Hospital Medicine

Alpha thalassemia

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Alpha thalassemia

I. What every physician needs to know.

Thalassemia's are disorders of globin chain synthesis resulting in hemoglobinopathies that are classified by the specific globin chain that is affected. Hence, alpha thalassemia occurs when there is a deletion of one or more of the four alpha globin loci. The severity of the disease depends on the number of loci deleted, and therefore the clinical symptoms can range from completely asymptomatic to incompatible with life.

Alpha thalassemia can be inherited as an autosomal recessive trait or can be the result of a mutation, specifically of chromosome 16p, thereby affecting alpha globin protein synthesis. Occasionally, the disease can actually be acquired, for example, as a sequela of myelodysplastic syndrome. Normal adult hemoglobin (hemoglobin A) is made of a pair of alpha globin chains and a pair of beta globin chains. A reduction in the production of normal alpha globin chains results in a compensatory increase in beta chains, which alters the physiology of the red blood cell and results in the characteristic clinical and/or laboratory findings of the four types of alpha thalassemia.

II. Diagnostic Confirmation: Are you sure your patient has alpha thalassemia?

The diagnosis of alpha thalassemia depends on which of the four types of alpha thalassemia the patient has based on clinical manifestations, genetic risk factors and laboratory values that may tip the clinician that the patient has an underlying hematologic abnormality. Diagnosis is confirmed with hemoglobin electrophoresis and/or genetic analysis.

For alpha thalassemia-2 trait (alpha thalassemia minima), in which one of the four alpha globin loci is deleted, patients do not have anemia and have a normal mean cell volume (MCV) and mean corpuscular hemoglobin concentration (MCHC); diagnosis can only be confirmed by genetic analysis and is found incidentally when investigating parental deoxyribonucleic acid (DNA) of an infant with hydrops fetalis.

Patients with alpha thalassemia-1 trait (alpha thalassemia minor) have two of the four globin loci deleted, and will have a mildly reduced MCV as well as MCHC with occasional target cells on a peripheral smear. However, hemoglobin electrophoresis may still be normal.

Hemoglobin H (HbH) disease is a form of alpha thalassemia with one out of four alpha chains present. There are two forms: deletional HbH disease (--/a-) and non-deletional disease (--/aaCS). Deletional HbH, which is most common, occurs with three out of four globin loci deletions and is usually caused by deletions within HBA1 and HBA2 (alpha-globin gene cluster). Because alpha globin synthesis is severely impaired, there is excess beta globin production, which forms a homotetramer called HbH. Anemia is moderate (mean Hb of 8.5 g/dL), with low MCV (mean MCV 54.0 fL), low MCH (mean 16.6 pg), and hemoglobin electrophoresis can show between 5 and 30% HbH. HbH has virtually no oxygen transport capacity and is generally insoluble. As it precipitates in circulating red blood cells (RBCs), hemolytic anemia develops. The mean age at first transfusion is 11 ± 5.5 years old.

Non-deletional HbH disease is more phenotypically severe since both HbH and another abnormal hemoglobin are present in this variant. The most common non-deletional HbH disease is Hemoglobin H Constant Spring (HCS), resulting from the deletion of 2 alpha-globin genes and the Constant Spring mutation. This compound heterozygous state produces a dearth of functional alpha-globin chains and leaves excess beta chains to form HbH. HCS presents with a distinct thalassemic syndrome that is associated with life-threatening anemia during febrile illnesses. Baseline anemia is more severe (mean Hb of 7.2 g/dL), with more frequent hemolytic events and earlier mean age at first transfusion (1.5 ± 2.1 years old).

If all four globin loci deletions occur, there can be no synthesis of any normal hemoglobin (HbA, HbA2, HbF). All hemoglobin produced is hemoglobin Barts, which is a tetramer of gamma chains. This causes a severe hemolytic anemia in utero (alpha thalassemia major) leading to high-output heart failure and anasarca in the fetus, or hydrops fetalis. If the fetus survives to term, newborns die within several hours after birth unless they undergo chronic massive exchange transfusions with iron chelation.

A. History Part I: Pattern Recognition:

The typical patient with alpha thalassemia minima is completely asymptomatic. The patient with alpha thalassemia minor has mild microcytic anemia and is also almost always asymptomatic, but findings are similar to beta thalassemia minor: incidentally palpable spleen tip, Hct > 30%, and MCV < 75 fL.

HbH disease is clinically similar to beta thalassemia intermedia. The typical patient had neonatal jaundice and hemolytic anemia, but did not start requiring transfusions until the second or third decade of life. The patient has hepatosplenomegaly or had the spleen removed in young adulthood. There is a history of bilirubin cholelithiasis. In addition to a microcytic hypochromic anemia, labs show indirect hyperbilirubinemia, low haptoglobin and high lactate dehydrogenase. Iron overload is expected unless the patient is already on chronic chelation therapy.

Hydrops fetalis is generally incompatible with extrauterine life. It most commonly presents with stillbirth.

B. History Part 2: Prevalence:

HbH, HCS and homozygous alpha thalassemia affect about 1 million individuals worldwide. HbH was previously rare in North America and Europe, but due to changing demographics it is becoming strikingly more common in these areas. There are 300 million carriers of hemoglobinopathies in the world, mostly in Southeast Asia.

It is estimated that 5% of the southern Chinese population are carriers for alpha thalassemia; it is the most common genetic risk in this group. In Thailand, the frequency of alpha thalassemia is 25%. Hemoglobin Constant Spring occurs in 1-10% of the population in Thailand, Laos, and Cambodia. In this region, the incidence of HbH disease is 4-20 per 1000 births; the incidence of hemoglobin Bart's syndrome and hydrops fetalis is 0.5-5 per 1000 births.

Antenatal screening should be considered in these ethnic groups who have immigrated, especially in those with a family history of anemia. Given the demographic shift with large numbers of Asian ethnic groups in California, all newborns are universally screened for HbH and HCS.

In adults, HbH disease can be acquired in 8% of patients with myelodysplastic syndrome.

C. History Part 3: Competing diagnoses that can mimic alpha thalassemia.

The differential diagnosis for microcytic, hypochromic anemia includes iron deficiency, anemia of chronic disease (ACD) and thalassemia. Iron studies in thalassemia will show normal to increased ferritin and serum iron. Transferrin will be low or normal. MCV is less than 75fL, which is significantly lower than in iron deficiency or ACD. Hemoglobin electrophoresis will confirm the diagnosis of thalassemia and differentiate among clinically significant alpha thalassemia (HbH disease), beta thalassemia and combined hemoglobinopathies.

D. Physical Examination Findings.

Alpha thalassemia minima has no discernible physical findings. Alpha thalassemia minor may present with signs of mild anemia such as pallor, but is otherwise unremarkable.

Infants with HbH disease are jaundiced and may have low growth rates. Exam findings in adult HbH patients are consistent with chronic hemolytic anemia and include pallor, jaundice, hepatosplenomegaly, and leg ulcers. The patient may have a history of bilirubin cholelithiasis. Post-surgical scars following splenectomy or cholecystectomy may be present.

Iron overload occurs in 70-75% of patients with HbH disease who are transfusion-dependent. Acquired hemochromatosis may manifest as hepatic fibrosis and/or cirrhosis, cardiomyopathy, hemosiderosis, and diabetes mellitus. As such, there may be generalized hyperpigmentation or "bronzing" of the skin, along with other expected physical findings in liver disease and congestive heart failure (CHF).

HbH does have a variable clinical phenotype and rarely presents like beta thalassemia major (BTM). Ineffective erythropoiesis and severe hemolysis result in notable skeletal changes, hypogonadism and other endocrinopathies, and delayed growth in these patients.

E. What diagnostic tests should be performed?

Family members of a fetus with hemoglobin Barts and members of high-risk ethnic groups should all be screened with carrier testing. Prenatal testing is done for couples at high risk of having a fetus with hemoglobin Bart's and where one member is a known carrier.

Alpha thalassemia minima can only be diagnosed by DNA analysis. Alpha thalassemia minor can be confirmed only with molecular genetic tests which may not be widely available.

In hemoglobin H disease, a complete blood count may show considerable variation. Initial anemia work-up is standard: complete blood count (CBC), reticulocyte count, and peripheral blood smear should be ordered.

Peripheral blood smear will show hypochromia, microcytosis, anisocytosis, poikilocytosis, and rare nucleated RBCs (erythroblasts). RBC inclusion bodies (better visualized using brilliant cresyl blue or methylene blue staining) can be seen in 5-80% of erythrocytes. Bone marrow biopsy, although not required to confirm the diagnosis, will show erythroid hyperplasia with erythroblasts containing inclusion bodies.

Hemoglobin analysis by electrophoresis can confirm the diagnosis by demonstrating the presence of HbH. Hemoglobin electrophoresis may not detect the low levels of Hb H in Hb HCS, in which case molecular testing may be necessary. Molecular genetic testing of HBA1 and HBA2 detects deletions in 90% and point mutations in 10% of affected individuals. An expanded multiplex gap-PCR was recently developed to detect non-deletional Hb HCS as well as common deletional variants of alpha thalassemia.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In deletional HbH, hemoglobin may vary between 70-129g/L, MCV can be 51-73 and there will be a 5-10% reticulocytosis. Red blood cell distribution width (RDW) may be normal due to ineffective erythropoiesis and production of uniformly microcytic RBCs.

In non-deletional HbH, anemia is more severe. Because of subsequently higher reticulocytosis, the MCV is also higher than in deletional HbH. Peripheral smear shows target cells, teardrop RBCs, polychromasia, moderate anisopoikilocytosis, and basophilic stippling.

Hemoglobin electrophoresis is normal in alpha thalassemia minima and minor. Electrophoresis will usually confirm the diagnosis of HbH disease, when up to 30% HbH can be detected. At birth, these patients will have 20-40% hemoglobin Bart's present. For non-deletional HbH disease such as Hb HCS, molecular genetic testing is often required.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiographic studies are not required for diagnosis. Hepatosplenomegaly may be incidentally found on computed tomography (CT) or ultrasound.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A.

III. Default Management.

Alpha thalassemia minima and alpha thalassemia minor do not require treatment.

Patients with the alpha thalassemia trait should be offered genetic counseling.

Of note, previously asymptomatic or minimally symptomatic forms of thalassemia may have initial clinical manifestations during periods of increased stress or oxidation, such as infection or pregnancy.

Management in HbH disease is supportive. Due to hemolysis and increased erythropoiesis, folic acid is generally recommended (2-5mg/day), particularly in pediatric patients and pregnant women. Patients may develop calcium, vitamin D, and antioxidant deficiency, so can be given multivitamin supplementation that does not contain iron. The CBC should be monitored closely with chronic transfusions given as needed; most patients with deletional HbH disease have good quality of life and do not require regular transfusions. Monitoring of ferritin, iron studies, and liver iron concentration (LIC) assessed by MRI should begin at 15 years of age. It is critical to avoid unnecessary iron supplementation and a high-iron diet. Also avoid oxidant medications like dapsone, sulfonamides and some antimalarial agents; these can precipitate hemolytic crisis.

A. Immediate management.

Patients with HbH disease and fevers should be urgently evaluated. The risk of hemolytic or aplastic crisis is high, and expeditious transfusions may be required.

In HbH disease with a hemolytic crisis:

1. Transfuse red blood cells to a goal hemoglobin of 8-9 g/dL.

a. Use filtered RBCs or leukocyte-depleted blood 5-12 mL/kg/dose depending on clinical severity.

b. Monitor hemodynamic and volume status closely.

c. Monitor at least daily Hb/Hct as hemolysis may be ongoing.

2. Administer adequate IV fluids to maintain euvolemia and hemodynamic stability.

3. Monitor electrolytes and replete as needed.

4. Attempt to normalize body temperature if febrile.

a. Acetaminophen 10-12 mg/kg q4-6hrs (unclear if NSAIDs are safe in hemolytic crisis of HbH).

b. Frequent cool compresses.

5. Identify the underlying cause of infection or inflammation and manage appropriately.

a. Check blood and urine cultures.b. Empiric antibiotics to cover gram-negative bacteria and/or encapsulated bacteria (if asplenic).

Hydrops fetalis found during pregnancy should prompt discussion of elective termination.

B. Physical Examination Tips to Guide Management.

Signs of acquired hemochromatosis on exam should prompt adjustments in iron chelation therapy.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

HbH patients need hematologic evaluation at least every 6-12 months to monitor hemoglobin levels. Children with HbH should have growth and development assessed every 6-12 months.

Iron studies including serum ferritin can be done at variable intervals, depending on transfusion frequency and symptoms. At a minimum, it should be checked annually.

D. Long-term management.

Alpha thalassemia minima and minor do not require specific long-term management.

HbH disease in the first decade of life may not require chronic transfusion support, but splenectomy is often necessary in the second to third decades of life. Splenectomy is recommended in the setting of massive splenomegaly or hypersplenism.

HbH disease will lead to iron overload due to ineffective erythropoiesis and transfusion dependence. Ineffective erythropoiesis results from apoptosis of erythroid precursors and limited erythroid differentiation. Therefore, affected patients are not eligible for phlebotomy. These patients require long-term chelation. Deferoxamine is a subcutaneous or intravenous infusion. Deferiprone and deferasirox are oral chelating agents.

Chelation therapy should be started when the serum ferritin is >800 ng/mL and/or the liver iron concentration (LIC) is >5 mg Fe/g dry weight. If the patient has a ferritin < 300 ng/mL or ferritin 300-800 ng/mL with LIC <5 mg Fe/g dry weight, no chelation is required; continue to monitor ferritin every 3 months and LIC annually. Once chelation therapy is begun, it can be discontinued when the ferritin decreases <300 ng/mL and/or the LIC decreases <3 mg Fe/g dry weight.

Hematopoietic stem-cell transplantation (SCT) can potentially cure the underlying disease, but is more commonly used in beta thalassemia major. Allogeneic SCT has a disease-free survival rate of 80% in these patients. However, a Cochrane review did not demonstrate any randomized controlled trials or quasi-randomized controlled trials on the effectiveness or safety of different types of allogeneic SCT in patients with severe transfusion-dependent beta thalassemia. It is unclear at this time if SCT has superior outcomes compared to standard therapy with transfusion and chelation.

If patients do undergo transplantation, post-SCT patients will often suffer from persistent iron overload. Unless there are contraindications, post-SCT patients should undergo phlebotomy and/or iron chelation therapy. They will be eligible for phlebotomy due to newly effective erythropoiesis. Patients with hemoglobin less than 9.5 g/dL or hypotension should not undergo phlebotomy. The goal ferritin level is less than 100 micrograms/L.

If the patient is not a phlebotomy candidate, then chelation can be used. Only deferoxamine has been studied in post-SCT patients. Deferiprone is generally avoided in this cohort due to the risk of neutropenia and agranulocytosis.

E. Common Pitfalls and Side-Effects of Management.

Frequent transfusion requirements put these patients at high risk for iron overload with subsequent clinical stigmata of hemochromatosis. It is imperative to follow ferritin levels and provide chelation therapy as needed.

Splenectomy puts the patient at risk of fulminant sepsis as well as life-threatening thromboemboli. Infectious symptoms should be assessed in a timely fashion. Post-splenectomy patients with marked thrombocytosis should also be started on low-dose aspirin.

A meta-analysis of transfusion-dependent patients with thalassemia major showed that there was no significant difference in efficacy between deferoxamine and deferiprone. Both chelators were found to reduce myocardial iron content by about 24%. There was no significant difference in left ventricular ejection fraction (LVEF), although there was a publication bias for LVEF.

Treatment with deferoxamine is very expensive and requires hours of continuous subcutaneous or intravenous infusion. Side effects from chronic use include visual and auditory neurotoxicity, so patients should receive baseline examinations by ophthalmology and ear, nose and throat (ENT) followed by annual exams to monitor for vision and hearing loss. Chronic deferoxamine use is also associated with increased risk of infection from mucormycosis, Yersinia spp., and Vibrio vulnificus. It is thought that the iron-chelate complex acts as a siderophore for these organisms and supports their growth.

Deferiprone and deferasirox are oral chelating agents. Deferiprone is associated with neutropenia and agranulocytosis, so weekly absolute neutrophil counts should be monitored. Other side effects include nausea, vomiting, abdominal pain, increased liver enzymes, arthralgia, and rarely, zinc deficiency in diabetic patients. LFT’s should be followed monthly and zinc levels every 3-6 months in diabetic patients.

Deferasirox has three black-box warnings:

  1. Fatal gastrointestinal (GI) hemorrhage has occurred with use, primarily in elderly patients with advanced hematologic malignancies and thrombocytopenia; caution should be used with concurrent non-steroidal anti-inflammatory drugs (NSAIDs), steroids and anticoagulants.

  2. Severe hepatic dysfunction and failure have occurred with use, primarily in patients more than 55 years old with underlying comorbidities including cirrhosis.

  3. Acute renal failure, in some cases fatal, has occurred with use in patients with multiple comorbidities.

Serum chemistries, BUN, creatinine, urine protein, urine creatinine, and CBC with differential should be monitored monthly in all patients on deferasirox. LF’s should be followed every 2 weeks for the first month, then spaced out to monthly testing. Deferasirox is contraindicated when platelets are less than 50,000, when Eastern Cooperative Oncology Group (ECOG) performance status is poor, in the setting of high-risk myelodysplastic syndrome, and if creatinine clearance (CrCl) is less than 40 mL/min or serum creatinine is >2 times the upper limit of normal for age

IV. Management with Co-Morbidities.

Pregnancy may cause an expansion in blood volume that worsens pre-existing anemia. This is most pronounced in HbH disease. In one study of 34 pregnancies among 29 women with HbH disease, 18% of patients developed pre-eclampsia, 9% CHF, there was one miscarriage, one perinatal death and there were three premature births. In another study of 58 pregnancies in 24 affected women, 12% miscarriages occurred.

Patients with thalassemia are recommended to receive preconception genetic counseling. Pregnant women with alpha thalassemia trait should consider chorionic villus sampling to diagnose hemoglobin Bart's. A multi-disciplinary approach to close follow-up should include referral to hematology in conjunction with routine obstetrics and gynecology care.

HbH disease that occurs with other hemoglobinopathies can present with anemia of varying degrees of severity.

A. Renal Insufficiency.

Iron chelation therapeutics should be dose-adjusted for creatinine clearance. Deferasirox is contraindicated when CrCl is less than 40 or creatinine is over two times the upper limit of age-appropriate normal value. Deferoxamine should be avoided completely in end stage renal disease patients. Rarely, hemolysis-associated acute kidney injury may occur in the presence of predisposing conditions like hypovolemia.

B. Liver Insufficiency.

Iron overload is associated with hepatic steatosis, non-alcoholic steatohepatitis and portal fibrosis. Concomitant viral hepatitis poses further increased risk of hepatocellular carcinoma and cirrhosis. Most thalassemia patients older than 25 years are infected with hepatitis C (HCV). Antiviral therapy for HCV has often been withheld due to concern for ribavirin-induced hemolysis.

There are no randomized controlled trials or large cohort studies that demonstrate worse outcomes. Rather, a prospective, open label, single-arm trial of 14 thalassemia patients with HCV who completed a full course of pegylated interferon and ribavirin did not show any significant increase in cardiac, liver or endocrine toxicities. However, median transfusions increased by 44%; neutropenia occurred in 52%. If thalassemia patients with HCV undergo antiviral treatment, it is critical to monitor transfusion requirements, viral response, iron toxicities, and neutropenia.

Of the iron chelators, both deferoxamine and deferasirox can cause transaminitis. Consider chelation-induced hepatic dysfunction if transaminases increase with therapy.

C. Systolic and Diastolic Heart Failure.

Severe progressive anemia will cause cardiac dilatation. However, long-term cardiac iron deposition is the most frequent cause of death in transfusion-dependent patients. A restrictive cardiomyopathy or life-threatening arrhythmia may develop without intensive chelation therapy. Cardiac magnetic resonance imaging (MRI) with T2* measurements can accurately assess cardiac iron load and guide chelation treatment. Management of CHF in thalassemia patients is otherwise as per standard of care.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Interestingly, a lower incidence of myocardial infarction has been reported in male subjects with heterozygous beta thalassemia trait. A meta-analysis of eight case-control studies suggests that beta thalassemic trait is protective against the development of coronary artery disease (CAD) in men, although similar studies with alpha thalassemia are lacking. Women have not been shown to benefit. Thalassemia trait is associated with decreased serum cholesterol, lower blood viscosity due to anemia and lower incidence of hypertension. Significant iron overload may increase the risk of atherosclerotic plaque formation. However, thalassemia minor does not appear to accelerate atherosclerosis.

On the other hand, thalassemia patients (not those with trait) have markedly increased expression of endothelial activation markers in peripheral blood lymphocytes. This is one explanation for thrombotic and vascular complications in this population and they may be useful markers to follow in vascular disease.

Caution should be used in the HbH patient with iron overload and concomitant CAD who undergoes deferasirox therapy. The risk of GI bleeding from chelation is notably compounded by anti-platelet agents and anticoagulation.

E. Diabetes or Other Endocrine Issues.

Insulin resistance syndrome occurs in 94% of patients with unspecified hepatic iron overload. The greater the amount of hepatic and pancreatic iron deposition, the greater the insulin resistance and risk for diabetes. Concomitant liver dysfunction is also an exacerbating factor. Although data in HbH patients are scarce, beta thalassemia patients with non-cirrhotic HCV infection have been found to be more insulin resistant and have delayed insulin secretion compared to thalassemia patients without HCV. Antihyperglycemic agents require dose adjustments for renal and hepatic insufficiency. Diabetes management is otherwise unchanged.

Other iron-induced endocrinopathies besides diabetes mellitus may be associated. Hypogonadism, hypothyroidism, hypoparathyroidism, and disorders of bone metabolism more often develop in beta thalassemia major. Severe and rare phenotypes of HbH disease can demonstrate similar complications. Osteopenia may be associated with deletional HbH as well.

F. Malignancy.

Chelation with deferasirox should be avoided in elderly patients with advanced malignancies or high-risk myelodysplastic syndrome.

G. Immunosuppression (HIV, chronic steroids, etc.).

Chronic chelation with deferoxamine is associated with increased risk of infection with Mucor, Yersinia, and V. vulnificus due to siderophore formation. Consider these in the setting of severe immunosuppression.

Post-splenectomy patients are at high risk of overwhelming sepsis. Pneumococcal, meningococcal, and influenza vaccines should be up to date. Asplenic children are usually given daily antibiotic prophylaxis until age 5. The asplenic adult with fever may have profound bacteremia; he should be evaluated urgently and started on appropriate broad-spectrum antibiotics.

H. Primary Lung Disease (COPD, Asthma, ILD).

Data are limited in the co-management of alpha thalassemia and lung disease. Pulmonary function tests in beta thalassemia major may show restrictive and obstructive defects with lower diffusing capacity of the lungs for carbon monoxide (DLCO); however, most patients are clinically asymptomatic. Pulmonary hypertension (PH) is a common complication of thalassemia.

Echocardiographic screening has shown that 40-50% of thalassemia intermedia and 10-75% of thalassemia major patients have PH. Risk factors for developing PH include increased age, presence of severe hemolysis, prothrombotic state, and iron overload. Adequate transfusion support and chelation can mitigate these risk factors. In thalassemic patients with PH, sildenafil is a treatment option, and L-carnitine has been shown to significantly reduce pulmonary artery systolic pressure.

I. Gastrointestinal or Nutrition Issues.

Deferasirox is associated with severe GI hemorrhage, so it should be avoided in patients with a past history of GI bleeds.

Aside from avoiding oral iron supplementation in thalassemic patients, nutrition is more of an issue for affected children. For example, hemolysis-associated zinc deficiency can lead to delayed growth and improves with repletion.

J. Hematologic or Coagulation Issues.

Alpha and beta thalassemia's are associated with a hypercoagulable state. In alpha thalassemia syndromes, there are increased circulating platelet aggregates. Platelet factor 3 and thrombin-antithrombin complex are also high. In addition, platelet aggregation activity and thrombosis are higher in splenectomized patients.

In splenectomized patients with alpha thalassemia, it is recommended to administer short-term antithrombotic prophylaxis both perioperatively and when there are increased prothrombotic risk factors (e.g. prolonged immobilization or pregnancy). Unfractionated or low molecular weight heparin should be implemented during and after surgery as short-term post-operative prophylaxis, although exact duration is unknown. Oral contraceptives should also be avoided.

K. Dementia or Psychiatric Illness/Treatment.

In clinically significant alpha thalassemia, ischemic brain damage and cerebral thrombosis have been observed. More than one antiplatelet agent may be considered in HbH patients with a known history of ischemic cerebrovascular accident.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

If starting medications overnight on an HbH patient, avoid those with oxidant potential. Consider medication or infection-induced hemolytic crisis in the setting of an acute drop in hemoglobin.

If this occurs, transfuse urgently, discontinue potentially offending agents and rule out infection.

In the setting of HbH disease with hemolytic crisis, transfuse to hemoglobin goal 8-9 g/dL (depending on clinical severity), maintain euvolemia, and look for causes of infection or inflammation.

B. Anticipated Length of Stay.

Length of stay is determined by co-morbidities and symptomatic severity of anemia. It can range from less than 1-2 days for work-up and symptomatic management to more than 30 days in those who undergo SCT that is complicated by prolonged neutropenia, infection or graft versus host disease.

C. When is the Patient Ready for Discharge.

When Hct appropriately rises and remains stable in response to transfusion, the patient is ready for discharge.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

Refer patients currently on iron chelation, or those who may imminently require chelation, to hematology. Chelation schedules are variable and dependent on comorbidities.

Patients who are eligible for deferoxamine treatment require baseline examinations with ophthalmology and ENT prior to starting therapy. They will also need to follow-up with both specialists every 12 months.

Routine hospital discharge follow-up with the primary care physician within 1-2 weeks is optimal.

Either the primary care physician or hematologist will need to check a CBC at least every 6-12 months and ferritin and LIC at least every 12 months. The frequency of lab draws should increase with higher transfusion frequency. It would be preferable for a specialist to follow these values in order to expedite chelation therapy as necessary.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

CBC and ferritin can be rechecked immediately prior to the first follow-up clinic visit.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

None.

E. Placement Considerations.

This condition should not affect transition of care to a chronic care facility, unless the patient with HbH is unable to independently follow-up with outpatient surveillance.

F. Prognosis and Patient Counseling.

Alpha thalassemia minima and minor have excellent prognoses.

HbH patients generally do not live past the age of 30 unless they undergo iron chelation therapy.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

There are no Joint Commission core indicators referable to alpha thalassemia.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Splenectomized patients with platelets greater than 600,000-800,000 should be started on low-dose aspirin indefinitely for VTE prophylaxis.

Affected patients undergoing surgery should be placed on unfractionated heparin or low molecular weight heparin to prevent thrombosis.

VII. What's the evidence?

Chui, DH, Fucharoen, S, Chan, V. "Hemoglobin H disease: not necessarily a benign disorder". Blood. vol. 101. 2003. pp. 791-800.

Cohen, AR, Galanello, R, Pennell, DJ, Cunningham, MJ, Vichinsky, E. "Thalassemia". Hematology Am Soc Hematol Educ Program. 2004. pp. 14-34.

Dentali, F, Romualdi, E, Ageno, W, Cappellini, MD, Mannucci, PM. "Thalassemia trait and arterial thromboembolic events: a systematic review and a meta-analysis of the literature". J Thromb Haemost. vol. 9. 2011. pp. 917-21.

Galanello, R, Cao, A, Pagon, RA, Bird, TD, Dolan, CR, Stephens, K, Adam, MP. "Alpha-Thalassemia". GeneReviews™. 2005.

Mamtani, M, Kulkarni, H. "Influence of iron chelators on myocardial iron and cardiac function in transfusion-dependent thalassemia: a systematic review and meta-analysis". Br J Haematol. vol. 141. 2008. pp. 882-90.

Taher, AT, Porter, JB, Viprakasit, V, Kattamis, A, Chuncharunee, S, Sutcharitchan, P, Siritanaratkul, N, Origa, R, Karakas, Z, Habr, D, Zhu, Z, Cappellini, MD. "Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassemia". Br J Haematol. vol. 168. 2015. pp. 284-90.

Vichinsky, E. "Advances in the treatment of alpha-thalassemia". Blood Reviews. vol. 26. 2012. pp. S31-S34.

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