Sickle cell anemia -SB

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					Sickle cell disease
• Hereditary hemoglobinopathy • Defective hemoglobin formation • Point mutation at 6th position of the B-globin chain ; glutamic acid Valine • HbS • Autosomal recessive inheritance • Provides protection against falciparum malaria

Sickle cell anemia (SCA)
• An autosomal recessive disease •HBB gene •Short arm (p) of chromosome 11 •Caused by a point mutation (SNP) in the hemoglobin beta gene (HBB)

Normal
DNA RNA Amino acid

G A

G

Glutamic acid

SCA

G

U

G

Valine

Hemoglobinopathy Genetics
• Homozygous: • Inheritance of two HbSgenes from each parent • Sickle cell disease • Heterozygous: Inheritance of one HbA and one HbS gene • Sickle cell trait • 40% HbS • Gene occurs in 8% of AfricanAmericans • One HbS and one HbC gene • HbSC

Sickle cell disease

Pathogenesis: • When de-oxygenated HbS → aggregation and polymerization • Initially reversible • With continued deoxygenation → sickle or hollyleaf shape; sticky

HbA

HbS

   

A
+O2 O2

S
+O2 - O2

+O2 - O2

+O2 - O2

Effects of Sickle cell anemia
• Chronic Hemolysis: Intravascular Extravascular • Microvascular occlusion

Microvascular occlusion - causes
•  Adhesiveness of sickled cells • Inflammation - upregulation of adhesion molecules • induction  endothelial ahdeshion moelcules • Arrest of cells, low oxygen tension – more sickling • Inactivation of NO by plasma hemoglobin

Factors affecting degree & rate of sickling

Amount of HbS and its interaction with other Hbs:
• • • • • • • Heterozygotes 40% HbS, 60% HbA HbA – prevents aggregation and polymerization Homozygous state - full blown sickle cell anemia Hemoglobins  HbS polymerization and sickling: HbF , HbA Hb  HbS polymerization and sickling: HbC

Concentration of Hb in cell:
•  MCHC (dehydration) -  sickling •  MCHC (Sickle cell /thalassemia) -  sickling ↓ pH -  oxygen affinity of Hb • Deoxygenation and  sickling

Duration of exposure to ↓ O2:

 Sickling

in sluggish microcirculation – spleen and bone marrow, slowing of flow in inflammation

Microvascular occlusion Infarcts – bone, lung, kidney,spleen

Irreversibly sickled cells

Spleen: Hemolysis, congestion, Infarction

Reversibly sickled

Membrane damage

 Adhesiveness

Sickle cell disease :CF
• • • • • • • Asymptomatic upto 3 months Hb F is protective As Hb S increases , symptoms manifest: Severe Anemia (Hematocrit –18-30%) Vaso-occlusive complications Jaundice Prone to infections : Impairment of splenic Pneumococci and H.infuenza function due to infarcts (pneumonia, meningitis), and autosplenectomy • Salmonella (osteomyelitis) Defects in complements

Sickle cell disease :”Crises” Vaso-occlusive crises (pain crises)hypoxic injury and infarction: • Painful bones- (DD from to osteomyelitis) • Hand-foot syndrome – dactylitis of bones of hands and feet Lung- acute chest syndrome: fever, cough, chest pain Brain –seizures or strokes Leg ulcers Kidney - ↓ con. Of urine → dehydration (hyposthenuria) Intra-retinal hemorrhages

Sickle cell disease :CF
• Sequestration crises: • Rapid splenic enlargement, hypovolemia, shock
• Aplastic crises – transient cessation of BM erythropoiesis due to parvovirus B19 infetion of Red cell progenitors.

Sickle cell disease : Lab findings

• ↓ Hb, ↓PCV • WBC, PLT – N to ↑ • • • • PS : sickle cells, polychromatophils, NRBC

• Reticulocyte count – 520%

• Sickling test : Sodium metabisulfite • Sodium metabisulfite • added to blood • Reduces oxygen tension sickling • Viewed microscopically

Hb Electrophoresis

A2/C Normal

S

F

A

Hb Electrophoresis

A2/C Normal

S

F

A

Hb SS

Hb Electrophoresis

- A2/C S

F

A

Normal
Hb SS

Hb Electrophoresis
- A2/C S F A

Normal
Hb SS Hb SC

Hb Electrophoresis
- A2/C Normal Hb SS S F A+

Hb AS
Hb SC Hb CC

• • • • • • •

Unconjugated hyperbilirubinemia S.haptoglobin ↓ ESR is low  urobilinogen and stercobilinogen ESR is low  serum iron ↓ osmotic fragility

•

Autosplenectomy :
• Early phases –spleen is mod enlarged upto 500gms (trapping of sickled cells) • Hypoxia, thrombosis, infarction, fibrosis • Progressive shrinkage of spleen • By adolescence reduced to small nubbin of fibrous tissue

Sickle cell disease : treatment
• Patient education • Prevention of infections –penicillin prophylaxis and pneumococcal vaccination • Hydroxyurea – ↑ HbF Anti-inflammation -  leukocytes  MCH oxidised by heme groups to NO • Folic acid supplements

• Transfusions – severe anemia, elective surgery
• Bone marrow transplantation


				
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posted:9/29/2008
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