteristic (palpable in 75% to 80% of cases). Aplastic crisis (transient depression of the bone marrow with rapid fall in hemoglobin) may occur as a complication of viral illness or folate deficiency. Occasionally, skin ulcers may develop over the ankles.

Diagnosis

A blood smear shows numerous spheres. Mean corpuscular volume is decreased; the mean cell hemoglobin concentration (MCHC) is increased. The Coombs' test is negative. The diagnosis is based on finding an osmotic fragility test which demonstrates increased hemolysis when the red cells are placed in hypotonic saline. Hemolysis is greatly increased if the cells are first incubated without glucose at body temperature for 24 hours (Figure 2).

Treatment

Splenectomy is usually "curative," with the hemoglobin and the reticulocyte count return to normal. The postsplenectomy period has been associated with overwhelming pneumococcal sepsis. Therefore polyvalent pneumococcal vaccine should be given before surgery.

Figure 2.
An Osmotic Fragility Test
Hereditary Elliptocytosis

This disorder is a milder form of membrane abnormality in which numerous elliptocytes are seen in blood smear. Usually, the patient is only mildly anemic and may have only a slightly elevated reticulocyte count. Splenectomy, if necessary, is curative.

Hemoglobinopathies

Inheritance is autosomal. Amino acid substitution in the globin chain results in solubility changes characteristic of the hemoglobin protein. As a result, hemoglobin molecules have a propensity to polymerize or precipitate, causing gross distortions in the shape of red cells, decreased deformability and filterability of the cells, and membrane damage. The cells lose their membranes and stiffen, shortening red cell survival and causing vascular occlusions in the microcirculation.

Most common hemoglobinopathies (hemoglobin S and C) occur with high frequency in peoples from Central Africa, probably because they offer a degree of protection against severe malaria infection.

Sickle Cell Disease (Hemoglobin SS Disease)

Sickle cell disease occurs in 1 in 400 American blacks. Homozygous state for substitution of valine for glutamic acid in the sixth position of the beta-chain of hemoglobin. With deoxygenation, this substitution allows weak bonds to form between hemoglobin molecules. The bonds lead to formation of crystallization of the hemoglobin, grossly distorting and decreasing deformability of the erythrocytes.

Clinical Findings

Clinical findings in sickle cell disease (see Clinical syndromes.) include persistent anemia (hemoglobin 7 to 11 g/dL) with elevated reticulocyte count. The blood smear shows irreversibly sickled cells, target cells, nucleated red cells and Howell-Jolly bodies. Hemoglobin electrophoresis or isoelectric focusing detects hemoglobin S because the change in the net charge of the protein.

Clinical Syndromes

Sickle cell pain episodes, vaso-occlusive or painful crisis, are thought to result from microinfarctions throughout the body. It is characterized by the sudden onset of joint, musculoskeletal, and abdominal pain without specific physical or laboratory findings. Episodes may be precipitated by hypoxia, infection, dehydration, fatigue, or emotional stress. An aplastic crisis occurs secondary to bone marrow suppression, usually by parvovirus infection or folate deficiency. It is characterized by a rapidly falling hemoglobin level with a decreased reticulocyte count. Hyperhemolytic or sequestration crisis results in rapidly falling hemoglobin levels with a high reticulocyte count and rapidly enlarging spleen or liver. It occurs in children with SS and adults with SC disease, especially during pregnancy.

Complications

Retarded growth and development with delayed puberty. Asplenism and hyposplenism are secondary to repeated splenic infarctions. Individuals become susceptible to overwhelming pneumococcal sepsis and other infections. Other frequent complications include recurrent infections of lungs, bones, and genitourinary tract; pulmonary infarctions; dyspnea on exertion; cardiac flow murmurs; S3 and S4; cardiac hypertrophy secondary to anemia; hematuria; renal papillary necrosis; and loss of renal concentrating ability; priapism; premature gallstones; hepatic fibrosis; avascular necrosis of the femur and humerus; cerebral vascular accidents (CVAs); seizures; visual disturbances; decreased fertility; increased fetal wastage; and maternal morbidity with pregnancy.

Prognosis

With applications of screening to large populations, it is becoming apparent that large numbers of patients are relatively asymptomatic or minimally symptomatic and may live into the fourth, fifth, sixth, and seventh decades of life. Median survival in modern series is about 45.

Treatment

No specific therapy exists. Good health care-stressing nutrition, vaccination, and early treatment of infections-appears to increase life expectancy. Folic acid should be administered to most. Polyvalent pneumococcal vaccine should be given; however, there are increasing reports of failure in protection, especially in children. Hydration, analgesia, and treatment of the precipitating causes are the only effective treatments for pain crisis. Hydroxyurea decreased frequency of pain episodes, need for transfusion, and episodes of acute chest syndrome. In children, hypertransfusion improves the prognosis after neurologic complications. Chronic hypertransfusion might be considered in patients with severe disease.

Hemoglobin SC Disease

Hemoglobin C has a substitution of lysine for glutamic acid in the sixth position of the beta-chain. SC disease results from the inheritance of the S gene from one parent and the C gene from the other. It occurs in about 1 in 800 births among American blacks.

Symptoms are similar to SS disease except the anemia is usually milder. It differs from SS disease in that splenomegaly is more frequent, more retinal and ocular problems develop, and a higher morbidity is seen with pregnancy. The hemoglobin level is usually somewhat higher. The blood smear shows more target cells and the presence of hemoglobin C crystals. The diagnosis is made by hemoglobin electrophoresis.

Sickle Cell Trait (Hemoglobin AS)

It occurs in about 10% of American blacks and is not a cause of anemia or reticulocytosis. Patients are asymptomatic. A renal concentrating defect is frequent, and hematuria occurs occasionally. Crisis and splenic infarction have been reported at extreme altitude or with severe hypoxia.

Homozygous Hemoglobin C Disease (Hemoglobin CC)

It causes a mild anemia with an elevated reticulocyte count. Numerous target cells are present on smear. Hemoglobin Crystals can be demonstrated especially if the erythrocytes are first partially dehydrated in hypertonic buffer. The diagnosis is established by hemoglobin electrophoresis.

Congenital Heinz Body Hemolytic Anemias

They constitute a group of rare inherited hemolytic anemias caused by amino acid substitutions that make the hemoglobin unstable. The hemoglobin precipitates with Heinz body formation. They can cause mild to severe hemolytic anemias. The diagnosis is established by staining for Heinz bodies, demonstrating hemoglobin instability, and performing a hemoglobin electrophoresis.

Enzyme Deficiencies (Congenital Nonspherocytic Hemolytic Anemia)

The erythrocyte is especially vulnerable to shortened survival secondary to enzyme deficiencies. Unlike other tissues, the mature erythrocyte cannot increase protein synthesis to maintain enzyme activity. Enzyme deficiencies occur when amino acid substitutions result in a poorly functioning enzyme (ie, decreased Vmax, decreased affinity for substrate); instability, so enzyme activity decreases rapidly as the erythrocyte ages; combinations of the first two abnormalities.

Two major metabolic pathways exist in the erythrocyte. Glucose is utilized to generate ATP, NADH, and NADPH. ATP is used to meet energy requirements and NADH to reduce methemoglobin. The NADPH is utilized to reduce oxidized glutathione which, in turn, is required to maintain protein sulfhydryl groups in a reduced state and to detoxify hydrogen peroxide. Numerous enzyme deficiencies have been described that interrupt either pathway and may result in hemolytic anemia.

G6PD Deficiency
Genetics, Biochemistry, and Pathophysiology

The inheritance of glucose-6-phosphate dehydrogenase (G6PD) deficiency is sex-linked. G6PD deficiency occurs in high frequency in African Americans. Approximately 11% of males are hemizygous and females are heterozygous for the African (A-) variant. The Mediterranean variant occurs in high frequency in Italian, Sardinian, and Greek populations. Over 150 different G6PD variants have been described, with activities ranging from mildly to severely deficient.

Deficiency of G6PD results in sensitivity of erythrocytes to oxidant-induced hemolysis. Exposure of deficient erythrocytes to oxidants results in Heinz body formation by precipitation of oxidized hemoglobin. The presence of Heinz bodies causes decreased deformability of the erythrocyte with trapping and destruction in the spleen, reticuloendothelial system, and in small blood vessels. In A- G6PD deficiency, the enzyme is unstable, so enzyme activity is normal in young erythrocytes. In the Mediterranean variant, the enzyme is both unstable and has decreased activity, so enzyme activity is low even in young cells.

Clinical Syndromes

Drug-induced hemolytic anemia occurs in patients with G6PD deficiency after exposure to certain oxidant drugs. Drugs that cause hemolysis in G6PD deficiency include analgesics (acetanilid, phenacetin, aspirin); sulfonamides and sulfones; antimalarials (primaquine, pamaquine, quinine); nonsulfonamide antibiotics (nitrofurantoin, furazolidone, para-aminosalicylic acid); miscellaneous (naphthalene, aniline, phenylhydrazine, quinidine, aqueous vitamin K, probenecid).

Depending on the drug exposed to and the type of enzyme deficiency, hemolysis may be mild or explosive. With the A- variant, the acute hemolytic episode is self-limited because the reticulocytes have normal enzyme activity.

Favism, a severe hemolytic anemia induced by exposure to the fava bean or pollen from the fava plant, occurs in persons with the Mediterranean variant. Not all families are affected, suggesting that a second genetic predisposition may be necessary.

Congenital nonspherocytic hemolytic anemia-Some rare variants of G6PD deficiency are so severe that hemolysis is constant. In these individuals, hemolysis will be aggravated by drugs and other factors that cause hemolysis in its milder forms.

Other factors that cause hemolysis are viral infection, especially influenza and hepatitis, which may cause hemolysis in G6PD deficiency. Diabetic ketoacidosis may precipitate hemolytic episodes.

Diagnosis

Suspect hemolytic anemia if it occurs after the administration of a drug in the presence of a negative Coombs' test. G6PD assays may be normal after the acute hemolytic episode in the A- variant. During hemolysis, Heinz bodies can usually be demonstrated.

Laboratory Tests

The presence of Heinz bodies, with and without incubation with oxidants, is used for screening. Specific tests based on nicotinamide adenine nucleotide phosphate (NADPH) generation include the spot test, based on the fluorescence of NADPH generated in normal but not deficient erythrocytes; methemoglobin reduction in the presence of methylene blue (NADPH requiring); and assay of enzyme activity, electrophoresis, and diagnosis using DNA based techniques.

Abnormalities of the Embden-Meyerhof (EM) Pathway

These rare disorders cause nonspherocytic hemolytic anemia. Hemolysis probably results from the decreased generation of adenosine triphosphate (ATP). Pyruvate kinase deficiency is most common in this group, but is still rare. Splenectomy may give a partial remission. Hexokinase deficiency involves the first enzyme of either the Embden-Meyerhof or pentose pathway. This deficiency causes severe hemolytic anemia.

Polycythemia

Definitions

Erythrocytosis can be defined as a rise in the hematocrit level measured electronically to above 50 mL/100 mL in women and 55 mL/100 mL in men or to above 48 mL/100 mL in women and 51 mL/100 mL in men when measured by packed red cell volume. Relative erythrocytosis refers to rises in the hematocrit that result when plasma volume falls but the red cell mass remains normal. Absolute erythrocytosis refers to true increases in the red cell mass.

Relative Erythrocytosis

In this situation, hematocrit rises when plasma volume contracts. This can occur acutely, secondary to fluid and plasma losses as seen with vomiting, severe diarrhea, fever, diabetic ketoacidosis, or burns. The hematocrit returns to normal after fluids are administered. A chronic form also occurs and has been termed "stress" erythrocytosis, Gaisbock's syndrome, and spurious polycythemia.

Diagnosis

The initial approach to patients with an elevated hematocrit includes evaluation and correcting the fluid or plasma loss. (Schema presented in Figure 3.) If the elevated hematocrit persists, red cell mass and plasma volume should be determined to find out whether a relative or true erythrocytosis is present. A red cell mass of <36 ml/kg in the male and <32 ml/kg in the female suggest spurious erythrocytosis. Spurious polycythemia can be divided into two groups: (a) secondary to a high normal red cell mass and a low normal plasma volume almost always associated with increased carboxyhemoglobin levels from smoking and (b) secondary to a low plasma volume and a normal red cell mass. The patients frequently have hypertension, hyperuricemia, and a high incidence of cardiovascular disease.

Treatment

The group with erythrocytosis secondary to a high-normal red cell mass and a low-normal plasma volume should stop smoking. In the group with a low plasma volume, the hypertension should be controlled, which may result in a normal hematocrit. Occasionally a patient may benefit from phlebotomy.

Absolute Erythrocytosis

An absolute rise in the red cell mass may be primary (polycythemia vera) or secondary (Table 11).  

Table 11.
Classification of Polycythemia

Polycythemia Vera (EP Independent)

Secondary Erythrocytosis (EP Dependent)

Physiologically Appropriate (Response to Tissue Hypoxia)

  • Chronic pulmonary disease
  • Cardiac disease with right to left shunt
  • High altitude
  • High-affinity hemoglobin

Physiologically Inappropriate EP Production

Renal Mechanism

  • Cysts
  • Hydronephrosis
  • Kidney transplants
  • Barter's syndrome

Tumor-Producing EP

  • Hypernephroma
  • Hepatoma
  • Hemangioblastoma of cerebellum
  • Uterine fibroids
  • Ovarian carcinoma

Cobalt

Relative Polycythemia

Polycythemia Vera

This is a myeloproliferative disease characterized by increased erythropoiesis independent of erythropoietin. It is a panmyelosis-ie, hematocrit, white count, and platelet count are generally all elevated. Glucose-6-phosphate dehydrogenase isozyme studies and culture studies of bone marrow indicate that polycythemia vera is a clonal disease in which erythroid precursors proliferate independent of erythropoietin, or have a markedly increased sensitivity to erythropoietin.

Clinical Findings

Patients present with headache, dizziness, vertigo, and visual disturbances. They may have a history of cerebrovascular accidents, myocardial infarction, angina, or venous thrombosis. Physical findings include ruddy cyanosis, splenomegaly (75%), and hepatomegaly (40% to 50%). A history of pruritus after bath or shower is recorded in 50% of patients.

Laboratory data reveal elevations in hematocrit, white cell count (60% to 70%), and platelet count (50%). Bone marrow is hypercellular with erythroid hyperplasia and a marked increase in megakaryocytes. Iron depletion is frequent. The leukocyte alkaline phosphatase score is elevated in 70% to 90% of patients. Uric acid and serum B12 may be increased. Levels of erythropoietin are low.

Diagnostic Criteria (From Polycythemia Vera Study Group)

The diagnosis of polycythemia is acceptable if all three parameters in category A or if A1, A2, and two parameters from category B are present.

Category A

A1. Increased red cell mass (men: >36 ml/kg; women: >32 ml/kg) by 51Cr-labeled red cells.

A2. Arterial oxygen saturation >92%.

A3. Splenomegaly.

Category B

B1. Thrombocytosis >400,000/qL.

B2. Leukocytosis >12,000/qL.

B3. Elevated B12 or unbound B12 binding capacity-B12 >900 pg/mL; UB12BC >2,200 pg/mL.

Course and Prognosis

Elevation in red cell mass results in an increased frequency of thrombotic complications. Increased platelet count and platelet function abnormalities result in an increased incidence of hemorrhage and thrombosis. Some patients develop marrow failure secondary to myelofibrosis or develop acute leukemia. Causes of death in polycythemia vera are thrombosis (40%), hemorrhage (9%), and leukemia-myelofibrosis (10%). With optimum control of the disease, the polycythemia vera study group has found that survival is similar to a group of age-matched controls.

Principles of Management

Secondary Erythrocytosis

Secondary erythrocytosis results from a normal bone marrow response to the production of erythropoietin, which may be physiologically appropriate, ie, induced by tissue hypoxia, or it may be produced independent of physiologic regulatory mechanisms.

Physiologically Appropriate Erythropoietin Production

Tissue hypoxia induced by arterial denaturation results in the increased production of erythropoietin. This may occur with pulmonary disease, right-to-left cardiac shunts, and residence at high altitudes. Familial polycythemia results with an inherited hemoglobin that has a high affinity for oxygen. Tissue hypoxia results because these hemoglobins will not release oxygen at the tensions normally present in the tissues. These abnormal hemoglobins can be detected by demonstrating a reduced P50 of blood (oxygen tension at which hemoglobin is 50% saturated). Cigarette smokers may develop erythrocytosis, because carbon monoxide displaces oxygen and increases hemoglobin oxygen affinity.

 

Figure 3.
Rational Sequence for the Evaluation of Patients with Elevated Hematocrits
 

Physiologically Inappropriate Erythropoietin Production

The kidney is normally responsible for most of the hemopoietin produced by the body. Disorders that result in local tissue hypoxia in the kidney will stimulate the production of erythropoietin (Table 11). Tumors produce erythropoietin independently of physiologic regulation. The administration of cobalt or industrial exposure results in the production of erythropoietin, probably interfering with oxygen metabolism in the tissues.

Principles of Management

Most patients with secondary erythrocytosis benefit from controlling the elevated hemoglobin level. Treatment of the underlying condition will often result in return of the hemoglobin level to normal. These is especially true if hypoxia can be corrected and smoking stopped. If the underlying condition is not possible, phlebotomy may produce symptomatic improvement and may reduce the incidence of thrombotic complications.


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  7. Logue GL, Rosse WF. Immunologic mechanisms in autoimmune hemolytic disease. Semin Hematol. 1976;13:277-289.
  8. Packman CH, Leddy JP. Acquired hemolytic anemia due to warm-reacting antibodies. In: Williams WJ, Beutler E, Erslev AJ, Lichtman MA, eds. Hematology. 4th ed. New York, NY: McGraw-Hill; 1990;666-675.
  9. Pirofsky B. Clinical aspects of autoimmune hemolytic anemia. Semin Hematol. 1976;13:251-265.
  10. Salama A, Mueller-Eckhart C. Immune-mediated blood cell dyscrasias related to drugs. Semin in Hematol. 1992;29:54-63.

Polycythemia

  1. Adamson JD. Familial polycythemia. Semin Hematol. 1975;12:383-396.
  2. Balcerzek SP, Bromberg PA. Secondary polycythemias. Semin Hematol. 1975;12:353-382.
  3. Berlin NI. Diagnosis and classification of the polycythemias. Semin Hematol. 1975;12:339-351.
  4. Cheivitz E, Thicoe T. Complications and causes of death in polycythemia vera. Acta Med Scand. 1962;172:513-523.
  5. Hoffman R, Wasserman LR. Natural history and management of polycythemia vera. Adv Intern Med. 1979;24:255-285.
  6. Wasserman LR, Gilbert HS. Surgery in polycythemia vera. N Engl J Med. 1963;269:1226-1230.
  7. Weinreb NJ, Shin CF. Spurious polycythemia. Semin Hematol. 1975;12:397-408.