Matthew M. Hsieh, John F. Tisdale and Griffin P. Rodgers
Normal hemoglobin within red blood cells is comprised of two α and two β chains, with α to β synthesis ratio of 1 to 1. Thalassemias are a group of quantitative disorders with insufficient production of α or βchains, leading to an imbalanced accumulation of β or α chains, respectively. In contrast, hemoglobinopathies (or abnormal hemoglobin structural variants) are a separate group of qualitative disorders, with abnormal β or α chains in normal quantity, of which sickle cell disease (SCD) is best recognized. While these two disorders share features of hemolytic anemia and transfusion-related complications, they differ in their pathophysiology, clinical manifestations, and management (Table 4.1). The thalassemias and hemoglobinopathies are commonly encountered in areas where malaria is endemic because abnormal genes offer protection against malaria.1
PATHOPHYSIOLOGY
Thalassemias
Normally there are four copies of α-globin gene, two copies on each chromatid of chromosome 16 (Table 4.2). α-Globin chains are essential in the synthesis of both fetal and adult hemoglobin. α-Thalassemia syndromes result from deletions of a large α-globin gene segment from unequal crossover or recombination, and less frequently from mutations. The deleted segments of DNA vary in size and can involve one (−+, same as α+ or trans) or both (−−, same as α0 or cis) alleles on the same chromatid. A deletion of one gene (−+/++) confers a silent carrier. A two-gene deletion (−−/++ or −+/−+) is commonly referred as α-thalassemia minor or trait with microcytosis, hypochromia, but little or no anemia (Fig. 4.1). The deletion of three genes (−−/−+) leads to Hb H (β4), which is an unstable form of hemoglobin. Hb H disease is manifested by hypochromia, moderately severe hemolytic anemia, and splenomegaly. The absence of all four genes leads to hydrops fetalis with Hb Bart (γ4). Hb Bart transports O2 poorly, causes profound tissue hypoxia, leads to heart and liver failure, and is almost always incompatible with life without in utero red cell transfusion.
Both α-globin gene deletion haplotypes, (−+) and (−−), occur equally in Southeast Asians, whereas the (−−) haplotype is much less common in Mediterraneans and rare in Africans. Hence all the α-thalassemic syndromes are seen in Southeast Asians, but hydrops fetalis is uncommon to rare in Mediterraneans and Africans. In addition to α-globin gene deletions, there are α-globin structural variants, which may occur alone or in combination with α-gene deletions, and lead to further reduction of α-globin synthesis. The best characterized α-globin variant is Hb Constant Spring.
In contrast to α-globin genes, there are only two β-globin genes, one on each chromatid of chromosome 11. Whereas there are close to 200 mutations described, only about 20 mutations account for the majority of ß-thalassemic individuals. Mutations are grouped by regional ethnic locations: Mediterranean basin, Southeast Asia, Africa, and Asian India. All disease-causing mutations alter β-globin gene mRNA transcription, processing, or translation. Some mutations decrease β-globin production by as little as 10% and some by as much as 90%. Homozygosity or heterozygosity of variably affected alleles explains the wide range of β-thalassemic syndromes.
Patients with one abnormal allele have β-thalassemia minor or trait: the synthesis of the β chain is reduced by about one-half. Although normal Hb A (α2β2) is mildly decreased, there is no accumulation of excess α-chains. There is hypochromia and microcytosis, but no clinically significant anemia, hemolysis, or ineffective erythropoiesis. Thalassemia intermedia refers to the condition in patients with a lesser degree of hemolytic anemia, usually secondary to compound heterozygosity of two mild β-thalassemia alleles, δ- and β-thalassemia, Hb E and β-thalassemia, β-thalassemia with hereditary persistence of fetal hemoglobin (HPFH), or co-existence of α- and β-thalassemia. The phenotype of two severe β-chain alleles is referred to as β-thalassemia major or Cooley’s anemia: β-chain synthesis and Hb A are virtually absent, with α-chains in great excess and consequently leading to severe hemolytic anemia. The compensatory increase in Hb A2 and F is inadequate to offset the lack of β chain production.
FIGURE 4.1 Diagram for α-thalassemia gene deletion and corresponding phenotypes. Hb, hemoglobin; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume.
Hemoglobinopathies: Hemoglobin Structural Variants
Hemoglobin variants of α or β chains, or the hemoglobinopathies, are most commonly caused by point mutations. The nomenclature of hemoglobinopathies employs alphabetic letters (S, C, or E), and sometimes occurs with locations of first discovery (OArab or DPunjab) or name of the index case (Lepore or Constant Spring), then followed by the chain, location, and amino acid substitution in that hemoglobin chain (β6 Glu→Val).
Hemoglobin S
Sickle hemoglobin (Hb S) is the best characterized hemoglobinopathy. SCD is an inherited disorder in which normal glutamic acid is substituted by valine in the 6th codon of β-globin chain (β6 Glu→Val), which favors bonding of hemoglobin molecules. As a result, Hb S is less soluble when deoxygenated (in the normal oxygenation–deoxygenation cycle), precipitates and polymerizes quickly in red cells, and causes a morphologic change to a crescent shape. These rigid sickle cells lead to hemolytic anemia and vaso-occlusion, which together cause all the complications of SCD.
The lifespan of sickle cells is about 10 to 20 days, compared to 120 days for normal red cells. In the absence of clinically significant pain episodes, there is a chronic hemolytic anemia with mean hemoglobin of 6 to 8 g/dL, despite compensatory reticulocytosis of greater than 5% or 150 k/µL. Most sickle erythrocytes are removed in the spleen; some are destroyed intravascularly by mechanical forces or oxidative stress. Hemolysis has been implicated to activate inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), thrombin, and platelet-activating factor.2 Leukocytosis is common at baseline, and higher leukocyte counts are often associated with more frequent pain crises, stroke, and a shorter life expectancy in homozygous sickle disease (Hb SS) patients. Free hemoglobin, released by hemolysis, can consume nitric oxide and participate in endothelial dysfunction to promote vasoconstriction.
Other Hemoglobinopathies (E, C, Lepore, D, OArab, Constant Spring)
Hb E is a common hemoglobin variant, present in about 15% to 30% of the individuals in southern China and Southeast Asia. Hb E results from replacement of the normal glutamic acid to lysine in the 26th amino acid of the β-chain (β26 Glu→Lys), and leads to only 50% of mRNAs being spliced normally. Individuals with heterozygous and homozygous Hb E have mild anemia, hypochromia, and microcytosis. When Hb E is combined with β-thalassemia, the clinical features resemble those of β-thalassemia intermedia.
Hb C results from substitution of the normal glutamic acid to lysine in the 6th amino acid of β-chain. Hb C is found mostly in individuals of African descent and is the second most common hemoglobinopathy in the United States and third most common worldwide. Carriers of Hb C are asymptomatic; homozygous individuals (Hb CC) exhibit mild hemolytic anemia but are largely asymptomatic. Hb C combined with β-thalassemia produces mild to moderate hemolytic anemia with some features of β-thalassemia major. Compound heterozygosity with Hb C and S (Hb SC) leads to milder anemia with fewer leg ulcers, pain crises, and osteonecrosis than with homozygous SCD (Hb SS); there is also a slightly lower risk of infection from encapsulated organisms. Retinal proliferative disease, avascular necrosis, and splenomegaly, however, manifest earlier and more frequently in Hb SC disease.
Hb Lepore is a fused globin chain, which consists of the N-terminal half of the δ-chain and the C-terminal half of the β-chain; it is produced at very low levels (2.5%) compared with normal β-chains. Although typically seen in Greeks or Italians, this variant can occur in many ethnic groups of northern European descent. Hb Lepore can occur alone or in combination with other β-thalassemic mutations, leading to symptoms similar to β-thalassemia major. Hb D (same as Hb Los Angeles or Hb Punjab), another β-chain variant, is seen in the Asian Indian population. When combined with β-thalassemia or SCD, the anemia is mild. Hb OArab, a rare β-chain variant, when combined with SCD (Hb SOArab), behaves similar to severe SCD.
Hb Constant Spring, present in 5% to 10% of Southeast Asians, is caused by a point mutation in the stop codon of α-chain mRNA, leading to an elongated α-chain (αCS). Because synthesis of αCS is much reduced (to about 1%), Hb Constant Spring behaves like an α-chain deletion. When αCS is combined with a cisα-thalassemic defect, it resembles Hb H disease (−−/αCS α). Fortunately αCS is typically coupled with a normal α-chain gene (αCS α) on the same allele, and hydrop fetalis has not been observed.
DIAGNOSIS AND SCREENING
The diagnosis of SCD and thalassemias is now accomplished by neonatal or prenatal testing. The goal of postnatal testing is to identify α- or β-thalassemia carriers, Hb S, C, E, and other clinically important hemoglobinopathies. The process typically begins with a complete blood count (CBC). When red cell indices are suggestive (Table 4.3), peripheral blood smear and high performance liquid chromatography (HPLC) provide a provisional diagnosis. HPLC has largely replaced traditional electrophoresis because it reliably quantitates the fraction of hemoglobin A2, F, and S. Hemoglobinopathies are confirmed by isoelectric focusing or gel electrophoresis under alkaline (separates Hb S from Hb D/G) or acidic (separates Hb C, E, and OArab) conditions. Specific thalassemia mutations require polymerase chain reaction (PCR) based DNA testing. Blood count indices vary widely and may deviate from typical values if there is concurrent iron deficiency or compound heterozygosity of other hemoglobinopathies. Any transfusion would also alter the hematologic parameters commonly found in each syndrome.
α-Thalassemia Trait and Disease
α-Thalassemia trait can been suspected with elevated total red blood cell number, normal or borderline Hb A2, mean corpuscular volume (MCV) less than 78 fL, and mean corpuscular hemoglobin (MCH) less than 25 pg. The peripheral blood smear in Hb H disease can be stained with cresol blue to show Hb H precipitates in erythrocytes and reticulocytes.
β-Thalassemia Trait and Major
β-Thalassemia trait can be suspected from an elevated total red blood cell number, MCV less than 78 fL, MCH less than 27 pg, and normal or slightly low hemoglobin. On HPLC, there is a characteristic elution pattern of variably elevated Hb F (higher in the Mediterranean variant, and lower in the African variant), normal Hb A, and >4% Hb A2. However, Hb A2 may be normal (less than 3%) in individuals with concurrent iron deficiency or α-thalassemia, compound heterozygous δ- and β-thalassemia, or those with certain β-chain mutations. With β-thalassemia major, the MCV is usually less than 70 fL, MCH is less than 25 pg, there is variably low hemoglobin (5–9 g/dL), and no Hb A on HPLC.
Sickle Cell Trait and Disease
Sickle cell trait (SCT) or disease can be diagnosed by the combination CBC, HPLC, and the sickle solubility test. SCT has near-normal red cell indices; hemoglobin may be slightly low to normal and the MCH and red cell distribution width (RDW) may be slightly elevated. Hb S will comprise 35% to 40% on HPLC. On the other hand in SCD, hemoglobin will range from 6 to 8 g/dL, and sickle erythrocytes will be seen on peripheral blood smear. Hb S will comprise 80% to 90% of total hemoglobin and slightly elevated Hb A2 on HPLC (due to co-elution of Hb S with Hb A2). Trait or SCD is then confirmed by sickle solubility test and acidic or alkaline gel electrophoresis to screen for other concurrent hemoglobinopathies, such as Hb D or G. Sickle SC disease is easily distinguished by HPLC. Additionally, the peripheral smear in Hb SC disease shows fewer sickle cells, more spherocytes and target cells, and an uneven distribution of hemoglobin among red blood cells.
CLINICAL SYNDROMES AND TREATMENT OF SICKLE CELL DISEASE
Vaso-Occlusive Episodes (Pain Crises)
Vaso-occlusive episode (VOE) is the most frequent clinical manifestation of SCD,3 and can occur spontaneously or precipitated by infection, stress, dehydration, or changes in weather/temperature. Frequent assessment and adjustment of pain therapy, involvement of a pain management service, and other consultations are important to address the complex etiology of pain in SCD. Evaluation begins by obtaining a full history of current and prior VOEs. Physical examination and vital signs identify any signs or symptoms related to a pain episode. Acute pain can affect multiple sites: bones, joints, the cardiopulmonary system, CNS, or abdominal visceral organs. Chronic pain is typically confined to leg ulcers and the skeletal system.
Mild acute pains are often managed in the outpatient setting with a combination of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and/or an oral opioid. Moderate to severe acute pain typically requires intervention in a day-hospital or emergency department, which begins with rapid assessment of the pain, hydration using 5% dextrose in half normal saline (D5 1/2 NS) and 20 mEq KCl, not exceeding 11/2 times maintenance, and an opioid analgesic (typically morphine, hydromorphone, or fentanyl). The choice, dose, and frequency of medication depend on the patient’s outpatient drug regimen and prior responses. Severe pain is managed by inpatient bolus and continuous infusion of an opioid analgesic, often through patient-controlled delivery (PCA) pumps. In those with poor intravenous access, subcutaneous injection is an acceptable short-term alternative; however, intramuscular injection should be avoided because the absorption varies. Parenteral meperidine should not be used as first-line treatment because the metabolite, normeperidine, has a long half-life and increases the risks of mood disturbances and seizures. Opioid agonists are metabolized by the liver and excreted variably by the kidney, and dose reduction may be necessary in those with hepatic impairment. Meperidine and morphine have active metabolites, and should be used with great caution in patients with renal impairment. The common side effects of all opioids—nausea, vomiting, pruritus, constipation, and respiratory depression—should be monitored and treated accordingly.
Non-opioid analgesics such as acetaminophen and NSAIDs have a ceiling effect and are often used with an oral opioid agonist. The total acetaminophen dose should not exceed 4 grams daily in adults with normal hepatic function. Gastrointestinal, renal, and hematologic toxicities should be monitored. Benzodiazepines, antidepressants, anti-emetics, and opioid agonist-antagonists (such as pentazocine, nalbuphine, and butorphanol), are useful adjuncts to opioid agonists and potentiate their analgesic effects. Gabapentin and tricyclic antidepressants can be useful for neuropathic pain.
In a recent review of chronic opioid therapy,4 failure to achieve desired analgesia may result from (i) opioid tolerance, where the number of opioid receptors is reduced; (ii) opioid-induced hypersensitivity, where an individual experiences increased tenderness from known noxious stimuli; or (iii) worsening pain from progressive tissue damage. Prolonged, high dose opioid therapy is associated with testosterone deficiency and suppression of immunity. Opioid dose de-escalation every 6 to 8 weeks or opioid rotation with a period of opioid abstinence may improve desired analgesia and minimize adverse effects in long-term analgesic therapy (Table 4.4).
Red cell transfusions are not routinely administered during typical VOEs, but are important for concurrent complications, such as acute chest syndrome (ACS), stroke, or other organ ischemia and damage.
Infections
Because of functional asplenia, SCD patients are at an increased risk of infection with encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Thus, fever should be evaluated and managed promptly as a potential sepsis event, and empiric antibiotics administered while awaiting blood or urine culture and chest radiograph results. Neonatal diagnosis enables prompt initiation of penicillin prophylaxis and family education about vigilant monitoring for infections. In a placebo-controlled clinical trial,5 prophylactic penicillin prevented 84% of life-threatening S. pneumoniae infections. Vaccinations against S. pneumoniae should begin concurrently with penicillin prophylaxis. Penicillin may be discontinued in those older than 5 years of age who have completed vaccination, because there was no statistically significant additional benefit compared to placebo. Patients allergic to penicillin can receive azithromycin (10 mg/kg, up to 250 mg/day).
Human parvovirus B19 is commonly spread among school-age children. B19 infects erythroid progenitors and causes transient red cell aplasia. While there is a wide range of clinical severity, influenzalike symptoms, fever, pain, and splenic sequestration can accompany an acute infection. Laboratory testing may reveal acute anemia, reticulocytopenia, and IgM antibody to parvovirus. Milder forms of SCD, e.g., Hb SC or Hb S/β+ thalassemia, hydroxyurea treatment, or chronic transfusions, do not protect SCD individuals from developing severe complications related to B19.6 Parvovirus infection is also known as Fifth Disease, but in patients suffering transient aplastic crisis, the characteristic facial rash is absent. B19 can cross the placenta and cause hydrop fetalis and stillbirths; therefore, pregnant staff should be strictly isolated.
Central Nervous System and Eye Disease
CNS (Stroke)
Stroke is a major complication more frequently observed in Hb SS than in Hb SC. Children tend to have thrombotic strokes, and adults hemorrhagic strokes. Because the incidence of stroke is 11% up to 20 years of age, children with Hb SS should be screened with transcranial Doppler (TCD) every 6 to 12 months from age 2 to 18 years. For primary stroke prevention, the Stroke Prevention (STOP) trial showed that children (age 2 to 16 years old) who had a TCD velocity greater than 200 cm/sec in the internal carotid or middle cerebral artery had improvement in the TCD velocity and a much lower incidence of brain infarction, when managed on long-term transfusions to maintain Hb S less than 30%, compared to supportive care (penicillin prophylaxis, vaccinations, folate supplementation, treatment of acute crises, and transfusions as needed).7 A follow-up study to the original STOP trial showed that when long-term transfusions were discontinued, TCD velocity quickly became abnormal and a few children developed acute strokes.8 Individuals 18 years and older tend to have lower transcranial velocities, thus TCD may not be a good screening tool.
Children with suspected stroke or transient ischemic attacks (TIAs) are evaluated promptly, and hydration, therapy for hypoxia or hyperthermia, and blood pressure stabilization should follow immediately. Tissue plasminogen activator (t-PA) has not been extensively used in children and therefore is not routinely recommended. The use of antiplatelet agents, aspirin, or clopidogrel, is uncertain, but may be appropriate in selected circumstances. If a thrombotic stroke is present, exchange transfusions are initiated to reduce the Hb S level to less than 30%. If a hemorrhagic stroke is present, the source and the extent of bleeding are identified and the treatments are individualized; exchange transfusions may be indicated to reduce the Hb S level to less than 30%. If imaging studies do not identify any abnormality, the next steps may involve observation, simple transfusions, and/or participation in clinical trials.
As the recurrence rate for thrombotic strokes is high, long-term transfusion therapy to maintain Hb S less than 30% until 16 to 18 years of age should be planned. Long-term transfusions can also be considered in hemorrhagic stroke or vasculopathy (aneurysm, arterial stenosis, or moyamoya disease). Allogeneic stem cell transplantation should be encouraged in those with HLA-matched siblings. A multicenter Stroke with Transfusion Changing to Hydroxyurea (SWiTCH) trial that compared long-term transfusions + iron chelation with hydroxyurea + phlebotomy for secondary prevention of stroke was stopped early. The results showed a non-statistically significant difference: no stroke in 66 patients in the transfusion arm and 7 strokes in 60 patients in the hydroxyurea arm.9 An international Silent Infarct Transfusion (SIT) trial that compares long-term transfusion with no transfusions in children who had silent infarct on brain MRI with normal TCD velocities is ongoing.
Adults with acute strokes or TIAs are managed similarly to children.3 If a thrombotic stroke is identified, t-PA, antiplatelet therapy, and/or exchange transfusions can be considered. If a hemorrhagic stroke is identified, treatment is based on the source and the extent of bleeding; exchange transfusion to reduce the Hb S level to less than 30% may be indicated. For long-term therapy or secondary prophylaxis, antiplatelet therapy may be continued, with or without chronic transfusions to maintain the Hb S level less than 30%. Warfarin or dipyridamole may be added to or may substitute antiplatelet therapy for patients with recurrent strokes. In general for secondary stroke prevention in adults, blood transfusions should be continued; switching to hydroxyurea should be done ideally in a clinical trial. Those with HLA-matched siblings should be encouraged to pursue allogeneic stem cell transplantation.
There is currently no single best screening method to identify adults who are at high risk for stroke. MRI/MRA of brain can be considered in those who have general risk factors of thrombotic strokes (age, prior TIAs, and systemic hypertension) or risk factors specific to SCD (prior history of ACSs, dactylitis, severe anemia, and leukocytosis).
Eye Disease
Neovascularization results from repetitive vaso-occlusive episodes within the eye and leads to visual impairment. These proliferative changes are often asymptomatic early in the disease process; clinically detectable retinal changes are typically discovered between 15 and 30 years of age. Patients with Hb SC and sickle-thalassemia are disproportionately more prone to develop clinically significant ophthalmologic problems. Annual eye examinations starting in adolescence, carefully evaluating visual acuity, papillary reactivity, and anterior and posterior structures are important. In stage I eye disease, there is peripheral arteriolar occlusion; in stages II and III, vascular remodeling and neovascularization; in stage IV, vitreous hemorrhage; and in stage V, retinal detachment.
In patients with SCD or SCT, direct eye trauma that causes bleeding into anterior chamber requires urgent evaluation, because RBCs can occlude the trabecular channels, increase intraocular pressure, and cause acute glaucoma.
Cardiovascular Manifestations
Individuals with SCD have lower blood pressures compared to individuals with other types of chronic anemia. Renal sodium wasting is postulated as one possible cause although other mechanisms may be present. Blood pressures in SCD correlate with age, hemoglobin, and body-mass index. When systolic or diastolic blood pressures approach those of age-, sex-, and race-matched normal individuals, the risk of stroke and mortality increases.
Other cardiac manifestations include frequent systolic flow murmurs, typically related to the degree of anemia. A loud P2 may suggest elevated right-sided pressure or pulmonary hypertension. On echocardiograms, small amount of pericardial effusions are found in approximately 10% of all studies; cardiac output, cardiac chamber size, and myocardial wall thickness are increased to improve the stroke volume without increasing the heart rate. With long-term and consistent increases in cardiac output, the ability to perform physical work is reduced by half in adults and by one-third in children. Congestive heart failure is uncommon, except in individuals with transfusional iron overload, leading to dilated cardiomyopathy. Myocardial infarction due to coronary arterial occlusion is rare, but damage from small vessel diseases may occur. Sudden death due to unexplained arrhythmia or autonomic dysfunction also has been described in adults with SCD, presumably from excess iron interfering with in the cardiac conduction system.
Pulmonary Complications
Acute Complications
ACS typically presents with cough, chest pain, and other respiratory symptoms, and is confirmed by a temperature higher than 38.5°C, a new pulmonary infiltrate on chest radiograph, and rales on auscultation (often in multiple lobes).10 Children tend to have more respiratory symptoms (wheezing, cough, and fever), while adults report musculoskeletal pain and dyspnea, and have a more severe course. Risk factors for ACS are Hb SS, low Hb F, high baseline hemoglobin (11 g/dL or greater), high white blood cell count (greater than 15 k/µL), and prior episodes of ACS. ACS is a frequent cause of death in both children and adults with SCD, the second leading cause of hospitalization, and the most frequent complication following surgery and anesthesia. Complications from ACS include CNS injury (anoxia, infarct, or hemorrhage), seizure, or respiratory compromise with or without multi-organ failure. Frequent ACS episodes are associated with shortened survival.
Only less than half of ACS events have identifiable causes. These include pneumonia, pulmonary infarction from vaso-occlusion within pulmonary vasculature, fat embolism, or pulmonary thromboembolism. Microbiologic culture of sputum may reveal a variety of atypical organisms (chlamydia or mycoplasma), viruses (respiratory syncytial virus), and bacteria (Staphylococcus aureus, S. pneumoniae, or H. influenzae ); up to 30% of microbiologic cultures are negative.11 Systemic fat embolism syndrome is rare, and occurs when there is infarcted/necrotic bone marrow and fat being released and lodged in the pulmonary vasculature. Fat embolization can precipitate or develop concurrently with ACS; multi-organ failure may result. Risk factors for developing systemic fat embolism syndrome are Hb SC genotype, pregnancy, and prior corticosteroid treatment.
Treatment for ACS includes oxygen, antibiotics coverage for atypical organisms, simple or exchange transfusions to improve oxygen saturation, bronchodilators (as airway hyperreactivity often accompanies ACS), and analgesia for pain. All these efforts are aimed at reducing the percentage of sickle erythrocytes and minimizing sickle polymerization. After an episode of ACS is successfully managed, strategies to prevent future episodes may include vaccinations (especially against S. pneumoniae), hydroxyurea, continuing transfusions, or allogeneic stem cell transplantation.
Chronic Complications
Pulmonary hypertension is multifactorial in its pathogenesis including sickle cell-related vasculopathy, pulmonary damage from recurrent ACS, high blood flow from anemia, chronic thromboembolic disease, and chronic hemolysis. Clinically, pulmonary hypertension can manifest as dyspnea, clubbing, loud second heart sound (P2), an enlarged right side of the heart on chest radiograph, and 95% or less oxygen saturation on room air at rest. Pulmonary hypertension can initially be screened with an echocardiogram showing a tricuspid regurgitation jet velocity (TRV) of ≥2.9 m/sec and subsequently confirmed by right heart catheterization with a mean pulmonary arterial pressure of ≥25 mmHg.12
There is currently no single preferred treatment for patients with pulmonary hypertension. Simple transfusion to maintain hemoglobin at approximately 9 g/dL can reduce pulmonary pressure in some, but the possible development of red cell antibodies limits the wide applicability of this approach. Hydroxyurea reduces the frequency and severity of vaso-occlusive crises and ACS, but may only delay the onset of pulmonary hypertension. Improving anemia, ruling out left-sided heart failure, sildenafil, anticoagulation with warfarin (target INR 2-3), prostacyclin analogs, endothelin receptor antagonists, and nitric oxide are adjunctive agents to consider; continuous or nocturnal oxygen can be considered.
Gall Bladder, Hepatic, and Splenic Manifestations
SCD can affect the hepato-biliary and splenic systems in multiple ways (Table 4.5). Hyperbilirubinemia (typically less than 4 mg/dL of unconjugated bilirubin) from chronic hemolysis is common. Other factors that increase total bilirubin level include: cholesterol intake, presence of Gilbert’s syndrome, and cephalosporin antibiotic use. Biliary sludge and cholelithiasis can occur as early as 2 to 4 years of age, can have similar clinical manifestations, and are managed similarly as those without SCD. Elevation in the direct or conjugated bilirubin from baseline of 0.1 to 0.4 mg/dL can indicate sickle-related liver disease.
Acute splenic sequestration is caused by trapping of erythrocytes, and presents with weakness, pallor, tachypnea, an acute drop in hemoglobin (typically 2 g/dL or greater than 20% from baseline), or abdominal fullness from acute splenomegaly (2 cm increase in palpated spleen size). This syndrome can be precipitated by infections, and is typically seen in children under age 5 with Hb SS, older children with Hb SC, or in a few adults with Hb S/β+ thalassemia. Children tend to have recurrent and severe episodes that require immediate attention with transfusion; a long-term plan of chronic transfusion therapy and/or splenectomy should be discussed. While splenic sequestration in children tends to be more severe, in adults it is typically self-limited requiring only supportive care and observation.
Renal Abnormalities
There are several sickle-related manifestations in the kidneys. There is supranormal creatinine secretion in the proximal tubules, which explains lower serum creatinine (near 0.5 mg/dL). A serum creatinine approaching 1.0 mg/dL can indicate subtle renal insufficiency. The renal medulla is composed of tubules and blood vessels collectively called the vasa recta; this region is chronically in an acidic, hypoxic, and hypertonic environment, and is thus very susceptible to Hb S polymerization. Over time, gradual loss of the vasa recta leads to an inability to concentrate urine. Hyposthenuria develops early in childhood, is frequently associated with nocturia, and is the chief reason why SCD individuals are so susceptible to dehydration. Hb S sickling can also lead to papillary necrosis and hematuria. Other renal manifestations include proteinuria from chronic glomerular damage, which in some individuals can progress to renal insufficiency or failure; angiotensin converting enzyme (ACE) inhibitors can ameliorate this progression. A decrease in hemoglobin from baseline due to renal insufficiency can be treated by erythropoietin injection (overlapped with hydroxyurea) and/or transfusion. Although serum erythropoietin levels are already elevated in renal failure, they are relatively lower when corrected for the degree of anemia.
Priapism
Priapism is a sustained painful erection that is stuttering (duration <3 hours and spontaneous resolution) or prolonged (>3 hours). Priapism begins early in puberty, and as many as 80% of men with SCD would have experienced at least one episode by 20 years of age. Priapism is caused by vaso-occlusion of the venous drainage of the penis, and physical examination will reveal a hard penis with a soft glans. Oral hydration and analgesia should be instituted at the onset of priapism. A prolonged priapism represents an urologic emergency and requires urgent evaluation, intravenous hydration, and analgesia. If not improved within 1 hour, blood aspiration and irrigation with dilute epinephrine to the corpus cavernosum under local anesthesia is needed.13 Simple or exchange transfusions are sometimes used.
Recurrent priapism can lead to impotence and fibrosis. No treatment has been well studied. A shunting procedure between the glans and distal corpus cavernosum (Winter’s procedure), α-adrenergics (e.g. pseudoephedrine), and medications reducing the frequency of erection, tricyclic antidepressants, β-blockers, or leuprolide, have all shown variable success. Simple or exchange transfusions can be considered. Recent studies have grouped patients into two potentially distinct phenotypic presentations: one group that has priapism and leg ulcers and the other that has frequent vaso-occlusive crises and osteonecrosis.
Skeletal Complications and Leg Ulcers
Repetitive vaso-occlusion in marrow sinusoids eventually causes bone infarction. Osteonecrosis ensues when ischemic necrosis of juxta-articular bone in femur, humerus, or tibia occurs. In children, prior to bone maturation, osteonecrosis is treated conservatively with analgesia, NSAIDs, and protected weight bearing. In adults, secondary degenerative arthritis can compound osteonecrosis, and the usual conservative treatment is ineffective. Core decompression and osteotomy with aggressive physical therapy have been reported to offer temporary relief of pain and increased joint mobility14; joint replacement is reserved for those with severe symptoms or advanced disease.
Dactylitis or “hand-foot” syndrome in infants and young children presents with pain or swelling in one or more extremities (hands or feet). Plain radiograph may show periosteal elevation and a motheaten appearance. This syndrome usually requires hydration and analgesia, but transfusions or antibiotics are not necessary. There are no associated long-term sequelae.
Bacteremia can lead to osteomyelitis or septic arthritis. Both present with warmth, tenderness, and edema caused by vaso-occlusion in bones; fever in the acute phase, increase in white blood cell count, and positive blood cultures help to distinguish infection from pain crisis. A positive microbial culture from aspiration of the bone or joint is diagnostic. Both of these infections are treated with surgical drainage and short-term (2–6 weeks) intravenous antibiotics. Additionally, temporary joint mobility with exercises to improve the range of motion in the convalescent phase may be indicated for septic arthritis.
Leg ulcers are seen in 10% to 20% of individuals with Hb SS, and much less in individuals with Hb SC or Hb S/β+-thalassemia. The frequency of leg ulcers increases with age and is associated with a lower mean hemoglobin (6 g/dL or less) and a higher LDH. Their exact etiology is unclear, but trauma, chronic vaso-occlusion, edema, and hemolysis have all been implicated.15 Ulcers tend to locate in the dorsum of the feet, ankles, or tibia; other sites are rare. They begin as small hyperpigmented areas with edema, pain, and dysesthesia, subsequently appearing as denuded and “punched out” ulcers. Ulcers are usually infected locally, and osteomyelitis is rare. Two principles are important in promoting wound healing: reduction of local edema by elevation and/or pressure dressing, and debridement of ulcers by frequent wet-to-dry dressing changes to maximize granulation. There are many topical treatments available, but no single therapy works uniformly. Topical or systemic antibiotics are generally not helpful and eventually select for drug-resistant organisms. Ulcers smaller than 4 cm usually heal in weeks; larger ones may require consultation with wound care service and plastic surgery for skin flaps. Transfusions can be considered for recurrent or persistent ulcers. The use of hydroxyurea in leg ulcer is controversial. There are reports of hydroxyurea causing leg ulcers in individuals with SCD and myeloproliferative disease. But in the Multicenter Study of Hydroxyurea (MSH), hydroxyurea did not appear to change the incidence of leg ulcers.16 Other reports, however, suggest that Hb F elevation is associated with reduced rates of leg ulcers.
THERAPY
Transfusions
Transfusions are an important therapy for SCD (Table 4.6), and are commonly used acutely, but also chronically for primary or secondary prevention of a specific complication. Transfusions can be separated into simple episodic, simple chronic, or exchange. It is important to notify blood bank of the type (simple or exchange), indication, and duration (episodic or chronic). A detailed transfusion history should be maintained that includes the total number of prior red cell units, presence of any red cell antibodies, percent Hb S, and the target hemoglobin or hematocrit.
Red cell antigen difference between sickle cell patients and blood donors (mostly Caucasians) is the major reason for the high rate of alloimmunization. Alloimmunization can be minimized by typing for other Rh (D, E/e, and C/c), and Kell (K) antigens, in addition to the usual ABO typing. In developing countries, nonroutine use of leukocyte filters is another reason for the high rate of alloimmunization. Prestorage leukocyte depletion is now commonly employed in blood banks. When a patient has a prior transfusion history, other minor antigens (Kidd, S, and Duffy) should also be typed. Other potential complications include the usual transfusion reactions that can occur in non-SCD patients: volume overload, acute/delayed hemolytic reactions, transfusion-transmitted infections, and iron overload.
Fetal Hemoglobin (Hb F) Induction
The beneficial effect of Hb F was first recognized from the observations that neonates with Hb SS do not develop SCD-related symptoms in the first 6 months, and patients with co-inheritance of SCD and HPFH, such as in Saudi Arabia and India, have milder symptoms. Currently, hydroxyurea is the only Food and Drug Administration (FDA)-approved drug for Hb F induction. Hydroxyurea is a cell cycle (S-phase)-specific agent that blocks the conversion of ribonucleotides to deoxyribonucleotides. Its primary clinical impact is Hb F induction, which inhibits Hb S polymerization, but other benefits may include reduced leukocyte and platelet counts, lessened hemolysis, decreased bone marrow cellularity, and generation of nitric oxide.
The MSH study was a randomized placebo-controlled clinical trial that confirmed the beneficial effects and the safety of hydroxyurea. The 150 hydroxyurea-treated patients had fewer pain episodes and ACS, required fewer transfusions, and experienced minimal toxicity.16 Approximately 70% of SCD patients are likely hydroxyurea-responsive: steady state Hb F should increase two fold from baseline or approximately 10% to 15%, total hemoglobin should increase by 1 to 2 g/dL, or there should be a subjective reduction in the severity and frequency of pain (Table 4.7). Whether hydroxyurea will prevent or reverse end organ damage is under active investigation.
Hydroxyurea can be started at 10 to 15 mg/kg daily, and adjusted by 5 mg/kg/day increments every 6 to 8 weeks, to a target of approximately 25 mg/kg daily. Compromised hepatic or renal function may require lower dosing. Within a week of therapy, Hb F-containing reticulocytes will rise; at the end of 2 to 3 weeks, Hb F-containing red cells will increase. Other hematologic effects include increase in MCV (to >100) and decrease in leukocytes (mostly neutrophils), platelets, and reticulocytes. Two to 3 months are usually required before the effects on Hb F and blood counts are stabilized; a trial of 6 to 12 months is adequate to assess clinical benefit. Hydroxyurea in several cohorts of children has shown to be safe and efficacious in reducing pain and sickle-related complications.21
There are other inducers of fetal hemoglobin available in research studies: 5-azacytadine, decitabine, and HDAC inhibitors. These drugs aim to “reactivate” gamma globin expression that has been silenced in the postnatal hemoglobin switching process.
Other Drugs
Agents that modify the pathophysiology of SCD are based on their ability to reduce Hb S polymerization in vitro. These include Hb S modifiers (urea, organic compounds), inhibitors of Gardos channel (clotrimazole, ICA 17403), chloride and cation channel blockers (dipyridamole, magnesium pidolate, NS-3623), and anti-adherence agents (Poloxamer 188, pentoxifylline). Erythropoietin, at doses 2 to 5 times those used in renal failure, in combination with hydroxyurea, can increase total hemoglobin.
SPECIAL TOPICS
Contraception and Pregnancy
Hydroxyurea is a teratogen in animal models, therefore both male and female patients on hydroxyurea should use contraception, and discontinue the drug if pregnancy is planned. Recent long-term updates from the MSH investigators indicated that neonates delivered from women receiving hydroxyurea therapy throughout pregnancy or from men taking hydroxyurea did not have any teratogenic effects,22 but any unplanned pregnancy should be discussed. Hydroxyurea is also secreted into breast milk, and breast feeding should be avoided.
Hydroxyurea is considered as an oral chemotherapeutic drug, thus it is not surprising that there is a perceived risk of developing malignancy. While there are case reports of SCD patients who have developed leukemia while receiving hydroxyurea, this rate is probably similar to the general population. No definitive risk increase has been directly attributed to hydroxyurea for individuals with myeloproliferative diseases or cyanotic heart disease.
Pregnant women with SCD are at an increased risk of miscarriage, preeclampsia, sickle pain crises, acute anemia or hemolysis, or infections.23,24 Maternal mortality rate is low and the overall outcome of the pregnancies is favorable, but infants tend to be born prematurely (average at 34–37 weeks) and are small for gestation age (less than tenth percentile). Hb SS women tend to have more frequent or severe complications than Hb SC women. Transfusions are usually reserved for pregnancies complicated by progressive anemia, increased pain episodes, preeclampsia, prior pregnancy loss, or multiple gestations; prophylactic transfusions are generally discouraged.
Anesthesia and Surgery
Surgery and general anesthesia have higher morbidity and mortality in SCD compared to the general population. The risk is higher in those with Hb SS or Hb S/β0 thalassemia than those with Hb SC or Hb S/β+ thalassemia.17Complications may be as frequent as in those receiving regional anesthesia. ACS and postoperative infection are the most common complications, followed by pain crisis and stroke (Table 4.8).
Table 4.8 Perioperative Considerations for Sickle Cell Patients
Preoperative
Postoperative
SICKLE CELL TRAIT (SCT)
Approximately 8% of African-Americans have SCT. Under physiologic conditions, vaso-occlusion does not occur. Carriers have normal life expectancy and many participate successfully in competitive sports or rigorous military training. There are exercise-related mortalities from rhabdomyolysis, which can be minimized by avoiding heat stress, dehydration, and sleep deprivation. Current controversy exists whether to implement universal sickle cell screening in competitive collegiate sports. However, most medical societies (including hematologists and pediatricians) agree that proper education, efforts to prevent dehydration, and vigilant monitoring for rhabdomyolysis, as currently employed by the US military services, are better than universal screening of athletes to prevent morbidity and mortality in trait carriers.
Compared to the general population, persons with SCT have normal risk of developing heart disease, stroke, leg ulcers, or arthritis. They are not more likely to develop complications from anesthetic agents. However, SCT is associated with increased risk for traumatic eye injury, hyposthenuria, hematuria, splenic infarction, pulmonary embolism, and proteinuria.25 If traumatic eye injury occurs with hemorrhage into anterior chamber (hyphema), erythrocytes may clog the trabecular outflow channels, increase intraocular pressure, and this may lead to acute glaucoma, requiring urgent evaluation and treatment. Pregnant women with SCT are at an increased risk for urinary tract infections.
CLINICAL SYNDROMES AND TREATMENT OF THALASSEMIAS
While the thalassemic syndromes are highly variable, severity is directly related to the imbalance of α to β chain ratio: higher the imbalance, more severe the phenotype where excess unpaired α or β chains precipitate in erythrocyte precursors, resulting in their early death and ineffective erythropoiesis. Excess unpaired α or β chains also denature intracellular hemoglobin, promoting splenic sequestration and hemolysis, and eventual splenomegaly and anemia. In β-thalassemia major, any genetic conditions that reduce α-chain excess (co-inheritance of α-thalassemia, or increase in δ- or γ-chain production) or preserve some β-chain synthesis (a mild or silent β-thalassemic allele) ameliorate the severity of β-thalassemia.
Without regular red cell transfusions, chronic hemolytic anemia and tissue hypoxia stimulate bone marrow expansion and produce skeletal and metabolic derangements: bony deformities, fractures, extramedullary hematopoiesis, and increased gastrointestinal iron absorption. In addition, red cell membrane damage, activation of platelets and endothelium, and abnormal levels of coagulation inhibitors (anti-thrombin III, protein C and S) all contribute to increased risk of thromboembolism.
Other complications of thalassemia include leg ulcers, gallstones, and folate deficiency. There are also rare forms of α-thalassemia with mental retardation and developmental abnormalities (mutations in the ATRX gene), and β-thalassemia minor with thrombocytopenia (mutation in GATA1).
Transfusions and Splenomegaly
Transfusions and iron chelation are the mainstay of therapy, and have improved the quality of life and extended life expectancy in thalassemia individuals. After the diagnosis in infancy or childhood, the decision to start transfusion depends on the degree of impact anemia has on the child: fatigue, reduced growth velocity, skeletal dysmorphism, poor weight gain, or organomegaly. Once started, the target hemoglobin of 9 to 10 g/dL is reasonable, although others have used a higher target. Transfusions are maintained every 2 to 4 weeks and continued through adulthood. Improvements in the clinical signs and symptoms can be seen in adequately transfused individuals. Red cell alloimmunization can be minimized as in SCD by typing for major and minor blood group antigens (ABO, Rh, Kell, Kidd, and Duffy) and prestorage leukocyte depletion.
Splenomegaly can be seen in those with inadequate transfusions or red cell alloimmunization, and is associated with worsening anemia, leukopenia, and thrombocytopenia. Hemoglobin will typically drop about 1.5 g/dL/week in non-splenectomized individuals; in hypersplenism, this rate of decline will be higher and eventually there will be an inadequate rise in post-transfusion hemoglobin. Splenectomy will improve these hematologic parameters and transfusion effectiveness, but should be performed after vaccination for encapsulated organisms (S. pneumoniae, H. influenzae, and N. meningitidis), and in children older than 5 years of age. Post-splenectomized transfusions should produce a 1 g/dL/week decrease in hemoglobin. Penicillin prophylaxis is appropriate. Post-splenectomy thrombocytosis can be variable, but generally does not require antiplatelet therapy.
Iron Overload and Chelation
Chronic transfusions and early iron chelation have shifted the major thalassemic complications from those secondary to the hemolytic anemia to the sequelae of iron overload. Iron chelation should start when ferritin is approaching 1,000 ng/L, approaching 20 units of red cells, or within 18 months from the start of chronic red cell transfusion. Excess iron from cumulative transfusions overwhelms the transferrin system and accumulates in the liver, heart, and various endocrine organs. The most serious result is nonuniform iron deposition in cardiac myocytes that eventually leads to heart failure and sudden unpredictable arrhythmia, which previously accounted for the majority of deaths in thalassemic individuals. MRI with T2* sequences is quickly becoming the standard method of cardiac evaluation: 5 to 10 ms is seen in severe overload, 10 to 20 ms in moderate overload, and >20 ms in normal non-overload states.26 Excess iron also accumulates in the liver, producing hepatic inflammation, dysfunction, and fibrosis. While MRI with T2* sequences, superconducting susceptometry (SQUID), and serum ferritin are helpful in estimating the amount of iron in liver, biopsy remains the standard. Furthermore, iron overload also affects endocrine organs and can cause reduced growth velocity in children, hypothyroidism, hypogonadism with pubertal delay or arrest, hypoparathyroidism leading to hypocalcemia and osteoporosis, and diabetes. All are managed in collaboration with endocrinologists.
The toxic effects of excess iron can be minimized by long-term maintenance of iron chelation. Deferoxamine (Desferal) can be administered as early as 21/2 years of age at 20 to 60 mg/kg (or 1.5–4.0 g per adolescent or adult) per day, delivered by subcutaneous or intravenous injection over 8 to 12 or 24 hours,27,28 and typically for at least 5 days a week. Twice a day subcutaneous bolus injection may also be efficacious.29 Side effects of deferoxamine are infrequent; they include impaired vision or hearing, motorsensory neuropathy, changes in renal or pulmonary function, joint pain, metaphyseal dysplasia or growth retardation. Oral deferasirox (Exjade) should be titrated to a target dose of 30 mg/kg/day, and 40 mg/kg/ day for those with cardiac iron deposition. Side effects include abdominal pain, diarrhea, rash, arthralgia, and mild increases in liver enzymes and serum creatinine. Oral deferiprone has recently been approved and has side effects such as gastrointestinal discomfort, joint pain, and agranulocytosis. These three chelators individually have been shown to reduce iron burden in the liver or heart; many hematologists prefer combination therapy for those with severe cardiac iron to quickly remove iron. Eye and audiology evaluations should be performed prior to iron chelation and yearly while on transfusions and chelation.
Fetal Hemoglobin Induction
The major endpoint for Hb F induction in thalassemia is an increase in total hemoglobin. Unfortunately, hydroxyurea has not been able to achieve this goal in most thalassemia major patients receiving chronic transfusions, possibly due to a loss of Hb F response with transfusion or due to certain mutations that are resistant to Hb F induction. Hydroxyurea, however, has had some effect in Hb Lepore/β-thalassemia, Hb E/β-thalassemia, and β-thalassemia intermedia. Erythropoietin also can be used with hydroxyurea but the response is variable. Other inducers of Hb F (such as decitabine) can be considered.
THERAPY WITH CURATIVE INTENT
Hematopoietic Stem Cell Transplantation
Myeloablative hematopoietic stem cell transplantation (HSCT) is currently the only cure for SCD and thalassemia,30,31 with the best outcome from HLA-matched sibling donors. In SCD, HSCT is typically recommended for patients less than 17 years of age, those non-responsive to hydroxyurea, or those who had prior SCD-related organ damage (e.g., stroke, ACS, frequent pain crises, and multiple sites of osteonecrosis). For thalassemia, HSCT is also typically recommended for those aged less than 17 years with signs of liver dysfunction or fibrosis from iron damage (Pesaro class II or III). The disease-free survival can be as high as 90% to 95% with a 10% risk of graft versus host disease (GVHD). Often the GVHD is easily treated, and most of the children can gradually discontinue immunosuppression. Post transplant they enjoy improved quality of life and growth velocity. The preexisting organ damage from the underlying disease and the long-term effects from HSCT (small increase in secondary cancer, reduction in gonadal hormones/sterility, changes in thyroid function) are closely monitored periodically.
Recent encouraging clinical data showed that non-myeloablative HSCT can achieve mixed donor and host hematopoiesis with successes approaching those of myeloablative HSCT.32 This non-ablative approach, with less toxicity from conditioning regimen, is a reasonable alternative for young or older adults who otherwise meet criteria for a standard myeloablative HSCT or for those with severe organ dysfunction. For patients without matched sibling donors, umbilical cord blood transplantation can be considered for pediatric patients. Approaches using matched unrelated donors for Caucasians and haploidentical donors for African Americans are currently being tested and optimized.
Gene Therapy
Autologous transplantation following the insertion of a normal or therapeutic globin gene into hematopoietic stem cells is continually being refined for SCD and thalassemia.33 Significant advances have been made toward this goal using lentiviral vector based on the human immunodeficiency virus. Therapeutic correction of murine models of both β-thalassemia and SCD has been achieved using this approach. There is additional progress in achieving moderate levels of engraftment of genetically modified cells in the nonhuman primate autologous transplant model. Clinical human gene therapy trials have begun and the results of the first reported patient with β-thalassemia/Hb E demonstrate the therapeutic potential of this approach.34 Further progress is clearly necessary as the therapeutic effect in this patient was derived from an equal contribution of endogenous Hb F, Hb E, and the therapeutic transgene. Summaries for SCD and thalassemias are provided in Tables 4.9 and 4.10.
References