ANEMIA
GENERAL PRINCIPLES
Definition
Anemia is defined as a decrease in circulating RBC mass, the usual criteria being an Hgb <12 g/dL or Hct <36% for women and an Hgb <14 g/dL or Hct <41% for men. Anemia is commonly encountered in inpatient medicine and thus a frequent reason for hematology consults. A systematic approach to anemia is best at narrowing down the diagnosis and guiding the subsequent diagnostic workup.
Etiology
While there can be some overlap, anemia can be divided into three broad categories: blood loss (acute or chronic), increased destruction of RBCs (hemolysis), and decreased production of RBCs. Blood loss can be evaluated by a careful evaluation of the patient, including volume status. The reticulocyte count will usually help differentiate between states with decreased production (reticulocyte index [RI] <2%; see below for description of RI) and those associated with increased destruction (implied when the RI is >2%).
DIAGNOSIS
Clinical Presentation
History
As with any other medical condition, the history and physical exam play key roles in approaching anemia. Based on symptomatology, one can discern the time line (acute, subacute, or chronic), the severity, and even the underlying etiology. Patients can be asymptomatic, but those patients with an Hgb <7 g/dL will usually have symptoms. Acute clinical manifestations include those typical of hypovolemia (pallor, visual impairment, syncope, hypotension, and tachycardia) and require immediate attention. Chronic symptoms will reflect tissue hypoxia (fatigue, headache, dyspnea, lightheadedness, and angina). In addition to the usual symptoms of anemia, iron deficiency is often associated with pica (consumption of nonfood substances such as corn starch or ice). A careful history of the clinical manifestations including initial presentation, time of onset, potential source of blood loss, family history, and medication history must be evaluated carefully.
Physical Exam
On exam, one can note pallor, alopecia, atrophic glossitis, angular cheilosis, congestive heart failure (with severe and chronic anemia), koilonychias (spoon nails), Plummer-Vinson or Patterson-Kelly syndrome (dysphagia, esophageal web, and atrophic glossitis with iron dficiency anemia), blue sclera, and brittle nails, as well as hypotension and tachycardia.
Diagnostic Testing
The complete blood count (CBC) measures WBCs, Hgb, Hct, platelets, as well as measures of the red cell indices. The Hgb is a measurement of mass of Hgb in blood (grams per deciliter), whereas the Hct is the physical amount of space that the Hgb occupies as a percentage of the whole that the red cells occupy. Remember that the Hgb and Hct are unreliable indicators of red cell volume in the setting of rapid shifts of intravascular volume (i.e., acute bleeding).
The most useful red cell indices include the mean corpuscular volume(MCV), red cell distribution width (RDW), and mean cell Hgb concentration (MCHC). MCV is the mean size of the red cells and the normal range is 80 to 100 fL. RBCs can be classi fied as microcytic when the MCV is <80 fL and macrocytic when it is >100 fL. RDW is a measure of variability in the size of the red cells and is calculated as: RDW = (standard deviation of red cell volume ÷ mean cell volume) × 100. An elevated RDW indicates increased variability in RBC size. The MCHC describes the concentration of Hgb in each cell.
The reticulocyte count measures the immature red cells in the blood as a percentage of the whole and reflects the bone marrow's (BM's) response to anemia (i.e., a normal BM response is to increase the production of red cells in anemia so that the observed reticulocyte count goes up). A nascent RBC lives on average for 120 days, and the BM is constantly replenishing the bloodstream with new RBCs, with the normal reticulocyte count bein ~1%. In the setting of anemia or blood loss, the BM should increase its production of RBC in proportion to loss of RBC, and thus a 1% reticulocyte count in the setting of anemia is inappropriate. The RI is calculated as percentage reticulocytes × (actual Hct/ normal Hct) and is important in determining if a patient's BM is responding appropriately to the level of anemia. In normal individuals, an RI of 1.0 to 2.0 is acceptable; however, an RI of <2 with anemia indicates decreased production of RBCs. An RI of >2 with anemia may indicate hemolysis or loss of RBC leading to increased compensatory production of reticulocytes.
The peripheral smear is a required part of the initial hematologic evaluation. Shapes, size, and orientation of cells in relation to each other are important factors to look for in a smear. RBCs can appear in many abnormal forms, such as acanthocytes, schistocytes, spherocytes, and teardrop cells, and abnormal orientations such as rouleaux formation.
A bone marrow biopsy may be indicated in cases of normocytic anemias with a low RI without an identifiable cause or anemia associated with other cytopenias. The biopsy may confirm myelophthisic process (i.e., presence of teardrop or fragmented cells, normoblasts, or immature WBCs on peripheral blood smear)in the setting of pancytopenias.
ANEMIAS ASSOCIATED WITH DECREASED PRODUCTION
The approach to an anemia associated with decreased production of red cells is to divide them into categories based on red cell size with the MCV. Depending on the MCV, microcytic (<80 fL), normocytic(80 to 100 fL), and macrocytic (>100 fL) anemias have distinct differential diagnoses.
MICROCYTIC ANEMIAS
Iron-deficiency anemia, sideroblastic anemia, and anemia of chronic disease make up the bulk of the microcytic anemias. The degree of microcytosis may give a clue to the possible underlying diagnoses. A very low MCV typically does not represent anemia of chronic disease or sideroblastic anemia (Table 3-1).
Iron-Deficiency Anemia
Etiology
Iron-deficiency anemia can be caused by decreased intake/absorption of iron or loss of iron from chronic blood loss. Dietary deficiency is usually seen in infants who are milk-fed. In early childhood, it can be seen in meat-deficient diets. It can also occur in the setting of increased requirements, such as pregnancy and early childhood. Malabsorption of iron can occur in the setting of partial gastrectomy, as hypochlorhydria/achlorhydria impairs iron absorption. Iron is most actively absorbed in the duodenum. Decreased transit time through duodenum, as seen in chronic diarrhea, may result in iron deficiency. Gastrointestinal causes for iron deficiency (e.g., atrophic gastritis, Helicobacter pylori gastritis, celiac disease) should be considered in patients with otherwise unexplained iron dficiency, especially when there is refractoriness to oral iron therapy.1
Chronic blood loss is the most common cause of iron deficiency in adults. It is usually lost via the GI tract by ulcerative disease, gastritis, cancer, hemorrhoids, or arteriovenous malformation, with ulcers and colon malignancies being the most common. Menorrhagia/menstruation, hematuria due to genitourinary cancer, frequent blood donation, and frequent phlebotomy in hospitalized patients are additional causes of chronic blood loss. It should be noted that the diagnosis of iron deficiency in an adult mandates evaluation for GI malignancy.
Diagnosis
Diagnosis involves serum testing of iron with an iron panel and ferritin level. The iron panel includes serum iron level, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), and transferrin saturation (Tsat).
Serum iron levels reflect the level of iron immediately available for blood production. TIBC is an indirect method of determining the transferrin level in serum. Transferrin is an iron-transporting protein that is capable of associating reversibly with up to 1.254 g of iron per 1 g of protein. In one series, a transferrin saturation less than 15% was 80% sensitive as an indicator of iron dficiency, but only 50% to 65% specific.
Serum ferritin (intracellular iron storage protein) should also be checked and, when low, almost always signifies iron deficiency. Virtually all patients with serum ferritin concentrations less than 10 to 15 ng/mL are iron deficient, with a sensitivity of 59% and a specificity of 99%.2 However, it is an acute phase reactant and can be falsely elevated in inflammatory states. The effect of inflammation is to elevate serum ferritin approximately threefold. A useful rule of thumb in such patients is to divide the patient's serum ferritin concentration by 3; a resulting value of 20 or less suggests concomitant iron deficiency.
Serum transferrin receptor (sTfR) provides a quantitative measure of total erythropoietic activity, since its concentration in serum is directly proportional to erythropoietic rate and inversely proportional to tissue iron availability. Typically, in iron-deficiency anemia, the iron level is low, the TIBC is in the normal to high range, sTfR is high, and ferritin is depleted. The Tsat, the percentage of transferrin that is bound to iron, can be a somewhat less reliable measure of iron. Low transferrin saturation is associated with iron-deficiency states, while high saturation is associated with excess iron. The gold standard for diagnosis of an iron-deficiency anemia is a BM biopsy with iron staining; however, this is rarely necessary.
Of note, patients can have microcytic normochromic (concentration of Hgb in the erythrocytes is within the normal range of 32% to 36%) anemia that eventually progresses to microcytic hypochromic as the anemia progresses. With worsening iron-deficiency anemia, there is a gradual increase in anisocytosis and poikilocytosis (abnormally shaped cells).
Treatment
In addition to diagnosing the patient with iron-deficiency anemia, it is important to discover and treat the underlying cause of the iron deficiency, if possible. Iron replacement may be given by oral iron salts, which should be given between meals because food or antacids may decrease absorption. Ascorbic acid given with iron sulfate may increase absorption. One replacement regimen is ferrous sulfate, 325 mg PO tid (equivalent of 65 mg elemental iron tid). Enteric-coated forms are not well absorbed and should not be used.
Parenteral iron is given when the patient is intolerant of oral iron, when iron losses exceed the capacity to replete orally, or in the setting of malabsorption. There is ~ 1 in 300 risks of a serious reaction including anaphylaxis. The absolute risk for life-threatening adverse reactions for iron sucrose, ferric gluconate complex, low MW dextran, and high MW dextran is 0.6, 0.9, 3.3, and 11.3 per million doses, respectively.
The amount of Fe needed can be calculated as the amount of Fe needed to replace the missing Hgb added to the amount necessary to replete the total body Fe stores (usually estimated as approximately 1000 mg) by the formula:
Total dose (mg) = {[normal Hgb(g/dL) — patient Hgb(g/dL)] × body weight [kg] × 2.2)} + 1000 mg
However, in practice, iron is often infused at a dose of 1 to 1.2 g without formal calculation of iron repletion.
One can expect an increase in the reticulocyte count within 7 to 10 days, and correction of anemia usually occurs within 6 to 8 weeks if ongoing blood loss is stopped. Treatment should continue for approximately 6 months (on PO iron) to fully restore tissue stores.
Sideroblastic Anemias
Sideroblastic anemias are characterized by ineffective erythropoiesis and the presence of ringed sideroblasts in the BM. The term ringed refers to the accumulation of iron in the mitochondria that surrounds the periphery of the nucleus. There are hereditary and idiopathic forms, as well as forms associated with drugs or toxins such as alcohol, lead, isoniazid (INH), zinc toxicity with resulting copper deficiency, and chloramphenicol. There is no cure for hereditary sideroblastic anemia, and treatment is aimed at preventing end-organ damage from iron overload (chelation therapy). Drug-induced sideroblastic anemias are commonly reversible when the offending agent is discontinued. For sideroblastic anemia caused by isoniazid treatment, high-dose pyridoxine supplementation (up to 200 mg/d PO) often reverses the anemia and allows for continuation of the drug.
Lead Poisoning
An additional diagnosis to consider in cases of microcytic, hypochromic anemias is lead poisoning. This is a rare but treatable form of microcytic anemia in adults and usually results from a work or an environmental exposure. The diagnosis is suggested by finding basophilic stippling on the peripheral smear.
Anemia of Chronic Disease
Anemia of chronic disease usually presents as a normocytic anemia; however, it can be microcytic (usually mild) in a minority of cases.
Thalassemias
Epidemiology
Beta-thalassemia is more common in Mediterranean, African, and Southeast Asian populations and is thought to offer resistance to falciparum malaria.
Pathophysiology
The major hemoglobin in adults is hemoglobin A, a tetramer consisting of one pair of alpha-globin chains and one pair of beta-globin chains. 3 In normal subjects, globin chain synthesis is very tightly controlled, such that the ratio of production of alpha to non-alpha chains is 1.00 ± 0.05. Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains, thus disrupting this closely regulated ratio.
Beta-thalassemia major results from a total lack of production of beta-globin chain. It causes lack of adequate Hgb A formation, leading to microcytic, hypochromic cells. Complications of severe beta-thalassemia include skeletal deformities resulting from erythropoietin-stimulated expansion of BM, hepatosplenomegaly from extramedullary hematopoiesis, and secondary hemochromatosis from repeat blood transfusions and increased dietary absorption of iron.
Beta-thalassemia minor is loss of only one of the two alleles coding for the beta-globulin gene. It is usually an asymptomatic condition manifested by microcytosis and a normal red cell distribution width. It is accompanied by a mild anemia (if any). On electrophoresis in patients with beta-thalassemia minor, over 90% of the hemoglobin will be hemoglobin A along with an elevation in the hemoglobin A2 value, sometime as high as 7% or 8%, and an increase in hemoglobin F in about 50% of patients.
Alpha-thalassemia results from decreased production of alpha-globin chains, of which there are four in total. The severity of anemia depends on the number of defective alpha genes. Hemoglobin H disease is due to the loss of three of the four alpha-globin loci. Adult patients have moderate degree of anemia, and their hemoglobin electrophoresis pattern shows 5% to 30% hemoglobin H (beta-4 tetramers). Hydrops fetalis with hemoglobin Barts (gamma-4 tetramers) is due to loss of all four alpha-globin loci. This condition is incompatible with extrauterine life. Diagnosis is by Hgb electrophoresis for beta-thalassemia and severe alpha-thalassemia. Mild alpha-thalassemia may be detected by alpha:beta ratio or by molecular testing, although neither is widely available.
Treatment
The treatment of thalassemias usually depends on the severity of the genetic defect and resultant clinical sequelae. The minor thalassemias are commonly asymptomatic and require no therapy. The major thalassemias may be treated by chronic transfusions, chelation therapy to avoid iron overload (due to transfusions), and splenectomy. For ferritin concentrations >1000 ng/mL, chelation therapy may reduce the long-term complications of iron overload. Options for chelation include the intramuscular or subcutaneous iron chelator deferoxamine and oral iron chelator deferasirox.
NORMOCYTIC ANEMIAS
Normocytic anemias can be associated with an elevated reticulocyte count, which represents hemolytic anemia (HA) or bleeding, whereas a decreased reticulocyte count typically represents a hypoproliferative disorder (Table 3-2). Normocytic anemia may be an early finding in BM failure. Aplastic anemia is actually a BM failure syndrome and is discussed in Chapter 8. Pure RBC aplasia involves a selective destruction of RBC precursors and can be congenital or acquired. It is often associated with viral infections (e.g., parvovirus). Symptoms are related to the anemia. Diagnosis is via BM biopsy showing absence of erythroid elements but with preservation of other cell lines. Treatment includes supportive measures with transfusions as needed.
Anemia of Chronic Disease (Anemia of Chronic Inflammation)
This condition is often associated with malignancy, infection, and inflammatory states. It may occur in patients with chronic infections (e.g., osteomyelitis), HIV, or inflammatory diseases (e.g., lupus or rheumatoid arthritis). These disorders have in common the inhibition of normal RBC synthesis due to the underlying disorder. They may act by inadequate release of or insensitivity to erythropoietin. Other etiologies include deficiency in mobilization of iron from the reticuloendothelial system. One acute phase protein that appears to be most directly involved in iron metabolism is hepcidin.4,5
The anemia is most often a normocytic, normochromic anemia with a decreased reticulocyte count but may also present as a mild microcytic anemia. The serum iron concentration and total iron-binding capacity are usually both low, often giving a normal transferrin saturation (although this may be low or low-normal range). Serum ferritin, however, is an acute phase reactant and is often elevated in inflammatory diseases and infections. BM exam, if done, typically shows present iron stores. Symptoms and physical exam of the anemia of chronic disease patient are dependent on the patient's underlying condition. The anemia is typically mild and does not require blood transfusion. The more appropriate treatment is to treat the underlying condition.
Myelophthisic Anemias
Myelophthisic anemias refer to those with evidence of hematopoiesis outside the BM or infiltration of the BM by nonhematologic cells. The most common cause is metastatic carcinoma to the BM (e.g., breast, lung, prostate, and kidney). Other causes include myeloproliferative disorders, multiple myeloma, leukemias, and lymphoma. These are often suspected by a typical appearance of the peripheral smear (nucleated RBC, teardrop-shaped RBCs, and immature WBCs) and a “dry tap” on BM aspiration. BM biopsy results are dependent on the underlying disease. Treatment is directed toward the underlying disorder.
Anemia of Chronic Renal Failure
Anemia of chronic renal failure is due to erythropoietin deficiency. The anemia generally starts when CrCl <45 mL/min and worsens with declining renal function. When possible, treatment involves first treating the underlying renal dysfunction. Erythropoietin can be given at 50 to 100 U/kg IV or SC 3 × /wk, with readjustments based on response. In follow-up, expect an increase in Hct in 8 to 12 weeks.
Endocrine Disorders
Anemia due to endocrine disorders is seen in hypothyroidism, adrenal insufficiency, and gonadal dysfunction. Estrogens tend to inhibit red cell synthesis, and testosterone tends to stimulate it. Correction of the underlying endocrine disorder may improve the anemia.
MACROCYTIC ANEMIAS
Anemias that have an MCV of more tha ~100 fL are macrocytic anemias. These may be separated into two categories based on features seen on peripheral smear: megaloblastic and nonmegaloblastic. Megaloblastic features include the presence of oval macrocytes and hypersegmentation of the PMNs. They are a consequence of abnormal maturation of these cells and nuclear/cellular asynchrony. Examples of megaloblastic anemia include vitamin B12deficiency, folate deficiency, and drug-induced megaloblastic anemia. Nonmegaloblastic features include the presence of round macrocytes without hypersegmentation of the PMNs. Causes of nonmegaloblastic macrocytic anemia include liver disease, hypothyroidism, alcohol-induced reticulocytosis and reticulocytosis secondary to HA, and myelodysplastic syndrome (see Chap. 8 for further discussion).
Vitamin B12 Deficiency
The daily requirement of vitamin B12 is 2 μg/d, and a typical diet provides 5 to 15 μg/d, with the liver capable of storing ~2000 to 5000 μg. Thus, it takes up to 3 to 6 years for deficiency to develop once absorption completely ceases.
Etiology
Etiologies include pernicious anemia (the most common cause), gastrectomy or gastric bypass surgery, ileal disorders (sprue, inflammatory bowel disease, and lymphoma), bacterial overgrowth in the small intestine, fish tapeworms, and inadequate intake (this is very rare and only occurs in the strict vegetarian).
Clinical Presentation
Symptoms include burning sensation of the tongue, vague abdominal pain, diarrhea, numbness, paresthesia, and mental impairment. On exam, one can note glossitis, smooth tongue, dorsal column findings (decreased vibration and proprioception), and corticospinal tract findings (motor weakness, spasticity, positive Babinski sign). Of note, patients can present with neurologic signs without overt anemia.
Diagnostic Testing
In cases of borderline-low B12 values, one can measure serum methylmalonic acid and homocysteine levels, which are elevated in vitamin B12 deficiency. Once dficiency is established, an attempt should be made to identify the etiology. The presence of anti-intrinsic factor antibodies or anti-parietal cell antibodies lends support to the diagnosis of pernicious anemia. Surgical history can reveal postsurgical etiologies. Suspicion of ileal disorder can be evaluated by endoscopy. Stool ova and parasites should be performed if suspicious for parasitic infection. A therapeutic trial of antibiotics may be given if bacterial overgrowth is suspected. The Schilling test is rarely used today but may delineate the underlying pathology.
Treatment
Treatment usually includes vitamin B12, 1 mg IM or SC daily for 7 days, then weekly for 1 month, followed by monthly doses thereafter. There are data suggesting that oral vitamin B12 at doses of 1 to 2 mg daily is just as effective as IM administration.6 Failure to correct or identify the underlying mechanism of deficiency may result in lifelong therapy.
Monitoring/Follow-up
Reticulocytosis should occur in 5 to 7 days, with resolution of hematologic abnormalities ~2 months. Resolution of neurologic abnormalities depends on their duration before treatment and may take up to 18 months but can also be permanent.
Folate Deficiency
The daily requirement of folate is 50 to 100 μg/d, with body stores of ~5 to 10 mg. Depletion can occur after ~2 to 4 months of persistent negative balance.
Etiologies include inadequate intake (e.g., alcoholics), decreased absorption (e.g., sprue, bacterial overgrowth, certain drugs such as phenytoin and oral contraceptives), or states of increased requirements (HA, pregnancy, chronic dialysis, exfoliative dermatitis). Folate deficiency can also be iatrogenic, such as treatment with folic acid antagonists (e.g., methotrexate, trimethoprim).
Symptoms and physical exam are similar to vitamin B12 deficiency except that neurologic features are not present. Both serum and RBC folate levels must be measured. Serum folate is more labile and subject to acute rise after a folate-rich meal; RBC folate is a better indicator of tissue stores.
It is important to rule out vitamin B12 deficiency before repletion with folate, because folate may improve the hematologic abnormalities in vitamin B12 deficiency but will not correct the neurologic manifestations.
Treatment is with oral folate (1 mg/d), with resolution of hematologic abnormalities ~2 months.
Drug-Induced Disorders
Several drugs can cause a macrocytic anemia by affecting DNA synthesis. Offenders include purine analogs (e.g., 6-mercaptopurine, azathioprine), pyrimidine analogs (5-fluorouracil, cytarabine), hydroxyurea, and anticonvulsants (phenytoin, phenobarbital). Reverse transcriptase inhibitors (AZT, etc.) may cause macrocytosis without anemia. Therapy is cessation of the offending agent or toleration of a mild anemia if the drug is therapeutically needed.
Nonmegaloblastic Anemia
Nonmegaloblastic anemias typically have round macrocytes without hypersegmentation of PMNs on peripheral smear. MCV of nonmegaloblastic anemias is rarely > 110 to 115. A value higher than this would tend to support a megaloblastic etiology. When the reticulocyte count is elevated, it suggests an etiology such as alcohol, hypothyroidism, or liver disease. HA can produce a macrocytosis via increased production of reticulocytes. Nonmegaloblastic anemias are usually treated by identifying and treating the underlying etiology, such as discontinuation of alcohol use and thyroid hormone replacement.
ANEMIAS ASSOCIATED WITH INCREASED DESTRUCTION
Table 3-3 lists causes of anemia associated with increased RBC destruction. Hemolytic anemias can be classified by the location of hemolysis or the mechanism of hemolysis.
Location of Hemolysis
Extravascular— Cell destruction occurs in the reticuloendothelial system, usually in the spleen.
Intravascular— RBC destruction takes place within the circulation.
Mechanism of Hemolysis
Intrinsic— Hemolysis is caused by a defect in the RBC membrane or contents.
Extrinsic— Factors outside the RBC, such as serum antibody, trauma within circulation, infection, etc., lead to RBC damage.
In general, most intrinsic causes are hereditary, and most extrinsic causes are acquired.
Hemolytic Anemias
General Principles
Hemolytic anemias are disorders in which the destruction of RBCs leads to a decrease in circulating RBC mass. Acute hemolysis may be accompanied by a wide variety of signs and symptoms, many of which may point to the underlying etiology.
Diagnosis
Patients may present with fever, chills, jaundice, back and abdominal pain, splenomegaly, and brown or red urine. Peripheral blood smear remains a useful tool both to confirm the diagnosis of hemolysis and to aid in discerning the underlying etiology. Some signs commonly found on peripheral smears include spherocytes (autoimmune HA, hereditary spherocytosis), helmet cells or schistocytes (microangiopathic HA), sickle cells and Howell-Jolly bodies (sickle cell anemia), spur cells (in liver diseases), bite cells or Heinz bodies (glucose-6-phosphate dehydrogenase [G-6-PD] deficiency), and agglutination (cold agglutinin). Laboratory abnormalities suggestive of hemolysis, though not specific, include increased lactate dehydrogenase, decreased haptoglobin, and increased unconjugated bilirubin. In addition, signs of compensatory increased RBC production such as an increase in reticulocyte count are typically present. Other useful lab tests include the direct Coombs test, which is a direct antiglobulin test that detects antibodies (usually IgG) or complement (usually C3) bound to the surface of circulating RBCs by mixing patient RBCswith anti-IgG. Positive results occur when allo- or autoantibodies to RBC antigens are present, or when there is nonspecific adherence of other Ig or immune complexes to the RBC surface. The indirect Coombs test, which mixes the patient's serum with normal RBCs, is used to detect the presence of any anti-RBC antibody in the serum.
Sickle Cell Anemia
Sickle cell anemia is caused by a defect in the beta-globin chain, resulting in sickling of RBC under oxidative stress. See Chapter 11 for further details.
Glucose-6-Phosphate Dehydrogenase Deficiency
G-6-PD deficiency is an X-linked disorder that is fully expressed in males and homozygous females and variably expressed in heterozygous females. G-6-PD is the rate-limiting enzyme in the pentose phosphate pathway that helps maintain intra-cellular levels of glutathione, which serves to protect RBC against oxidative damage.
In patients with G-6-PD deficiency, the presence of oxidative stress results in an inability to maintain Hgb in a reduced state, which, in turn, leads to Hgb precipitation within RBCs (Heinz body formation) and intravascular hemolysis. Two main variants of G-6-PD lead to clinically significant hemolysis: G-6-PD A- and G-6-PD Mediterranean. G-6-PD A-, which occurs in 10% of black individuals, has normal enzyme activity in young RBCs but a marked deficiency of enzyme activity in older cells. Therefore, when oxidatively challenged, only the older cells lyse. This form is typically milder and self-limited. The G-6-PD Mediterranean variant occurs in people of Middle Eastern and Mediterranean descent, and is characterized by a nearly complete lack of G-6-PD. Hemolysis in this form tends to be more severe compared to the A- variant.
The diagnosis of G-6-PD deficiency is suspected when hemolysis occurs after any form of oxidative stress, most commonly from starting on drugs known to precipitate hemolysis in a G-6-PD-deficient patient (Table 3-4). Other triggers of hemolytic crises include certain foods, most notably fava beans, illnesses such as severe infections, and diabetic ketoacidosis. Findings on the peripheral blood smear suggestive of the diagnosis include Heinz bodies and “bite” cells. Heinz bodies are Hgb precipitants in the RBC, while bite cells are deformed RBCs that result from attempts by macrophages in the spleen to remove the Heinz bodies.
Definitive diagnosis is made by measuring G-6-PD enzyme activity level. In suspected G-6-PD A2 variant, enzyme levels should not be measured during acute hemolysis. In these patients, older RBCs containing the defective enzymes have mostly been lysed during acute hemolysis, and the normal enzyme activities in the remaining younger RBCs and reticulocytes will provide a false-negative result. It is, therefore, advisable to wait 3 to 4 weeks after the acute episode to get a true representation of the enzyme activity level. The same does not apply to the Mediterranean variant, as both younger and older red cells are affected.
Treatment is supportive, with transfusions as needed, and preventive, with avoidance of oxidative precipitant.
Hereditary Spherocytosis (Membrane Defect)
Hereditary spherocytosis is an autosomal dominant disorder most common in patients of Northern European descent. In these patients, a defect in a membrane cytoskeletal protein leads to loss of surface area on the RBCs, resulting in spherocyte formation. Hemolysis of the spherocytic RBCs occurs primarily in the spleen.
Clinical presentation may vary from asymptomatic to profound anemia and jaundice, depending on the severity of spherocytosis. Some patients may present with cholelithiasis. Splenomegaly is detected in most patients due to extravascular hemolysis. Peripheral blood smears reveal spherocytes. The MCV is normal or slightly low and is of little diagnostic value. However, considering the degree of reticulocytosis, the MCV is actually low. In unsplenectomized children, for example, elevations in MCHC (> 35 g/dL [normal 31.1–34 g/dL]) and RDW (> 14 [normal mean 12.6]) have a sensitivity of 63% and specificity of 100% for the diagnosis of HS, making these combined indices a powerful screening tool. 7 The osmotic fragility test, which measures the RBC resistance to hemolysis when incubated in hypotonic saline, will show increased hemolysis.
Treatment is largely supportive, with transfusions as needed and folate supplement to support increased erythropoiesis. Splenectomy, which corrects the anemia but not the underlying defect, can be curative and may be considered in patients with severe anemia.
Acquired Immune Hemolytic Anemia
Warm Antibody
Warm antibody is the most common form of autoimmune HA. The most common antibodies involved are IgG and they are most active at 37 ? C. Sixty percent of cases are idiopathic (or primary), whereas 40% are secondary.Secondary causes include chronic lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, auto-immune disorders (such as systemic lupus erythematosus), and drugs. Drug-related antibodies can occur by three main mechanisms:
Autoantibody— Antibody against Rhesus (e.g., methyldopa) is produced.
Hapten— Drug binds to the RBC membrane, acting as hapten, which serves as a target for antibodies. Hemolysis typically occurs 1 to 2 weeks after treatment (e.g., penicillin, cephalosporins).
Immune complex— Drug binds to plasma protein, evoking an antibody response. The drug-protein-antibody complex then nonspecifically coats RBCs, resulting in complement-mediated lysis (e.g., quinidine, INH, sulfonamides).
Warm antibodies usually cause extravascular hemolysis by the spleen, leading to splenomegaly. Almost all are panagglutinins (i.e., react with most donor RBCs), thus making crossmatching difficult. Treatment for drug-induced hemolysis is withdrawal of the offending agent, as hemolysis will stop with clearance of the drug. Steroids (prednisone) and immunoglobulins remain the most commonly used initial therapies. Prednisone up to 1 mg/kg/d may be used for severe hemolysis in idiopathic forms, until Hgb reaches normal levels over a few weeks, and then tapered. Intravenous immunoglobulins may be effective in controlling hemolysis, though its benefits tend to be short-lived. Splenectomy is an option for patients who fail or relapse after steroid taper. If steroids and splenectomy both fail, other immunosuppressives such as rituximab, cyclosporine, azathioprine, and cyclophosphamide should be considered. Transfusions should be avoided, if possible, as they may result in more hemolysis.
Cold Antibody
Most cold antibodies are IgM and active at <30°C. Acute onset is often associated with infectious causes such as mycoplasma pneumonia and infectious mononucleosis, whereas chronic forms occur with lymphoproliferative disorders or are idiopathic.
The two main manifestations are acrocyanosis (ears, nose, and distal extremities) and hemolysis (complement mediated). Symptoms mainly occur in distal body parts, where the temperature often drops below 30°C. In these cold temperatures, IgM will bind to the RBCs, leading to complement fiation and hemolysis. The antibody dissociates from the RBCs as the temperature rises above 30°C. Hemolysis is not usually seen unless cold agglutinin titers are above 1 in 1000. Treatment mainly involves avoidance of cold exposure and treatment of the underlying disorder. While certain immunosuppressive agents and plasmapheresis may be effective, splenectomy and steroids are of limited therapeutic value.
Acquired Nonimmune Hemolytic Anemia
Acquired causes of nonimmune HA are often secondary to physical damages from the environment, chemical changes, or infections. Microangiopathic and macroangiopathic HAs represent the most common causes of environmental damages. In these cases, changes in the vasculature result in the destruction of RBCs due to physical stress. Conditions associated with these forms of HAs include disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), prosthetic heart valves, and severe aortic stenosis. DIC, TTP, and HUS are discussed in Chapter 4. Osmotic changes and certain snake and spider venom are examples of chemical damages to RBCs. HA is a characteristic feature of malarial infections. Table 3-5 lists the causes of acquired nonimmune HA.
POLYCYTHEMIA
Secondary polycythemia refers to erythrocytosis, which is defined as increased RBC mass. Chronic generalized or local hypoxia causes the body to respond by producing RBC mass to compensate. Chronic hypoxia from congenital heart disease, lung diseases including chronic obstructive lung disease and smoking with increased carboxy-hemoglobin levels, or even local hypoxia to kidneys may increase erythropoietin levels from the kidneys (appropriate or inappropriate), resulting in increased production of RBCs. On physical exam, a ruddy complexion can be seen in patients with secondary polycythemia. In patients who are suffering from chronic hypoxia at severe levels, clubbing or even cyanosis may be found. Usually, no therapy is indicated in patients with erythrocytosis, as it is a physiological response to hypoxia and is a compensatory mechanism.
Secondary polycythemia can be distinguished from primary polycythemia (polycythemia vera) by the erythropoietin level, which is elevated in secondary polycythemia and low or normal in polycythemia vera. Polycythemia vera is a stem cell disorder leading to increased RBC mass, which is discussed further in Chapter 9.
REFERENCES
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