NEWER THERAPEUTIC OPTIONS IN SICKLE CELL DISEASE

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INTRODUCTION

            Sickle cell disease is an autosomal dominant disorder, sickle haemiglobin is the abnormal haemoglobin b chain glutamin acid is replaced by valine. Sickle haemoglobin has the unique property of forming polymersdeoxygenated state. These polymers deform the RBCS to sickle cell.  Formation of polymers depends on the concentration of HbS inside the cell. So small reductions in HbS concentration inside the cell might result in significant clinical benefits. That is the reason why sickle cell trait is clinically silent were the HbS concentration is low. With better understanding of pathophysiology of sickle cell disease and its complications, it treatment has also progressed.

            Among the haemolytic anaemias, vasoocclusive features are unique in SCD. Now it is well understood that vasoocclusion and tissue ischaemia in SCD involve not only the polymerization of HbS but also interaction between RBCs, endothelium, leucocytes, platelets and plasma factors. Intracellular polymerization of HbS is decreased by a rise in foetal haemoglobin and there increasing HbF is the most clinically studied approach against sickling. Infections, brain injury, renal disease , pain priapism can now be prevented. Complications from lung injury, surgery and transfusion can be minimized.

Management of SCD

Apart from general measures and treatment for symptomatic relief , now the newer therapeutic agents are directed towards prevent of complications.

THERAPEUTIC STRATEGIES FOR PREVENTION OF COMPLICATIONS

Sickling can be interrupted at several key pathways:

1. HbF Augmentation

Most promising agent in hydroxyurea, a ribonucleotide reductase inhibitor, causes myelosuppressive – induced HbF synthesis, resulting in improved red cell survival and decreased sickling. Hydroxyurea is orally active, effective , safe in short term and beneficial in most patients, in the dose of 10-15mg/kg to a maximum of 35 mg/kg. Before starting hydroxyurea, base line evaluation like blood counts, MCV, HbF concentration and serum chemical values and test for pregnancy ( a contraindication) to be done. Blood counts should be performed every 4-6 weeks intervals, granulocyte count should be at least 2000/mm³ and platelet counts at least 80,000/mm³ before or during treatment. An initial Hb concentration below 5.5 gm% is not a contraindication to treatment with hydroxyurea. Adults with higher TLC and reticulocyte counts and larger treatment associated decreases in these counts tends to have greater increases in HbF production  and hence better response to hydroxyurea. Although hydroxyurea lowers pain episodes, pulmonary events and hospitalizations, 40% of treated patients do not respond or have progressive organ failure, the reason for this is yet to be settled.

Clinical advances in treatment of SCD

Other drugs which can increase HBF concentration are short chain fatty acids like valproic acid, 2-deoxy- 5 azacytidine , erythropoitein.

Other emerging therapeutic agents

2. Antisickling agent (through multiple pathway)

            Nitric oxide (NO) is a critical factor in the pathphysiology of SCD and hence a potential treatment option. NO regulates vessel tone , endothelial adhesion, leucocytes and platelet activity, an important factor in ischaemia reperfusion injury and sickle cell induced ischaemia. In SCD, more adhesion molecules are produced due to decreased availability of NO. Oral arginine supplementation induces NO production, reduces red cell sickling by inhibiting the Gardos channel (Calcium activiated K = Channel). Treatment of sickle – cell patients with NO or its precursor L arginine have shown promising antisickling activity with vasodilator properties. NO or arginine supplementation may be synergistic with hydroxyurea and seems to further increase. No release and decrease adhesive molecules.

CONCLUSION:

            The need to study new applications of current treatment and to devise new treatments direct at disrupting multiple factors of the pathophysiology of the disease remains most important. New therapeutic options like hydroxyurea. No or L-Arginine, BMT, gene therapy appears promising. While awaiting the new treatments for the underlying disease, several partial problems remains unsolved. For example, how should the acute chest syndrome be managed, which patients should undergo exchange transfusion? How aggressively should be blood pressure be lower to decrease the risk of stroke? Can we better understand the cause of striking  variability in sickle cell disease, so that hazardous treatment can be directed to the patients who are most likely to have the worst disease complications?

REFERENCES:

1.      Bunn H.F. Pathogenesis and treatment of sickle cell disease. N. Engl J Med 1997; 337:762-9.

2. Steinberg M.H. Management of sickle cell disease. N. Engl j Med 1999;340:1021 – 30.
3. Morris C.R., Kuypers A., Larkin S et al : Arginine therapy : a novel strategy to induce nitric oxide production in sickle cell disease. Br J Haematol 2000; 111-498-500.