Alpha Thalassemia

Background

Alpha thalassemia is characterized by quantitative defects in the alpha globin chain, one of the backbone proteins of the hemoglobin molecule. These defects lead to decreases in hemoglobin production with resulting anemia. The genes are located on chromosome 16 and sophisticated mapping techniques can determine the specific mutation. Depending upon the deletion, this disease can be categorized within the following groups: Silent Carrier, Alpha Thalassemia Trait, Hemoglobin H disease, Hemoglobin H-Constant Spring, and Alpha Thalassemia major.

OUTLINE

Disease Associations

Laboratory/Radiologic/Other Diagnostic Testing

Prognosis and Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

COAGULOPATHY

Haemostatic disorders in nonsplenectomized and splenectomized thalassaemic children.

Shebl SS, el-Sharkawy HM, el-Fadaly NH.

Department of Paediatrics, Faculty of Medicine, University of Tanta, Tanta, Egypt
East Mediterr Health J 1999 Nov;5(6):1171-7 Abstract quote
A group of 40 thalassaemic patients (20 splenectomized and 20 nonsplenectomized) from the Haematology Unit of Tanta University Hospital (age range: 3-14 years) were studied to identify the mechanisms by which haemorrhagic and thrombotic complications occur in thalassaemic patients. The patients' levels of protein C, antithrombin III and in vitro platelet aggregation in response to collagen were compared with those of 20 controls.

The study suggests that thrombocytosis, increased platelet aggregation and decreased natural coagulation inhibitors (protein C and antithrombin III) in splenectomized thalassaemic children may be significant in thrombotic complications in such patients. Defective platelet aggregation and prothrombin activity in nonsplenectomized children may also give rise to haemorrhagic tendencies.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

PCR

Evaluation of a Single-Tube Multiplex Polymerase Chain Reaction Screen for Detection of Common alpha-Thalassemia Genotypes in a Clinical Laboratory

Alana K. Bergstrome Jones, MSc, and Annette Poon, MB, BCh, FRCP(C)

Am J Clin Pathol 2002;118:18-24 Abstract quote

We prospectively compared a single-tube multiplex polymerase chain reaction (PCR) for detecting alpha-thalassemia with our current approach using 452 blood samples.

Initial evaluation of 89 specimens revealed sensitivity and specificity, respectively, for the hemoglobin H inclusion body test (HbH prep) vs PCR for detecting alpha0-thalassemia carriers of 0.79 and 0.96 and for a mean corpuscular volume (MCV) of 82 µm3 (82 fL) or less, 1.0 and 0.45. Detection of all alpha-thalassemia genotypes was significantly lower for HbH prep and MCV (sensitivity and specificity, respectively: HbH prep, 0.48 and 0.96; MCV, 0.87 and 0.47). In a follow-up evaluation of patients with positive HbH prep results or suspected alpha-thalassemia prescreened by low MCV, the sensitivity and specificity, respectively, of HbH prep vs PCR increased to 0.97 and 0.93 for alpha0-thalassemia and 0.83 and 0.92 for any alpha-thalassemia. PCR detected alpha-thalassemia in 37.2% of 298 suspected alpha-thalassemia cases with suggestive indices but negative HbH prep results and no detectable hemoglobinopathy.

This multiplex approach was more sensitive than the HbH prep for detecting all alpha-thalassemia genotypes, particularly alpha+-thalassemia; was particularly valuable for identifying carriers of alpha0-thalassemia at risk for offspring with hemoglobin Bart hydrops fetalis, regardless of other diagnosed hemoglobinopathies; and is an ideal adjunct to standard clinical screening protocols for detecting alpha-globin deletions.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

TREATMENT

BONE MARROW TRANSPLANTATION

Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation.

Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G, Lucarelli G.

Unita Operativa di Ematologia e Centro Trapianto di Midollo Osseo di Muraglia, Azienda Ospedale di Pesaro, Italy.
Blood 2002 Jul 1;100(1):17-21 Abstract quote
To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy.

Two hundred eleven patients (mean age, 8.7 +/- 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors.

None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years.

Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

DEFERIPRONE

Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial.

Maggio A, D'Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, Di Gregorio F, Garozzo G, Malizia R, Magnano C, Mangiagli A, Quarta G, Rizzo M, D'Ascola DG, Rizzo A, Midiri M.

Divisione di Ematologia II e Unita di Ricerca Piera Cutino, Azienda Ospedaliera V. Cervello, Palermo, Italy.
Blood Cells Mol Dis 2002 Mar-Apr;28(2):196-208 Abstract quote
Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major.

To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups.

Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.

Commonly Used Terms

Red Blood Cells

Internet Links

Northern California Comprehensive Thalassemia Center

Last Updated 7/8/2002

Send mail to psdermpath@earthlink.net with questions or comments about this web site.
Copyright � 2002 The Doctor's Doctor

Disease Associations
Laboratory/Radiologic/Other Diagnostic Testing
Prognosis and Treatment
Commonly Used Terms
Internet Links

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
PCR
Evaluation of a Single-Tube Multiplex Polymerase Chain Reaction Screen for Detection of Common alpha-Thalassemia Genotypes in a Clinical Laboratory Alana K. Bergstrome Jones, MSc, and Annette Poon, MB, BCh, FRCP(C)	Am J Clin Pathol 2002;118:18-24 Abstract quote We prospectively compared a single-tube multiplex polymerase chain reaction (PCR) for detecting alpha-thalassemia with our current approach using 452 blood samples. Initial evaluation of 89 specimens revealed sensitivity and specificity, respectively, for the hemoglobin H inclusion body test (HbH prep) vs PCR for detecting alpha0-thalassemia carriers of 0.79 and 0.96 and for a mean corpuscular volume (MCV) of 82 µm3 (82 fL) or less, 1.0 and 0.45. Detection of all alpha-thalassemia genotypes was significantly lower for HbH prep and MCV (sensitivity and specificity, respectively: HbH prep, 0.48 and 0.96; MCV, 0.87 and 0.47). In a follow-up evaluation of patients with positive HbH prep results or suspected alpha-thalassemia prescreened by low MCV, the sensitivity and specificity, respectively, of HbH prep vs PCR increased to 0.97 and 0.93 for alpha0-thalassemia and 0.83 and 0.92 for any alpha-thalassemia. PCR detected alpha-thalassemia in 37.2% of 298 suspected alpha-thalassemia cases with suggestive indices but negative HbH prep results and no detectable hemoglobinopathy. This multiplex approach was more sensitive than the HbH prep for detecting all alpha-thalassemia genotypes, particularly alpha+-thalassemia; was particularly valuable for identifying carriers of alpha0-thalassemia at risk for offspring with hemoglobin Bart hydrops fetalis, regardless of other diagnosed hemoglobinopathies; and is an ideal adjunct to standard clinical screening protocols for detecting alpha-globin deletions.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
TREATMENT
BONE MARROW TRANSPLANTATION
Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G, Lucarelli G. Unita Operativa di Ematologia e Centro Trapianto di Midollo Osseo di Muraglia, Azienda Ospedale di Pesaro, Italy.	Blood 2002 Jul 1;100(1):17-21 Abstract quote To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 +/- 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.
DEFERIPRONE
Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Maggio A, D'Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, Di Gregorio F, Garozzo G, Malizia R, Magnano C, Mangiagli A, Quarta G, Rizzo M, D'Ascola DG, Rizzo A, Midiri M. Divisione di Ematologia II e Unita di Ricerca Piera Cutino, Azienda Ospedaliera V. Cervello, Palermo, Italy.	Blood Cells Mol Dis 2002 Mar-Apr;28(2):196-208 Abstract quote Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major. To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups. Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.