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BibliU-Print-9780071843140.pdf

BibliU-Print-9780071843140.pdf

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ions perioperatively? When should hydroxyurea be used?

ANEMIA

INTRODUCTION

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

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

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

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

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In addition to the RBC count, hemoglobin, and hematocrit, which make the diagnosis ofanemia possible, the complete blood count (CBC) provides essential information thathelps 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% to14.5%. Normally between 0.5% and 2.5%, the reticulocyte count is calculated as apercentage of the total RBC; therefore, it must be corrected in the presence of anemia. Thereticulocyte production index (RPI) is one method frequently used. The RPI = %reticulocytes × (patient Hct/45)/maturation time. With increasingly severe anemia, morereticulocytes are released from the marrow. The maturation time equals 1 if the patient’sHct is 45. Each 10-point drop in the patient’s Hct increases the maturation time by 1.5days. A low reticulocyte count suggests an underlying defect in RBC production; anelevated reticulocyte count suggests an underlying problem in RBC survival. Likewise, anRPI less than 2.5 suggests that the anemia stems from a hypoproliferative process; an RPIgreater than 2.5 suggests that the anemia is due to bleeding or hemolysis. Examination ofthe peripheral smear may reveal morphologic abnormalities of the RBC that permit anaccurate 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, thromboticthrombocytopenic 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 orwho 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 byvarious mechanisms and can be broadly categorized as intrinsic red cell defects orextrinsic 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), thehemoglobin (eg, sickle cell anemia) or the deficiency of glycolytic pathway enzymes(glucose-6 phosphate dehydrogenase [G6PD] and pyruvate kinase [PK]) result in shorterlife span. External mechanisms can be further classified as immune-mediated ornonimmune resulting from infection, drugs, or mechanical injury. Hemolysis can occurintravascularly or extravascularly (ie, via the reticuloendothelial system), although manytimes it may be difficult to determine the site of cell destruction due to overlap inoverwhelming acute cases.

The differential diagnosis of chronic anemia, whether microcytic, normocytic, ormacrocytic, is broad. One of the most common causes of chronic blood loss is occultblood loss, particularly from the GI tract, or in younger women through menses, leading toiron-deficiency anemia. Once the bone marrow receives the signal from erythropoietin, itrequires 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 dietarydeficiency 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 tosignal the need for new red blood cell production. In renal impairment, a decreasederythropoietin 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 anemiaby 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 RBCprogenitors 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 HealthOrganization (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 beevaluated in an outpatient setting. However, any patient with acute and/or severe anemiawill benefit from the intensive investigations, monitoring, and treatment offered in thehospital. Anyone who is hemodynamically unstable due to blood loss should receive carein a monitored setting. After the diagnosis of anemia is confirmed, the next step is todetermine why so that appropriate treatment can be administered (Figure 169-1).

Since the potential causes of anemia are numerous, a thorough and broad historyshould include query about:

Any associated symptoms, in particular, bleeding (gastrointestinal, including melena,menses, hematuria) and constitutional B symptomsPast medical history, in particular, autoimmune/inflammatory disorder, chronicinfection, liver disease, renal impairment, thyroid dysfunction, previous diagnosis,and treatment of anemiaMedication historySocial history, in particular, dietary intake, alcohol use, risk of sexually transmittedinfectionsFamily history of anemiaFull review of systems, which may uncover symptoms of previously undiagnosedinflammatory disorders or organ dysfunction

Most prominent symptoms in severe anemia include fatigue, dizziness, palpitations, orbreathlessness on physical exertion. Information about the onset of symptoms may helpto determine whether the anemia is acute or chronic. The patient should also bequestioned 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. Ifanemia is due to underproduction alone, the hemoglobin should decrease by less than25% in a 30-day period (roughly 0.1 g/dL/d).

The physical examination may reveal evidence of decompensation as in acute bloodloss (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 palmarcreases, or tachycardia and the presence of a flow murmur), or help to identify previouslyunknown systemic disease (eg, signs of chronic liver disease).

Recent blood tests showing a previously normal hemoglobin level may confirm that theanemia is acute. Elevated reticulocyte count or reticulocyte percent is suggestive of acuteor ongoing blood loss or hemolysis. If the anemia is not acute, workup can be guided bythe 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

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the white blood cell and platelet counts. Pancytopenia can be seen in aplastic anemia,vitamin B12 deficiency, myelodysplastic syndrome, primary bone marrow malignancies, orin liver disease with portal hypertension and splenomegaly. A normal white blood cell andplatelet count with isolated anemia is unlikely to be due to marrow failure, with theexception of pure red cell aplasia. The reticulocyte count may also be useful to distinguishconditions associated with hyporegenerative anemia having low values of < 50 × 109/L(aplastic anemia, pure red cell aplasia, or marrow infiltration) from a regenerative anemiaseen with hemolysis or hemorrhage.

The appearance of the red cells in a peripheral blood film can be associated with thedifferent 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 toacute or chronic blood loss, decreased production of red blood cells, or increaseddestruction. The first step is a complete history and physical examination, followed bya review of the complete blood count, the reticulocyte count, and the peripheral bloodsmear. The objective is to make the correct diagnosis without subjecting the patient tounnecessary laboratory tests and invasive procedures.

MICROCYTIC ANEMIA

Peripheral blood smear in iron-deficiency anemia (IDA) shows small (“microcytic” or lowMCV) red blood cells that are very pale (“hypochromic”) containing less hemoglobin asindicated by a reduced mean corpuscular hemoglobin (MCH). Other changes of note mayinclude anisocytosis (variable size of red blood cells) and poikilocytosis (variable shape ofRBCs, eg, target cells and pencil cells). Based on the blood smear alone it is difficult todiscern IDA from a thalassemia trait. Therefore, further laboratory testing to investigateiron 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 inotherwise healthy patients are reflective of iron deficiency. However, ferritin is an acutephase 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 theconfirmation of a diagnosis in microcytic anemia include serum iron, total iron-bindingcapacity (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 andAnemia of Chronic Disease

Biochemical Marker Iron-Deficiency AnemiaAnemia of ChronicDisease/Inflammation

Serum ferritin Decreased Normal or increased

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Serum iron Decreased Deceased or normalTotal iron-bindingcapacity

Normal to increased Decreased or normal

Transferrin saturation Decreased Decreased or normalSerum transferrinreceptor

Increased Normal

ZPP or FEP Increased Increased

FEP, free erythrocyte protoporphyrin; ZPP, zinc protoporphyrin.

PRACTICE POINT

Stages of iron deficiency are1. 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 oftransferrin saturation can predict the presence or absence of bone marrow iron in mostpatients 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 isknown to commonly have thalassemia or variant hemoglobins associated withmicrocytosis (HbE). Initial hemoglobinopathy investigations will quantify normal andabnormal 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 ormutations. Pregnant women with microcytosis should always be considered forhemoglobinopathy testing regardless of iron status due to the risk of genetic transmissionof a severe form of hemoglobinopathy or thalassemia to the fetus.

NORMOCYTIC ANEMIA

Normocytic anemia is the most frequently encountered category of anemia, and is oftenthe most difficult to workup because it can result from many disparate disorders; it can bedue to decreased RBC production, either primary (eg, aplastic anemia, acute leukemia) orsecondary (eg, renal failure, anemia of chronic disease). Hemolytic anemia, both immuneand 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 orchronic and well compensated, or anything in between. Therefore most patientspresenting with anemia of unclear etiology should be screened for hemolysis. The redcells 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 hereditaryspherocytosis when the patient has a negative Coombs test. Sickle cell anemia manifestswith characteristic sickle-shaped cells. Schistocytes are a hallmark of red cell destructionand can be correlated with platelet numbers for differentiating a microangiopathichemolytic anemia from macroangiopathic hemolytic conditions caused by heart valves.Decreased platelets are seen in disseminated intravascular coagulation (DIC), thromboticthrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS). Platelets arenormal in macroangiopathic hemolytic conditions caused by heart valves.

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

Often further specialized testing is required to confirm and identify the cause ofhemolytic anemia. This can include direct antiglobulin test (DAT or Coombs test),hemoglobinopathy testing, and/or enzymopathy testing, as indicated. The DAT identifiesIgG and/or complement on the RBC surface and can be positive in AIHA, drug-inducedanemia, or a hemolytic transfusion reaction. A hemoglobinopathy investigation separatesand quantifies the expected hemoglobins (HbA, A2, and F) but will also identify manyvariant hemoglobins (eg, HbS, C, or E) or other rarer unstable hemoglobin variants (eg, HbKöln, Hb Hasharon) known to cause hemolysis. To assess for enzyme deficiencies,quantitative testing of red cell pyruvate kinase and G6PD is performed. More recently, flowcytometry has been used to identify paroxysmal nocturnal hemoglobinuria (PNH) usingthe GPI-anchored antigens CD55 and CD59 on red cells or neutrophils. The osmoticfragility (OF) test is useful for confirmation of hereditary spherocytosis. However, theeosin-5-maleimide (EMA) dye binding test by flow cytometry has shown to have higherspecificity 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 confirmedwith a bone marrow aspirate and/or biopsy. Serum erythropoietin level will be low orinappropriately normal in any of the secondary causes of normocytic anemia, particularlyin renal dysfunction. Moderate renal impairment can present with anemia, therefore renalfunction testing is essential, regardless of serum EPO level.

Anemia of chronic disease (ACD) is a difficult diagnosis to pin down. Essentially it is aclinical diagnosis in a patient who has had a sufficient and negative workup for othercauses of anemia, and who has an underlying inflammatory condition. Measurement ofiron 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 revealnormal or increased amounts of stored iron and decreased iron staining in erythroidprecursors, 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 to5 mg, primarily stored in the liver. Approximately 2 to 5 mcg of B12 is lost daily, most ofwhich is excreted in the bile.

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

In patients with gastritis, gastric atrophy, or history of gastrectomy, absence of gastricacid 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 freecobalamin in the gastrointestinal tract and facilitates cobalamin absorption in theterminal ileum, may be impaired. Malabsorption can also occur if there is inadequateabsorption at the terminal ileum, due to prior resection or Crohn disease.

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

Vitamin B12 deficiency presents most commonly with hematologic abnormalitiesand/or neuropsychiatric signs and symptoms. Macrocytic anemia, with macro-ovalocyteson peripheral blood smear, is the classic hematologic abnormality. Neutrophils havehypersegmented nuclei. There may also be leukopenia and/or thrombocytopenia. Bonemarrow examination reveals megaloblastosis.

The classic neurological manifestation is subacute combined degeneration of thespinal cord, resulting in sensory and motor disturbances that cause ataxia. Peripheral andcranial neuropathies may also be seen. In severe cases, patients may present with strokeor dementia-like syndromes. Physical examination may reveal classic findings such asglossitis and jaundice.

A serum B12 level <200 ng/L (148 pmol/L) is very sensitive (97%) for the diagnosis ofB12 deficiency. Because some patients with normal or low-normal serum B12 levels maybe truly deficient and benefit from vitamin replacement, elevated methylmalonic acid(MMA) and homocysteine can help to clarify the diagnosis. Elevated MMA andhemocysteine are both sensitive early markers of B12 deficiency. Elevated levels should,however, be interpreted in the context of individual patients: homocysteine is also elevatedin folate deficiency and hereditary homocyteinemia. Methylmalonic acid may be elevatedin renal insufficiency and methylmalonic aciduria, and in some patients with folatedeficiency. Serum MMA may be lowered in B12-deficient patients receiving antibiotictreatment. A Schilling test, involving oral administration of radiolabeledcocyanocobalamin, has historically been used to assess vitamin B12 absorption.Unfortunately, the Schilling test is not widely available. Anti-intrinsic factor antibodies arehighly specific for pernicious anemia (specificity >95%) and therefore, if positive, help toconfirm 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 commoncause of folate deficiency is inadequate nutritional intake. With universal folatesupplementation, folate deficiency has become increasingly rare. However, patients withalcohol abuse remain at risk due to folate malabsorption and impaired folate metabolismin the liver. Individuals with increased folate requirements are also at increased risk. Thisincludes pregnant women (for whom folate deficiency is associated with an increased riskof fetal spina bifida) and patients with chronic hemolytic anemia. The widespread use ofroutine, 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 folatedeficiency; therefore if there is still a high index of suspicion, red blood cell folate shouldbe tested.

Drug-induced anemia

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

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

Other causes of macrocytic anemia

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

PRACTICE POINT

Many anemias in their early stages have a normal MCV and then become eithermicrocytic or macrocytic.The peripheral smear may provide important clues such as a myelopthisis(elliptocytes, teardrop cells, immature myeloid forms, nucleated RBCs), sickle celldisease (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 untilserum ferritin has increased to approximately 50 mg/L. Iron is given orally unless thepatient 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 ironFerrous sulfate: 300 mg 60 mg elemental ironFerrous fumarate: 300 mg 100 mg elemental ironPolysaccharide iron complex: 150 mg 150 mg elemental iron

In the absence of ongoing blood loss, hemoglobin should increase by 1 to 2 g/dLwithin 3 weeks of starting adequate oral replacement, and iron stores should be replete in3 months. Failure to respond may be due to nonadherence, poor iron absorption, or anincorrect diagnosis. If instead the patient has thalassemia, iron supplementation could beharmful, in that it will increase iron overload.

To improve iron absorption, the iron tablets should be taken on an empty stomach orwith orange juice or a tablet of ascorbic acid. Concurrent administration of antacidsshould be avoided. Many patients complain of nausea or dyspepsia 30 to 60 minutesfollowing 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 symptomsand maintain adequate absorption.

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

B12 deficiency

Vitamin B12 replacement can be divided into initial management (designed to quicklybuild up the tissue stores) and long-term maintenance treatment. A common initialregimen 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 weekafter the first dose. In particular, there should be a noticeable increase in the reticulocytecount. If reticulocytosis is mild or absent, the original diagnosis should be questioned. Bythe eighth week, the MCV should have returned to the normal range.

Maintenance treatment can be given parenterally or orally. Parenteral cyanocobalaminmay be given at a dose of 1000 mcg/month until the cause of deficiency is corrected, orlifelong in pernicious anemia. Oral therapy for pernicious anemia is 1000 mcg/d. Lowerdoses (eg, 125-500 mcg/d) can be given for other causes of deficiency; however the costand risk of a higher dose are negligible and a standard dose of 1000 mcg/d is commonlyprescribed.

Folate deficiency

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Treatment is with oral folic acid (1-5 mg/d) until complete hematologic recovery. Patientswith an ongoing cause of folate deficiency (eg, chronic hemolytic anemia or pregnancy)should continue on long-term supplementation. Because treatment with folic acid canpartially reverse the hematologic abnormalities seen in vitamin B12 deficiency, but do notattenuate the progression of neurologic sequelae, serum vitamin B12 levels should bemeasured prior to therapy.

Anemia of chronic renal disease

As the glomerular filtration rates decline, anemia becomes increasingly common inpatients with chronic renal disease. Erythropoiesis-stimulating agents (ESAs) are widelyused 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 peritonealdialysis patients, and if the hemoglobin is ≤ 11 g/dL in dialysis patients. Adequate ironstores should be confirmed, and other causes of anemia should be ruled out. Epoetinalpha or darbepoeitin may be used with a target hemoglobin of 10 to 12 g/dL. Levelsabove 13 g/dL have been associated with increased risk of thrombotic events. Epoetinalpha can be started at a dose of 10,000 units subcutaneously once weekly or 20,000units subcutaneously every other week. Lower starting doses may be appropriate forsmaller patients or those with higher pretreatment hemoglobin. For dialysis patients, EPOcan be administered intravenously during hemodialysis sessions. Throughout ESAtherapy, 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 areevaluating the precise determinants of cardiovascular risk and the optimal hemoglobintarget. Updated clinical practice guidelines should be consulted.

Hemolytic anemia

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

Myelodysplastic syndromes

The anemia of myelodysplatsic syndromes (MDS) is typically treated with chronictransfusions or erythropoiesis-stimulating agents (ESAs). Patients with MDS-relatedanemia with serum EPO level < 100 to 200 mU/mL and lower-risk disease are most likelyto respond to ESAs. Relatively high doses of epoetin alpha or darbepoetin are usuallyrequired. Patients who do not qualify for or respond to ESAs are likely to require chronicred blood cell transfusions. Unfortunately, transfusion-dependent MDS patients havedecreased overall survival, especially those in lower-risk categories. Decreased overallsurvival in these individuals is linked to elevated ferritin levels, indicating thattransfusional iron overload is at least partially responsible for worsened outcomes. Serumferritin and transferrin iron saturation should be monitored in transfusion-dependent MDSpatients. T2-weighted magnetic resonance imaging (MRI) may be used to evaluate forcardiac and liver iron deposition. Chelation therapy should be considered in patients withevidence of iron overload.

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COMPLICATIONS

Bone marrow examination may aid diagnosis if anemia is apparently due tounderproduction, or if anemia is associated with leukopenia, thrombocytopenia, and/orother morphologic abnormalities suggesting bone marrow disease. Rarely, bone marrowexamination is necessary to help quantify iron stores in a patient with normal serumferritin but microcytic anemia is felt to be due to iron deficiency.

Consultation with a hematologist should be considered in complex cases and forpatients with thalassemia, sickle cell disease, other variant hemoglobins, bone marrowfailure 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 ultralarge multimers of von Willebrand factor, causing increased platelet aggregation in smallvessels. Thrombotic thrombocytopenic purpura presents with hemolytic anemia andthrombocytopenia. 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 forparoxysmal nocturnal hemoglobinuria (PNH), which typically presents with episodes ofintravascular hemolysis and red urine. As a result of chronic and recurrent hemoglobinuria,patients can become iron deficient. Paroxysmal nocturnal hemoglobinuria is a clonaldisorder that can result in aplastic anemia or acute leukemia. Patients with PNH are atincreased risk of thromboembolism. The diagnosis of PNH is made when flow cytometryshows 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 lifelonganemia. These include Diamond-Blackfan anemia, Fanconi anemia, Schwachman-Diamond syndrome, and congential dyserythropoietic anemia. These disorders willtypically present in early childhood and require ongoing follow-up. First diagnosis inadulthood is rare but does occur.

QUALITY IMPROVEMENT

Anemia is a common finding in hospitalized patients. Typically, low hemoglobin is causedby 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, inparticular those with preexisting anemia, blood sampling should be minimized by carefuluse of laboratory investigations. In any patient diagnosed with anemia, dischargeplanning should include a plan for routine monitoring of hemoglobin. The frequency andduration 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/orred blood cell count. An increased red blood cell count is a medical concern for two

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reasons: (1) It can be the “red flag” for some underlying medical problem that needsattention and (2) erythrocytosis itself can cause problems with sluggish blood flow andsubsequent 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 ashaving both an increased hematocrit and an increased red cell mass that can be classifiedas either primary or secondary. Primary erythrocytosis is due to a group of clonal bonemarrow disorders known as myeloproliferative disorders (MPD) that include polycythemiarubra vera resulting in autonomous production of too many red blood cells, essentialthrombocythemia 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 increasederythropoietin (EPO) signaling in the bone marrow.

1. “Appropriate” increase in EPO production: In healthy homeostasis, the kidneysmake 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 asignal to the bone marrow that the blood needs increased oxygen-carrying capacityin the form of hemoglobin. Oxygen delivery to the body tissues may be decreasedas a result of hypoxemia or anemia. Hypoxemia may be due to reasons listed inTable169-4. Relative renal hypoxia due to renal artery stenosis will cause increasedEPO by the same mechanism.

TABLE 169-4 Classification of Absolute Erythrocytosis

Primary erythrocytosisPolycythemia vera (and other myeloproliferative neoplasms)Secondary erythrocytosisCongenital

Chuvash polycythemia (VHL mutation)Other defects in oxygen sensing pathway (eg, PHD2 or HIF-2α mutations)EPO receptor mutationHigh oxygen-affinity hemoglobin2,3-Biphosphoglycerate mutase deficiency

AcquiredEPO Mediated

Central hypoxiaHigh altitudeRight-to-left cardiopulmonary vascular shuntsChronic lung diseaseObstructive sleep apneaCarbon monoxide poisoning

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SmokingLocal renal hypoxia

Renal artery stenosisRenal cystsPost-renal transplant erythrocytosis

Pathologic EPO productionRenal cell carcinomaHepatocellular carcinomaCerebellar hemangiomaMeningiomaUterine fibroids (leiomyomas)Pheochromocytoma

DrugsTestosterone administrationEPO agonist administration

Idiopathic erythrocytosis

EPO, erythropoeitin.Data from McMullen MF, et al. Guidelines for the diagnosis, investigation and management ofpolycythaemia/erythrocytosis. Br J Haematol. 2005;130:174-195.

2. Autonomously produced erythropoietin: Several types of neoplasm are known toproduce excess EPO, including renal cell carcinoma, uterine fibroids,hemangioblastoma, and hepatocellular carcinoma. EPO production can also beincreased following renal transplant, although this dysregulated EPO productioneffect is not completely understood. Inherited causes of upregulated EPOproduction due to defects in the oxygen-sensing pathway have been described withgenetic mutations in the von Hippel-Lindau (VHL) gene including the Chuvashpolycythemia (VHL 598C > T) mutation.

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

EPO production is also increased with elevated testosterone levels. Elevatedtestosterone levels stimulate EPO release, and also increase bone marrow activity and ironincorporation into RBCs. This is why the hemoglobin reference range for men is higherthan that for women. Exogenous androgen administration (eg, “blood doping” by somebody 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 hasreduced plasma volume, giving a false increase in hemoglobin concentration. Commoncauses of dehydration should be excluded (eg, illness, diuretic medications, caffeine-containing beverages, smoking).

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DIAGNOSIS: WHY DOES THIS PATIENT HAVE POLYCYTHEMIA?

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

History should include:

History of prior polycythemiaDate and results of most recent CBCQuestions about possible causes of secondary polycythemiaSymptoms and complications resulting from polycythemia, which can include:Thromboembolic—transient ischemic attack (TIA) or stroke, myocardial infarction,venous thromboembolismHyperviscosity—headache, dizziness, tinnitus, dyspnea, chest painErythromelalgia (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 maysuggest hypoxemia as the cause of polycythemia. Polycythemia can lead to chronichypertension. True polycythemia will commonly be accompanied by “plethora,” a ruddyappearance of the skin, particularly apparent on the face. If cyanosis is present, it may bedue to polycythemia alone (increased red blood cell mass and relatively increaseddeoxygenated hemoglobin) or may reflect an underlying hypoxemic condition. Presence ofsplenomegaly suggests a myeloproliferative disorder.

BLOOD TESTS

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

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

To classify absolute polycythemia as primary or secondary (Table 169-1), a serumerythropoietin level is essential. Evidence of chronic respiratory disease or hypoxemia onphysical examination should be followed up with arterial blood gas to confirm low arterialoxygen 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 likelyunderlying cause of polycythemia, but may include screening tests for renal and liverfunction, serum ferritin level, hemoglobin electrophoresis, hemoglobin oxygen-affinity(p50) testing, and JAK2 mutation analysis (see MPD in Chapter 174 [HematologicMalignancies]).

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IMAGING

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

OTHER INVESTIGATIONS

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

TRIAGE AND HOSPITAL ADMISSION

Many of the conditions causing secondary polycythemia can present with acute illnessand these cases should be triaged accordingly. Polycythemia in and of itself is not anindication for hospital admission, but it can be associated with severe symptoms andcomplications (see Diagnosis earlier in this ch

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