Anemia is a common problem, affecting an estimated one-third of the world's population. Worldwide, the most common causes of anemia include iron deficiency, thalassemia, hemoglobinopathies, and folate deficiencies. Within the United States, the most common causes are iron deficiency, thalassemia, and anemia of chronic disease. Not only is anemia common in the general population, but also the prevalence of anemia increases with age. Given the ubiquity of this entity, some patients who present to the emergency department with anemia will be symptomatic, whereas anemia will be an incidental finding in other patients.
Anemia is defined as a reduced concentration of RBCs. Erythropoiesis ensures that the number of RBCs present is adequate to meet the body's demand for oxygen and that RBC destruction equals production with an average lifespan of 120 days for circulating erythrocytes. Any process or condition that impairs the production, increases the rate of destruction, or increases the loss of erythrocytes will result in anemia if the body cannot produce enough new RBCs to keep up with the loss.
Quantification of the RBC concentration is reflected in the RBC count per microliter, hemoglobin concentration, or hematocrit. Normal RBC values for adults vary slightly between males and females (Table 41–10). Anemia has been categorized into three types on the basis of RBC values (Table 41–11).
Regardless of the cause of anemia, many of the clinical manifestations are the same. The severity of symptoms and signs related to anemia depends on several factors: the rate of development of anemia, the extent of anemia present, the patient's age, the patient's general physical condition, and other existing comorbid illnesses. Patients with chronic and slowly developing anemia may have almost no complaints even with hemoglobin levels as low as 5–6 g/dL. More typically, most people will begin to be symptomatic with hemoglobin levels at about 7 g/dL. Patients with chronic anemia may complain of weakness, fatigue, lethargy, dyspnea with minimal exertion, palpitations, and orthostatic symptoms. Physical examination findings in patients with significant chronic anemia may include orthostatic hypotension; tachycardia; skin, nail bed, and mucosal pallor; systolic ejection murmur; bounding pulse; or widened pulse pressure.
Patients who develop anemia in a rapid fashion frequently have more pronounced symptoms. Additionally, these patients may have hypotension, resting and exertional dyspnea, palpitations, diaphoresis, anxiety, severe weakness that may progress to lethargy, and altered mental status. Loss of more than 40% of blood volume leads to severe symptoms that are due more to intravascular volume depletion than to anemia.
The diagnosis of anemia is established by the finding of a decreased RBC count, hemoglobin, or hematocrit on the routine CBC. A specific cause of anemia need not be established in the emergency department; however, appropriate workup should be initiated to help expedite a diagnosis, and initial studies should be started before the transfusion of packed RBCs. The basic evaluation of a patient newly diagnosed with anemia includes the following: RBC indices (provided with the CBC), reticulocyte count, and peripheral blood smear. The mean cellular volume (MCV) is the most useful guide to the possible cause of an anemia. The reticulocyte count reflects activity in the bone marrow. The red cell distribution width (RDW) measures the size variability of the RBC population, and in early nutritional-deficiency anemias (iron, vitamin B12, or folate) the RDW may be increased before the MCV becomes abnormal. As part of the general evaluation, the two most common sources of blood loss should be investigated: gastrointestinal (eg, checking the stool for occult blood) and uterine bleeding (eg, history of hypermenorrhea).
Iron-deficiency anemia occurs when body iron content is insufficient for erythropoiesis; it manifests as a microcytic, hypochromic anemia. Iron deficiency is seen with either inadequate iron intake (usually in undeveloped countries with little meat in the diet) or from a combination of iron loss (hemorrhage) and inadequate intake (in developed countries). Heme iron (as found in meat) is absorbed more efficiently than is nonheme iron (found in vegetables) and accounts for the higher incidence of iron deficiency in vegetarians. Total body iron content varies with age and gender at 35–60 mg/kg of body weight. Each gram of hemoglobin contains 3.47 mg of iron. The recommended daily intake of iron is about 7 mg in a man, 12–16 mg in a menstruating woman, and 5–7 mg in a postmenopausal woman.
The symptoms of iron-deficiency anemia (fatigue and weakness) are primarily those seen with any chronic anemia. Occasionally, patients may describe a desire to chew ice or cold food (termed pagophagia) or leg cramps on climbing stairs. Gastrointestinal epithelial (angular stomatitis, glossitis, esophageal webs, and gastric atrophy) and nail (koilonychia) abnormalities have been described in iron deficiency, although their frequency varies and these findings are uncommon in the United States.
Patients with iron-deficiency anemia have both microcytic (low MCV) and hypochromic (low MCHC) erythrocytes. The platelet count is often elevated. Examination of the peripheral smear is useful to exclude thalassemia; target cells are not seen in iron-deficiency anemia. Combined iron deficiency and folate deficiency produces variation in red cell size, some macrocytic and others microcytic, such that the measured MCV can be within the normal range, although the RDW should be significantly increased. Iron-deficiency anemia produces a low serum ferritin, low serum iron, and elevated total iron-binding capacity.
The most accurate initial diagnostic test for iron-deficiency anemia is the serum ferritin measurement. Serum ferritin values greater than 100 ng/mL (100 μg/L) indicate adequate iron stores and low likelihood of iron-deficiency anemia. Serum ferritin levels of 25 ng/mL (25 μg/L) have a very high probablility of being iron deficient. The use of serum iron, total iron-binding capacity, and transferrin saturation are recommended as follow-up tests in patients with an intermediate ferritin level as a strategy to reduce the need for bone marrow biopsy.
The gold standard is the absence of stainable iron on bone marrow aspirate and establishes the diagnosis without other tests. Possible blood loss should be investigated in a patient with iron-deficiency anemia and often requires testing for occult blood loss from either the gastrointestinal tract (stool for occult blood) or the kidneys (hemoglobinuria or hemosiderinuria).
The first line of therapy for iron-deficiency anemia is oral iron therapy using ferrous sulfate, 325 mg (children, 1–2 mg/kg), with each meal 3 times daily. A response with increased reticulocytes is seen within 3–4 days and peaks in 7–10 days, with the hemoglobin level increasing about 1 g/dL per week. Once normal hemoglobin levels are achieved, oral iron therapy should continue to replenish total body iron stores.
Transfusion should be considered for patients of any age who are symptomatic with complaints of fatigue or dyspnea on exertion. Cardiac patients with a hemoglobin level less than 10 g/dL should also be considered for transfusion therapy.
Parenteral iron therapy is reserved for the rare patient who cannot absorb oral iron, but parenteral preparations are expensive and associated with adverse effects, including fatal anaphylactic reactions. Red cell transfusion is used for the patient with ongoing blood loss or acute symptoms of inadequate oxygen delivery to the brain or heart.
The immune-mediated hemolytic anemias traditionally have been divided into three categories: autoimmune, alloimmune, and drug related.
Autoimmune Hemolytic Anemia
Individuals with autoimmune hemolytic anemia (AIHA) make antibodies against their own RBCs or against the body's higher-incidence antigens. The overall incidence of AIHA is approximately 1–3 cases per 100,000 population per year. The incidence of AIHA in infants and children is less, approximately 0.2 cases per 100,000 population per year in those younger than 20 years. AIHA in children is commonly associated with viral or respiratory infections; is mediated by immunoglobulin G (IgG); and causes acute, fulminant hemolysis. Pregnant women have a 5 times greater risk of developing autoantibodies, but significant RBC destruction is not common.
Diagnosis of AIHA requires evidence of an autoantibody against RBCs in the form of (1) detection of the autoantibody on the patient's red cells (positive DAT) and (2) identification of an autoantibody. To make the diagnosis of AIHA, serologic evidence of autoantibodies should be correlated with clinical and other routine laboratory evidence of hemolytic anemia, including decreased hemoglobin, decreased haptoglobin, elevated reticulocyte count, elevated unconjugated (indirect) bilirubin, elevated LDH, or hemoglobinuria.
AIHA can be divided into primary and secondary varieties. Primary AIHA refers to cases without an underlying cause (idiopathic), and secondary AIHA refers to cases seen with an underlying disorder (Table 41–12). Primary AIHA is more common in women, with peak incidence during the 4th and 5th decades. The hemolytic process in AIHA can take place within the vascular space or in the liver or spleen. AIHA is also categorized according to autoantibody type: warm type, cold type, and mixed type.
Table 41–12. Causes of Secondary Autoimmune Hemolytic Anemia. ||Download (.pdf)
Table 41–12. Causes of Secondary Autoimmune Hemolytic Anemia.
- Lymphoproliferative disease: chronic lymphocytic leukemia, lymphoma, Hodgkin disease, Waldenström macroglobulinemia, multiple myeloma.
- Autoimmune disease: systemic lupus, rheumatoid arthritis, polyarteritis nodosa, pernicious anemia, autoimmune thyroid disease, scleroderma, ulcerative colitis, Crohn's disease
- Infection: infectious mononucleosis, cytomegalovirus infection, viral hepatitis, malaria, pediatric viral respiratory illness
- Immunodeficiency syndrome: HIV, X-linked agammaglobulinemia, common variable immunodeficiency, IgA deficiency, Wiskott–Aldrich syndrome, dysglobulinemia
- Nonlymphoid tumors: ovarian carcinoma and dermoid cysts, teratomas, Kaposi sarcoma, thymoma
Warm-type AIHA comprises 70% of AIHA cases and is usually mediated by an IgG antibody directed against surface antigens of the RhD-erythrocyte system. Autoantibodies of the warm type react most strongly near 37°C. These autoantibodies are usually pan-reactive and produce hemolysis both in the patient's RBCs and in transfused RBCs. Warm-type autoantibody-mediated hemolysis is predominantly extravascular, occurring in the spleen. Warm-type AIHA carries a 2:1 female preference but has no racial predilection. About half of warm-type AIHA cases can be labeled as primary or idiopathic. Secondary cases are most often associated with lymphoproliferative disorders (in about half) or a systemic autoimmune disease. Viral-induced or HIV-associated warm-type AIHA is often mild and self-limited.
Warm-type AIHA is initially treated with oral prednisone, 1–1.5 mg/kg/d for 1–3 weeks. Improvement is usually noted within 1 week, and 70–80% of patients are improved within 3 weeks. Once the patient's hemoglobin level stabilizes, the steroids can be tapered. Complete remission is achieved in 15–20% of new-onset cases of warm-type AIHA, but half of patients will need low-dose prednisone for several months.
Between 10% and 20% of steroid-treated patients will fail to respond adequately or will require unacceptably high doses to maintain the desired response. In such patients the AIHA is treated with either splenectomy or cytotoxic drugs. Splenectomy removes both the main site of extravascular hemolysis and a major site of general autoantibody production. Splenectomy produces a 65–70% response rate and has the potential for long-term remission or a complete cure.
Cytotoxic drugs produce a 40–60% response rate and have been used for patients who have not responded to steroids or splenectomy. Severe hemolysis in cases of warm-type AIHA may be treated with plasmapheresis as a transient stabilizing measure while waiting for steroids or cytotoxic agents to take effect. Intravenous immunoglobulin has been used in children with mixed results and should only be considered in the most refractory cases. Danazol, an attenuated androgen with fewer side effects than glucocorticoids, can produce remission in occasional patients.
For patients with life-threatening anemia, RBC transfusion of the least incompatible units may be carried out slowly with close monitoring. Transfusion may precipitate further production of autoantibodies as well as introduce a source for the production of allogeneic antibodies.
Cold-Type AIHA: General Considerations
Cold-type AIHA autoantibodies are usually immunoglobulin M (IgM) and are most strongly hemolytic at 0–4°C. The presence of cold-type autoantibodies leads to clumping or agglutination of RBCs on peripheral smear at cooler temperatures. Hemolysis occurs in both the extravascular and intravascular spaces, and Kupffer cells in the liver are responsible for most of the extravascular RBC destruction. The two common cold-type AIHA disorders are cold agglutinin syndrome (CAS) and paroxysmal cold hemoglobinuria (PCH). Fifty percent of secondary cold-type AIHA cases are associated with lymphoproliferative disorders.
Cold-Type AIHA: Cold Agglutinin Syndrome
Cold agglutinin syndrome (CAS) accounts for up to one-third of all AIHA cases and is typically IgM mediated and directed against the I/i blood group antigens. Primary CAS is seen in older adults, particularly females, with a peak incidence at age 70 years. The hemolysis associated with the primary and chronic secondary forms of CAS tends to be mild and stable with hemoglobin levels of 9–12 g/dL. Secondary CAS can also occur as an acute attack, such as that seen in patients who have preceding infectious illnesses, including from Mycoplasma pneumoniae, Epstein–Barr virus (EBV), adenovirus, CMV, influenza, varicella zoster virus (VZV), HIV, E. coli, Listeria monocytogenes, and Treponema pallidum.
Symptom onset corresponds with the peak antibody response to infection, usually 2–3 weeks after the onset of illness. The triggered cold-type AIHA resolves approximately 2–3 weeks later. Chronic cold-type AIHA associated with lymphoproliferative diseases, such as chronic lymphocytic leukemia, lymphomas, and Waldenström macroglobulinemia, produces high autoantibody levels with the potential for significant hemolysis. Cold weather exacerbates CAS with more episodes of acute hemolysis seen during winter. Patients are apt to develop acrocyanosis because the peripheral circulation is typically cooler than the central circulation. Raynaud phenomenon, vascular occlusion, and tissue necrosis may complicate CAS. Clumping of cold agglutinins will elevate the MCV and decrease the RBC count. Peripheral smear findings include the spherocytosis caused by RBC membrane destruction as well as anisocytosis, poikilocytosis, polychromasia, and agglutination. As with other forms of hemolytic anemia, patients will have elevated LDH and unconjugated bilirubin with moderate disease, and decreased haptoglobin, hemoglobinemia, and hemoglobinuria with severe, intravascular hemolysis.
In primary and chronic CAS with mild anemia, treatment is symptomatic and involves simply keeping extremities, noses, and ears warm in cold weather. Patients with CAS should take daily folate supplements. Treatment for severe hemolysis has been successful with immunosuppressive or cytotoxic agents. As in warm-type AIHA, plasmapheresis may prove helpful as a temporizing measure by removing autoantibodies. Unlike warm-type AIHA, CAS rarely responds to steroids, although such treatment may be considered in atypical cases. Splenic macrophages play a lesser role in IgM-mediated cold-antibody disease; thus splenectomy is not as helpful for cold-antibody-mediated extravascular hemolysis. Transfusions should be limited because they may worsen ongoing hemolysis. Transfusion carries the risk of producing alloantibodies to transfused RBCs. RBC transfusion can be performed for patients at risk for significant cardiac or cerebrovascular ischemia, but transfused blood should be kept at 37°C using a blood warmer.
Cold-Type AIHA: Paroxysmal Cold Hemoglobinuria
Paroxysmal cold hemoglobinuria (PCH) is caused by a biphasic IgG autoantibody called the Donath–Landsteiner antibody. The PCH autoantibody is directed against the P antigen system found on most RBCs. Despite the name, hemolysis may occur at both cold and normal temperatures.
Symptoms include high fever, chills, headache, abdominal cramps, nausea and vomiting, diarrhea, and leg and back pain that develops with cold exposure. Cold urticaria, extremity paresthesias, and Raynaud phenomenon may also develop. Primary PCH and PCH secondary to congenital or late-stage syphilis are characterized by chronic disease with cold-induced relapses. Secondary PCH caused by other infectious agents is most common in children and is one of the more common causes of childhood hemolytic anemia. Postinfection PCH is usually associated with measles, mumps, EBV, CMV, VZV, adenovirus, influenza A, M. pneumoniae, Haemophilus influenzae, and E. coli. Most cases of postinfectious PCH are self-limited, but severe cases may take weeks to resolve. With severe hemolysis, hemoglobinuria is common and methemoglobinuria may be seen. Acute renal failure may develop as a complication of PCH.
Keep patients with PCH warm. Consider steroids in children with severe hemolytic anemia but because infection-related PCH tends to be self-limited, the benefit is uncertain. PCH secondary to syphilis responds to effective antibiotic treatment. Splenectomy is not helpful, and plasmapheresis should be used only as a temporizing measure in life-threatening cases. RBC transfusion using a blood warmer should be limited to patients with severe hemolysis because most donor units are P antigen positive and may stimulate further production of PCH autoantibodies.
Mixed-type AIHA occurs as primary or secondary disease (usually lymphoproliferative or autoimmune diseases). The course of illness is usually chronic with severe exacerbations. Like warm-type AIHA, mixed-type AIHA is steroid responsive, can be treated with splenectomy, and responds to cytotoxic therapy. Because relapses are not triggered by cold exposure, acrocyanosis and the Raynaud phenomenon are not characteristically seen. As with any secondary AIHA, treatment of the underlying disorder will reduce hemolytic activity.
Alloimmune Hemolytic Anemia
Alloimmune hemolytic anemia requires exposure to allogeneic RBCs with subsequent formation of alloantibodies that react specifically with the allogeneic RBCs that triggered their production. These antibodies do not react against a patient's own RBCs. A well-known example of alloimmune hemolytic anemia is when the RhD-negative maternal immune system develops IgG alloantibodies on exposure to RhD-positive fetal RBCs. The maternal alloantibodies can then cross the placenta to inflict fetal RBC destruction in a condition termed hemolytic disease of the newborn. Anemia can range from mild to potentially fatal producing intrauterine fetal death. By still uncertain mechanisms, administration of anti-D IgG with any fetomaternal hemorrhage event and soon after delivery will suppress maternal alloantibody formation and prevent hemolytic disease of the newborn. Treatment of established disease employs intrauterine and intravascular fetal transfusion and may include plasma exchange or intravenous immunoglobulin therapy.
Most adults who develop alloimmune hemolytic anemia have a history of RBC transfusion, which sensitizes patients to allogeneic RBC antigens. A subsequent transfusion can result in immediate alloantibody production, resulting in the fever, chest and flank pain, tachypnea, tachycardia, hypotension, hemoglobinuria, and oliguria seen in the hemolytic transfusion reaction. In patients with high alloantibody titers, the hemolytic reaction can be immediate. Patients with lower alloantibody levels develop delayed hemolysis occurring 3–7 days posttransfusion.
Drug-related AIHA can be divided into three types: autoimmune, drug adsorption, and neoantigen. Steroids can be used in cases of drug-related severe hemolysis. RBC transfusion will aggravate hemolysis if the recipient's serum contains antibodies against antigens found on the transfused RBCs.
Autoimmune Drug-Related AIHA
Autoimmune drug-related AIHA results when the offending drug triggers formation of autoantibodies that bind with RBC self-antigens, leading to a hemolytic process serologically indistinct from that seen in warm-type AIHA. The diagnosis is proved when the hemolytic process abates on withdrawal of the offending drug. Drugs implicated include α-methyldopa, levodopa, mefenamic acid, procainamide, diclofenac, quinidine, phenacetin, and the second- and third-generation cephalosporins (particularly cefotetan and ceftriaxone). Up to 71 drugs have been associated with development of a positive DAT (direct antiglobulin test); however, significant hemolysis is seen only occasionally. An extended drug exposure is usually required for autoantibodies to form. A positive DAT does not indicate that hemolysis will occur or that a drug must be discontinued. Within days of stopping the offending drug, hemolysis usually stops, although it may take months to see full resolution of the process.
Drug Adsorption–Type AIHA
Drug adsorption–type AIHA requires that the drug incite the formation of antidrug antibodies and that the drug bind to the RBCs with significant affinity. Antibodies formed against the drug will react against the drug bound to the RBC surface, producing hemolysis. This type of hemolysis has also been called drug requiring because the absence of the offending drug eliminates the hemolytic reaction completely.
Neoantigen-Type Drug-Related AIHA
Neoantigen-type drug-related AIHA involves weak binding of the offending drug to normal RBCs. The body's immune system, seeing the formed immune complexes as foreign, will generate an immune response that then produces hemolytic disease. The classic causative agent is penicillin, and isolated cases of diphtheria–tetanus–pertussis vaccination in children have been associated with hemolysis possibly via this neoantigen mechanism.
Sickle cell anemia is caused by the substitution of the amino acid valine for glutamine at position 6 in the β-globin chain, producing an abnormal hemoglobin tetramer termed hemoglobin S (HbS). As a result of this mutation, deoxygenated HbS polymerizes, deforming the RBC and producing the characteristic sickled appearance. The distorted cell results in premature RBC destruction and also increases the viscosity of blood, leading to obstruction within the microvasculature. The overall effect is chronic ongoing hemolysis and episodic periods of vascular occlusion resulting in tissue ischemia affecting most organ systems.
This defect is inherited as an autosomal recessive trait, and disease is seen in patients who are homozygous for the sickle gene (HbSS). People with sickle cell trait (HbAS; heterozygous with one gene for normal β-globin chain and one gene for a β-globin chain with the sickle mutation) have a normal lifespan and are usually asymptomatic except in rare cases of severe physiologic stress when they may have an acute pain crisis, splenic infarction, or cerebrovascular complications. Approximately 8% of the African-American population carries sickle cell trait (heterozygous for the sickle cell gene), and approximately 0.15–0.2% of African-American newborns have sickle cell disease (homozygous for the sickle gene). A lesser percentage of individuals of Middle Eastern, eastern Mediterranean, and Indian descent may have the HbS gene.
Patients with sickle cell disease typically present to the emergency department because of complications (Table 41–13). Acute painful (vaso-occlusive) sickle cell crisis is a common problem, and the average patient with sickle cell disease has 1–4 severe attacks per year. The initiating event may not be identifiable, but stressors such as infection, cold, dehydration, and altitude have been implicated. As a result of intravascular sickling and small vessel occlusion, infarction of bone, viscera, and soft tissue occurs. Infarction manifests as diffuse bone, muscle, and joint pain and, in some cases, symptoms related to a specific affected organ. Initial management includes aggressive pain management and hydration, an assessment of the cause of the current crisis, and a search for additional complications.
Table 41–13. Emergencies in Sickle Cell Disease. ||Download (.pdf)
Table 41–13. Emergencies in Sickle Cell Disease.
|Vaso-occlusive crises||Musculoskeletal pain (typical painful crisis)|
- Dactylitis (hand-foot syndrome)
- Acute chest pain syndrome
|Hematologic crises||Splenic sequestration|
- Aplastic crisis
- Hemolytic crisis
- Urinary tract infections
Generally, a CBC and reticulocyte count help assess the degree of anemia and ensure that the marrow is still producing red cells. If the reticulocyte count is not available, the presence of polychromasia in the peripheral blood smear can indicate continued red cell production. Patients with sickle cell disease sometimes have a low-grade fever and an elevated white blood cell (WBC) count. This combination can make it difficult to determine whether an infection is present during a crisis. Consider infection if the WBC count has a left shift and is elevated above 20,000/μL. Because of the chronic hemolysis, mild elevations in bilirubin and serum LDH are common.
Supplemental oxygen is commonly used for painful crises, but unless the patient is systemically hypoxemic, it has not proved to be of routine benefit. Treatment of acute pain requires opioids, and patients with severe pain should receive parenteral agents. A potent opioid, such as morphine or diamorphine, is recommended, whereas meperidine, with the potential for neurotoxicity from the metabolite normeperidine, is not recommended. Some patients may be tolerant because of prior opioid treatment, and large doses may be required. Regular doses of analgesics for a few hours to several days are typically required. Patient-controlled analgesia can be used in selected patients. NSAIDs can be used for their additive effect in pain management of sickle cell crisis. Because patients with sickle cell disease and a painful crisis have an absolute or relative hypovolemia due to their disease (deficient renal concentrating ability) or crisis (anorexia, vomiting, fever), aggressive oral or intravenous rehydration is commonly carried out. Induced hyponatremia and purified poloxamer 188 shorten the duration and severity of an acute crisis, but the effect is small, and no approach to shortening the duration and severity of a painful sickle cell crisis has proved reliable, safe, and appropriate for routine use. A common and recommended practice is to develop an individualized assessment and treatment protocol for specific patients who frequently present to the emergency department with painful crises. Sickle cell pain is complex and varied, and often requires extraordinary doses of narcotics. Nonpharmacologic treatments (distraction, massage, TENS units) may be helpful, and nonanalgesic adjuvants such as antihistamines, TCAs, and anticonvulsants may be more effective than narcotics at relieving chronic and neuropathic components of sickle cell pain.
The goal of treating sickle cell disease is to prevent complications. Specific treatments such as penicillin prophylaxis, pain medications, and blood transfusions can be instituted in the emergency department. Hydroxyurea has now been shown to be successful in reducing the number and recurrences of pain crisis and acute chest syndrome, but is useful only in compliant patients as it requires daily dosing, and is outside the scope of the emergency department.
Sickle Cell Complications
Bone pain is common during a sickle cell crisis and may include the back and the extremities. Usually, the pain is diffuse, and no physical findings are present. However, redness, warmth, or swelling suggests infection (cellulitis or osteomyelitis). The complaint of localized pain to the hip with difficulty ambulating suggests the possibility of aseptic necrosis of the femoral head, and approximately 30% of those with sickle cell disease develop hip pathology by age 30 years. Bone infarctions may cause symptoms similar to osteomyelitis. Plain radiographs may show evidence of aseptic necrosis or osteomyelitis, whereas bone infarcts are not usually visible on radiographs. Joint effusions are occasionally seen as a complication of sickle cell crisis, but arthrocentesis is often necessary to determine if the joint is infected.
In young children an early manifestation of sickle cell disease is dactylitis (hand-foot syndrome). The syndrome is thought to be due to infarction of the red marrow with associated periosteal inflammation. It manifests as fever and painful swelling of the hands, feet, or both, and some redness and warmth may be present. As the child grows, the hematopoietic tissue in the metacarpal and phalangeal marrow is replaced by fatty tissue, making this entity less likely.
The acute chest syndrome is used to describe a sickle cell crisis with pulmonary symptoms and a new pulmonary infiltrate found on radiograph. The patient might have pleuritic chest pain, shortness of breath, fever, nonproductive cough, and tachypnea. The exact cause of the chest syndrome is unclear, but infection, infarction (ribs or lung), and pulmonary fat embolism (from ischemic marrow fat necrosis) have all been implicated. Although a chest radiograph is not routinely required in all patients with painful sickle cell crisis, it is indicated in those with pulmonary symptoms or signs of fever. The onset of acute chest syndrome may be associated with a fall in hemoglobin level from the normal baseline. Pulmonary infiltrates may be present in one lobe or be diffuse and bilateral, and pleural effusions may be present. Severe cases may progress rapidly to respiratory failure. Treatment involves close monitoring of fluid status, oxygen, and pain control. Broad-spectrum antibiotics to cover S. pneumoniae and M. pneumoniae are recommended. In severe cases, simple transfusion or exchange transfusion can be done. Acute chest syndrome is currently the leading cause of death from sickle cell disease in the United States.
Generalized and constant abdominal pain is a common complaint during an acute sickle cell crisis, and it may be difficult to distinguish between infarction of the abdominal and retroperitoneal organs associated with a sickle cell crisis and a focal abdominal problem such as cholecystitis or appendicitis. Frequently, the patient can determine that the pain is similar to or different from prior episodes. Patients with a typical vaso-occlusive episode should not have evidence of peritonitis (rebound). Hepatic infarction may cause the acute onset of jaundice and abdominal pain and can be difficult to distinguish from hepatitis or cholecystitis. Biliary disease is common because pigment-related cholelithiasis is seen in 30–70% of patients with sickle cell disease. Severe right upper quadrant pain and marked elevations of bilirubin may be due to intrahepatic cholestasis.
Vaso-occlusive events involving the kidneys are common but often asymptomatic. Infarction in the renal medulla may cause flank pain, renal colic-type pain, and costovertebral angle tenderness, mimicking pyelonephritis. Papillary necrosis may result in either gross or microscopic hematuria, but red cell casts are uncommon. Renal imaging studies are generally necessary for correct diagnosis. Priapism occurs in up to 30% of males with sickle cell disease. Initial treatment is fluid hydration, pain control, and transfusion. Urinary tract infections are more common in patients with sickle cell disease, and urinalysis is recommended.
The spleen is particularly susceptible to the effects of sickled cells. During childhood, microinfarctions result in a nonfunctional spleen (in 14% of patients by age 6 months and 94% by age 5 years). Immunizations, prophylactic penicillin therapy, and parental education are critical to minimize the risk of infection and prompt early evaluation of fever in these patients. As sickle cell patients age, their risk of overwhelming sepsis decreases, but they remain predisposed to infection.
Splenic sequestration is more common in children than in adults, and it is a potential cause of death that can be averted with treatment. This syndrome is manifested by sudden enlargement of the spleen with an acute fall in the hemoglobin level due to sequestration of the blood volume within the spleen. Symptoms include tachycardia, hypotension, pallor, lethargy, and abdominal fullness. Left upper quadrant pain may or may not be present. The spleen is usually enlarged and firm. Platelets may also be sequestered, resulting in moderate thrombocytopenia. Therapy includes volume resuscitation, which may mobilize some of the red cells trapped within the spleen. Transfusion or exchange transfusion may be necessary; rarely, splenectomy is necessary. Unfortunately, recurrence of this syndrome is common.
Patients with sickle cell disease have a chronic hemolytic process with a baseline hemoglobin level usually between 6 and 9 g/dL; the reticulocyte count is 5–15%. With infections the hemolytic process may worsen and hemoglobin may drop from previous baseline. Typically, reticulocytosis will increase in response to the increased red cell destruction but may not be enough to compensate for the increased hemolysis. Acutely, the patient may notice symptoms of worsening fatigue, shortness of breath, dyspnea on exertion, and scleral icterus. The hemolysis is rarely severe enough to require transfusion.
Aplastic crisis results when the production of red cells declines significantly, producing a rapid decrease in the hemoglobin level with reticulocytopenia. The most common cause of aplastic crisis appears to be infection, specifically from parvovirus. Folate deficiency and bone marrow necrosis also may play a role. Aplastic crisis is more common in pediatric patients than in adults. The hemoglobin level will be unusually low, and few or no reticulocytes will be present (reticulocyte count typically <0.5%). The WBC and platelet levels are usually normal. Generally, this syndrome is self-limiting, and the marrow will begin producing red cells spontaneously within a week. Transfusion may be required in the interim.
Complications of sickle cell disease include stroke and subarachnoid hemorrhage. The cause of strokes in most patients is cerebral infarction due to occlusion or narrowing of large cerebral vessels. Approximately 10% of patients with sickle cell disease experience a stroke before age 20 years. Acute treatment is simple or partial exchange transfusion on an emergency basis. Unfortunately, children who suffer a stroke are at 70–90% risk for recurrence. Chronic transfusion therapy is indicated to prevent recurrent stoke after the initial event. Cerebral aneurysms are also more common in sickle cell patients, perhaps due to local vessel occlusion or ischemia.
Patients with sickle cell disease are functionally asplenic after early childhood, making them susceptible to infections from encapsulated organisms, such as H. influenzae and S. pneumoniae. Other common infections associated with sickle cell disease include pneumonia caused by these organisms as well as M. pneumoniae, meningitis, and osteomyelitis due to Salmonella typhimurium, Staphylococcus aureus, and E. coli. Although low-grade fever sometimes occurs during an acute crisis, unexplained fevers of 38°C (101°F) or higher require evaluation for bacterial infection and consideration for early treatment with broad-spectrum antibiotics.
Cardiomegaly is common and correlates with the degree of chronic anemia. Additionally, cardiac dysfunction may occur from microinfarcts and hemosiderin deposition from hemolysis and blood transfusion. Because of the chronic anemia, enhanced cardiac contractility is present to maintain adequate systemic oxygen delivery producing a widely radiating systolic ejection murmur.
Chronic, poorly healing leg ulcers around the malleoli are common in older patients with sickle cell disease. Minor injury, impaired microcirculation due to repeated sickling episodes and microinfarcts, and infections all contribute to the development and persistence of these ulcers.
Most sickle cell pain crises last 2–3 days. Patients with adequate clinical response and no indications for hospital admission can be discharged with oral pain medications and referred for follow-up with their primary care physician in the next 24–48 hours. The following are guidelines for hospital admission for sickle cell patients: (1) pulmonary or neurologic complications, (2) significant bacterial infection, (3) splenic sequestration or aplastic crisis, or (4) pain that remains poorly controlled or patients are unable to maintain adequate hydration.
The thalassemias are a diverse group of disorders characterized by defective synthesis of globin chains, resulting in the inability to produce normal adult hemoglobin. With β-thalassemias, unpaired α4 tetramers accumulate in the cell membrane of RBCs, causing intravascular hemolysis. With α-thalassemias, b4 tetramers accumulate, but are less severe due to HbH being more soluble and stable, resulting in less precipitate. The hallmark of these disorders is a microcytic, hypochromic, hemolytic anemia. These disorders are most common in individuals of Mediterranean, Middle Eastern, African, or Southeast Asian descent. Thalassemia red cells contain decreased hemoglobin, which accounts for the hypochromia and target cell formation. Individuals with either α- or β-thalassemia can be minimally to severely affected due to the specific genotype and whether the mutation produces complete or partial reduction in globin chains.
α-Thalassemia Carrier and Trait
α-Thalassemia carriers have normal RBC size, shape, and number and have no clinical consequences from this inherited gene. Those with α-thalassemia trait are detected by the findings of microcytic RBCs and a normal hemoglobin level.
Hemoglobin H disease is a disorder in which one out of four α-globin chain genes is functional. Patients with hemoglobin H disease usually present in the neonatal period with a severe hypochromic anemia. Later in life the clinical picture includes a hypochromic, microcytic anemia with jaundice and hepatosplenomegaly. These patients may not require regular transfusions, but a transfusion may be necessary in conditions of increased oxidative stress (which may cause precipitation of the unstable hemoglobin H resulting in hemolysis) or infection. Most of these patients will know their diagnosis, and the emergency physician needs to provide only supportive care and blood transfusion when necessary. Medications that may precipitate hemolysis should be avoided in this population (Table 41–14).
Table 41–14. Drugs that Produce Oxidative Stress on Red Blood Cells and May Induce Hemolysis.
β-Thalassemia Minor (β-Thalassemia Trait)
Patients with β-thalassemia minor are heterozygous for the β-globin mutation and have only mild microcystic anemia. Splenomegaly may be present. These patients may exhibit microcytosis, hypochromia, and basophilic stippling on blood smear. An elevated hemoglobin A2 level, typically 4–6%, confirms the diagnosis. These patients will generally not have clinical manifestations, and this form of thalassemia may come to the clinician's attention only during routine blood work.
β-Thalassemia Major (Cooley Anemia)
In patients with β-thalassemia major, both β-globin genes are defective and production of β-globin chains is severely impaired. β-Thalassemia major is characterized by a severe anemia that begins within the first year of life after the conversion from fetal hemoglobin synthesis to adult hemoglobin synthesis. These children develop hepatosplenomegaly, jaundice, expansion of the erythroid marrow (causing bone changes and osteoporosis), and increased susceptibility to infection. The anemia is severe and requires regular and lifelong blood transfusions. These transfusions and enhanced iron absorption eventually cause iron overload, which, if untreated, results in hemochromatosis with cardiac, hepatic, and endocrine dysfunction. The RBCs of these children show a low MCV with microcytic and hypochromic cells. Variation in size and shape of the RBCs will be notable (increased RDW) as will the presence of nucleated cells. Consider this diagnosis in any child with a severe microcytic anemia and the appropriate ethnic background. For those with a known diagnosis, who present to the emergency department with significant symptoms related to anemia or hemolysis, consider transfusion and search for precipitating events.
Glucose-6-Phosphate Dehydrogenase Deficiency
Glucose-6-phosphate dehydrogenase deficiency is the most common enzyme deficiency world wide. Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme responsible for preventing oxidative damage to intraerythrocytic hemoglobin. Over 300 variant mutations are described for G6PD; the highest prevalence is in individuals of African, Asian, or Mediterranean descent. Because the gene for G6PD is carried on the X chromosome, males are affected when they are hemizygous. Females must carry two defective genes to be severely affected, but because expression of this gene is variable, women with one dysfunctional gene may show some symptoms. The severity of G6PD disease is related to the magnitude of enzyme deficiency; patients with severe deficiencies have less than 10% of normal enzyme activity, and patients with moderate deficiencies have 10–60% of normal activity. G6PD deficiency is seen in approximately 10–15% of black males in the United States.
Oxidization of the hemoglobin sulfhydryl groups causes hemoglobin to precipitate within the cell; it is recognized by the presence of Heinz bodies on the peripheral blood smear. The affected RBC is removed from the circulation by the spleen. Oxidant damage also occurs at the RBC membrane, producing both extravascular and intravascular hemolysis.
A history of neonatal jaundice 1–4 days after birth is common. Patients with severe variants may have a severe chronic hemolytic anemia. In the more common variants of G6PD deficiency, the patient is usually asymptomatic except for acute hemolytic crises that occur due to bacterial and viral infections, exposure to oxidant drugs (most commonly sulfonamides, antimalarials, and nitrofurantoin), metabolic acidosis (such as diabetic ketoacidosis), renal failure, and, in some patients, ingestion of fava beans (see Table 41–14). These episodes are usually self-limited and well tolerated because only the older RBCs will hemolyze. The incidence of pigmented gallstones and splenomegaly is increased in patients with G6PD deficiency. Treatment for this disease is supportive and preventative.
Hereditary spherocytosis is a common hereditary disorder that is characterized by anemia, jaundice, and splenomegaly. It is a result of an erythrocyte membrane defect and is the most prevalent hereditary hemolytic anemia among people of northern European descent. The disease is typically inherited in an autosomal dominant pattern, although a less common autosomal recessive variant exists; in up to 20% of patients the disease is the result of an apparent spontaneous mutation. The abnormal shape of the RBC results from molecular abnormalities in the cytoskeleton of the cell membrane, resulting in red cells with a microspherocytic shape, which is not pliable enough to pass through the spleen, leading to an increased rate of destruction and a compensatory increase in RBC production. The clinical spectrum of hereditary spherocytosis includes (1) mild disease, occurring in 20–30% of cases, with an autosomal dominant inheritance, (2) moderate disease, occurring in 60–75% of cases, with primarily autosomal dominant inheritance, and (3) severe disease, in about 5% of cases, occurring with autosomal recessive inheritance.
Neonatal jaundice during the 1st week of life occurs in 30–50% of hereditary spherocytosis patients. After the neonatal period, the symptoms and signs depend on the severity of ongoing hemolysis. Patients with mild disease usually have a normal hemoglobin level and little or no splenomegaly but are susceptible to hemolytic or aplastic episodes triggered by infection. Patients with moderate disease have mild to moderate anemia, modest splenomegaly, periodic episodes of hemolysis with jaundice, and an increased incidence of pigmented gallstones. The rare patient with severe hereditary spherocytosis has chronic jaundice, an enlarged spleen, and significant hemolytic anemia requiring episodic blood transfusions. Folate therapy is only indicated for patients with severe hemolysis.
The peripheral blood smear shows spherocytes with a normal to low MCV and increased MCHC (>36%). The diagnosis of hereditary spherocytosis is established by the osmotic fragility test. In severe cases, splenectomy will generally reverse the anemia except in the unusual cases of autosomal recessive variants. After splenectomy, spherocytes are still present.
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