Key Clinical Questions Anemia
Polycythemia and Secondary Erythrocytosis
How does peripheral blood smear aid in the diagnosis of anemia?
How do I interpret iron studies?
What are the best tests to diagnose hemolytic anemia?
How do I determine the cause of hemolytic anemia?
When should I investigate for hemoglobinopathy?
What factors suggest the need for bone marrow examination?
What is the most effective way to administer oral iron?
When and how should I use erythropoietin (EPO) in anemia of renal dysfunction or anemia of chronic disease? (How is it dosed and when should I expect a response?)
Thalassemia and Hemoglobinopathies
How do I distinguish primary and secondary erythrocytosis in a patient who smokes or has chronic lung disease?
When should I be concerned about carbon monoxide poisoning?
How do I manage secondary erythrocytosis?
What tests should I do to rule out a myeloproliferative disorder?
What complications can occur in patients with myeloproliferative disorders?
When is phlebotomy indicated?
How frequently should phlebotomy be performed and what are the monitoring parameters?
Is there a role for antiplatelet agents and anticoagulants in patients with a myeloproliferative disorder?
Sickle Cell Disease
Which hemoglobinopathies are considered to be clinically significant?
How is thalassemia differentiated from iron deficiency anemia?
When should one investigate for hemoglobinopathies?
When should transfusion therapy be considered?
What are the common complications in patients with thalassemia?
What are triggers for admission in a patient with sickle cell disease?
What is appropriate hydration for acute chest syndrome or painful crisis?
What clinical presentations benefit from red blood cell transfusion or red cell exchange?
What is an appropriate transfusion threshold?
How is pain optimally managed?
What are special considerations in management of sickle cell disease in pregnancy or in labor?
What are special considerations perioperatively?
When should hydroxyurea be used?
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 169-1World Health Organization’s Hemoglobin Threshold Used to Define Anemia ||Download (.pdf) 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 |
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 169-2The Peripheral Smear ||Download (.pdf) TABLE 169-2 The Peripheral Smear
|RBC Size and Hemoglobin Content || ||Etiology |
Hypochromic microcytic anemia with
RDW > 15%
RBC < 4.6 × 1012
| || |
Iron-deficiency anemia (low serum ferritin <12 μg/L; low iron, high TIBC, <9% TS, high RDW)
Anemia of chronic disease (normal/high ferritin, low serum iron, low TIBC, >9% TS, normal RDW)
Sideroblastic anemia (Dimorphic population of hypochromic and normochromic cells, normal/high ferritin, high serum iron, normal TIBC, normal RDW)
Hypochromic microcytic anemia with
RDW < 15%
RBC > 4.6 × 1012
Smear—uniform RBCs with basophilic stippling and target cells
| || |
Thalassemia (normal/high ferritin, normal/high serum iron, normal TIBC, normal/high RDW—check Hb electrophoresis and HbA2 quantitation)
Anemia of chronic disease (normal pattern, increased iron stores, <15% ringed sideroblasts RS)
Aplastic anemia, myelofibrosis, anemia from metastatic cancer (normal to increased iron stores, <15% RS)
Refractory anemia with RS, lead poisoning (>15% RS)
Normochromic normocytic anemia with
Immature myeloid cells
Teardrop cells and/or
| || |
Early iron deficiency
Secondary BM failure; due to liver disease, hypothyrodism, inflammation or renal impairment
|Normochromic normocytic anemia without abnormal cells on smear || || |
Early iron deficiency
Secondary BM failure from liver disease, hypothyroidism, inflammation, uremia
|Macrocytic anemia with hypersegmented neutrophils (one six-lobed nucleus or five-lobed nucleus in >5% of neutrophils) || ||Megaloblastic anemia (check serum B12, serum folate, RBC folate; if all normal, BM for myedysplastic syndrome and myeloproliferative disorder) |
|Macrocytic anemia without macroovalocytes and hypersegmented neutrophils || || |
Cold agglutinin disease
|Abnormal cell type || || |
|Basophilic stippling || ||Hemolytic anemias, thalassemias, lead poisoning |
|Bite cells (Heinz bodies removed by splenic macrophages) || ||G6PD deficiency, oxidative drugs or unstable hemoglobin |
|Burr cells, spur cells (acanthocytes) || ||Liver disease, uremia, hypersplenism |
|Elliptocytes || || |
|Hemolysis of RBC || ||Hemolytic anemia |
|Howell-Jolly bodies || ||Postsplenectomy or functional asplenia |
|Abnormal cell type || || |
Schistocytes (fragmented RBCs)
| ||Microangiopathic or macroangiopathic hemolysis eg, DIC, TTP |
|Sickled forms || ||Sickle cell disease |
|Spherocytes (RBCs lack central pallor) || ||Immune-mediated hemolysis, hereditary spherocytosis, hypersplenism |
|Target cells || ||Thalassemias, hemoglobin C, hemoglobin E, hemoglobin S, liver disease, postsplenectomy |
|Teardrop cells || ||Myelopthisis, hypersplenism |
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).
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.
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
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.
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 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).
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.
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 169-3Typical Patterns of Iron Investigations in Iron Deficiency Anemia and Anemia of Chronic Disease ||Download (.pdf) 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 |
|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 |
Stages of iron deficiency are
Storage iron depletion (decrease in serum ferritin levels, a reflection of total iron body stores).
Iron-deficient erythropoiesis (a transferrin saturation <9%, an indicator of impaired iron supply for the developing RBC).
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 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
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 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.
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%).
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.
A number of drugs can cause macrocytosis or macrocytic anemia. These include the following:
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.
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).
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.
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.
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.
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.
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.
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.
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
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 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.
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.
“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 Table 169-4. Relative renal hypoxia due to renal artery stenosis will cause increased EPO by the same mechanism.
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.
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.
TABLE 169-4Classification of Absolute Erythrocytosis ||Download (.pdf) TABLE 169-4 Classification of Absolute Erythrocytosis
|Primary erythrocytosis |
|Polycythemia vera (and other myeloproliferative neoplasms) |
|Secondary erythrocytosis |
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
Right-to-left cardiopulmonary vascular shunts
Chronic lung disease
Obstructive sleep apnea
Carbon monoxide poisoning
Local renal hypoxia
Renal artery stenosis
Post-renal transplant erythrocytosis
Pathologic EPO production
Renal cell carcinoma
Uterine fibroids (leiomyomas)
EPO agonist administration
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 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 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])
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.
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]).
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.
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 (see Diagnosis earlier in this chapter), which may necessitate acute medical attention.
Goals of treatment in primary polycythemia include decreasing chronic symptoms due to hyperviscosity and increased RBC turnover, and reducing the long-term risk of thrombotic complications. Reduction of hemoglobin concentration may be achieved by a program of repeated phlebotomies and/or cytoreductive agents, such as hydroxyurea. A randomized trial showed lower rates of cardiovascular and thrombotic complications in polycythemia vera patients who were kept at a target hematocrit of less than 45%. Acetylsalicylic acid has been shown to reduce the risk of thrombotic events in polycythemia vera with minimal increase in risk of bleeding. Traditional risk factors for vascular disease should be managed as appropriate.
For patients with secondary erythrocytosis, the main principle of management is treatment of the underlying disorder.
Complications of primary polycythemia can include venous or arterial thrombotic events. Over time, a small percentage of patients develop myelofibrosis or, more rarely, acute myeloid leukemia. Bone marrow examination should be performed if progression of marrow disease is suspected.
RARE CAUSES FOR CONSIDERATION
In rare instances, primary or secondary polycythemia can be congenital. Congenital mutation of the EPO receptor can result in the EPO receptor being chronically “switched on.” Congenital low 2,3-bisphosphoglycerate is associated with less off-loading of oxygen by hemoglobin at the peripheral tissues, and a compensatory increase in endogenous EPO.
In any patient diagnosed with polycythemia, discharge planning should include a plan for routine monitoring of hemoglobin and hematocrit. The frequency and duration of follow-up will be tailored to the cause and severity of polycythemia.
THALASSEMIA AND HEMOGLOBINOPATHIES
The hemoglobinopathies are genetic disorders affecting the production, structure, or function of the globin chains that form hemoglobin contained within red cells. These are one of most common genetic diseases known, with worldwide estimates of 270 million carriers, and more than 300,000 infants born each year with clinically severe abnormalities. The hemoglobin tetramer is made from two pairs of globin chains, each attached to a heme group. Normally three types are of hemoglobin can be detected by electrophoretic techniques: HbA (α2β2), the predominant adult form; HbF (α2γ2), found at high levels in newborns; and a minor amount of HbA2 (α2δ2). The genes responsible for producing these globin proteins are found on two gene clusters; chromosome 16p13.3 is the location for two alpha (α) globin genes, and on chromosome 11p15.5 are the beta (β), delta (δ), and gamma (γ) globin genes. Currently more than 1400 mutations have been described in the α, β, δ, and γ globin genes, which are categorized and listed on the World Wide Web (http://globin.cse.psu.edu) with novel mutations continually being discovered. Heterozygous carriers of globin gene mutations are typically asymptomatic but can present with microcytosis, hemolysis, anemia, cyanosis, or erythrocytosis, depending on the underlying defect. Individuals who are homozygous or compound heterozygous for specific types of globin gene mutations can present with serious disease states ranging from thalassemia major, a condition that requires lifelong transfusion therapy, to severe sickling syndromes presenting with chronic hemolysis and periodic painful sickle cell crises. The detection and diagnosis of the hemoglobinopathies largely relies on a good clinical history and the correlation of physical findings, such as splenomegaly, with results of diagnostic laboratory tests. The most common hemoglobin disorders—sickle cell disease and thalassemia—can be diagnosed easily in most clinical laboratories; however, complex unusual cases may require further more sophisticated investigations including DNA-based procedures. Sickle cell disease is covered in more detail in this chapter.
The hemoglobin (Hb) tetramer contains four subunits, each containing a globin attached to a molecule of heme, a protein structure that transports oxygen efficiently. The major hemoglobin found in individuals older than 6 months is HbA, or adult hemoglobin, consisting of two α- and two β-globin subunits. The hemoglobin disorders are genetic mutations in these globin chains that can be divided into two broad categories: the “variants,” in which qualitative changes in the globin chain structure may result in an abnormal function or electrophoretic properties, and the “thalassemias,” in which reduced production of globin chains leads to a decrease in hemoglobin, resulting in a microcytic, hypochromic anemia. Hemoglobin disorders are most commonly found in people from malaria-endemic regions, where high gene prevalence has been attributed to a survival advantage for carriers. However, due to global population migration, these disorders are now found in all regions, including North America and northern Europe. Thus, consideration for an individual’s ethnicity may be useful, but should not be the sole criterion to determine if a search for a hemoglobin disorder is indicated.
Most hemoglobin variants are due to single nucleotide point mutations in the globin genes that change the amino acid sequence. A variant hemoglobin can also result from deletions or gene rearrangements that lead to fusion of two globin genes, changes in the stop codon of the globin gene resulting in extending globin chains, or multiple nucleic acid substitutions at two different positions in the globin gene. Although most mutations are rare and of no clinical consequence, some can cause severe or lifelong conditions. Examples are HbS (β codon 6 GAG > GTG Glu > Val) causing sickle cell disease or HbC (β codon 6 GAG > AAG Glu > Lys), which, when combined with HbS, also causes a significant sickling disorder; and HbE (β codon 26 GAG > AAG or Glu > Lys), which can contribute to severe β-thalassemia syndromes. Other common variants are HbD, Hb Lepore, HbO, and Hb Constant Spring.
The most important thalassemia syndromes are those that affect either the α- or β-globin chains. Thalassemias can be caused by point mutations that reduce or eliminate the globin gene production. Thalassemia may also be the result of insertions or deletions in the gene itself that downregulate gene expression, or from a total deletion of the globin gene. Abnormalities affecting α-globin chain production are termed α-thalassemia and those affecting β-globin production are called β-thalassemia. Some mutations that affect globin gene expression may also produce detectable hemoglobin variants. The most common variants that present with a thalassemia phenotype are HbE (β codon 26 GAG > AAG or Glu →Lys), Hb Lepore (caused by a δ-β fusion globin chain), or Hb Constant Spring (α2 codon 142 TAA > CAA or Ter →Gln).
CLINICALLY SIGNIFICANT HEMOGLOBINOPATHIES
The most common clinically significant hemoglobinopathies can be divided into three distinct syndromes: the sickle cell syndromes, the α-thalassemia syndromes, and the β-thalassemia syndromes. They are normally inherited as autosomal recessive abnormalities (ie, heterozygous individuals are asymptomatic), whereas homozygous or compound heterozygous individuals are severely affected. Other rare globin gene mutations may be inherited as autosomal dominant expression. These include the unstable hemoglobins (implicated in Heinz body-induced hemolysis), the high oxygen affinity hemoglobins (presenting with secondary compensated erythrocytosis), the low oxygen affinity hemoglobins, and HbM variants.
Therefore, reasons to correctly diagnose the hemoglobinoapthies are:
Diagnosis of serious or life-threatening hemoglobin abnormalities to plan for appropriate preventative management (eg, penicillin prophylaxis and pneumococcal vaccination in infants with sickle cell disease) and medical treatment (eg, chronic transfusion program and chelation therapy in β-thalassemia major).
Investigation of microcytic anemia to identify individuals with thalassemia trait so that unnecessary investigations (eg, endoscopy) and treatment for presumed iron deficiency can be avoided.
Identification of individuals of reproductive age who are carriers of clinically significant hemoglobin mutations to initiate proper genetic counseling and guide future reproductive decisions.
Normally, individuals have four α globin genes—two on each chromosome 16. Carriers of α thalassemia have deletions of one (α/αα) or two (-/αα or α/-α) of the α globin genes. Deletion of three α globin genes results in hemoglobin H disease (HbH: -/-α). Deletion of all four α globin genes typically results in hydrops fetalis, which is not compatible with life unless antenatal diagnosis is followed by in utero transfusion. Rarely, α-thalassemia syndromes are caused by nondeletional mutations, such as Hb Constant Spring, which have the same effect as a single α gene deletion. Deletion of one α globin gene (referred to as α+-thalassemia) is often seen in individuals of African, Mediterranean, and Southeast Asian ethnic backgrounds, while deletion of two α globin genes in cis (- -αα; referred to as α0-thalassemia) is most often seen in the Southeast Asian population. The most commonly reported α-thalassemia genotypes are presented with the clinical presentation and reproductive significance in Table 169-5.
TABLE 169-5The Clinical Presentation, Genotypes, and Reproductive Significance of the Various α–Thalassemia Syndromes ||Download (.pdf) TABLE 169-5 The Clinical Presentation, Genotypes, and Reproductive Significance of the Various α–Thalassemia Syndromes
|Hemoglobinopathy ||Clinical Presentation ||Genotypes ||Reproductive Significance |
|α+-Thalassemia heterozygous ||Normal to mild microcytosis ||–α/αα or αTα/αα ||Carrier for Hb H disease |
|Hb Constant Spring ||Normal to mild microcytosis ||αCSα/αα ||Carrier for Hb H/Hb Constant Spring Disease |
|Homozygous α+-thalassemia ||Microcytosis, normal Hb or mild anemia ||–α/–α ||Carrier for Hb H disease |
|α0-Thalassemia trait ||Microcytosis, normal Hb or mild anemia ||– –/–αα ||Carrier for Hb Bart Hydrops fetalis, and Hb H disease |
|Hb H disease, Hb H/Hb Constant Spring disease ||Mild to moderate microcytosis with hemolytic anemia ||– –/–α or αTα/– – or αCSα/– – ||Carrier for Hb Bart hydrops fetalis and Hb H disease |
|Hb Bart hydrops fetalis ||High-risk pregnancy with fetal death without in utero transfusion interventions ||– –/– – ||Carrier for Hb Bart hydrops fetalis and Hb H disease |
Normally, individuals inherit two β-globin genes, one on each chromosome 11. β-Thalassemia syndromes are most often a result of point mutations, or small deletions or insertions in the β-globin gene. These mutations either reduce the β-globin chain production (β+-thalassemia mutations) or completely eliminate β-globin production from the affected gene (β0-thalassemia mutations). Also some β-chain variants can present as thalassemia phenotypes that are clinically severe when inherited as compound heterozygous (eg, HbE/β-thalassemia and Hb Lepore/β-thalassemia). There is a high prevalence of β-thalassemia in the African, Mediterranean, Middle Eastern, Indian, and Southeast Asian ethnic populations. Hemoglobin E is most commonly found in Southeast Asian populations, while Hb Lepore is found in Mediterranean, African, and Southeast Asian populations. These most commonly detected β-thalassemia genotypes are presented with the clinical presentation and reproductive significance in Table 169-5. “β-thalassemia major” is used to describe patients who are transfusion dependent from infancy or early childhood (usually due to homozygosity or compound heterozygosity for β0-thalassemia), whereas “β-thalassemia intermedia” refers to patients with anemia that is more severe than that of someone with β-thalassemia trait, but less severe than typical β-thalassemia major (Table 169-6).
TABLE 169-6The Clinical Presentation and Reproductive Significance of the Various β-Thalassemia Syndromes ||Download (.pdf) TABLE 169-6 The Clinical Presentation and Reproductive Significance of the Various β-Thalassemia Syndromes
|Hemoglobinopathy ||Clinical Presentation ||Genotypes ||Reproductive Significance |
|β-Thalassemia trait ||Microcytosis with normal Hb or mild anemia, elevated HbA2 ||βA/β0, βA/β+ ||Carrier for β-thalassemia major or β-thalassemia intermedia or HbS/β-thalassemia |
|δ-β-Thalassemia trait ||Microcytosis with normal Hb or mild anemia, normal HbA2 and elevated HbF ||βA /δβ Thal ||Carrier for β-thalassemia intermedia |
|HbE trait or homozygous HbE ||Normal to microcytosis, normal Hb or mild anemia ||βA /δE or βE/βE ||Carrier for β-thalassemia intermedia or major |
|Hb Lepore trait ||Microcytosis with normal Hb or mild anemia ||βA /βLepore ||Carrier for β-thalassemia intermedia or major |
|β-Thalassemia intermedia ||Moderate microcytosis with anemia sometimes requiring intermittent transfusion ||β+ /βE or β+ /β+ or β+ /β0 or β+ /βLepore or β0/δβ, or β+/δβ or δβ/δβ or β Thal with excess α globin genes ||Carrier for β-thalassemia intermedia or major or HbS/β+ or HbS/β0-thalassemia |
|β-Thalassemia major ||Transfusion-dependent microcytic anemia ||β0/β0 or β0/βE or β0/βLepore or βLepore/βLepore ||Carrier for β-thalassemia intermedia or major |
DIAGNOSIS: DOES THIS PATIENT HAVE A CLINICALLY SIGNIFICANT HEMOGLOBINOPATHY?
A patient who has an ethnic background with a high prevalence of hemoglobinopathies and a positive family history of anemia, chronic transfusions, painful sickle cell crises, or hydrops fetalis should alert the physician to the possibility of congenital hemoglobin disorders. However, heterozygous carriers of most hemoglobinopathies are asymptomatic and clinically well. A good clinical history is important, including demographic information.
The laboratory diagnosis of hemoglobinoapthies begins with a CBC and peripheral blood smear, specifically looking at the appearance of the RBCs, the hemoglobin level, and erythrocyte indices (Figure 169-2).
Preliminary hemoglobinopathy considerations based on the MCV/MCH. (A normal RDW is not a reliable indicator of the thalassemia trait as it can be normal in some genotypes of thalassemia and abnormal in others.) MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin. (Adapted, with permission, from Lafferty JD, Waye JS, Chui DH, et al. Good practice guidelines for laboratory investigation of hemoglobinopathies. Lab Hematol. 2003;9(4):237-245.)
A low mean corpuscular volume and mean corpuscular hemoglobin (MCH) are associated with microcytosis and hypochromasia. These values may be indicative of thalassemia but need to be differentiated from iron-deficiency anemia or anemia of chronic disease (ACD), which may also present with microcytic, hypochromic anemia (see the Anemia section earlier in this chapter). Individuals with uncomplicated α- or β-thalassemia trait will usually have normal iron studies. However, a diagnosis of IDA or ACD does not rule out coexisting thalassemia trait.
Separation of the hemoglobin fractions are used to detect variant hemoglobins. In a normal adult, HbA, HbA2, and HbF should all be present. Traditionally, hemoglobin separation has been done using alkaline and acid electrophoresis. Although these methods are still used in some laboratories as initial screening for variant hemoglobin identification, automated methods are available that not only separate the hemoglobin fractions but also provide accurate quantification of the hemoglobin fractions.
High performance liquid chromatography (HPLC): One of the automated systems commonly used for hemoglobinopathy screening is a cation-exchange HPLC, a method based on elution of hemoglobin fractions on a chromatography column. The HPLC system quantifies the hemoglobin fractions, provides accurate levels of HbA, HbA2, and HbF, and has good resolving power to detect many of the variant hemoglobins.
Capillary electrophoresis (CE): Capillary electrophoresis is an automated system available for hemoglobin separation and quantification. A hemoglobin solution migrates through a buffer solution contained in fine capillary tubes when an electrical current is applied. These automated systems have excellent resolving power, providing a rapid and sensitive method of hemoglobin separation and quantification.
P50 analysis: Hemoglobins that have changed oxygen affinity can be identified by performing a P50 analysis or oxygen dissociation curve. Some variant hemoglobins will have a high O2 affinity resulting in erythrocytosis or low oxygen affinity causing anemia or cyanosis. Several of these hemoglobin variants will show no differences in electrophoretic mobility from HbA.
Stability testing: Hemoglobin instability can be demonstrated by exposing hemoglobin to excessive heat or incubating it with a buffered isopropyl alcohol. These unstable hemoglobin variants may also be identified by increased Heinz body detection and the presence of bite cells and dense fragments in the peripheral red cell morphology.
HbM testing: Some variants will produce a methemoglobinemia that can be identified through performing a unique absorption spectral scan. These are a specific group of variant hemoglobins that produce methemoglobin called the HbMs.
Molecular diagnostics: Molecular diagnosis and DNA analysis are used for positive characterization of variant hemoglobins or confirmation of thalassemia. These are performed on DNA and include polymerize chain reaction (PCR), direct nucleotide sequencing, southern hybridization and multiplex ligation-dependent probe amplification (MLPA) techniques.
INTERPRETATION OF LABORATORY INVESTIGATIONS
In the setting of a suspected hemoglobin disorder, one must correlate laboratory findings with the patient’s age, gender, ethnicity, and reproductive status. Standard investigations cannot definitively diagnose all clinically important variant hemoglobins. Interpretation of hemoglobinopathy investigations can be challenging. Therefore guidance from a knowledgeable laboratory professional can be helpful in determining if a clinically significant hemoglobin disorder is present.
Alpha-thalassemia syndromes are associated with microcytosis (see Table 169-5). Silent carriers (-α/αα) may have microcytosis without significant anemia, whereas individuals with two α genes deleted (-/αα or -α/-α) generally have a mild microcytic anemia. HbH disease (-/-α) is associated with moderate microcytic anemia that becomes more severe during pregnancy or acute illness. Unfortunately, hemoglobin separation methods do not always add additional information when α-thalassemia syndromes are suspected; it is most common to find normal proportions of HbA, HbF, and HbA2. If HbH (β4) is detected, it can aid in diagnosis. However, this hemoglobin is fast moving on gel electrophoresis, and may run off the gel prior to completion of the test. Furthermore, HbH is not always present in sufficient quantities for detection by standard methods. In practice, DNA analysis is often required to confirm α-thalassemia syndromes. After sufficient investigations have ruled out other common causes of microcytic anemia (eg, IDA, ACD), DNA analysis for α-thalassemia may be required to confirm most α-thalassemia syndromes. DNA testing for α thalassemia is advised in all pregnant women with unexplained microcytic anemia.
β-thalassemia trait is also associated with a microcytic anemia (see Table 169-6). Furthermore, HbA2 is characteristically elevated (>3.5%) (Table 169-7). In cases in which there is δβ-thalassemia trait or β-thalassemia trait with a coexisting δ-globin mutation, HbA2 level may be normal. In β-thalassemia major, the patient, by definition, is making very little or no HbA. In practice, because these patients require routine transfusion of donor blood, hemoglobin separation methods will show normal proportions of HbA, HbF, and HbA2 expected from donor RBCs. Thalassemias can also be diagnosed in patients that have an elevated HbF quantity in the presence of a low MCV and MCH. Alternately, elevated HbF can be seen in individuals with hereditary persistence of fetal hemoglobin (HPFH), who are clinically well, with a normal MCV and MCH.
TABLE 169-7Typical Adult Hemoglobin Patterns* ||Download (.pdf) TABLE 169-7 Typical Adult Hemoglobin Patterns*
| ||HbA ||HbA2 ||Other Hemoglobins |
|Normal ||95%-98% ||<3.5% ||— |
|α-Thalassemia—all types ||95%-98% ||<3.5% ||— |
|β-Thalassemia trait ||95% ||>3.5% ||— |
|δ-β-Thalassemia trait ||80%-90% ||<3.5% ||Will have elevated HbF (5%-15%) |
|HbE trait ||~70% ||<5% ||HbE = 25%-30% |
|HbE homozygous ||— ||<5% ||HbE = 85%-95% |
HbE is another cause of microcytic anemia. Heterozygous HbE is asymptomatic and is not associated with anemia, but RBCs can be slightly microcytic (MCV 80 ± 5 fL). Homozygous HbE is also asymptomatic, with most individuals having a mild anemia (11.4 ± 1.8) and microcytosis (MCV 70 ± 4 fL). Target cells represent 20% to 80% of RBCs. Typical adult hemoglobin patterns are presented in Table 169-7.
Homozygosity for the HbS mutation (HbSS), or compound heterozygosity for HbS and other β-globin mutations (eg, β-thalassemia, HbC, HbO, HbD) are associated with important clinical complications (see Sickle Cell Disease section of this chapter). Most other variant hemoglobins are not clinically significant and do not cause disease. An individual who is heterozygous for a β-globin gene mutation will present with one variant hemoglobin in a quantity slightly less in amount than HbA (eg, HbE in Table 169-7). When a patient is heterozygous for an α-globin gene mutations, he or she will usually have one variant hemoglobin in a quantity of approximately 10% to 25%, and the majority of the remaining hemoglobin will be normal HbA.
TRIAGE AND HOSPITAL ADMISSION
The thalassemias and hemoglobinopathies can present in diverse ways. Heterozygosity for globin gene deletions and mutations is usually asymptomatic or may be associated with mild anemia. These patients can be investigated as an outpatient.
Individuals with clinically significant disorders of hemoglobin, including β-thalassemia major, are usually diagnosed in early childhood and require close medical care and follow-up. Illness requiring inpatient treatment may develop due to acute worsening of anemia or transfusion related complications, including organ dysfunction due to chronic iron overload (see Complications below).
Patients with β-thalassemia major (also referred to as transfusion-dependent thalassemia) require routine, chronic transfusion of RBCs (eg, every 3 to 4 weeks). For most patients, a target pretransfusion hemoglobin of 9 to 11 g/dL is appropriate. Higher levels (11-12 g/dL) may be necessary for patients with cardiorespiratory disease. Post-transfusion hemoglobin should not exceed 14 to 15g/dL.
As a result of the frequency and volume of RBC transfusions, most patients develop significant iron overload early in childhood and require lifelong chelation therapy. Care of these patients is optimally provided by a specialized, multidisciplinary, comprehensive care clinic.
Complications of thalassemia can be divided into complications of the disease itself, and complications of transfusion therapy. Historically, patients who have received inadequate chronic transfusion develop diffuse bone marrow expansion. Expansion of marrow production in atypical sites (eg, skull and maxillary bones) leads to the characteristic “thalassemic facies,” with frontal bossing and prominent maxillae. Expansion of bone marrow in the pelvis and long bones leads to thinning of the bony cortex, high risk of fractures, and delayed growth.
With modern practices of regular RBC transfusion, many of these historical complications are now avoided. However, RBC transfusion is associated with risks that may include hemolytic transfusion reactions, alloimmunization, febrile nonhemolytic transfusion reaction, or transfusion-transmitted infection. All patients who are on a program of chronic transfusion should be vaccinated for hepatitis B virus.
Iron overload is an expected complication in all chronically transfused patients, since each milliliter of RBC transfusion contains 1 mg of iron—at least 200 mg of iron per unit of RBCs transfused. Since the human body has no mechanism for excreting excess iron, once body iron stores are replete, unnecessary free iron is deposited in the tissues, leading to organ dysfunction. Serum ferritin and transferrin saturation are easy tests to screen for iron overload. Although there is no widely accepted target for serum ferritin, it is well understood that increasing serum ferritin concentrations are associated with increased risk of iron deposition in the liver. Over time, significant iron overload of the heart, pancreas, and pituitary will follow if chelation is not initiated. Current practice in patients with β-thalassemia major is to start chelation after the first 20 transfusion or when the serum ferritin level rises above 1000. Chelation treatment usually commences at 2 to 3 years of age and continues throughout life. Three chelating agents are currently available: deferoxamine (parenteral), deferasirox (oral), and deferiprone (oral) (Table 169-8).
TABLE 169-8Dosing, Administration, and Possible Adverse Effects with Iron Chelating Agents ||Download (.pdf) TABLE 169-8 Dosing, Administration, and Possible Adverse Effects with Iron Chelating Agents
| ||Common Starting Dose and Administration ||Maximum Daily Dose ||Possible Adverse Effects |
|Deferoxamine ||20 mg/kg administered by subcutaneous infusion over 8-12 h, 5-7 nights/wk (up to a maximum of) ||60 mg/kg ||Infusion site reactions; vision or hearing abnormalities; skeletal and growth abnormalities; zinc deficiency; Yersinia enterocolitica infection |
|Deferasirox ||20-40 mg/kg administered by mouth daily (suspended in water) ||40 mg/kg ||Rash, GI symptoms; mild elevation in transaminases; hearing impairment; nonprogressive elevation in serum creatinine |
|Deferiprone ||75 mg/kg/d in three divided doses ||100 mg/kg ||Agranulocytosis; arthalgias, zinc deficiency; mild GI symptoms and mild aminotransferase elevations |
RARE CAUSES FOR CONSIDERATION: DETECTION AND DIAGNOSIS OF RARE HEMOGLOBIN VARIANTS
To date more than 1400 globin chain mutations have been described. The majority is not clinically significant and can be detected by routine testing. Variants found in patients who are clinically well and hematologically normal are unlikely to be clinically significant. However, some rare variants that are clinically significant are difficult to detect through conventional hemoglobin separation techniques and may require further specialized analysis as outlined in Table 169-9. Deoxyribonucleic acid investigation may be the only analysis that can definitively identify these hemoglobins and should be considered in patients who have pertinent symptoms.
TABLE 169-9Detection and Diagnosis of Clinically Significant Rare Hemoglobinopathy Syndromes ||Download (.pdf) TABLE 169-9 Detection and Diagnosis of Clinically Significant Rare Hemoglobinopathy Syndromes
|Rare Syndrome ||Presentation ||Detection ||Hb Variant Identification |
|Unstable hemoglobins ||Chronic or sporadic hemolytic anemia || |
Abnormal erythrocyte morphology
Elevated Heinz body counts
Abnormal Hb instability testing (heat or isopropanol)
Suspicious HbH inclusion bodies
|DNA sequencing |
|High oxygen affinity ||Erythrocytosis ||Hb oxygen affinity analysis -(p50) ||DNA sequencing |
|Low oxygen affinity ||Anemia, cyanosis ||Hb oxygen affinity analysis -(p50) ||DNA sequencing |
|Hemoglobin M ||Cyanosis ||Methemoglobin absorption spectrum ||DNA sequencing |
Rare hemoglobin variants may denature readily, causing chronic hemolysis and anemia. The denatured globin precipitates in the RBC, producing Heinz bodies that are removed from the red cells by the spleen. Peripheral blood smear shows bite cells, irregularly contracted erythrocytes, or dense fragments. Other laboratory findings provide supporting evidence for active hemolysis (eg, elevated reticulocyte count, reduced haptoglobin). Unstable hemoglobins can fall into two categories: spontaneously unstable variants that result in congenital Heinz body hemolysis (eg, Hb Köln) or milder forms that present with hemolysis after ingestion of oxidative drugs. The unstable hemoglobins can be difficult to detect using conventional hemoglobin variant detection techniques and the diagnosis may rely on the erythrocyte morphology, Heinz body count, specialized tests to demonstrate in vitro instability, and DNA investigations.
HIGH OXYGEN AFFINITY HEMOGLOBIN VARIANTS
Hemoglobin variants that hold on to oxygen more avidly than HbA are called “high oxygen affinity” hemoglobins. Increased oxygen affinity results in tissue hypoxia that stimulates the production of erythropoietin leading to an erythrocytosis. These patients tend to be asymptomatic but can present with symptoms of increased blood viscosity. Since many of these variants do not separate by routine hemoglobin separation techniques, specialized analysis to measure oxygen equilibration curve and the partial pressure of oxygen at 50% saturation (called the P50 value) can be used in diagnosis. Alternately the P50 can be calculated by venous blood gas values. DNA analysis can confirm and characterize high oxygen affinity variants.
LOW OXYGEN AFFINITY HEMOGLOBIN VARIANTS
Some hemoglobin variants have a lower affinity for oxygen and therefore release oxygen more readily than HbA. This can suppress the production of erythropoietin, leading to a lower hemoglobin level. Like the unstable and high oxygen affinity variants, many hemoglobins with a low oxygen affinity will not separate from HbA using conventional Hb-separation techniques. The detection of an abnormal low oxygen affinity often relies on the clinical presentation correlated with the P50 value and a DNA investigation.
Patients presenting with cyanosis can also have an HbM. These hemoglobin variants have an accumulation of methemoglobin in the circulating red cells that causes a pseudocyanosis or brownish/slate pigmentation of the skin. The M hemoglobins also can be difficult to detect using conventional Hb variant-detection techniques. Detection relies on demonstration of abnormal absorption spectra followed by DNA investigation.
Close follow-up should be arranged for patients with complications of hemoglobinopathy. For patients with clinically symptomatic thalassemia syndromes, follow-up with a comprehensive care clinic is suggested.
Sickle cell disease (SCD) is characterized by atypical red cells that assume a sickle shape when deoxygenated. The inheritance of a single sickle cell gene (heterozygous HbS, or sickle cell trait) offers a survival advantage against malaria, which has contributed to the high gene prevalence of HbS in many regions of Sub-Saharan Africa, the Middle East, India, and the Mediterranean. In part due to global immigration patterns, sickle cell disease has become one of the most common hemoglobinopathies seen worldwide. Patients with sickle cell disease are homozygous for the sickle gene (HbSS) or compound heterozygous for the HbS gene mutation and another β-globin gene mutation. Individuals with SCD have a decreased life expectancy and may present with severe clinical complications that can lead to death if not properly treated. Screening for this disorder has been the focus for many newborn screening programs across most of North America and Europe to ensure early prophylaxis is given for reduced mortality and morbidity.
Hemoglobin S is the result of a substitution of valine for glutamic acid at the sixth amino acid of the β-globin chain that decreases the solubility of the hemoglobin molecule in the deoxygenated state causing hemoglobin polymerization and sickle cell formation. The homozygous expression of HbS and the corresponding absence of HbA cause a severe sickling disorder, in which hemoglobin polymerization initiates an elaborate pathophysiological cascade involving RBC injury, release of free hemoglobin into the blood, and adhesive interactions among sickle RBCs, endothelial cells, and other blood cells. Damaged RBCs initiate vessel occlusion and ischemia. Furthermore, the ongoing premature destruction of these sickle cells leads to chronic anemia.
The compound heterozygous inheritance of HbS with other β-globin chain variants (HbC, HbD, HbOArab, or β-thalassemia trait) may also result in an absence of HbA and a severe sickling syndrome. These genotypes are detailed in Table 169-10. Sickle cell disease is associated with an increased risk of death from sepsis, acute chest syndrome or stroke, and chronic complications that accumulate with age.
TABLE 169-10The Genotypes, Clinical Presentation, and Reproductive Significance of the Sickle Cell Syndromes ||Download (.pdf) TABLE 169-10 The Genotypes, Clinical Presentation, and Reproductive Significance of the Sickle Cell Syndromes
|Hemoglobinopathy ||Clinical Presentation ||Genotypes ||Reproductive Significance |
|HbS trait ||None ||βA/βS ||Carrier for all sickling disorders |
|HbC trait ||None ||βA/βC ||Carrier for HbSC disease and HbC disease |
|HbC disease ||Occasional mild hemolytic anemia ||βC/βC ||Carrier for HbSC disease and HbC disease |
|HbD trait ||None ||βA/βD ||Carrier for HbSD disease |
|HbOArab trait ||None ||βA/βOArab ||Carrier for HbSO disease |
|β-Thalassemia trait ||Microcytosis with normal Hb or mild anemia ||βA/β0 or βA/β+ ||Carrier for HbS/β-thalassemia |
|Sickle cell disease ||Severe sickling abnormality ||βS/βS ||Carrier for all sickling disorders |
|HbSβ0-thalassemia, ||Microcytosis, severe sickling abnormality ||βS/β0 ||Carrier for all sickling disorders or HbSβ0-thalassemia or thalassemia intermedia or major |
|HbSD disease ||Severe sickling abnormality ||βS/βD ||Carrier for HbSD or all sickling disorders |
|HbSβ+-thalassemia ||Microcytosis, mild to moderate sickling abnormality ||βS/β+ ||Carrier for all sickling disorders or HbSβ+-thalassemia or β-thalassemia intermedia |
|HbSC disease, HbSO disease ||Mild to moderate sickling abnormality ||βS/βC or βS/βOArab ||Carrier for all sickling disorders |
DIAGNOSIS: DOES THIS PATIENT HAVE ACUTE COMPLICATIONS OF SICKLE CELL DISEASE?
Evaluation of a patient with sickle cell disease will begin with a thorough history and physical. History should include details of clinical symptoms (eg, bony pain, chest pain, or shortness of breath) and a history of previous complications and medical care. In patients with pain, it is critical to determine whether the pain is due to a vaso-occlusive crisis (pain related to sickling of RBCs) or whether another process may be responsible (eg, abdominal pain due to acute cholecytitis). As the patient is likely to have had numerous sickle painful episodes in his or her lifetime, asking the patient, “Is this your typical sickle cell pain?” can help guide whether further investigations are required.
Vital signs should be measured, including pulse oximetry. Hypoxemia can suggest an underlying acute chest syndrome, pneumonia or pulmonary embolism. Hypoxemia is also a risk factor for worsened RBC sickling.
Adult patients are usually aware of their diagnosis of sickle cell disease. However, if the diagnosis or the genotype is in question, further testing may be performed. A CBC will show variable degrees of anemia. Peripheral blood smear should show sickled RBCs. Target cells and Howell-Jolly bodies suggest functional asplenia, associated with splenic autoinfarction—a common complication of sickle cell disease in childhood. Reticulocytes are elevated due to hemolysis of sickle cells. White blood cell count may be elevated if infection is present.
The sickle solubility test
The HbS solubility test is a simple screening test able to detect HbS. When reduced with sodium dithionite, HbS is insoluble and precipitates in high molarity phosphate buffer at neutral pH. An HbS solubility test is useful as a screening test for HbS in adult patients and as a confirmatory test when HbS is detected by either electrophoresis or HPLC, helping to distinguish HbS from other variants with similar migrating mobility as HbS. The sickle solubility test cannot distinguish between sickle cell trait, sickle cell disease, or HbS/β-thalassemia. The test is negative when the concentration of HbS is less than 15%, and thus it is not used to test blood samples from infants or patients who have received RBC transfusion. Importantly, the test cannot detect hemoglobin variants such as HbS, C, D Punjab, and OArab, which can cause a sickling disorder in combination with HbS. Thus, HbS solubility tests should not be used for assessment of potential reproductive risk, for genetic counseling, or as a primary diagnostic test.
Hemoglobin separation and molecular diagnostics
Methods such as gel electrophoresis, HPLC, and CE are effective for identifying the presence of HbS and/or other variant hemoglobins involved in compound heterozygous sickle cell disease. For more details on these methods, see Hemoglobin Separation in Thalassemia and Hemoglobinopathies section of this chapter. Molecular diagnostics and DNA analysis are used for positive characterization of the variant hemoglobin(s). Methods used include PCR, direct nucleotide sequencing, and southern hybridization.
Triage and hospital admission
Painful episodes are the most frequent complication in sickle cell disease. Patients who have had recurrent episodes may be treated at home with oral analgesics (acetaminophen, NSAIDs, or opiates). If the episode is more severe, they may require higher-dose therapy in a hospital-based setting. Severe pain requiring repeated doses of IV analgesia is best treated as an inpatient. Other supportive care should include judicious administration of intravenous fluid. Supplemental oxygen is indicated if the SpO2 or SaO2 are low. Painful episodes may take several days to a week or more to resolve.
Other indications for admission include acute chest syndrome, sepsis, stroke, and hyperhemolysis. These complications are best managed in an intensive care setting.
Outpatient treatment of sickle cell disease can be divided into preventative care and symptom management. Preventative care includes penicillin prophylaxis in children, immunizations (especially against encapsulated organisms such as Streptococcus pneumoniae, Hemophilus influenzae, and Neisseria meningitides) and patient education to avoid extremes of heat, remain hydrated, and seek rapid medical attention in case of symptoms. In pediatric populations, there is evidence that chronic RBC transfusion is effective at preventing stroke in certain high-risk groups.
Hydroxyurea is increasingly used to prevent vaso-occlusive crises and hemolysis. There is good evidence in patients with HbSS that hydroxyurea leads to significantly fewer painful episodes, fewer episodes of chest syndrome, and reduced need for transfusion and hospitalization, with few side effects. Long-term follow-up data suggest that there is also a decrease in mortality proportional to the number of years on hydroxyurea therapy. The exact mechanism of improved clinical outcomes with hydroxyurea in SCD is unknown, although it is known that hemoglobin level and HbF percentage improve while on the medication, both of which are associated with less severe sickle cell disease phenotype. Hydroxyurea also results in reduced leukocyte count, which may have an anti-inflammatory effect.
The goal of hydroxyurea is to titrate to the maximal tolerated dose for each patient, based on maintaining safe blood counts. Laboratory testing of CBC, reticulocyte count, HbF levels, renal, and liver function tests should be performed prior to initiating hydroxyurea and should be repeated at regular intervals thereafter. Although the expected decrease in WBC and platelets and increase in HbF can be seen within weeks to months, a clinical response may not be seen until after 3 to 6 months of treatment. In addition to laboratory monitoring and dose adjustment, follow-up appointments should be used to assess symptoms and to encourage continued adherence. Because of increased rates of leukemia and skin cancers in patients who have taken hydroxyurea for myeloproliferative disorders, there has been concern about the risk of malignancy after long-term use of hydroxyurea in SCD. However, rates of cancer do not seem to be elevated in adults or children who have taken hydroxyurea for SCD. Although unsubstantiated in human studies, concern remains about possible teratogenesis and impaired spermatogenesis based on animal studies. As a result, contraception is advised for both men and women taking hydroxyurea, and hydroxyurea is contraindicated during pregnancy or breastfeeding.
Other preventative care in SCD disease involves monitoring for end-organ complications, including proliferative sickle retinopathy, pulmonary hypertension, renal impairment, avascular necrosis, and iron overload.
Inpatient treatment may be required for management of acute complications, the diagnosis and treatment of which are discussed in the proceeding section.
Patients with SCD will be anemic at baseline, even during periods of good physical health. The anemia in sickle cell disease is caused by red cell destruction or hemolysis. Red cell survival is only 10 to 20 days, compared with 120 days in individuals without SCD. The bone marrow increases RBC production dramatically, but it is unable to keep pace with the destruction. Red cell production increases by 5- to 10-fold in most patients with sickle cell disease.
However, anemia in SCD may become more severe acutely, due to acute-on-chronic hemolysis, sepsis, hyperhemolysis, or aplastic crisis (eg, pure red cell aplasia due to parvovirus B19), or patients may become more symptomatic due to hypoxemia or increased oxygen demand. Red cell transfusions increase the oxygen-carrying capacity of blood, decrease the percentage of sickle RBCs, and improve microvascular perfusion. Simple transfusion is used when the patient has symptoms of anemia and the therapeutic goal is an increase in hemoglobin level. Transfusion is not advised in uncomplicated painful episodes.
Exchange transfusion involves removing the patient’s RBCs and replacing them with HbS-negative donor RBCs. The main advantage of exchange transfusions over simple transfusions is avoidance of hyperviscosity and volume overload, while reducing the percentage of sickle hemoglobin. Acute chest syndrome and stroke are two indications for exchange transfusion. Exchange transfusion requires the availability of skilled staff to perform the procedure as well as adequate vascular access in the patient. For automated exchange transfusion (erythrocytapheresis), specialized equipment is also required. Any patient who is expected to need RBC transfusion should be vaccinated for hepatitis B virus.
Painful episodes (sometimes referred to as “painful crises” or “vaso-occlusive crises”) are the most frequent complication in sickle cell disease, and are presumed to be due to vaso-occlusive ischemia in bones and other tissues. Triggers may include hypoxia, dehydration, cold, or fever. The frequency and duration of the vaso-occlusive crisis may vary considerably between patients but it is the most common cause of morbidity and mortality in sickle cell disease. Patients who have had recurrent episodes should have a supply of appropriate oral analgesics (acetaminophen, NSAIDs, or opiates) at home so that pain can be treated quickly and effectively. If the episode is more severe, patients may require higher-dose therapy in a hospital-based setting. Often parenteral therapy (eg, NSAIDs or opiates) is most effective. Patients should be taken at their word about the severity of their pain. There is no objective measure of severity of a vaso-occlusive episode, and undertreatment or delays in analgesic administration lead to unnecessary suffering and weakening of the patient-provider relationship.
Acute chest syndrome (ACS) is an acute complication of SCD that may be defined as fever and respiratory symptoms in the presence of a new pulmonary infiltrate on chest x-ray. Acute chest syndrome is a leading cause of hospitalization in patients with SCD and a significant risk factor for early mortality. The incidence of ACS is highest in patients with HbSS genotype. Causes of ACS include pulmonary infections (eg, influenza, bacterial, or viral pneumonia), pulmonary infarction, or fat embolism from necrotic bone marrow. Sickle cell disease patients who have undergone abdominal surgery are at risk of developing ACS in the immediate postoperative period. Sickle cell disease patients with asthma are twice as likely to develop ACS as SCD patients who do not have asthma. The most frequent symptoms at diagnosis of ACS include fever, cough, chest pain, shortness of breath, and tachypnea. Acute chest syndrome requires admission to the hospital. If signs and symptoms are severe, patients should be treated in an intensive care setting. Supplemental oxygen should be administered to maintain oxygen saturation of ≥ 95%. Adequate analgesia is required for pain. Complete blood count, CXR, arterial blood gases, blood cultures (if febrile), sputum cultures, RBC blood grouping, and crossmatch should be done rapidly. Regardless of the etiology, management of ACS includes intravenous broad-spectrum antibiotics, bronchodilators, incentive spirometry, and careful hydration. Patients who are hypoxemic (SaO2 < 80 mm Hb) should receive supplemental oxygen. Transfusion can be an important adjunct, especially if the patient is hypoxemic. There have been no randomized trials comparing simple and exchange transfusions in this setting. It is generally accepted that in severe acute chest syndrome, the goal of transfusion is to maintain a hemoglobin concentration > 10 g/dL and a HbS level of < 30%.
Individuals with SCD are at higher risk of stroke than the general population. Patients with the homozygous form of SCD, HbSS, have the highest risk, with an 11% chance of developing a first stroke by the age of 20 years, compared with a 2% risk for patients with HbSC disease. Those age 2 to 5 years have the highest incidence of first stroke followed by those between 6 and 9 years of age. Most strokes in children with SCD are ischemic. Clinical features of ischemic stroke include focal weakness (usually hemiparesis); seizures; altered consciousness and mentation; confusion; and visual, speech, and sensory disturbances. In children, symptoms may be transient.
Known risk factors include low hemoglobin levels, high white cell count, hypertension, and a recent history of acute chest syndrome. Genetic factors and nocturnal hypoxemia may also contribute to stroke risk. Transcranial Doppler ultrasonography (TCD) is used as a screening tool for stroke prevention in children with SCD. Children with abnormal TCD receive prophylactic blood transfusion, based on the results of a randomized trial showing a 92% reduction in stroke risk with a chronic RBC transfusion strategy versus observation.
No large studies of stroke prevention have been done in adults with SCD. Early detection is important. Although treatment of acute stroke in children focuses on hydration and exchange transfusion, there is less consensus on SCD-specific interventions for adults with stroke. Practice guidelines from the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) are based on current recommendations for prevention and management of stroke in adults without SCD.
Patients with sickle cell disease are at increased risk of infection and bacteremia. Increased incidence of infection is partially explained by functional asplenia—immunization against encapsulated organisms should help to decrease the risk. Sickle cell disease patients with fever should receive an appropriate septic workup, with consideration of their immunization status and past history of sickle cell complications. Acute chest syndrome, osteomyelitis, and skin and soft tissue infections should be ruled out, as appropriate.
Priapism occurs in 30% to 45% of male patients with SCD and it is defined as a prolonged, unwanted, and uncomfortable or painful erection. Priapism occurs when sickle veno-occlusion causes a pathologic decrease in venous outflow from the penile vascular chambers. Minor episodes can be uncomfortable but tolerable and self-limited, lasting up to several hours. Major episodes can last a few hours to several days and are often extremely painful. Prolonged priapism (>4 hours) can lead to ischemia and fibrosis and is considered a medical emergency. Prolonged or recurrent priapism can result in impotence.
Initial self-treatment by patients has some reported benefit, including analgesia, oral hydration, and exercise. However, for some patients the duration of the episode seems unresponsive to conservative measures. If a patient presents for medical attention, he should be treated rapidly and in a sensitive manner. First-line intervention includes supportive care measures such as intravenous hydration and narcotic analgesia. If the episode persists for more than 2 hours, additional measures must be considered. Use of exchange transfusion in this setting is controversial because of conflicting evidence for efficacy and reports of ASPEN syndrome (association of sickle cell disease, priapism, exchange transfusion, and neurologic events). If the episode does not resolve rapidly, a urology specialist should become involved.
Bone and soft tissue complications
In SCD patients presenting with bone pain, clinicians must distinguish between common causes, including acute vaso-occlusive crisis, osteomyelitis (OM), and avascular necrosis, while also considering more rare complications such as abscesses or septic arthritis. It is useful to know that bone pain in sickle cell disease is much more likely to be due to vaso-occlusion than to OM; in one pediatric series, VOC was at least 50 times more likely.
A thorough evaluation begins with assessing historical features of the pain. If the onset of symptoms was acute, it may be suggestive of vaso-occlusion or OM versus the chronic pain and disability caused by AVN. Concurrent infectious symptoms (eg, fever, rigors) may be present in OM. Any prior history of bony complications can also guide further investigations.
Physical examination should include a musculoskeletal examination, targeting the joint or other location of symptoms. Elevated temperature may be suggestive of OM or other infectious etiology, while other abnormalities in vital signs (eg, tachycardia, hypotension) would be late signs and potentially indicative of progression to sepsis.
Leukocytosis and increased erythrocyte sedimentation rate (ESR) are nonspecific findings that may be present in both infectious and noninfectious processes. If infection is suspected, blood cultures should be drawn. Cultures of the suspected site of infection also aid in diagnosis (eg, joint aspiration, abscess drainage, bone aspirate, or bone biopsy), as indicated by clinical suspicion and results of imaging.
Plain radiography, radioisotope bone scanning, and radio-labeled leukocyte scanning are not always useful in the routine diagnostic evaluation of bone pain in SCD as these modalities can detect acute infarction but changes are often difficult to distinguish from those seen in OM. Ultrasonography is a rapid, simple, and noninvasive modality that is moderately sensitive for detecting acute osteomyelitis. The main ultrasonographic finding in OM is subperiosteal fluid. Magnetic resonance imaging can be useful in the diagnosis of OM. As with other imaging modalities, there is overlap between the changes seen in infection and infarction. Although still not 100% specific for differentiating OM from VOC, gadolinium enhancement improves the accuracy of MRI.
Management of bone pain may include oral, intravenous, or subcutaneous opiates, depending on severity of pain. More specific management should be tailored to the underlying process.
Surgical procedures such as splenectomy, cholecystectomy, or orthopedic surgery are commonly required in patients due to complications of their SCD. In addition, patients with SCD may require surgeries due to unrelated medical problems during their lifetimes. Patients with SCD have a higher risk of perioperative complications than the general population for several reasons. First, patients with SCD are already anemic and any procedural bleeding will further drop hemoglobin levels, leading to more severe anemia and decreased oxygen-carrying capacity. Second, intraoperative hypoxia, postoperative atelectasis, and decreased oral intake can trigger sickling of red blood cells. Sickling of red blood cells can lead to painful crisis or acute chest syndrome, among other SCD-related complications. All patients should undergo consultation with an anesthesiologist prior to surgery. Patients undergoing medium- and high-risk surgery should receive prophylactic red blood cell transfusions to target hemoglobin of 100 mg/L. If preoperative baseline hemoglobin level is 90 or higher, partial manual exchange transfusion should be performed to achieve a target HbS <60%. Red cell exchange apheresis can be considered prior to very high-risk procedures (eg, orthopedic surgery requiring tourniquet, vascular surgery requiring arterial clamping) or in patients with a history of postoperative complications. Cross-matched units of red blood cells should be on hold in the blood bank. Importantly, all patients should receive adequate hydration prior to surgery. If the patient is required to remain in NPO status prior to surgery, he or she should be admitted for intravenous hydration with isotonic solution during the NPO period. Postoperatively, isotonic intravenous fluids should be administered until the patient is drinking and eating well. Supplemental oxygen should be used as needed. Deep breathing exercises and/or incentive spirometry may be used to reduce the risk of postoperative atelectasis.
An in-depth discussion of chronic complications of SCD is beyond the scope of this chapter. An excellent resource for further information is the NIH/NHLBI Guidelines (2014) (The Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014). Full document available at https://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines. Close follow-up should be arranged for patients with complications of SCD.
Discharge considerations: Patients admitted for complications od sickle cell disease require close monitoring of symptoms and laboratory parameters during their hospital stay. If they are being treated for a painful episode, doses of pain medication should be carefully titrated downward as pain symptoms improve. Intravenuos opiates should be switched over equianalgesic doses of oral medication prior to discharge. Eligibility for discharge will depend on stable clinical status and ability of the patient to manage symptoms effectively at home. Follow-up with a comprehensive care clinic is suggested.
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