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beta thalassemia major (Cooley's anemia)
Pathology:
- absence of both beta-globin genes
- severe anemia requiring transfusions at an early age
- child is not anemic at birth because of the predominance of fetal hemoglobin
- transfusion-related iron overload
- hemolytic anemia
Clinical manifestations:
1) skeletal abnormalities:
a) results form hypertrophy & expansion of marrow
b) osteoporosis
c) maxillary overgrowth gives rise to facial appearance of Cooley's anemia
2) hepatic changes:
a) enlarged liver due to extramedullary hematopoiesis
b) cirrhosis with nodular regeneration
c) iron deposition (iron overload from transfusions)
d) gallstones in 15% of patients over 15 years of age
3) cardiopulmonary:
a) congestive heart failure secondary to severe anemia
b) myocardial hemosiderosis from transfusion overload
c) EKG changes
- increased PR interval
- premature ventricular contractions (PVC)
- premature atrial contraction (PAC)
- ST segment depression
d) pericarditis, sterile
e) pericardial effusion
4) enlarged kidney
5) splenomegaly in untransfused patients
6) growth retardation
7) hypogonadism
Laboratory:
1) complete blood count (CDV)
a) anemia: blood hemoglobin levels may drop below 4 mg/dL
b) child is not anemic at birth because of the predominance of fetal hemoglobin
c) MCV is low: microcytosis
2) peripheral blood smear
- microcytosis
- target cells
3) reticulocyte count is high: reticulocytosis
4) hemoglobin electrophoresis:
a) hemoglobin F 10-90%
b) hemoglobin A2 7-90%
5) evidence of hemolysis
a) increased serum LDH
b) increased serum bilirubin
6) iron studies
a) serum ferritin is normal
b) serum iron, TIBC & % transferrin saturation are normal
7) beta globin gene mutation
Special laboratory:
- echocardiogram is pulmonary hypertension suspected
Complications:
- pulmonary hypertension (most common)
Management:
1) transfusion support
- maintaining Hgb > 10 g/dL suppresses endogenous hematopoiesis & prevents skeletal abnormalities & cardiomegaly
2) iron chelation
a) deferoxamine 40 mg/kg max 2 gm over 8 hours (IV)
b) few patients survive to adulthood without aggressive iron chelation or BMT
c) deferiprone (Ferriprox) for deferoxamine failure
3) splenectomy for transfusion-dependent thalassemia
- splenectomy reduces transfusion requirements [1]
4) bone marrow transplantation (BMT) for severe disease
5) gene therapy
- autologous CD34+ cells were transduced with a BB305 vector which encodes beta-globin with a T87Q amino acid substitution
- cells were then reinfused after the patients had undergone myeloablative busulfan conditioning
- this gene therapy procedure reduced or eliminated need for long-term packed RBC transfusions in 22 of 22 patients [3]
Interactions
disease interactions
General
beta thalassemia
References
- Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 18, 19.
American College of Physicians, Philadelphia 1998, 2006, 2012, 2018, 2022.
- Hershko C.
Pathogenesis and management of iron toxicity in thalassemia.
Ann N Y Acad Sci. 2010 Aug;1202:1-9.
PMID: 20712765
- Thompson AA, Walters MC, Kwiatkowski J et al
Gene Therapy in Patients with Transfusion-Dependent beta-
Thalassemia.
N Engl J Med 2018; 378:1479-1493. April 19, 2018
PMID: 29669226
http://www.nejm.org/doi/full/10.1056/NEJMoa1705342
- Biffi A.
Gene Therapy as a Curative Option for beta-Thalassemia.
N Engl J Med 2018; 378:1551-1552. April 19, 2018
PMID: 29669229
http://www.nejm.org/doi/full/10.1056/NEJMe1802169