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Benign Hematology 

Benign Hematology
Chapter:
Benign Hematology
Author(s):

Alexandra P. Wolanskyj

DOI:
10.1093/med/9780199948949.003.0034
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Goals

  • Describe the approach to evaluation of microcytic, macrocytic, and normocytic anemias.

  • Differentiate causes of hemolytic anemia.

  • Review various types of transfusion reactions.

Anemias

Evaluation of Anemia

Anemia is a reduction in the mass of healthy circulating red blood cells (RBCs). Anemia occurs as a result of 1 of 3 mechanisms: 1) inadequate production of RBCs by the bone marrow (ie, marrow failure, intrinsic RBC synthetic defects, or lack of essential RBC components such as vitamins); 2) blood loss; and 3) premature destruction of RBCs (ie, hemolysis). After a complete history and physical examination, evaluation of anemia includes a complete blood cell count, so that anemia can be classified as microcytic, macrocytic, or normocytic on the basis of mean corpuscular volume (MCV).

Microcytic Anemias

Microcytic anemia indicates the presence of small RBCs (MCV <80 fL). The most common forms of anemia are microcytic (Tables 34.1 and 34.2).

Table 34.1 Typical Features of Uncomplicated Microcytic Anemias (Decreased MCV)

Variable

Type of Anemia

Thalassemia

Iron Deficiency

RBC count, ×1012/L

≥5.0

<5.0

RBC distribution width, %

<16

≥16

Abbreviations: MCV, mean corpuscular volume; RBC, red blood cell.

Table 34.2 Comparison of the Most Common Hypochromic Microcytic Anemias

Disease State

MCV

Red Blood Cell Count

TIBC

Transferrin Saturation

Serum Ferritin

Marrow Iron

Iron deficiency anemia

Decreased

Decreased

Increased

Low

Low

Absent

Anemia of chronic disease

Normal or decreased

Decreased

Normal

Normal or increased

Normal or increased

Normal or increased

Thalassemia minor

Decreased

Usually increased

Normal

Normal

Normal or increased

Normal

Abbreviations: MCV, mean corpuscular volume; TIBC, total iron-binding capacity.

Adapted from Savage RA. Cost-effective laboratory diagnosis of microcytic anemias of complex origin. ASCP check sample H84-10(H-153). Used with permission.

The causes of hypochromic microcytic anemias can be remembered with the mnemonic TAILS (thalassemia, anemia of chronic disease, iron deficiency, lead poisoning, and sideroblastic anemia). Other, less common causes of microcytosis include vitamin C deficiency, vitamin B6 deficiency, copper deficiency, sirolimus or mycophenolate, primary myelofibrosis, renal cell carcinoma, and Hodgkin lymphoma.

A complete blood cell count and iron parameters aid in making a diagnosis (Table 34.2). Blood loss should be considered in all patients with anemia, especially those with microcytic anemia. Investigating the gastrointestinal tract is essential in the work-up of microcytic anemia, since it is the most common site of occult blood loss.

  • Use TAILS (thalassemia, anemia of chronic disease, iron deficiency, lead poisoning, and sideroblastic anemia) to remember causes of microcytic anemia.

Iron Deficiency

Iron deficiency is the most common cause of anemia in the world and is especially common among menstruating women and the elderly (Figure 34.1).

Figure 34.1 Hypochromic Microcytic Anemia. The erythrocytes are small with increased central pallor and assorted aberrations in size (anisocytosis) and shape (poikilocytosis). This pattern is characteristic of iron deficiency rather than thalessemia; in thalassemia, red blood cells are small but more uniform. If a mature lymphocyte is available for reference, the diameter of a normal erythrocyte (7 µm) should be similar to the diameter of the nucleus of the lymphocyte (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.1
Hypochromic Microcytic Anemia. The erythrocytes are small with increased central pallor and assorted aberrations in size (anisocytosis) and shape (poikilocytosis). This pattern is characteristic of iron deficiency rather than thalessemia; in thalassemia, red blood cells are small but more uniform. If a mature lymphocyte is available for reference, the diameter of a normal erythrocyte (7 µm) should be similar to the diameter of the nucleus of the lymphocyte (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Mechanisms of iron deficiency include the following:

  1. 1. Blood loss, including gastrointestinal tract disorders (eg, ulcers, malignancy, telangiectasia, arteriovenous malformations, hiatal hernia, and long-distance runner’s anemia); respiratory disorders (eg, malignancy and pulmonary hemosiderosis); menstruation; phlebotomy (eg, blood donation, diagnostic phlebotomy, treatment of polycythemia vera or hemochromatosis, and self-inflicted or factitious injury); trauma; and surgery

  2. 2. Increased requirements in relation to intake (as in pregnancy)

  3. 3. Decreased absorption, including partial gastrectomy and malabsorption syndromes (eg, celiac disease)

Patients with early iron deficiency may have a normal MCV. Patients with iron deficiency may also have a normal MCV if they have a condition that causes macrocytosis (eg, iron deficiency in combination with folate deficiency).

The serum ferritin test is the most useful initial test for iron deficiency. A ferritin level less than 15 ng/mL almost always indicates iron deficiency. Ferritin testing is useful in pregnant women, in whom transferrin saturation is often elevated. Ferritin is an acute phase reactant, and the level is increased in inflammatory states. Thus, patients with these conditions may have iron deficiency even if the ferritin level is normal or increased. Notably, an elevated soluble transferrin receptor (sTfR) measurement, which is not an acute-phase reactant, also signifies iron deficiency.

  • The serum ferritin test is the most useful initial test for iron deficiency.

  • When iron deficiency anemia is discovered, identify the underlying cause.

Oral iron replacement therapy is the treatment of choice for iron deficiency. Gastric acid is required for optimal iron absorption; thus, antacids may interfere with absorption. Reticulocytosis is seen in 4 to 7 days after initiating oral iron replacement therapy, improvement in anemia in 3 to 4 weeks, and correction of anemia in 6 weeks—if the cause of anemia is solely iron deficiency. Continue iron replacement therapy for another 6 months to replenish bone marrow reserves.

Indications for intravenous iron therapy include renal dialysis (with recombinant erythropoietin) and inability to tolerate or absorb iron taken orally.

  • Oral iron replacement therapy is the treatment of choice for iron deficiency.

Thalassemias

The thalassemias are common single-gene disorders. β‎-Thalassemia results when β‎-globin chains are decreased or absent in relation to α‎-globin. In α‎-thalassemia, the converse is true: excess β‎-globin chains precipitate as tetramers called hemoglobin H. Genetic counseling is indicated after the diagnosis of α‎- or β‎-thalassemia has been established.

β‎-Thalassemia

Point mutations result in β‎-thalassemia of varying severity. Clinically, β‎-thalassemia is categorized as follows:

  1. 1. β‎-Thalassemia trait—microcytosis and either normal hemoglobin or mild anemia

  2. 2. β‎-Thalassemia intermedia—microcytosis and moderate anemia without long-term transfusion dependence

  3. 3. β‎-Thalassemia major (also known as Cooley anemia)—profound anemia and lifelong transfusion dependence

In β‎-thalassemia, the hemoglobin A2 level is elevated (Figure 34.2). However, if the patient has iron deficiency, the hemoglobin A2 level may be normal, since iron deficiency decreases the hemoglobin A2 level.

Figure 34.2 Algorithm for Approach to Diagnosis of Hypochromic Microcytic Anemia With an Increased Total Red Blood Cell (RBC) Count and a Normal RBC Distribution Width (RDW) Index. (Adapted from Savage RA. Cost-effective laboratory diagnosis of microcytic anemias of complex origin. ASCP check sample H84-10[H-153]. Used with permission.)

Figure 34.2
Algorithm for Approach to Diagnosis of Hypochromic Microcytic Anemia With an Increased Total Red Blood Cell (RBC) Count and a Normal RBC Distribution Width (RDW) Index. (Adapted from Savage RA. Cost-effective laboratory diagnosis of microcytic anemias of complex origin. ASCP check sample H84-10[H-153]. Used with permission.)

α‎-Thalassemia

Normally, a person has 4 α‎-globin genes, but only 2 β‎-chain loci. α‎-Thalassemia is classifed as follows:

  1. 1. α‎-Thalassemia minor (α‎-thalassemia trait)—absence of 1 or 2 of the 4 α‎-globin genes (patients are asymptomatic, usually with a low-normal MCV and normal hemoglobin)

  2. 2. Hemoglobin H disease—absence of 3 α‎-globin genes (patients have chronic hemolytic anemia of moderate severity, and they may benefit from splenectomy if hemolysis becomes problematic)

  3. 3. Absence of all 4 α‎-globin genes is not compatible with life and results in stillbirth

Vitamin C Deficiency

Patients with vitamin C deficiency (scurvy) present with microcytic anemia, purpura, gingival disease, and peripheral edema.

Sideroblastic Anemias

The sideroblastic anemias are characterized by microcytic, normocytic, or macrocytic anemia and ring sideroblasts in the bone marrow (Figure 34.3), which are abnormal erythroid precursors ineffective at heme synthesis and often seen in myelodysplastic syndromes. Reactive causes include alcohol, zinc toxicity, and drugs such as isoniazid and pyrazinamide. Several forms of congenital sideroblastic anemia may respond to vitamin B6 (pyridoxine) therapy.

Figure 34.3 Ring Sideroblasts. Seen on iron staining of a bone marrow aspirate, ring sideroblasts can be reactive, congenital, or part of a myelodysplastic syndrome or other clonal myeloid disorder (bone marrow aspirate; iron stain with potassium ferrocyanide and nuclear fast red counterstain). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.3
Ring Sideroblasts. Seen on iron staining of a bone marrow aspirate, ring sideroblasts can be reactive, congenital, or part of a myelodysplastic syndrome or other clonal myeloid disorder (bone marrow aspirate; iron stain with potassium ferrocyanide and nuclear fast red counterstain). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Macrocytic Anemias

Macrocytic anemia indicates the presence of large RBCs (MCV >100 fL). The differential diagnosis of macrocytic anemias includes vitamin B12 deficiency, folate deficiency, drugs, liver disease, alcohol abuse, hypothyroidism, heavy tobacco use, myelodysplasia or other primary bone marrow disorders, cold agglutinin disease (artifactual clumping of cells in an automated counter), and reticulocytosis (reticulocytes are larger than mature RBCs). A laboratory approach to macrocytic anemias is outlined in Figure 34.4. An MCV greater than 115 fL almost always indicates a deficiency of either vitamin B12 or folate or an artifact due to RBC agglutination. Common drug-related causes of macrocytosis are chemotherapy drugs that inhibit purine or pyrimidine synthesis (eg, azathioprine and 5-fluorouracil), deoxyribonucleotide synthesis (hydroxyurea and cytarabine), and dihydrofolate reductase (methotrexate).

  • An MCV >115 fL almost always indicates a deficiency of either vitamin B12 or folate or an artifact due to RBC agglutination.

  • Multiple drugs cause macrocytosis.

Figure 34.4 Laboratory Approach to Macrocytic Anemias. MCV indicates mean corpuscular volume. (Adapted from Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am. 1992 May;76[3]:581–97. Used with permission.)

Figure 34.4
Laboratory Approach to Macrocytic Anemias. MCV indicates mean corpuscular volume. (Adapted from Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am. 1992 May;76[3]:581–97. Used with permission.)

Vitamin B12 Deficiency

Vitamin B12 (cobalamin) is present in animal products and in small quantities in some plant-derived foods. Hydrochloric acid is necessary to free cobalamin from food; thus, patients with achlorhydria cannot absorb vitamin B12. Free cobalamin is immediately bound by R-binders, which protect cobalamin from the acidic gastric environment. As the complex passes into the duodenum, pancreatic proteases facilitate release of the R-binders. The free cobalamin combines with intrinsic factor and is absorbed in the ileum. Thus, sufficient ileal mucosal surface and a normally functioning pancreas are required for adequate absorption of vitamin B12.Causes of vitamin B12 deficiency include pernicious anemia (defective production of intrinsic factor, usually due to autoimmune production of anti–intrinsic factor or anti–parietal cell antibodies), atrophic gastritis, total or partial gastrectomy, ileal resection or Crohn disease involving the ileum, bacterial overgrowth syndromes, infection with Diphyllobothrium latum, and pancreatic insufficiency (most commonly from chronic pancreatitis or cystic fibrosis). Nitrous oxide inactivates vitamin B12, and abuse of this anesthetic (eg, by dentists or dental office workers) can lead to rapid development of severe vitamin B12 deficiency. Vitamin B12 deficiency due to inadequate dietary intake is very rare.

The symptoms and signs of vitamin B12 deficiency include a beefy and atrophic tongue, diarrhea, and neurologic signs (eg, paresthesias, gait disturbance, mental status changes [“B12 madness”], vibratory/position sense impairment [dorsal column “dropout”], the absence of ankle reflexes, and extensor plantar responses).

The MCV is increased, and hypersegmented neutrophils are usually present (Figure 34.5). As in folate deficiency, serum homocysteine levels are increased; however, unlike in folate deficiency, serum and urinary levels of methylmalonic acid are also increased. A serum vitamin B12 level less than 200 pg/mL strongly suggests vitamin B12 deficiency. Vitamin B12 levels of 200 to 400 pg/mL (borderline or low-normal range) can also indicate deficiency; if clinical suspicion is high, methylmalonic acid levels can help establish the diagnosis. When present, an abnormal intrinsic factor antibody confirms pernicious anemia as the cause of vitamin B12 deficiency. Serum gastrin levels are typically high. The Schilling test is frequently described in textbooks but rarely performed in clinical practice.

Figure 34.5 Hypersegmented Neutrophil. Polymorphonuclear leukocytes with 5 or more nuclear lobes are characteristic of vitamin B12 or folate deficiency and are not typically seen in other causes of macrocytic anemia (peripheral blood smear; Wright-Giemsa).

Figure 34.5
Hypersegmented Neutrophil. Polymorphonuclear leukocytes with 5 or more nuclear lobes are characteristic of vitamin B12 or folate deficiency and are not typically seen in other causes of macrocytic anemia (peripheral blood smear; Wright-Giemsa).

Vitamin B12 deficiency, including pernicious anemia, is treated with oral or intramuscular vitamin B12. Lifelong maintenance treatment is required. Vitamin B12 levels may be spuriously low in patients who are pregnant or using oral contraceptives and are falsely elevated in patients who have myeloproliferative disorders, because of alterations in levels of vitamin B12-binding proteins.

  • Homocysteine levels are elevated in both folate deficiency and vitamin B12 deficiency.

  • Methylmalonic acid levels are increased only in vitamin B12 deficiency.

Folate Deficiency

In contrast to anemia caused by vitamin B12 deficiency, macrocytic anemia caused by folate deficiency develops quickly (ie, within months) in patients with inadequate dietary intake of folic acid. Folate is present in green leafy vegetables and some fruits. It is absorbed in the duodenum and proximal jejunum. Notably, folate deficiency has decreased in the United States with folic acid fortification of grain products. Mechanisms of folate deficiency include increased requirements (eg, pregnancy, hemolytic anemia), poor folate intake (eg, alcoholics, persons following extremely restrictive diets), poor absorption, and interference with the recycling of folate from liver stores to tissue (eg, alcohol).

Anemia due to folate deficiency is indistinguishable from anemia due to vitamin B12 deficiency. The possibility of coexistent vitamin B12 or iron deficiency should be considered if response to replacement folate therapy is not optimal. Folate helps convert homocysteine to methionine; thus, folate deficiency leads to an increased homocysteine level. In contrast to vitamin B12 deficiency, in folate deficiency the level of methylmalonic acid is normal. RBC folate levels are more accurate than serum folate levels in detecting true folate deficiency, since serum folate levels fluctuate quickly with dietary changes. A single day of healthy meals in the hospital may normalize a patient’s serum folate level and lead to a false-negative result.

  • If anemia due to folate deficiency does not respond optimally to folate replacement, consider coexistent vitamin B12 or iron deficiency.

  • Unlike vitamin B12 deficiency, folate deficiency develops quickly with inadequate dietary intake.

Normocytic Anemias

Normocytic anemia is defined as anemia with an MCV of 80 to 100 fL. Diagnosing the cause of a normochromic normocytic anemia can be challenging. The differential diagnosis includes mixed nutritional deficiency (eg, concomitant folate and iron deficiency), erythropoietic failure (aplastic anemia and RBC aplasia), marrow replacement (malignancy and fibrosis), kidney disease with lack of erythropoietin production, hemolysis, acute hemorrhage, some myelodysplastic syndromes, chemotherapy, anemia of acute disease, and anemia of chronic disease (eg, infections, neoplasia, rheumatoid arthritis, and other inflammatory rheumatologic conditions).

Anemia of Chronic Disease

Anemia of chronic disease (ACD) is usually moderate (ie, hemoglobin 9–11 g/dL), MCV is normal or modestly decreased, and the reticulocyte count is low. ACD is sometimes called anemia of chronic inflammation, since it results from the inhibitory effects of inflammatory cytokines on the bone marrow. A peptide produced by the liver, hepcidin, is elevated in ACD. Hepcidin sequesters iron and decreases iron absorption. As a consequence, serum iron levels are low in ACD, but unlike in iron deficiency, total iron-binding capacity is normal or low and ferritin is usually normal or elevated (Table 34.2).

In evaluating patients with suspected ACD, it is important to exclude hemolysis and gastrointestinal tract blood loss early in the evaluation. No single blood test confirms ACD, but diagnosis is probable if 1) inflammatory markers are present; 2) results of iron studies are typical (ie, normal total iron-binding capacity, normal or increased serum ferritin, and normal or increased transferrin saturation); 3) another cause for the normocytic anemia is not apparent; and 4) the clinical setting is appropriate. The sTfR concentration is normal in ACD in contrast to iron deficiency anemia, in which sTfR is usually elevated. Patients with ACD do not benefit from iron therapy.

Aplastic Anemia

Aplastic anemia is a rare disorder characterized by pancytopenia, bone marrow hypocellularity, and absence of another disorder that would explain the hypocellularity (eg, myelodysplastic syndrome, T-cell clonal disorders, or other congenital bone marrow failure syndromes). Acquired aplastic anemia is often idiopathic. Common causes include drugs (eg, chloramphenicol, sulfonamides, gold, and benzene), toxins, radiation, infections (eg, hepatitis A, Epstein-Barr virus [EBV], cytomegalovirus, human immunodeficiency virus [HIV], and human parvovirus B19), and autoimmune marrow suppression. The criteria for severe aplastic anemia include less than 25% of expected marrow cellularity and 2 of the following: 1) neutrophil count less than 0.5×109/L, 2) platelet count less than 20×109/L, and 3) a corrected reticulocyte count less than 1%.

  • Aplastic anemia is characterized by pancytopenia, hypocellular bone marrow, and absence of another cause of marrow hypoplasia.

  • Common causes of aplastic anemia include autoimmune marrow suppression, idiopathic causes, drug reaction, toxins, radiation, and viral infections.

Allogeneic hematopoietic stem cell transplant is the therapy of choice for patients with an identical twin and patients younger than 20 years, or high-risk patients between the ages of 20 and 40 who have an HLA match. For patients older than 40, the treatment of choice is antithymocyte globulin in combination with corticosteroids and cyclosporine, although it is usually not curative. Without treatment, 80% of patients who have severe aplastic anemia die within 2 years of diagnosis.

  • Full recovery in aplastic anemia is uncommon without treatment.

Sickle Cell Disorders

Classification and Pathophysiology

The sickle cell disorders include sickle cell anemia (homozygous hemoglobin S), sickle cell trait (heterozygous hemoglobin S), and compound states (hemoglobin S with thalassemia or other hemoglobinopathies).

Sickle cell anemia occurs in persons of sub-Saharan African descent and, less commonly, in persons of Middle Eastern or South Asian origin. Approximately 1 of every 8 African Americans carries 1 copy of the sickle cell gene, with sickle cell disease occurring in 1 of 500. Hemoglobin S substitutes valine for glutamic acid at the sixth position of the β‎ chain. Deoxygenated hemoglobin S distorts the cell into a sickle shape and injures the cell membrane (Figure 34.6). Vasoocclusion is a function of decreased RBC deformability, increased viscosity, and increased RBC adherence to altered endothelium.

Figure 34.6 Sickle Cell Anemia. Several irreversibly sickled cells are seen. Abundant target cells indicate hyposplenism from autoinfarction of the spleen. Liver disease due to transfusional hemosiderosis was also a contributing factor to these target cells (peripheral blood smear; Wright-Giemsa).

Figure 34.6
Sickle Cell Anemia. Several irreversibly sickled cells are seen. Abundant target cells indicate hyposplenism from autoinfarction of the spleen. Liver disease due to transfusional hemosiderosis was also a contributing factor to these target cells (peripheral blood smear; Wright-Giemsa).

Sickling is inhibited by hemoglobin F, and symptoms are not apparent until after 6 months of age owing to high levels of fetal hemoglobin in early life. The first episode of vasoocclusive disease typically develops between the ages of 12 months and 6 years and results from obstruction of the microcirculation by intravascular sickling.

Acute complications of sickle cell anemia include vasoocclusive episodes, acute chest syndrome, dactylitis, splenic sequestration, stroke, aplastic crisis, infection, acute cholecystitis, priapism, and renal papillary necrosis. Acute chest syndrome, accounting for up to 25% of deaths, is the leading cause of death in sickle cell anemia; clinical features include fever, chest pain, tachypnea, leukocytosis, and pulmonary infiltrates. When infection is present, causative organisms include pneumococci, Mycoplasma, Haemophilus, Salmonella, and Escherichia coli. Aplastic crises usually follow a febrile illness and are often associated with human parvovirus B19 infection in adults. In sickle cell patients, osteomyelitis is caused by Salmonella, Staphylococcus, and pneumococci.

Chronic complications include hemolytic anemia, growth retardation, pulmonary hypertension, folate deficiency, retinopathy, chronic renal insufficiency, accelerated cardiovascular disease, transfusional hemochromatosis, nonhealing skin ulcers, osteopenia, avascular necrosis, and growth retardation. Although disease manifestations do not increase during pregnancy, maternal mortality is 5% to 8% and fetal mortality 20%.

Laboratory findings include severe anemia (hemoglobin, 5.5–9.5 g/dL), sickled cells, ovalocytes, target cells, basophilic stippling, polychromatophilia, reticulocytosis (3%-12%), and hyposplenia with Howell-Jolly bodies (Figure 34.7). A persistent increase in the white blood cell count to 12×109/L to 15×109/L (in the absence of infection) with eosinophilia is characteristic. Evidence of chronic hemolysis may be present. Liver test results are often increased. Routine diagnostic tests include the sickle solubility test, electrophoresis, and chromatography.

  • Acute complications of sickle cell anemia include vasoocclusive episodes, acute chest syndrome, dactylitis, splenic sequestration, aplastic crisis, infection, priapism, renal papillary necrosis, and cerebrovascular accidents.

  • Chronic complications include hemolytic anemia, pulmonary hypertension, folate deficiency, retinopathy, chronic renal insufficiency, accelerated cardiovascular disease, transfusional hemosiderosis, nonhealing skin ulcers, osteopenia, and growth retardation.

  • Acute chest syndrome is the leading cause of death in sickle cell anemia.

  • Maternal and fetal mortality are increased.

Figure 34.7 Howell-Jolly Bodies. These small, round blue inclusions are seen with Wright-Giemsa or a comparable stain. These are characteristic of hyposplenism due to splenectomy or to a functionally defective spleen. Howell-Jolly bodies should not be confused with Heinz bodies, which require a special preparation (Heinz body preparation) to observe and are not seen on a conventional peripheral smear (peripheral blood smear; Wright-Giemsa).

Figure 34.7
Howell-Jolly Bodies. These small, round blue inclusions are seen with Wright-Giemsa or a comparable stain. These are characteristic of hyposplenism due to splenectomy or to a functionally defective spleen. Howell-Jolly bodies should not be confused with Heinz bodies, which require a special preparation (Heinz body preparation) to observe and are not seen on a conventional peripheral smear (peripheral blood smear; Wright-Giemsa).

Treatment

Many sickle cell crises can be prevented by avoiding infection, fever, dehydration, acidosis, hypoxemia, cold, and high altitude. Most patients with sickle cell disease undergo autosplenectomy through recurrent infarction by age 5. Immunizations for encapsulated organisms, penicillin prophylaxis, and folate supplementation are indicated. For painful crises, the cornerstone of treatment includes gentle hydration and pain control. Analgesics, including opioids, are essential and should not be withheld because of concern about drug-seeking behavior. Acetaminophen is used for fever because aspirin contributes to acid load. A temperature greater than 40.6°C implies infection rather than just infarction. Blood transfusion and exchange transfusions are the most effective means of treatment for severe complications. Exchange transfusion is indicated for stroke, stroke prevention in patients at high risk, acute chest syndrome, priapism, and progressive retinopathy. For life-threatening complications, exchange transfusion is recommended with a goal for the hemoglobin S fraction of less than 30%. Posttransfusion increases in hemoglobin to more than 10 to 11 g/dL should be avoided except preoperatively. Iron chelation is recommended if the transfusion requirement is high and the ferritin level is elevated.

Treatment with hydroxyurea decreases the frequency of painful vasoocclusive crises (by about 50%), the frequency of acute chest syndrome, and the number of transfusions and hospitalizations. It is indicated for patients who have had severe complications such as acute chest syndrome and for patients who have frequent, painful crises.

Hematopoietic stem cell transplant with marrow or umbilical cord blood from HLA-identical siblings may be curative. The present indications for transplant include stroke and recurrent acute chest syndrome.

  • Hydroxyurea decreases the frequency of painful vasoocclusive crises by 50% and decreases the frequency of acute chest syndrome.

  • Death in sickle cell disease is associated with acute pain, acute chest syndrome, stroke, and infection.

  • Achieving a hemoglobin S level of <30% with exchange transfusion is recommended for life-threatening complications, including acute chest syndrome and stroke.

  • A posttransfusion increase in hemoglobin to >10 g/dL should be avoided except before elective surgery.

Sickle Cell Trait and Compound States

Sickle cell trait (heterozygous hemoglobin S) is not associated with anemia, RBC abnormalities, increased risk of infections, or increased mortality. Associations with sickle cell trait include hematuria due to renal papillary necrosis, splenic infarction at high altitude (>3,030 m), hyposthenuria, pyelonephritis in pregnancy, and pulmonary embolism. Compound states such as sickle cell–hemoglobin C disease and hemoglobin S/β‎-thalassemia are generally milder than sickle cell disease, depending on the hemoglobin concentrations.

Hemolytic Anemias

There are many causes of hemolysis. If hemolytic anemia is suspected, the first step is to confirm the presence of hemolysis. Hemolytic anemias are characterized as follows:

  1. 1. Increased RBC destruction

    1. a. Elevated indirect bilirubin level (>8 mg/dL suggests concomitant liver disease)

    2. b. Elevated lactate dehydrogenase (LDH) level

    3. c. Decreased haptoglobin level (haptoglobin is a scavenger of free hemoglobin and may be transiently decreased after transfusion or hemodialysis)

  2. 2. Increased RBC production

    1. a. Elevated reticulocyte count

    2. b. Marrow erythroid hyperplasia

Peripheral smear findings such as the following can assist in making a diagnosis:

  1. 1. Spherocytes (Figure 34.8) are associated with hereditary spherocytosis, alcohol, and autoimmune hemolytic anemia.

  2. 2. Basophilic stippling occurs in lead poisoning, β‎-thalassemia, and arsenic poisoning.

  3. 3. Hypochromia occurs in thalassemia, sideroblastic anemia, and lead poisoning.

  4. 4. Target cells are present in thalassemia and liver disease and after splenectomy (Figure 34.9).

  5. 5. Agglutination is present in cold agglutinin disease (Figure 34.10).

  6. 6. Stomatocytes are associated with acute alcoholism; they also occur as an artifact.

  7. 7. Spur cells (acanthocytes) (Figure 34.11) are present in chronic severe liver disease, abetalipoproteinemia, and malabsorption.

  8. 8. Burr cells (echinocytes) occur in uremia (Figure 34.12) and disappear with hemodialysis.

  9. 9. Heinz bodies are present in glucose-6-phosphate dehydrogenase (G6PD) deficiency; they are seen with supravital stain.

  10. 10. Howell-Jolly bodies indicate hyposplenism (Figure 34.7).

  11. 11. Polychromasia indicates reticulocytosis (Figure 34.13).

  12. 12. Intraerythrocytic parasitic inclusions occur in malaria and babesiosis (Figure 34.14).

Figure 34.8 Spherocytes. Spherocytes are the smooth, small, and spheroidal darkly stained cells with minimal or no central pallor. They are most commonly seen in hereditary spherocytosis or autoimmune hemolytic anemia (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.8
Spherocytes. Spherocytes are the smooth, small, and spheroidal darkly stained cells with minimal or no central pallor. They are most commonly seen in hereditary spherocytosis or autoimmune hemolytic anemia (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.9 Target Cells. Target cells are the red blood cells with a broad diameter and dark center with a pale surrounding halo. They are most commonly seen in hemoglobin C disease, thalassemia, or liver disease or after splenectomy (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.9
Target Cells. Target cells are the red blood cells with a broad diameter and dark center with a pale surrounding halo. They are most commonly seen in hemoglobin C disease, thalassemia, or liver disease or after splenectomy (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.10 Agglutination. The random clumping of red blood cells most commonly indicates cold agglutinin disease or laboratory artifact. It is important to distinguish agglutination from rouleaux (see Figure 34.16) (peripheral blood smear; Wright-Giemsa).

Figure 34.10
Agglutination. The random clumping of red blood cells most commonly indicates cold agglutinin disease or laboratory artifact. It is important to distinguish agglutination from rouleaux (see Figure 34.16) (peripheral blood smear; Wright-Giemsa).

Figure 34.11 Spur Cells (Acanthocytes). Note the thin, thorny, or finger-like projections. Spur cells are characteristic of advanced liver disease and must be distinguished from burr cells (echinocytes) (see Figure 34.12) (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.11
Spur Cells (Acanthocytes). Note the thin, thorny, or finger-like projections. Spur cells are characteristic of advanced liver disease and must be distinguished from burr cells (echinocytes) (see Figure 34.12) (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.12 Burr Cells (Echinocytes). Burr cell projections are much smaller and more uniform in size than spur cell projections. Burr cells are characteristic of uremia, and the membrane abnormality is reversible with hemodialysis (peripheral blood smear; Wright-Giemsa).

Figure 34.12
Burr Cells (Echinocytes). Burr cell projections are much smaller and more uniform in size than spur cell projections. Burr cells are characteristic of uremia, and the membrane abnormality is reversible with hemodialysis (peripheral blood smear; Wright-Giemsa).

Figure 34.13 Polychromasia. The larger cells are reticulocytes. These are often seen in high numbers during recovery from blood loss or hemolysis (peripheral blood smear; Wright-Giemsa).

Figure 34.13
Polychromasia. The larger cells are reticulocytes. These are often seen in high numbers during recovery from blood loss or hemolysis (peripheral blood smear; Wright-Giemsa).

Figure 34.14 Intraerythrocytic Ring-Shaped Parasites of Babesiosis. Malaria is the other common disease with an intraerythrocytic parasite (peripheral blood smear; Wright-Giemsa).

Figure 34.14
Intraerythrocytic Ring-Shaped Parasites of Babesiosis. Malaria is the other common disease with an intraerythrocytic parasite (peripheral blood smear; Wright-Giemsa).

Hemolytic anemias may result from factors that are intrinsic or extrinsic to the RBC and may be direct Coombs-negative or Coombs-positive (Figure 34.15). A positive direct Coombs test (also called the direct antiglobulin test [DAT]) indicates the presence of complement component C3 or IgG (or both) on the surface of RBCs. Notably, an aplastic crisis may occur in chronic hemolytic anemia and usually results from the development of folate deficiency or infection with parvovirus.

  • Hemolytic anemias may be hereditary or acquired, from factors intrinsic or extrinsic to the RBC, and Coombs-positive or Coombs-negative.

  • Evidence of increased RBC destruction includes elevated LDH, indirect hyperbilirubinemia, and a low haptoglobin level.

  • Reticulocytosis is the normal marrow response to hemolysis.

Figure 34.15 Differential Diagnosis of Hemolytic Anemia. HUS indicates hemolytic uremic syndrome; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.

Figure 34.15
Differential Diagnosis of Hemolytic Anemia. HUS indicates hemolytic uremic syndrome; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.

Intravascular Hemolysis Compared with Extravascular Hemolysis

In intravascular hemolysis, RBCs are destroyed while circulating within blood vessels. Their destruction releases free hemoglobin into the bloodstream, leading to hemoglobinemia, hemoglobinuria, and hemosiderinuria, all of which occur exclusively with intravascular hemolysis. Hemosiderinuria indicates that desquamated renal tubular cells absorbed free hemoglobin days to weeks earlier. Causes of intravascular hemolysis include transfusion reactions from ABO blood group antibodies, microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, paroxysmal cold hemoglobinuria, cold agglutinin syndrome, immune-complex drug-induced hemolytic anemia, infections (including falciparum malaria and clostridial sepsis), and G6PD deficiency. All other forms of hemolysis are primarily extravascular, in which the RBCs are lysed in the macrophages of the spleen and liver.

  • Hemoglobinuria and hemosiderinuria are signs of intravascular hemolysis.

  • Most hemolysis is extravascular.

Autoimmune Hemolytic Anemia

Mechanisms of Drug-Induced Hemolytic Anemia

There are 3 distinct mechanisms of drug-induced hemolytic anemia:

  1. 1. Autoantibody mechanism—Methyldopa may form autoantibodies that can induce hemolysis. Direct Coombs test results are positive in 3 to 6 months. Discontinuing the use of methyldopa usually leads to a rapid reversal in hemolysis.

  2. 2. Drug adsorption mechanism—The use of high doses of penicillins or cephalosporins for more than 7 days may lead to immunohemolytic anemia due to antibodies formed against the drug–RBC membrane antigen complex. In 3% of patients, the direct Coombs test is positive.

  3. 3. Immune complex mechanism—Exposure to quinidine may cause an antidrug antibody to form and create an immune complex, which is adsorbed on the RBCs and may activate complement. The direct Coombs test is positive because of the complement on the RBC surface.

  • Autoantibody mechanism: methyldopa.

  • Drug adsorption mechanism: penicillin.

  • Immune-complex mechanism: quinine and quinidine.

  • Typical clinical scenario: A patient has evidence of hemolysis (increased reticulocyte count, LDH, and indirect bilirubin), positive Coombs test with or without splenomegaly, and jaundice with a history of exposure to a common offending drug.

Cold Agglutinin Syndrome (Primary Cold Agglutinin Disease)

Cold agglutinin syndrome is characterized by chronic hemolytic anemia, agglutination, and a positive direct Coombs test (anti–complement component C3). IgM autoantibodies are reactive at temperatures below 37°C. The cause is most commonly idiopathic but can also be secondary to infection (most commonly Mycoplasma pneumoniae and EBV) or malignancy (B-cell lymphoma, chronic lymphocytic leukemia, multiple myeloma, and Waldenström macroglobulinemia).

Clinical signs and symptoms relate to small-vessel occlusion, including acrocyanosis of the finger, toes, ears, and tip of the nose. All digits may be affected equally in contrast to Raynaud phenomenon, in which 1 or 2 fingers turn from white to blue to red.

The peripheral blood smear shows RBC agglutination that disappears if prepared at 37°C (Figure 34.10). Agglutinated RBCs clump together, spuriously elevating the MCV. Therapy includes avoidance of the cold. In severe cases rituximab and cytotoxic agents are used. Agglutination should not be confused with rouleaux, in which RBCs stack in a linear pattern (Figure 34.16).

  • Cold agglutinins are often associated with Mycoplasma pneumoniae, EBV (infectious mononucleosis), and malignancy.

  • Differentiate from Raynaud phenomenon with Coombs-positive hemolytic anemia.

  • Typical clinical scenario: The patient has hemolytic anemia and acrocyanosis of the ears, tip of the nose, toes, and fingers. The diagnosis of cold agglutinin syndrome is made by finding RBC agglutination on a peripheral blood smear only if prepared at temperatures <37°C.

Figure 34.16 Rouleaux. Stacking of red blood cells in a linear pattern distinguishes rouleaux from agglutination (see Figure 34.10). Rouleaux are most commonly associated with hypergammaglobulinemia, especially in human immunodeficiency virus infection or monoclonal plasma cell disorders (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.16
Rouleaux. Stacking of red blood cells in a linear pattern distinguishes rouleaux from agglutination (see Figure 34.10). Rouleaux are most commonly associated with hypergammaglobulinemia, especially in human immunodeficiency virus infection or monoclonal plasma cell disorders (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Autoimmune Hemolytic Anemia: Warm Agglutinins

Warm agglutinins are IgG antibodies that bind to RBCs at physiologic temperatures rather than primarily in the cold. The direct Coombs test is positive for both IgG and complement component C3. Associated causes include autoimmune disorders (systemic lupus erythematosus), lymphoproliferative disorders (chronic lymphocytic leukemia), drugs, and transfusion. The first general principle in the treatment of warm agglutinin autoimmune hemolytic anemia is to treat the underlying disease (if one can be identified) and to discontinue the use of drugs that have been implicated in hemolysis.

Paroxysmal Cold Hemoglobinuria (Complement-Mediated Lysis)

Paroxysmal cold hemoglobinuria is the least common cause of autoimmune hemolytic anemia. A positive Donath-Landsteiner test is diagnostic; it detects an IgG antibody that binds to RBCs at low temperatures, causing hemolysis. Paroxysmal cold hemoglobinuria is often idiopathic and can be associated with syphilis (congenital and late), mononucleosis, mycoplasma, and childhood exanthems. The overall prognosis is good, and the condition usually resolves after the infection clears.

Coombs-Negative Hemolytic Anemia

The differential diagnosis of Coombs-negative hemolytic anemia is broad and includes hereditary RBC disorders such as enzymopathies (eg, G6PD deficiency and pyruvate kinase deficiency), hemoglobinopathies, and membrane disorders; paroxysmal nocturnal hemoglobinuria; Wilson disease; and microangiopathic conditions, including thrombotic thrombocytopenic purpura (TTP). Rarely, warm autoimmune hemolytic anemia is Coombs-negative owing to low antibody titers.

G6PD Deficiency

G6PD deficiency is the most common RBC enzyme deficiency. It causes decreased levels of glutathione (an antioxidant), making RBCs more sensitive to oxidative damage by infections, toxins (eg, naphthalene in mothballs), or drugs. Except for G6PD and phosphoglycerate kinase deficiences, which are sex-linked, all other RBC enzymopathies are autosomal recessive. Rarely, a female who is heterozygous for abnormal G6PD may be clinically affected because of unfavorable lyonization. G6PD deficiency confers some protection against falciparum malaria and extends to both males and heterozygous females.

Anemia or RBC defects do not occur in the steady state with the most common G6PD variants. Risk of hemolysis increases with concurrent kidney or liver disease, viral or bacterial infection, diabetic ketoacidosis, ingestion of fava beans (seen only in G6PD Mediterranean), and drugs. Even mild infections can cause hemolytic anemia; this occurs more often than drug-induced hemolysis. Drugs that commonly cause hemolytic anemia in G6PD deficiency include antimalarial agents (eg, primaquine and chloroquine), dapsone, sulfonamides, nitrofurantoin, high-dose aspirin, probenecid, and nitrites.

Abnormal laboratory findings include intravascular hemolysis, methemoglobinemia, and methemalbuminemia (specific for intravascular hemolysis due to enzymopathy). Supravital staining for Heinz bodies is a good screening test, but their absence does not rule out the diagnosis. The G6PD assay is the definitive test but should not be done during acute hemolysis in patients of African ancestry. Therapy includes treating the underlying infection and withdrawing use of the offending drug.

  • G6PD deficiency is the most common RBC enzyme deficiency and is inherited on the X chromosome.

  • G6PD deficiency provides some protection against falciparum malaria.

  • Anemia or RBC defects do not occur in the steady state with the most common G6PD variants.

  • Hemolysis is induced by infection more commonly than by drugs.

  • A good screening test: Heinz bodies seen on supravital staining of peripheral blood.

  • Treat underlying infections and withdraw the use of offending drugs.

Hereditary Spherocytosis

Hereditary spherocytosis is typically an autosomal dominant disorder, but it can be autosomal recessive or sporadic. It is caused by an underlying defect in the RBC cytoskeleton because of a partial gene deficiency (eg, in ankyrin or spectrin). The osmotic fragility test is almost always abnormal and is the most reliable diagnostic test. Features include jaundice, splenomegaly, negative direct Coombs test, spherocytes, and increased osmotic fragility. Pigment gallstones are present in most patients by age 50. Treatment is splenectomy after the first decade of life for moderate or severe hemolysis, which invariably reduces hemolysis. Asymptomatic adults may be observed if the hemoglobin concentration is greater than 11 g/dL and the reticulocyte count is less than 6%.

  • Hereditary spherocytosis: mostly autosomal dominant but may be autosomal recessive or sporadic.

  • Splenomegaly is invariably present; pigment gallstones are common.

  • Features include negative direct Coombs test and increased osmotic fragility.

  • Treatment: splenectomy after the first decade of life for patients with moderate or severe hemolysis.

  • Asymptomatic adults with hemoglobin >11 g/dL and a reticulocyte count <6% may be observed.

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, chronic, clonal, hematologic stem cell disorder. Blood cells are unusually sensitive to activated complement and are lysed, primarily at night when plasma is more acidotic from sleep-related physiology (eg, relative hypoxia). The disorder is characterized by abnormal hematopoietic stem cells, reticulocytopenia, leukopenia, or thrombocytopenia due to lysis by complement-mediated mechanisms.

A mutation in the PIGA gene causes cells in PNH to have a decrease or absence of glycosylphosphatidylinositol (GPI)-linked proteins, including CD14, CD55, and CD59. Clinically, PNH is characterized by chronic intravascular hemolytic anemia, episodic abdominal pain, and venous thrombosis of the portal system, brain, and extremities. Budd-Chiari syndrome (hepatic vein thrombosis) is the main cause of death. In up to 10% of patients, myelodysplasia or acute myeloid leukemia develops. PNH and aplastic anemia can coexist.

The most useful assay for diagnosis of PNH is flow cytometry to establish the absence of the GPI-linked antigens. Up to 60% of patients respond to prednisone; eculizumab is a monoclonal antibody that can be used for long-term therapy for hemolysis in PNH.

  • PNH is associated with venous thrombosis, especially Budd-Chiari syndrome, and is the main cause of death.

  • Acute myelogenous leukemia or myelodysplasia occurs in 5%-10% of patients.

  • Diagnosis: flow cytometry studies for GPI-linked proteins.

Thrombotic Microangiopathies: Differential Diagnosis

In microangiopathic hemolytic anemia, RBCs are fragmented and deformed by fibrin deposits in the peripheral blood (Figure 34.17). Direct Coombs testing is negative. The associated disorders, characterized by widespread microvascular thrombosis leading to end-organ injury, include TTP, hemolytic uremic syndrome (HUS), malignant hypertension, pulmonary hypertension, acute glomerulonephritis, renal allograft rejection, obstetric catastrophes, HELLP syndrome (hemolysis, elevated liver function tests, and low platelet count), disseminated intravascular coagulopathy, collagen vascular diseases, vascular malformations including Kasabach-Merritt syndrome (giant hemangiomas that trap platelets), viral infections (HIV), bacterial infections (E coli O157:H7), drug-induced disorders (eg, mitomycin C, quinine, ticlopidine, tacrolimus, cisplatin, and cyclosporine), acute radiation nephropathy, bone marrow transplant, and solid organ transplant.

Figure 34.17 Schistocytes. A and B, Fragmented red blood cells are shaped like helmets, triangles, or kites. These are characteristic of any microangiopathic hemolytic process (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Figure 34.17
Schistocytes. A and B, Fragmented red blood cells are shaped like helmets, triangles, or kites. These are characteristic of any microangiopathic hemolytic process (peripheral blood smear; Wright-Giemsa). (Courtesy of Curtis A. Hanson, MD, Mayo Clinic, Rochester, Minnesota. Used with permission.)

Thrombotic Thrombocytopenic Purpura

The features of TTP include the pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic signs, fever, and kidney abnormalities. Most patients do not manifest all 5 features before the diagnosis is made. The primary criteria are thrombocytopenia and microangiopathy, and these are sufficient to establish the diagnosis. The anemia is normochromic normocytic, with microangiopathic hemolytic features (Figure 34.17). Direct Coombs test results are negative. Results of coagulation studies are normal or only mildly abnormal, in contrast to results in disseminated intravascular coagulopathy. The cause of TTP is unknown in more than 90% of the patients. TTP is associated with pregnancy and the use of oral contraceptives, HIV infection, cancer, bone marrow transplant, certain chemotherapy drugs (especially mitomycin C and bleomycin), and other drugs (eg, crack cocaine, ticlopidine, and cyclosporine).

Clinically, thrombocytopenia is associated with bleeding in 96% of patients. Neurologic signs often wax and wane and include headache, coma, mental changes, paresis, seizure and coma, aphasia, syncope, visual symptoms, dysarthria, vertigo, agitation, confusion, and delirium. Kidney abnormalities include abnormal urinary sediment and elevated creatinine level. Patients with TTP are deficient in the von Willebrand factor–cleaving protease ADAMTS13. Even when ADAMTS13 assays are available, results can take days to return; thus, the assay is not useful for initial treatment decisions.

Without treatment, more than 90% of patients die of multiorgan failure, but with treatment, 70% to 80% survive the disease and have few or no sequelae. The treatment of choice is plasma exchange. Relapses are also managed with plasma exchange. The management of refractory TTP includes intravenous vincristine, rituximab, splenectomy, or intravenous high-dose γ‎-globulin. Platelet transfusion should be used only when required for an invasive procedure since it can exacerbate the disease.

  • TTP: the pentad of microangiopathic hemolytic anemia, fever, thrombocytopenia, neurologic signs, and renal abnormalities.

  • The treatment of choice is plasma exchange.

Hemolytic Uremic Syndrome

HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Fever and neurologic signs are usually not present. It is associated with infections (E coli O157:H7, Shigella dysenteriae), pregnancy, bone marrow transplant, chemotherapy, and immunosuppressive medications such as cyclosporine. HUS is usually not associated with a decrease in ADAMTS13 activity. Management of HUS is supportive. In adults, treatment with plasma exchange is indicated, but response is variable.

  • HUS: hemolytic anemia, thrombocytopenia, and acute kidney injury.

Transfusion Reactions

The primary cause of major transfusion reactions and transfusion-related deaths is medical error, which includes bypassed safeguards, similar patient names, and verbal or faxed communications. The major transfusion reactions include acute hemolytic transfusion reactions, transfusions associated with anti-IgA antibodies, transfusion-related acute lung injury (TRALI), adult respiratory distress syndrome, delayed hemolytic transfusion reactions, febrile transfusion reactions, urticarial (allergic) transfusion reactions, and circulatory overload (Table 34.3).

Table 34.3 Risks of Complications From Transfusions in the United States

Complication

Risk Per Unit

Minor allergic reaction

3/100

Circulatory overload

Variable

Febrile, nonhemolytic

3/100

Delayed hemolytic transfusion reaction

1/4,000

TRALI

1/10,000

Acute hemolytic transfusion reaction

1/2.5×104 to 1/1.0×106

HIV infection

1/2.1×106

Hepatitis B virus infection

1/2.0×105

Hepatitis C virus infection

1/1.9×105

HTLV type I or II infection

1/2.0×105

West Nile virus infection

Unknown

Bacterial infections

1/2,000 to 1/5.0×105

IgA-related anaphylaxis

1/1.0×105

Graft-vs-host disease

Rare

Immunosuppression

Unknown

Posttransfusion purpura

Rare

Prion infection

Unknown

Abbreviations: HIV, human immunodeficiency virus; HTLV, human T-cell leukemia virus; TRALI, transfusion-related acute lung injury.

Acute Hemolytic Transfusion Reactions

Acute hemolytic transfusion reactions are the most life-threatening tranfusion reactions and occur within minutes to hours. The recipient’s RBC antibodies (usually IgM) react against the donor’s RBCs and cause complement-mediated hemolysis. The most common cause is human error, especially when blood is released emergently. Mortality rate is about 20%; of the fatal transfusion reactions, 85% involve ABO incompatibility. ABO compatibility is illustrated in Table 34.4. Other, nonclerical causes include antibodies not detected before transfusion, such as Kell, Duffy (Fya), and Kidd (Jka). Clinically, patients experience pain at the intravenous site, a sense of impending doom, back pain, abdominal pain, fever, chills, chest pain, hypotension, nausea, flushing, and dyspnea. Direct Coombs testing is positive in most cases.

Table 34.4 Blood Product Compatibility in the ABO Systema

Recipient ABO Group

Acceptable Donor ABO Groups

Packed Red Blood Cells

Platelets & Fresh Frozen Plasma

Whole Blood (Rarely Used)

O

O

AB, A, B, or O

O

A

A or O

A or AB

A

B

B or O

B or AB

B

AB

AB, A, B, or O

AB

AB

a Natural alloimmunization against A and B antigens occurs in people lacking these antigens. Upon transfusion of ABO-incompatible blood, preformed antibodies serve as hemagglutinins, resulting in life-threatening acute hemolysis and complement activation. Hemagglutinins are found primarily in plasma; platelets are considered similar to plasma products with respect to ABO compatibility.

Complications include oliguria, acute kidney injury, and disseminated intravascular coagulation. Treatment includes immediate termination of the transfusion, vigorous administration of fluids, and furosemide to increase renal cortical blood flow.

  • The most common cause of acute hemolytic transfusion reaction is human error.

  • Most mortality is related to ABO incompatibility.

Allergic Transfusion Reactions

Allergic transfusion reactions are a complication in 3% of transfusions and are caused by a recipient’s antibody against foreign-donor serum proteins. Transfusion reactions can also be associated with anti-IgA antibodies. These include anaphylactic reactions, which occur most commonly in patients with IgA deficiency who may have circulating complement-binding anti-IgA antibodies that react with donor IgA. Clinical features are similar to those of an acute hemolytic transfusion reaction. Treatment includes stopping the transfusion and giving antihistamines and conventional antianaphylactic drugs. Transfusion protocols for patients include use of washed RBCs and IgA-deficient plasma.

  • Allergic transfusion reactions are often associated with anti-IgA antibodies.

Transfusion-Related Acute Lung Injury

Transfusion-associated acute respiratory distress syndrome or TRALI results from an interaction between the recipient’s leukocytes and donor antileukocyte antibodies. TRALI often is unrecognized and ranks third among causes of transfusion-related deaths. It is characterized by acute respiratory distress during transfusion or within 6 hours after completion of transfusion, hypotension, bilateral pulmonary infiltrates, normal or low pulmonary capillary wedge pressure, no evidence of circulatory overload, and fever. With appropriate supportive care, recovery is rapid, occurring in 24 to 48 hours.

  • Treatment of TRALI is primarily supportive care.

Delayed Hemolytic Transfusion Reactions

Delayed hemolytic transfusion reactions (occurring in 1 in 4,000 transfusions) occur because of the inability to detect clinically significant recipient antibodies before transfusion. They usually occur 5 to 10 days after transfusion and are less dangerous than an acute hemolytic reaction. The recipient’s plasma contains antibody before transfusion because of a previous transfusion or previous pregnancy. There is evidence of hemolysis and direct Coombs testing is positive. One-third of the patients are asymptomatic, and the reactions are detected by the recurrence of laboratory-detected anemia without clear cause; other patients present with symptoms of anemia, chills, jaundice, and fever. Management consists of monitoring hemoglobin concentration and renal output and avoiding the use of units with the offending antigen in the future.

  • Delayed hemolytic transfusion reactions usually occur 5–10 days after transfusion and are less dangerous than acute hemolytic reactions.

Febrile Transfusion Reactions

Febrile transfusion reactions are characterized by chills, fever, flushing, headache, tachycardia, myalgias, and arthralgias. They usually begin about 1 hour after the transfusion starts and last for 8 to 10 hours. They occur in 1% of all transfusions. Causes include cytokines from leukocytes and platelets against donor antigens and antiserum protein antibodies. Treatment consists of stopping the transfusion to evaluate the patient; initially, a febrile reaction cannot be distinguished from a hemolytic transfusion reaction. Preventive methods include leukoreduction.

  • Febrile transfusion reactions usually begin about 1 hour after the start of a transfusion.

Circulatory Overload

Circulatory overload may cause tightness in the chest, dry cough, and acute edema. It occurs in patients who already have an increased intravascular volume or decreased cardiac reserve, with symptoms generally developing within several hours after transfusion. Management includes slowing the transfusion to 100 mL per hour, placing the patient in the sitting position, and giving diuretics.

  • Symptoms of circulatory overload develop within hours of transfusion and affect patients with increased intravascular volume or decreased cardiac reserve.

Posttransfusion Purpura

Posttransfusion purpura is a rare syndrome in which the recipient makes antiplatelet antibodies, which cause an abrupt onset of severe thrombocytopenia 5 to 10 days after blood transfusion. Most cases involve patients who lack human platelet antigen 1a and who have an antibody from a previous pregnancy or transfusion.

  • Posttransfusion purpura usually occurs in patients who have an antibody from a previous pregnancy or transfusion.

Infection

Pathogen transmission may occur with transfusions. These risks and other risks of transfusion are summarized in Table 34.3.

Porphyria

The porphyrias are enzyme disorders that are autosomal dominant with low disease penetrance, except for congenital erythropoietic porphyria (which is autosomal recessive) and porphyria cutanea tarda (which may be acquired and is associated with hepatitis C and hemochromatosis). Most persons remain biochemically and clinically normal throughout most of their lives. Clinical expression is linked to environmental and acquired factors.

Disease manifestations depend on the type of excess porphyrin intermediate. When there is an excess of the earlier precursor molecules (δ‎-aminolevulinic acid and porphobilinogen), the clinical manifestations are neuropsychiatric, including autonomic dysfunction (abdominal pain, vomiting, constipation, tachycardia, and hypertension), psychiatric symptoms, fever, leukocytosis, and paresthesias. If the excess is in the distal intermediates (uroporphyrins, coproporphyrins, and protoporphyrins), the manifestations are cutaneous (photosensitivity, blister formation, facial hypertrichosis, and hyperpigmentation). If there is excess of both early and late porphyrins, there are both neuropsychiatric and cutaneous manifestations.

Porphobilinogen production and excretion are increased during marked symptoms caused by the 3 neuropathic porphyrias, which include acute intermittent porphyria, hereditary coproporphyria, and porphyria variegata. In hereditary coproporphyria and porphyria variegata, there is an accumulation of coproporphyrinogen/coproporphyrin or protoporphyrinogen/protoporphyrin and a concomitant increase in δ‎-aminolevulinic acid and porphobilinogen. In the acute porphyrias, determine the 24-hour urinary porphobilinogen level during an attack. Patients with acute intermittent porphyria lack skin lesions. It is important to check fecal porphyrins in protoporphyria, porphyria variegata, and coproporphyria. An elevated coproporphyrin level alone, therefore, does not support a diagnosis of porphyria. The porphyrias are compared in Table 34.5.

  • In suspected acute porphyria, determine the 24-hour urinary porphobilinogen level during the acute episode.

  • Mild coproporphyrin elevation is nonspecific and not diagnostic of porphyria.

  • Porphyria cutanea tarda is associated with chronic hepatitis C and with hemochromatosis.

Table 34.5 Comparison of Porphyrias

Porphyria Cutanea Tarda

Acute Intermittent Porphyria

Porphyria Variegata

Features

Most common type of porphyria Iron overload

Skin lesions on light-exposed areas

Hypertrichosis (usually mild)

Increased uroporphyrins in urine

No neuropathic features

Increased urinary δ‎-aminolevulinic acid & porphobilinogen during acute symptomatic episodes; often normal levels between episodes

Neurologic symptoms: abdominal pain of 3–5 days’ duration without anatomical cause, focal neurologic problems such as polyneuropathy & motor paresis, psychiatric problems with hallucinations, confusion, psychosis, seizures

Decreased porphobilinogen deaminase activity

Normal protoporphyrin & coproporphyrin in stool

Clinically: photosensitivity, abdominal pain, neurologic problems (similar to acute intermittent porphyria)

Increased protoporphyrin & coproporphyrin in stool

Associations

Alcoholic liver disease, chronic hepatitis C, hemochromatosis

Estrogens: females, males treated for prostatic carcinoma

Hexachlorobenzene

Drugs can precipitate crises (eg, sulfonamides, barbiturates, alcohol)

Menstrual cycle can exacerbate symptoms

Infection or surgery can precipitate crisis

Inadequate nutrition can precipitate crisis

Common in South Africa (due to founder effect), Holland

Treatment

Phlebotomy to remove iron

Chloroquine

Low-dose antimalarials

Avoid prolonged fasting & crash diets

Large amounts of carbohydrate (400 g daily)

Intravenous hematin

Luteinizing hormone–releasing hormone agonists for suppression of hormonal fluctuation

Same as for acute intermittent porphyria

Summary

  • Iron deficiency anemia should prompt a search for the underlying cause.

  • Hemolytic anemias may be hereditary or acquired, from factors intrinsic or extrinsic to the RBC, and Coombs-positive or Coombs-negative.

  • The most common cause of acute hemolytic transfusion reaction is human error.