Physicomimetics

Thalassemia intermedia are the clinical appellation for patients with two

-thalassemia genes but whose phenotype is less severe than thalassemia major. The most commonly associated genotypes are ⁺/⁺ or ⁺/⁰, with a relatively high -globin producing ⁺ mutation. The disease is extremely heterogenous at the genotypic level. Coinheritance of -thalassemia or hereditary persistence of fetal hemoglobin reduces disease severity and may transform what would have been a thalassemia major phenotype into thalassemia intermedia. Affected persons are typically asymptomatic, but the spectrum of disability is broad. The most frequent complications are hypersplenism, gallstones, and ankle ulcers.

Patients with thalassemia intermedia should be given folate supplementation and periodic red blood cell transfusions and be monitored for iron overload.

Beta Thalassemia Major

It is the homogenous state for either the B⁰ or B⁺ thalassemia gene or, less commonly, the compound heterozygous state for the two genes.

Clinical Features

The newborn infant with Beta thalassemia is not anemic.(within first year of life and in severe cases within a few weeks of birth. Anemia (insidious) but in severe anemia cardiac dilatation is present. Splenomegaly and hepatomegaly are common.

Changes of skletel system (Mongoloid facies) are due to expansion of the marrow in the malar bones, and X-ray change in skull, long bones, hands and feet.

Severe infection (pericarditis), hypersplenism, anemia, and thrombocytopenia are also common.

Organ dysfunction due to increase in body iron secondary to frequent transfusions and increase intestinal absorption lead to pancreatic hemosiderosis (DM, Cirrhosis) or/and cardiac hemosiderosis (CCF, arrhythmiasis, Heart block).

Blood Picture

Blood picture resembles iron deficiency anemia. Hb of 3-9 g/dl.

Blood smear charcterized by presence of anisocytosis and poikilocytosis, which are often bizarre. Microcytosis (predominant), polychromasia and punctate basophilia are usually present. Hypochromia is a sticking feature.

Target cells are prominent. Tear drops cells often seen. Some cells are macrocytic. Occasionally spherocytic RBCs are present. Normoblast present in large number in postsplenectmy patients.

MCV and MCH are significantly reduced. MCHC also reduced.Reticulocyte increased in 10% or more. WBC is increased of 15-40,000/L or more with shift to left. Some myelocytes are commonly present. Platlets count is normal, but may be reduced in hypersplenism.

The osmotic fragility decreased. (Increase resistance to hemolysis). There is evidence of intravascular hemolysis. The serum bilirubin slightly increased.

Haptoglobin decreased.

Dark-brown urine is commonly observed. Serum uric acid frequently elevated and clinical gout may occur.

The serum iron and ferritin are invariably elevated and transferrin completely saturated.

Serum and red cells folate is often reduced.

Bone Marrow Aspiration

Hyperplastic erythropoiesis is proportional to the anemia. Increase proportion of basophilic and polychromatic normoblast (micronormoblast).

Siderotic granules are commonly scattered through the cytoplasm of the normoblast. Ring sideroblst occasionally seen.

Hb-Electrophoresis

HbF (10-98) estimated also by acid elution and alkali denaturation tests.

HbA very little or absent and HbA2 is variable

Treatment of Thalassemia

1. Packed RBCs transfusion: 10- 15 ml/kg every 4-6 weeks to keep Hb level above 10 gm/dl (Hypertransfusion). Recently, a more extensive program of transfusion aims to keep Hb above 12 gm/dl (supertransfusion) The packed RBCs should be better washed with saline and carefully cross-matched.

Recently, neocyte transfusions (Juvenile RBCs separated by special techniques), and single donor transfusions have been shown to be more advantageous to the patient. These RBCs survive longer.

2. Iron chelation therapy: Is essential especially in the high transfusion programs, to prevent "Hemosiderosis".

(a) Desferal: is given IV, IM or SC injection. Most recently IgM is given by continuous SC infusion, using an electric infusion pump for 12h/d, repeated 4 times/week. This permits a negative iron balance.

(b) SHAM: SHAM is a new promising oral iron-chelating agent of salicyl Hydroxamic acid). It is given orally 20-40 mg/kg/day in divided doses, 5 days every week, which minimizes the discomfort of injections as in desferal. It may lead to hypocalcemia, as it also chelates calcium. Therefore, Calcium intake should be increased in the other 2 days of the week.It is less active in iron chelation than desferal.

Both drugs cause red discoloration of the urine (passage of iron chelates).

Exjade approved in 2005, orally ingested. highly bioavailable chelator that is absorbed in the GI tract. Dose-dependent t½ of 12-18 hours given once daily 20-40 mg/kg

2. Fetal hemoglobin stimulator are : 5-Azacytidine/decitabine ,butyrate, — pomalidomide(animal models) and combinations of different

compounds have also been tried with some success

4. Splenectomy: Is indicated only if there are manifestations of hypersplenism. This presents by clinical and laboratory manifestations of pancytopenia. There is an increased need for frequent transfusions. A patient who does need more than 300 ml packed RBCs/kg/year is said to have hypersplenism. It should be postponed after 5 years of age

5. Folic acid: 1mg/day prevent megaloblastc crises.

6. Never give iron to these patients. They already have iron over-load.

7. Thalassemia minor requires no treatment.

8. HSC Transplantation is the only cure for thalassemia patients. It should be considered in all patients who have an acceptable donor.

Patients are classified on the basis of their risk factors which include:

inadequate chelation, presence of liver fibrosis and hepatomegaly 9. Gene therapy: Why ß-thalassemia, SCD are excellent candidates for genetic approaches: Monogenic disorders and it could cured by introducing or correcting a single gene