TREATMENT OF SICKLE CELL

DISEASE

Prepared by: Halah O.Hassan

Sickle cell disease: A type of structural haemoglobinopathy. Defined as inherited chronic hemolytic anemia

resulting

from point mutation affecting one base in the gene coding for amino acids of the globin chain. Substitution of thymine for adenine at position

6 of glutamic acid DNA codon resulting in substitution of valine for glutamate.

This structural changes lead to polymerization of HB, redudes deformability of RBC and sickling of the red cells.

CLINICAL FEATURES & MANAGEMENT: The typial course of sickle cell anemia is

characterized by the presense of chronic haemolysis & anemia (usually well tolerated anemia) interrupted by Crises.

Hb S has a low affinity to O2, so the oxygen is rapidly delivered to tissues,so symptoms of aemia are better tolerated with little or no tissue hypoxia

The clinical course, presentation and complications of patient with sickle cell disease will determine the type of treatment to be implicated.

TREATMENT:1- The usual clinical course of the disease

in which both extra & intravascular hemolysis present with anemia (well tolerated) can be treated with:-

A) a daily dose of 5 mg folic acid to over come folate loss due to continuous RBC break down.

B) Preventive measures :avoidance of conditions that may cause or increase RBC sickling & precipitate any crises which include:

*febrile illness (infections):require the use of proper antibiotic ,antipyretic to relief fever (salicylate to be avoided to decrease acid load), good hydration

*avoidance of cold exposure( cause vasoconstriction with subsequent hypoxia and sickling).

*avoidance of sudden transition to higher altitude (cause in O2 tention).

*prophylactic penicillin to prevent pneumococcal infection

*pnemococal vaccination especialy for splenectomized children with SCD.

2-Crises & their treatment:( 4 types of crises )

A) Vaso- oclusive crises:

The most common clinical manifestation, results from occlusion of micro vasculature by adherent normal & sickled RBCs ,WBCs ,platelets and inflammatory cytokines. Characterized by pain in chest, back, extremities and abdominal pain (can affect any organ).

Hand-Foot syndrome :painful dactylitis caused by infarction of small bones.Could be the first manifestation in children.

Acute chest syndrome:chest pain, dyspnea, tachypnea, fever and hypoxia

Leg ulcers:occlusion of small blood vessles in the legs will cause tissue ischemia with future ulcerations

Hepatobiliary:occlusion of hepatic sinosoids , further impairment of liver function & cholilithiasis

Treated with :

1) Adequate hydration .

2) Pain control is vital in the management , ( acetaminophen, NSAID, opioids-morphin 0.1-0.15 mg/kg, hydromorphon 0.015-0.02 mg/kg I.V )

3) Good oxygen supply.

4) Control of fever.

5) Specific treatment of the precipitating cause ( as infection).

6) Blood transfusion in severe acute crises.

7) For leg ulcers:bed rest, leg elevation, dressing, gentle debridment.

B) Aplastic crises :

Acute sever drop in Hb level due to sessation of red cell production from B.M. in the face of ongoig haemolysis.

Mostly caused by parvo virus B19 infection affecting erythroid progenitors. Although pancytopenia may occur.

Treatment :

Supportive care must be given including red cell transfusion until bone marrow output is restored to normal .

If pancytopenia is present platelet transfusion with protection against infection is needed.

C) Sequestration crises :

Sudden massive pooling of RBCs mainly in the spleen resulting in hypovolemic shock with circulatory collapse (mainly in children).

Patient present with rapidly enlarging spleen , pallor , abdominal pain, hypoxia and shock.

** It may occur in liver also.

Treatment : • Oxygenation• Red cell transfusion or exchange transfusion.• Splenectomy may be performed if high

frequency of this crises is present.

D) Hyperhaemolytic crises :

Episodes of accelerated haemolysis occur in patients with Hx of repeated blood transfusion that cause alloimmunization (decrease Hb level- reticulocytosis- hyperbilirubinemia- increase LDH).

Treatment: • Adequate hydration .• Oxygenation.• Blood transfusion.• High dose of folic acid (5mg / day)

NEW APPROACHES TO THERAPY:

a) Activation of Hb F SYNTHESIS:( Hydroxyurea)

a cytotoxic drug with no effect on DNA methylation , increase Hb F synthesis in patient with severe sickle cell anemia.• It is a myelosuppresive drug arrest the

development of mature erythroid precursors, resulting in recruitment of earlier erythroid progenitors with a greater capacity for Hb synthesis.

• It may have a direct effect on Reprograming of globin synthesis by early progenitors.

• It increase the intravascular & intaerythrocytic NO • its maximum dose is 25 mg/kg /day

OTHER THERAPUTIC INTERVENTIONS:

iron chelation therapy if repeated blood transfusion is needed.(deferiprone, deferoxamine)

Antiplatelet therapy to decrease platelet aggregation.

Intravenous immunoglobulin neutrophil antiselectin red cell antiselectin

The last two interventions are to dedrease aggregation & adhesion of RBCS & WBCS

b) Anti-sickling agents:

Poloxamer- nonionic copolymer emulsifying agent that counteract the tendency of sickled cell to adhere to endothelium by reducing yhe interaction red cells and fibrenogene

c) Reduction of red cell haemoglobin concentration:

Long-acting antidiuretic hormone desmopressin, salt restriction & water loading.all cause sufficient hyponatremia and osmotic swelling of RBCs to reduce the MCHC by 2-3 gm/dl

Complications: fluctuating Na level, poor compliance, neurological manefistations

d) Bone marrow(stem cell) transplantation: Provide a definitive cure of SCD but with higher

rate of morbidity & mortality A donor must be HLA- identical sibling to the

recipient Pre-transplantation conditioning regimin

includes: busulfan or cyclophosphamide with or without antithymocyte globulin.

Source of stem cells are:peripheral blood, bone marrow,

cord blood of a new born. The transplanted stem cells are administered

intravenously to the recipient to be engrafted in the hemopoietic tissue space.

e) Gene therapy: Provide a potential cure for sickle cell

disease but there are current concerns about random genomic insertion that must be resolved.

previously, gene transfer to stem cells has alimited progress

recently, the use of lentiviral vector derived from HIV genome allow more efficient transduction of human cells

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