ANEMIA

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ANEMIA

INTRODUCTION

Anemia is one of the most common blood disorders worldwide and, in developed countries, commonly affects older adults. The primary function of a red blood cell is to deliver oxygen to the tissues. Red blood cells are made in the bone marrow and must contain adequate amounts of hemoglobin to perform this function. Normal production is dependent on the availability of the required “ingredients” (ie, iron, folic acid, vitamin B12), a normal functioning bone marrow, and erythropoietin for stimulation of red cell production. Anemia can result from defects affecting hemoglobin production, dozens of disease states, including renal impairment and chronic inflammatory conditions, and may also be caused by other external or internal factors influencing the circulatory survival of red blood cells through premature destruction or blood loss. This chapter will provide a framework for investigation in order to navigate the many diagnostic tests and treatment options.

Anemia is defined as a reduction in the number of circulating red cells that results in a hemoglobin level lower than an age- and sex-matched population (Table 169-1).

TABLE 169-1 World Health Organization’s Hemoglobin Threshold Used to Define Anemia

Age or Gender Group Hb Threshold (g/dL) Children (0.5-5.0 y) 11.0 Children (5-12 y) 11.5 Children (12-15 y) 12.0 Women, nonpregnant (>15 y) 12.0 Women, pregnant 11.0 Men (>15 y) 13.0

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In addition to the RBC count, hemoglobin, and hematocrit, which make the diagnosis of anemia possible, the complete blood count (CBC) provides essential information that helps tailor the investigation. One of the RBC indices, the mean corpuscular volume (MCV), permits classification of hypoproliferative anemias into hypochromic microcytic anemia (MCV <80 fl), normocytic anemia (MCV 80-100 fl), or macrocytic anemia (MCV > 100 fl). An increase in the reticulocyte count by 1% will increase the MCV by approximately 2 fl. The red cell distribution width (RDW) reflects the variation in RBC size or anisocytosis. Useful in distinguishing between certain hypoproliferative anemias, it is normally 11.5% to 14.5%. Normally between 0.5% and 2.5%, the reticulocyte count is calculated as a percentage of the total RBC; therefore, it must be corrected in the presence of anemia. The reticulocyte production index (RPI) is one method frequently used. The RPI = % reticulocytes × (patient Hct/45)/maturation time. With increasingly severe anemia, more reticulocytes are released from the marrow. The maturation time equals 1 if the patient’s Hct is 45. Each 10-point drop in the patient’s Hct increases the maturation time by 1.5 days. A low reticulocyte count suggests an underlying defect in RBC production; an elevated reticulocyte count suggests an underlying problem in RBC survival. Likewise, an RPI less than 2.5 suggests that the anemia stems from a hypoproliferative process; an RPI greater than 2.5 suggests that the anemia is due to bleeding or hemolysis. Examination of the peripheral smear may reveal morphologic abnormalities of the RBC that permit an accurate and timely diagnosis (Table 169-2).

TABLE 169-2 The Peripheral Smear

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BM, bone marrow; CML, chronic myelogenous leukemia; DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; RBC, red blood cell; RDW, red cell distribution width; RS, ringed sideroblasts; TIBC, total iron binding capacity; TS, transferrin saturation; TTP, thrombotic thrombocytopenic purpura.

PATHOPHYSIOLOGY

Although there are many causes of anemia, clinicians most commonly encounter iron- deficiency anemia, thalassemia trait, and anemia of chronic disease.

Acute anemia results from bleeding or hemolysis. In someone who has been injured or who has suffered complications of surgery, the source of acute bleeding is normally clear. Hemolysis-related anemia due to increased destruction of red blood cells occurs by various mechanisms and can be broadly categorized as intrinsic red cell defects or extrinsic processes (Figure 169-1).

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Figure 169-1 Differential diagnosis of anemia. AIHA, autoimmune hemolytic anemia.

Internally, problems of the red cell membrane (hereditary spherocytosis), the hemoglobin (eg, sickle cell anemia) or the deficiency of glycolytic pathway enzymes (glucose-6 phosphate dehydrogenase [G6PD] and pyruvate kinase [PK]) result in shorter life span. External mechanisms can be further classified as immune-mediated or nonimmune resulting from infection, drugs, or mechanical injury. Hemolysis can occur intravascularly or extravascularly (ie, via the reticuloendothelial system), although many times it may be difficult to determine the site of cell destruction due to overlap in overwhelming acute cases.

The differential diagnosis of chronic anemia, whether microcytic, normocytic, or macrocytic, is broad. One of the most common causes of chronic blood loss is occult blood loss, particularly from the GI tract, or in younger women through menses, leading to iron-deficiency anemia. Once the bone marrow receives the signal from erythropoietin, it requires building blocks from which to assemble the components of the red blood cell. Iron deficiency is one of the most common causes of anemia, often due to dietary deficiency or occult blood loss.

Underproduction of RBC results from a number of chronic diseases. The bone marrow, which produces the majority of red cells, relies on erythropoietin secreted by the kidneys to signal the need for new red blood cell production. In renal impairment, a decreased erythropoietin level leads to chronic anemia. In bone marrow failure states, underproduction may be caused by a decrease of precursor cells (eg, aplastic anemia, pure red cell aplasia), crowding out of normal RBC precursors by malignant cells (eg, leukemia, metastatic cancer) or abnormal maturation (eg, myelodysplastic syndrome, vitamin B12, or folate deficiency). Inflammatory conditions can also cause chronic anemia by a combination of mechanisms due to proinflammatory cytokines that produce a “functional” iron deficiency in which iron is trapped in storage (eg, inside macrophages) instead of being available for hemoglobin production, abnormal proliferation of RBC progenitors in the bone marrow, insufficient erythropoietin, and reduced RBC life span.

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DIAGNOSIS: HOW DO I DETERMINE THE CAUSE OF ANEMIA?

A complete blood count is the backbone for the evaluation of anemia. The World Health Organization (WHO) defines anemia in an adult as a hemoglobin < 13 g/dL for men and < 12 g/dL for women. A patient with chronic, mild, stable anemia can comfortably be evaluated in an outpatient setting. However, any patient with acute and/or severe anemia will benefit from the intensive investigations, monitoring, and treatment offered in the hospital. Anyone who is hemodynamically unstable due to blood loss should receive care in a monitored setting. After the diagnosis of anemia is confirmed, the next step is to determine why so that appropriate treatment can be administered (Figure 169-1). Since the potential causes of anemia are numerous, a thorough and broad history should include query about: Any associated symptoms, in particular, bleeding (gastrointestinal, including melena, menses, hematuria) and constitutional B symptoms Past medical history, in particular, autoimmune/inflammatory disorder, chronic infection, liver disease, renal impairment, thyroid dysfunction, previous diagnosis, and treatment of anemia Medication history Social history, in particular, dietary intake, alcohol use, risk of sexually transmitted infections Family history of anemia Full review of systems, which may uncover symptoms of previously undiagnosed inflammatory disorders or organ dysfunction Most prominent symptoms in severe anemia include fatigue, dizziness, palpitations, or breathlessness on physical exertion. Information about the onset of symptoms may help to determine whether the anemia is acute or chronic. The patient should also be questioned as to whether he or she has had a recent complete blood count. PRACTICE POINT The average red blood cell survives for 120 days after it is released into circulation. If anemia is due to underproduction alone, the hemoglobin should decrease by less than 25% in a 30-day period (roughly 0.1 g/dL/d). The physical examination may reveal evidence of decompensation as in acute blood loss (eg, unstable vital signs) or chronic extreme anemia (eg, congestive heart failure), signs of severe anemia (eg, pallor of the skin, conjunctivae, tongue, nail beds, and palmar creases, or tachycardia and the presence of a flow murmur), or help to identify previously unknown systemic disease (eg, signs of chronic liver disease). Recent blood tests showing a previously normal hemoglobin level may confirm that the anemia is acute. Elevated reticulocyte count or reticulocyte percent is suggestive of acute or ongoing blood loss or hemolysis. If the anemia is not acute, workup can be guided by the peripheral blood smear and the mean corpuscular volume of the red blood cells—small (microcytic), large (macrocytic), or normal size (normocytic). It is also important to note 1578185 - McGraw-Hill Professional © the white blood cell and platelet counts. Pancytopenia can be seen in aplastic anemia, vitamin B12 deficiency, myelodysplastic syndrome, primary bone marrow malignancies, or in liver disease with portal hypertension and splenomegaly. A normal white blood cell and platelet count with isolated anemia is unlikely to be due to marrow failure, with the exception of pure red cell aplasia. The reticulocyte count may also be useful to distinguish conditions associated with hyporegenerative anemia having low values of < 50 × 109/L (aplastic anemia, pure red cell aplasia, or marrow infiltration) from a regenerative anemia seen with hemolysis or hemorrhage. The appearance of the red cells in a peripheral blood film can be associated with the different causes of anemia, and offers suggestions for relevant subsequent investigations (Table 169-2). PRACTICE POINT The first question to ask in the evaluation of anemia is whether the anemia is due to acute or chronic blood loss, decreased production of red blood cells, or increased destruction. The first step is a complete history and physical examination, followed by a review of the complete blood count, the reticulocyte count, and the peripheral blood smear. The objective is to make the correct diagnosis without subjecting the patient to unnecessary laboratory tests and invasive procedures. MICROCYTIC ANEMIA Peripheral blood smear in iron-deficiency anemia (IDA) shows small (“microcytic” or low MCV) red blood cells that are very pale (“hypochromic”) containing less hemoglobin as indicated by a reduced mean corpuscular hemoglobin (MCH). Other changes of note may include anisocytosis (variable size of red blood cells) and poikilocytosis (variable shape of RBCs, eg, target cells and pencil cells). Based on the blood smear alone it is difficult to discern IDA from a thalassemia trait. Therefore, further laboratory testing to investigate iron status and for exclusion of a possible hemoglobinopathy may be required. Serum ferritin is considered a good measure of iron stores; levels below 30 mg/L in otherwise healthy patients are reflective of iron deficiency. However, ferritin is an acute phase reactant and may be higher in iron deficient patients with other medical problems. For this reason, the ferritin threshold may need to be increased. If the diagnosis is unclear, bone marrow examination, which is considered the “gold standard” test to confirm iron- deficiency anemia, should be considered. Other tests that may be useful for the confirmation of a diagnosis in microcytic anemia include serum iron, total iron-binding capacity (TIBC), serum transferrin receptor, and measurement of zinc protoporphyrin (ZPP) and free erythrocyte protoporphyrins (FEP) (Table 169-3). TABLE 169-3 Typical Patterns of Iron Investigations in Iron Deficiency Anemia and Anemia of Chronic Disease Biochemical Marker Iron-Deficiency Anemia Anemia of Chronic Disease/Inflammation Serum ferritin Decreased Normal or increased 1578185 - McGraw-Hill Professional © Serum iron Decreased Deceased or normal Total iron-binding capacity Normal to increased Decreased or normal Transferrin saturation Decreased Decreased or normal Serum transferrin receptor Increased Normal ZPP or FEP Increased Increased FEP, free erythrocyte protoporphyrin; ZPP, zinc protoporphyrin. PRACTICE POINT Stages of iron deficiency are 1. Storage iron depletion (decrease in serum ferritin levels, a reflection of total iron body stores). 2. Iron-deficient erythropoiesis (a transferrin saturation <9%, an indicator of impaired iron supply for the developing RBC). 3. Microcytic hypochromic RBCs (RDW > 15% and variation in RBC shape,

poikilocytosis, unlike Thalassemia). The bottom line: The MCV, serum iron, total iron-binding capacity, and percentage of transferrin saturation can predict the presence or absence of bone marrow iron in most patients without requiring a bone marrow examination.

A hemoglobinopathy should be considered if the patient is healthy, not iron deficient, has a family history of microcytic anemia or thalassemia, or if the patient’s ethnic group is known to commonly have thalassemia or variant hemoglobins associated with microcytosis (HbE). Initial hemoglobinopathy investigations will quantify normal and abnormal hemoglobins to identify beta-thalassemia trait, homozygous beta-thalassemia, and HbE. However, further DNA analysis may be required for diagnosis of alpha- thalassemia or may be useful to confirm the presence of other globin gene deletions or mutations. Pregnant women with microcytosis should always be considered for hemoglobinopathy testing regardless of iron status due to the risk of genetic transmission of a severe form of hemoglobinopathy or thalassemia to the fetus.

NORMOCYTIC ANEMIA

Normocytic anemia is the most frequently encountered category of anemia, and is often the most difficult to workup because it can result from many disparate disorders; it can be due to decreased RBC production, either primary (eg, aplastic anemia, acute leukemia) or secondary (eg, renal failure, anemia of chronic disease). Hemolytic anemia, both immune and nonimmune, and acute bleeding can also present as normocytic anemia.

Hemolytic anemia: increased red cell destruction

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Hemolytic anemia may present in many ways; it can be acute and uncompensated or chronic and well compensated, or anything in between. Therefore most patients presenting with anemia of unclear etiology should be screened for hemolysis. The red cells in hemolytic anemia often vary in appearance depending on the underlying process. Examination of the peripheral smear is a useful tool for the differential diagnosis. Spherocytes can be present in autoimmune hemolytic anemia (AIHA) or in hereditary spherocytosis when the patient has a negative Coombs test. Sickle cell anemia manifests with characteristic sickle-shaped cells. Schistocytes are a hallmark of red cell destruction and can be correlated with platelet numbers for differentiating a microangiopathic hemolytic anemia from macroangiopathic hemolytic conditions caused by heart valves. Decreased platelets are seen in disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS). Platelets are normal in macroangiopathic hemolytic conditions caused by heart valves.

Screening tests that suggest the possibility of hemolysis include elevated lactate dehydrogenase, elevated unconjugated bilirubin, and elevated reticulocyte count. The level of haptoglobin, a protein that binds free hemoglobin in the circulation, may be a useful indicator for hemolysis. A low level or absence of haptoglobin, along with the presence of free hemoglobin in circulation, is suggestive of hemolysis. However, low haptoglobin can also be seen in liver disease. Haptoglobins are an acute phase reactant and therefore may be falsely elevated during any inflammatory process.

Often further specialized testing is required to confirm and identify the cause of hemolytic anemia. This can include direct antiglobulin test (DAT or Coombs test), hemoglobinopathy testing, and/or enzymopathy testing, as indicated. The DAT identifies IgG and/or complement on the RBC surface and can be positive in AIHA, drug-induced anemia, or a hemolytic transfusion reaction. A hemoglobinopathy investigation separates and quantifies the expected hemoglobins (HbA, A2, and F) but will also identify many variant hemoglobins (eg, HbS, C, or E) or other rarer unstable hemoglobin variants (eg, Hb Köln, Hb Hasharon) known to cause hemolysis. To assess for enzyme deficiencies, quantitative testing of red cell pyruvate kinase and G6PD is performed. More recently, flow cytometry has been used to identify paroxysmal nocturnal hemoglobinuria (PNH) using the GPI-anchored antigens CD55 and CD59 on red cells or neutrophils. The osmotic fragility (OF) test is useful for confirmation of hereditary spherocytosis. However, the eosin-5-maleimide (EMA) dye binding test by flow cytometry has shown to have higher specificity and sensitivity than OF for red cell cytoskeleton disorders causing hemolysis.

Decreased red blood cell production

If anemia is due to decreased RBC production, the reticulocyte count will be low or “inappropriately normal.” Serum erythropoietin level can be helpful but it is nondiagnostic; if it is high, it may indicate a primary bone marrow problem, which could be confirmed with a bone marrow aspirate and/or biopsy. Serum erythropoietin level will be low or inappropriately normal in any of the secondary causes of normocytic anemia, particularly in renal dysfunction. Moderate renal impairment can present with anemia, therefore renal function testing is essential, regardless of serum EPO level.

Anemia of chronic disease (ACD) is a difficult diagnosis to pin down. Essentially it is a clinical diagnosis in a patient who has had a sufficient and negative workup for other causes of anemia, and who has an underlying inflammatory condition. Measurement of iron indices or inflammatory markers (eg, erythrocyte sedimentation rate or C-reactive

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protein) may be a useful adjunct in testing. Bone marrow examination should reveal normal or increased amounts of stored iron and decreased iron staining in erythroid precursors, reflecting impaired iron utilization.

MACROCYTIC ANEMIA

B12 deficiency

Vitamin B12 (also known as cobalamin) is obtained by intake of animal products, including red meat, poultry, fish, dairy, and eggs. The total body store of vitamin B12 is 2 to 5 mg, primarily stored in the liver. Approximately 2 to 5 mcg of B12 is lost daily, most of which is excreted in the bile.

Although a typical Western diet contains 5 to 20 mcg/d of vitamin B12, which is more than sufficient to replace daily losses, B12 deficiency can occur in individuals following a strict vegan diet.

In patients with gastritis, gastric atrophy, or history of gastrectomy, absence of gastric acid and pepsin prevents release of cobalamin from the protein to which it is bound. Furthermore, production of gastric intrinsic factor (IF), a molecule that binds free cobalamin in the gastrointestinal tract and facilitates cobalamin absorption in the terminal ileum, may be impaired. Malabsorption can also occur if there is inadequate absorption at the terminal ileum, due to prior resection or Crohn disease.

One of the most common causes of B12 deficiency is pernicious anemia, in which there is a deficiency of IF due to presumed autoimmune destruction of gastric parietal cells or the IF itself.

Vitamin B12 deficiency presents most commonly with hematologic abnormalities and/or neuropsychiatric signs and symptoms. Macrocytic anemia, with macro-ovalocytes on peripheral blood smear, is the classic hematologic abnormality. Neutrophils have hypersegmented nuclei. There may also be leukopenia and/or thrombocytopenia. Bone marrow examination reveals megaloblastosis.

The classic neurological manifestation is subacute combined degeneration of the spinal cord, resulting in sensory and motor disturbances that cause ataxia. Peripheral and cranial neuropathies may also be seen. In severe cases, patients may present with stroke or dementia-like syndromes. Physical examination may reveal classic findings such as glossitis and jaundice.

A serum B12 level <200 ng/L (148 pmol/L) is very sensitive (97%) for the diagnosis of B12 deficiency. Because some patients with normal or low-normal serum B12 levels may be truly deficient and benefit from vitamin replacement, elevated methylmalonic acid (MMA) and homocysteine can help to clarify the diagnosis. Elevated MMA and hemocysteine are both sensitive early markers of B12 deficiency. Elevated levels should, however, be interpreted in the context of individual patients: homocysteine is also elevated in folate deficiency and hereditary homocyteinemia. Methylmalonic acid may be elevated in renal insufficiency and methylmalonic aciduria, and in some patients with folate deficiency. Serum MMA may be lowered in B12-deficient patients receiving antibiotic treatment. A Schilling test, involving oral administration of radiolabeled cocyanocobalamin, has historically been used to assess vitamin B12 absorption. Unfortunately, the Schilling test is not widely available. Anti-intrinsic factor antibodies are highly specific for pernicious anemia (specificity >95%) and therefore, if positive, help to confirm the diagnosis; however sensitivity is poor (50%-70%).

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Folate deficiency

Folate is found in animal products and leafy green vegetables. As such, the most common cause of folate deficiency is inadequate nutritional intake. With universal folate supplementation, folate deficiency has become increasingly rare. However, patients with alcohol abuse remain at risk due to folate malabsorption and impaired folate metabolism in the liver. Individuals with increased folate requirements are also at increased risk. This includes pregnant women (for whom folate deficiency is associated with an increased risk of fetal spina bifida) and patients with chronic hemolytic anemia. The widespread use of routine, prophylactic folic acid supplementation in these groups can prevent deficiency. Use of some drugs has been linked to folate deficiency, including trimethoprim, pyrimethamin, methotrexate, and phenytoin.

Similar to vitamin B12 deficiency, folate deficiency can result in megaloblastic anemia. However, folate deficiency has no neurologic sequelae.

Diagnosis is made when the serum or red blood cell folate is below the normal range. Serum folate concentration may be normal in approximately 5% of individuals with folate deficiency; therefore if there is still a high index of suspicion, red blood cell folate should be tested.

Drug-induced anemia

A number of drugs can cause macrocytosis or macrocytic anemia. These include the following:

Pyrimidine and purine analogs that inhibit DNA synthesis (eg, 5-FU, azathioprine) Antifolates (eg, methotrexate) Hydroxyurea Zidovudine

Other causes of macrocytic anemia

Occasionally, an exceptionally brisk reticulocytosis in response to anemia results in the average red blood cell being larger, thus increasing the MCV measurement. Other causes of macrocytosis that should be considered include liver disease, hypothyroidism, alcohol abuse, and myelodysplastic syndrome.

PRACTICE POINT

Many anemias in their early stages have a normal MCV and then become either microcytic or macrocytic. The peripheral smear may provide important clues such as a myelopthisis (elliptocytes, teardrop cells, immature myeloid forms, nucleated RBCs), sickle cell disease (sickled RBCs), infectious disease (malaria).

TREATMENT

Iron-deficiency anemia

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The goal of treatment for IDA is to improve the hemoglobin level and replenish iron stores. This typically requires 150 to 200 mg elemental iron per day for 4 to 6 months, or until serum ferritin has increased to approximately 50 mg/L. Iron is given orally unless the patient has severe gastrointestinal intolerance, malabsorption, or uncontrolled blood loss. The relative amounts of elemental iron in different preparations are listed below:

Ferrous gluconate: 300 mg 35 mg elemental iron Ferrous sulfate: 300 mg 60 mg elemental iron Ferrous fumarate: 300 mg 100 mg elemental iron Polysaccharide iron complex: 150 mg 150 mg elemental iron

In the absence of ongoing blood loss, hemoglobin should increase by 1 to 2 g/dL within 3 weeks of starting adequate oral replacement, and iron stores should be replete in 3 months. Failure to respond may be due to nonadherence, poor iron absorption, or an incorrect diagnosis. If instead the patient has thalassemia, iron supplementation could be harmful, in that it will increase iron overload.

To improve iron absorption, the iron tablets should be taken on an empty stomach or with orange juice or a tablet of ascorbic acid. Concurrent administration of antacids should be avoided. Many patients complain of nausea or dyspepsia 30 to 60 minutes following a dose. This often subsides with ongoing treatment but, if it is an ongoing issue, night time dosing or administration of higher doses with food may improve symptoms and maintain adequate absorption.

Intravenous iron is an option for patients who are intolerant of or who do not respond to oral iron. These must be administered in a medically supervised area because of risks of hypotension, allergic, or anaphylactic reactions. Several iron preparations are available for intravenous administration, of which iron dextran has the highest risk of adverse reactions.

B12 deficiency

Vitamin B12 replacement can be divided into initial management (designed to quickly build up the tissue stores) and long-term maintenance treatment. A common initial regimen consists of intramuscular cyanocobalamin 1000 mcg/d for 1 or 2 weeks, followed by 1000 mcg/week for 1 month. Hematologic response should be evident 1 week after the first dose. In particular, there should be a noticeable increase in the reticulocyte count. If reticulocytosis is mild or absent, the original diagnosis should be questioned. By the eighth week, the MCV should have returned to the normal range.

Maintenance treatment can be given parenterally or orally. Parenteral cyanocobalamin may be given at a dose of 1000 mcg/month until the cause of deficiency is corrected, or lifelong in pernicious anemia. Oral therapy for pernicious anemia is 1000 mcg/d. Lower doses (eg, 125-500 mcg/d) can be given for other causes of deficiency; however the cost and risk of a higher dose are negligible and a standard dose of 1000 mcg/d is commonly prescribed.

Folate deficiency

Treatment is with oral folic acid (1-5 mg/d) until complete hematologic recovery. Patients with an ongoing cause of folate deficiency (eg, chronic hemolytic anemia or pregnancy) should continue on long-term supplementation. Because treatment with folic acid can partially reverse the hematologic abnormalities seen in vitamin B12 deficiency, but do not attenuate the progression of neurologic sequelae, serum vitamin B12 levels should be measured prior to therapy.

Anemia of chronic renal disease

As the glomerular filtration rates decline, anemia becomes increasingly common in patients with chronic renal disease. Erythropoiesis-stimulating agents (ESAs) are widely used in treatment. Other options include red blood cell transfusions or androgens.

ESAs may be started if the hemoglobin level is ≤ 10 g/dL for predialysis and peritoneal dialysis patients, and if the hemoglobin is ≤ 11 g/dL in dialysis patients. Adequate iron stores should be confirmed, and other causes of anemia should be ruled out. Epoetin alpha or darbepoeitin may be used with a target hemoglobin of 10 to 12 g/dL. Levels above 13 g/dL have been associated with increased risk of thrombotic events. Epoetin alpha can be started at a dose of 10,000 units subcutaneously once weekly or 20,000 units subcutaneously every other week. Lower starting doses may be appropriate for smaller patients or those with higher pretreatment hemoglobin. For dialysis patients, EPO can be administered intravenously during hemodialysis sessions. Throughout ESA therapy, iron supplementation should be used to maintain a transferrin saturation of 20% to 50% and a serum ferritin level of 100 to 500 ng/mL. Ongoing clinical trials are evaluating the precise determinants of cardiovascular risk and the optimal hemoglobin target. Updated clinical practice guidelines should be consulted.

Hemolytic anemia

Any hemolysis caused by an underlying disorder (eg, AIHA due to a lymphoproliferative disorder) is treated in the long term by bringing the disease under control. A short-term treatment may include high-dose oral corticosteroids. Hemolytic anemia caused by cold agglutinins typically improves with avoidance of cold exposure.

Myelodysplastic syndromes

The anemia of myelodysplatsic syndromes (MDS) is typically treated with chronic transfusions or erythropoiesis-stimulating agents (ESAs). Patients with MDS-related anemia with serum EPO level < 100 to 200 mU/mL and lower-risk disease are most likely to respond to ESAs. Relatively high doses of epoetin alpha or darbepoetin are usually required. Patients who do not qualify for or respond to ESAs are likely to require chronic red blood cell transfusions. Unfortunately, transfusion-dependent MDS patients have decreased overall survival, especially those in lower-risk categories. Decreased overall survival in these individuals is linked to elevated ferritin levels, indicating that transfusional iron overload is at least partially responsible for worsened outcomes. Serum ferritin and transferrin iron saturation should be monitored in transfusion-dependent MDS patients. T2-weighted magnetic resonance imaging (MRI) may be used to evaluate for cardiac and liver iron deposition. Chelation therapy should be considered in patients with evidence of iron overload. 1578185 - McGraw-Hill Professional © COMPLICATIONS Bone marrow examination may aid diagnosis if anemia is apparently due to underproduction, or if anemia is associated with leukopenia, thrombocytopenia, and/or other morphologic abnormalities suggesting bone marrow disease. Rarely, bone marrow examination is necessary to help quantify iron stores in a patient with normal serum ferritin but microcytic anemia is felt to be due to iron deficiency. Consultation with a hematologist should be considered in complex cases and for patients with thalassemia, sickle cell disease, other variant hemoglobins, bone marrow failure syndromes, or autoimmune hemolytic anemia. Patients with anemia due to end- stage renal disease may be best managed by a renal specialist. RARE CAUSES FOR CONSIDERATION Thrombotic thrombocytopenic purpura (TTP) is caused by impaired cleavage of ultra large multimers of von Willebrand factor, causing increased platelet aggregation in small vessels. Thrombotic thrombocytopenic purpura presents with hemolytic anemia and thrombocytopenia. Other features can include fever, neurologic symptoms (headache, seizures, or coma), and acute renal impairment. Blood film shows red blood cell fragments (schistocytes) that result from damage to red cells in the microvasculature. When a cause of microcytic or normocytic anemia is not found, remember to test for paroxysmal nocturnal hemoglobinuria (PNH), which typically presents with episodes of intravascular hemolysis and red urine. As a result of chronic and recurrent hemoglobinuria, patients can become iron deficient. Paroxysmal nocturnal hemoglobinuria is a clonal disorder that can result in aplastic anemia or acute leukemia. Patients with PNH are at increased risk of thromboembolism. The diagnosis of PNH is made when flow cytometry shows a clone of WBCs (PB or BM) lacking cell markers CD55 or CD59 or by FLAER (flourescein-labeled proaerolysin). There are several rare congential bone marrow failure syndromes that result in lifelong anemia. These include Diamond-Blackfan anemia, Fanconi anemia, Schwachman- Diamond syndrome, and congential dyserythropoietic anemia. These disorders will typically present in early childhood and require ongoing follow-up. First diagnosis in adulthood is rare but does occur. QUALITY IMPROVEMENT Anemia is a common finding in hospitalized patients. Typically, low hemoglobin is caused by one or more of the numerous underlying problems describe above. However, daily in- hospital blood testing can exacerbate anemia. As a result, in all hospital patients, in particular those with preexisting anemia, blood sampling should be minimized by careful use of laboratory investigations. In any patient diagnosed with anemia, discharge planning should include a plan for routine monitoring of hemoglobin. The frequency and duration of follow-up will be tailored to the cause and severity of anemia. POLYCYTHEMIA AND SECONDARY ERYTHROCYTOSIS INTRODUCTION Erythrocytosis is the term used to describe unusually high hematocrit, hemoglobin, and/or red blood cell count. An increased red blood cell count is a medical concern for two 1578185 - McGraw-Hill Professional © reasons: (1) It can be the “red flag” for some underlying medical problem that needs attention and (2) erythrocytosis itself can cause problems with sluggish blood flow and subsequent ischemic phenomena, particularly neurologic signs and symptoms. Investigations to determine the cause of erythrocytosis enable proper classification (ie, primary or secondary process), which guides the therapeutic strategy. PATHOPHYSIOLOGY True erythrocytosis (as opposed to spurious erythrocytosis, see below) is defined as having both an increased hematocrit and an increased red cell mass that can be classified as either primary or secondary. Primary erythrocytosis is due to a group of clonal bone marrow disorders known as myeloproliferative disorders (MPD) that include polycythemia rubra vera resulting in autonomous production of too many red blood cells, essential thrombocythemia in which the platelet counts are elevated, and primary myelofibrosis. The MPDs are discussed in Chapter 174 [Hematologic Malignancies]. Secondary erythrocytosis can occur by three mechanisms, all involving increased erythropoietin (EPO) signaling in the bone marrow. 1. “Appropriate” increase in EPO production: In healthy homeostasis, the kidneys make and secrete EPO based on the oxygen tension (PO2) in the renal blood vessels. If oxygen delivered to the kidneys decreases, the kidneys release more EPO as a signal to the bone marrow that the blood needs increased oxygen-carrying capacity in the form of hemoglobin. Oxygen delivery to the body tissues may be decreased as a result of hypoxemia or anemia. Hypoxemia may be due to reasons listed in Table169-4. Relative renal hypoxia due to renal artery stenosis will cause increased EPO by the same mechanism. TABLE 169-4 Classification of Absolute Erythrocytosis Primary erythrocytosis Polycythemia vera (and other myeloproliferative neoplasms) Secondary erythrocytosis Congenital Chuvash polycythemia (VHL mutation) Other defects in oxygen sensing pathway (eg, PHD2 or HIF-2α mutations) EPO receptor mutation High oxygen-affinity hemoglobin 2,3-Biphosphoglycerate mutase deficiency Acquired EPO Mediated Central hypoxia High altitude Right-to-left cardiopulmonary vascular shunts Chronic lung disease Obstructive sleep apnea Carbon monoxide poisoning file://view/books/9780071843140/epub/EPUB/xhtml/214_Chapter174.html 1578185 - McGraw-Hill Professional © Smoking Local renal hypoxia Renal artery stenosis Renal cysts Post-renal transplant erythrocytosis Pathologic EPO production Renal cell carcinoma Hepatocellular carcinoma Cerebellar hemangioma Meningioma Uterine fibroids (leiomyomas) Pheochromocytoma Drugs Testosterone administration EPO agonist administration Idiopathic erythrocytosis EPO, erythropoeitin. Data from McMullen MF, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol. 2005;130:174-195. 2. Autonomously produced erythropoietin: Several types of neoplasm are known to produce excess EPO, including renal cell carcinoma, uterine fibroids, hemangioblastoma, and hepatocellular carcinoma. EPO production can also be increased following renal transplant, although this dysregulated EPO production effect is not completely understood. Inherited causes of upregulated EPO production due to defects in the oxygen-sensing pathway have been described with genetic mutations in the von Hippel-Lindau (VHL) gene including the Chuvash polycythemia (VHL 598C > T) mutation.

3. Exogenous EPO: Patients with anemia of renal disease or anemia that is associated with cancer may be on erythropoietin-stimulating agents. If the prescribed dose is too high or the patient takes the medication incorrectly, it can result in erythrocytosis.

EPO production is also increased with elevated testosterone levels. Elevated testosterone levels stimulate EPO release, and also increase bone marrow activity and iron incorporation into RBCs. This is why the hemoglobin reference range for men is higher than that for women. Exogenous androgen administration (eg, “blood doping” by some body builders and athletes) or increased endogenous testosterone (eg, germ cell tumors) can result in increased hemoglobin.

Spurious erythrocytosis

Spurious erythrocytosis occurs when either the patient or the patient’s blood sample has reduced plasma volume, giving a false increase in hemoglobin concentration. Common causes of dehydration should be excluded (eg, illness, diuretic medications, caffeine- containing beverages, smoking).

DIAGNOSIS: WHY DOES THIS PATIENT HAVE POLYCYTHEMIA?

The detection of erythrocytosis is largely based on laboratory findings of increased hemoglobin, hematocrit, and red cell counts; however, some findings on history and physical examination can suggest a primary polycythemia. As well, a good clinical evaluation of the patient may direct the clinician to the underlying cause of erythrocytosis.

History should include:

History of prior polycythemia Date and results of most recent CBC Questions about possible causes of secondary polycythemia Symptoms and complications resulting from polycythemia, which can include: Thromboembolic—transient ischemic attack (TIA) or stroke, myocardial infarction, venous thromboembolism Hyperviscosity—headache, dizziness, tinnitus, dyspnea, chest pain Erythromelalgia (painful paresthesias in the hands and feet) Aquagenic pruritis (itch after skin exposure to water [eg, after a bath]) Gout

Physical examination should be performed, with particular attention to vital signs, cardiac, and respiratory examinations. Low oxygen saturation on pulse oximetry may suggest hypoxemia as the cause of polycythemia. Polycythemia can lead to chronic hypertension. True polycythemia will commonly be accompanied by “plethora,” a ruddy appearance of the skin, particularly apparent on the face. If cyanosis is present, it may be due to polycythemia alone (increased red blood cell mass and relatively increased deoxygenated hemoglobin) or may reflect an underlying hypoxemic condition. Presence of splenomegaly suggests a myeloproliferative disorder.

BLOOD TESTS

As per WHO guidelines, polycythemia is suspected when complete blood count results show a hemoglobin of > 16.5 in women or > 18.5 g/dL in men or other evidence of increased red cell volume (eg, hematocrit >99th percentile of method-specific reference range for age, sex, and altitude of residence). A patient with polycythemia may also have an elevated red blood cell count. However, this may not be reliable as it also occurs in patients with thalassemia minor or having high O2 affinity hemoglobin variants.

When polycythemia is suspected, spurious polycythemia should be ruled out. Repeat CBC may be done to rule out transient clinical dehydration or laboratory error.

To classify absolute polycythemia as primary or secondary (Table 169-1), a serum erythropoietin level is essential. Evidence of chronic respiratory disease or hypoxemia on physical examination should be followed up with arterial blood gas to confirm low arterial oxygen saturation. Co-oximetry of arterial blood can also quantify carboxyhemoglobin, which will be elevated in polycythemia caused by chronic carbon monoxide exposure. Other laboratory investigations should be guided by clinical assessment of the most likely underlying cause of polycythemia, but may include screening tests for renal and liver function, serum ferritin level, hemoglobin electrophoresis, hemoglobin oxygen-affinity (p50) testing, and JAK2 mutation analysis (see MPD in Chapter 174 [Hematologic Malignancies]).

IMAGING

Chest x-ray and/or computed tomography (CT) scan may be used to confirm findings on clinical evaluation or to exclude occult disease. Ultrasound can evaluate for splenomegaly (associated with MPDs), local renal vascular disease, or neoplastic processes causing increased EPO or testosterone production.

OTHER INVESTIGATIONS

A formal sleep study is indicated if the patient has clear signs and symptoms of obstructive sleep apnea. Bone marrow exam is rarely indicated in the workup of polycythemia.

TRIAGE AND HOSPITAL ADMISSION

Many of the conditions causing secondary polycythemia can present with acute illness and these cases should be triaged accordingly. Polycythemia in and of itself is not an indication for hospital admission, but it can be associated with severe symptoms and complications

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