1049 e1 Diagnosis α genes1 Hgb (g/dL) MCV2 Fl BCB3 HbA2 4 FM M F Normal αα / αα – nl87 6±5 589 1±5 0114 0±0 915 9±1 0 Silent carrier α / αα or α / αα 12 6±1 214 3±1 4 81 2±6 9 ↑or– ↑↑ ↑↑↑ nl Trait α /[.]
1049.e1 Diagnosis αgenes1 MCV2 Fl Hgb (g/dL) M F M F 89.1±5.01 87.6±5.5 BCB3 HbA24 – nl Normal αα / αα 15.9±1.0 14.0±0.9 Silent carrier -α / αα or α- / αα 14.3±1.4 12.6±1.2 81.2±6.9 ↑or– nl Trait -α / -α or / αα 13.9±1.74 12.0±1.04 71.6±4.14 ↑↑ nl HbH Disease / -α 10.9±1.0 9.5±0.8 61±4 ↑↑↑ nl Hydrops fetalis / N/A N/A N/A N/A Pattern of α-globin genes α and – are the presence of active and deleted genes, respectively The two genes on one chromosome are separated from those on the other by a slash Must use age-specific values MCV can be lowered by β-thalassemia trait Brilliant cresyl blue or inclusion body prep Results vary by lab, but this can be done semiquantitatively This assay is unreliable in the presence of other hemoglobins (e.g., HbS or HbE) This can be negative when both α- and β-thalassemia are present HbA2 results vary depending on laboratory method Values are lower for a two-gene deletion in cis ( / αα) than in trans (-α / -α) • eFig 88.25 Red blood cell indices in adults with a-thalassemia Table shows typical results; exceptions occur Hgb, hemoglobin; N/A, not available nl, normal (Data from Higgs DR, Bowden DK Clinical and laboratory features of alpha-thalassemia syndromes In: Steinberg MH, Forget BG, Higgs DR, et al, eds: Disorders of Hemoglobin Cambridge, UK: Cambridge University Press; 2001; and Galanello R, Cao A Alpha-Thalassemia Genereviews at Genetests: Medical Genetics Information Resource Seattle: University of Washington; 2008.) 1050 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology approximately 200 mg of iron in each unit of blood Although previous focus was on hepatic iron overload and cirrhosis, there is increasing awareness of iron overload in the heart, pituitary, pancreas, and endocrine organs This leads to dysfunction and excessive melanin production, resulting in bronze pigmentation Iron overload requires chelation; a summary of chelation drugs and potential toxicities can be found in eFig 88.26 When to initiate chelation varies depending on center and resources While there is an increasing acknowledgment of early, preventive chelation, this chapter focuses on emergent intervention Cardiac Complications Cardiac failure due to iron overload, defined as a low ejection fraction with a component of cardiomyopathy, is the major cause of ICU admission and death in thalassemic patients.168,172–174 A thalassemic patient in failure should be assumed to have cardiac iron overload and chelated until proven otherwise.167,169,173 Contributing factors include both iron-dependent and iron-independent processes.173 Chronic anemia leads to increased end-diastolic volumes, stroke volume, and heart rate, resulting in an elevated cardiac index To compensate for the high-output state, a lowering of peripheral vasculature resistance leads to low diastolic pressures and wide pulse pressures and a high ejection fraction at baseline Iron accumulates predominantly in the epicardial portion of the ventricular septum and ventricular free walls, stimulating the production of free radicals and resulting in peroxidative tissue damage Initial cardiac iron deposition increases the influx of additional iron resulting in a rapid accumulation and the potential for rapid decline in patients dependent on a high-output compensatory state Patients can present with a wide range of dysrhythmias, decreased contractility, and failure after years of normal function.172,173 Arrhythmias include atrial fibrillation and ventricular tachycardia, as well as conduction disturbances and heart block Risk factors for failure include transfusion history and underchelation Untreated overload can also lead to dysrhythmias The clinical presentation is that of congestive heart failure; however, some present with subtle findings of abdominal pain due to liver distention Clinicians must maintain a low threshold to evaluate for cardiac dysfunction With advances in transfusion, cardiac imaging identifying those at highest risk, and chelation therapy, it is easier to prevent failure Survival is increasing but is highly dependent on the underlying thalassemia as well as access to these expensive interventions Assessments ardiac iron accumulation and function must both be assessed C and, more recently, MRI-based assessment of fibrosis has proved useful.159,166,172,175–177 Iron assessment by T2* is invaluable, as it assesses, liver, pancreatic, and cardiac iron—the later correlates with function and predicting decline.159,172,175–177 A T2* of over 20 ms is not associated with increased cardiac risk In contrast, a value of 10 to 20 ms denotes overload and increased cardiac risk, and a T2* of under 10 ms portends a high risk of cardiac dysfunction and an emergent situation requiring aggressive chelation (eFig 88.27).160,167,172,178 Echocardiography is essential, and left ventricular dysfunction is highly suggestive of iron overload Given the high output state, some suggest that the cutoff for a normal ejection fraction in thalassemia should be 60% Electrocardiogram often reveals biventricular dysfunction with left ventricular hypertrophy, a prolonged PR interval, bradycardia, ST-T wave change, and T-wave inversions Iron-related diabetes mellitus, parathyroid and thyroid and adrenal dysfunction, as well as vitamin D and thiamine status should be investigated, as they may impact cardiac function It is important to work with radiology and an iron specialist, as imaging techniques and algorithms for decision-making are rapidly improving Cardiac iron overload occurs well after the liver becomes overloaded, and pancreatic loading can be used as a marker for pending cardiac accumulation.159 MRI assessment of late gadolinium enhancement detects myocardial fibrosis; this, combined with assessment of ventricular function, also predicts failure.179 Management e key to management of iron-related cardiac dysfunction is Th chelation For details, refer to these guidelines, two with online links167,169,173 (see eFig 88.27) High-risk cardiac patients (failure, arrhythmias, a cardiac T2* less than 10 ms, or a liver iron concentration greater than 30 mg/g dry weight) demand emergent intervention As optimal chelation strategies are evolving rapidly, an expert on chelation should be consulted.167,169,173 Conservative therapy consists of 24-hour continuous deferoxamine IV infusion at 50 mg/kg per day (assuming adequate renal function) days a week.167,169,173 Deferoxamine can lead to histaminemediated hypotension when given IV; thus, blood pressure should be monitored closely After initiation, deferiprone (25 mg/kg, PO, TID) should be started.173,180 Although ascorbic acid releases iron, facilitating chelation, it should not be used initially, as the increased release of iron may lead to cardiac damage Arrhythmias often resolve promptly with chelation and are commonly treated with amiodarone.167,169,173 Due to the diffuse injury and reversibility with chelation, ablation is not recommended Hgb should be maintained between 10 and 12 g/dL, which may need to be done in small increments or by exchange Very gentle diuresis should be considered, keeping in mind that many patients have stiff vasculature, making them sensitive to hypovolemia Aggressive inotropic support should be avoided, as it may worsen iron-mediated oxidative stress It should be assumed that there is adrenal insufficiency; thus, stress dose steroids should be given after a random cortisol level is obtained Serial echocardiograms are indicated to follow shortening and ejection fractions Additional measures to optimize cardiac function include protecting oxidative damage with carnitine, correcting thyroid and parathyroid deficiencies, and administering IV calcium with oral vitamin D to maintain cardiac contractility and monitoring glucose closely Unless emergent, interventions such as pacemakers and cardiac transplant should not be considered until after cardiac iron has been reduced because dysfunction is often reversible with chelation ACE inhibitors and b-blockers should be considered after the acute phase Hepatic and Renal Dysfunction in Thalassemia For a detailed discussion of these topics, see eBox 88.3 Thrombosis and Pulmonary Emboli Thrombotic complications of pulmonary emboli, arterial occlusion, portal thrombosis, deep vein thrombosis, and stroke are increased in thalassemia, especially after splenectomy Enhanced thrombin generation due to factor V and factor VIII alterations as well as decreased protein C and S levels and increased platelet aggregation and microparticles lead to a thrombotic state, resulting in increased venous thrombosis and emboli Pulmonary Hypertension Although pulmonary hypertension is common in thalassemia, the true prevalence is not known As with SCD, NO destruction secondary to free hemoglobin from hemolysis contributes to 1050.e1 Agent Route Half-life of drug (hours) Schedule Clearance Side effects and toxicity Deferoxamine (Desferal) Slow infusion: intravenous or subcutaneous 0.5 Eight to 24 hours per day, to days per week Renal, hepatic Dermatological, ocular, auditory Deferasirox (Exjade) Oral 12 to 16 Once daily Hepatobiliary Gastrointestinal, renal, hepatic Deferiprone (L1) Oral to Three times per day Renal, cardiac Hematological (neutropenia, agranulocytosis), arthropathic • eFig 88.26 Iron chelator properties (From Vichinsky E, Levine L, et al Standards of Care Guidelines for Thalassemia Oakland, CA: Children’s Hospital & Research Center Oakland; 2012.) 1050.e2 Liver iron concentration (LIC) Ferritin Recommended chelation Monitoring Comments 2,500 ng/mL Intensive chelation Monitor ferritin every to months, and check LIC within months Note changes in trends More aggressive therapy may be indicated, depending on organ dysfunction Excess cardiac iron without cardiac dysfunction; T2* < 20 ms Intensive chelation Monitor ferritin every to months, and check LIC within months Intensive chelation consists of at least 12 hours of deferoxamine per day, days per week, or maximum tolerated deferasirox, as well as consideration of combination therapy Iron-induced cardiomyopathy, T2*