Sickle cell anemia Dr. Kalpana Malla MD Pediatrics Manipal Teaching HospitalDownload more documents and slide shows on The Medical Post [ www.themedicalpost.net ]
Introduction:• Abnormal haemoglobin (HbS) which has a propensity for sickling and rapid haemolysis under adverse conditions• Valine, a hydrophobic amino acid replaces glutamic, a hydrophilic amino acid at the sixth amino acid position in the beta polypeptide chain.
EPIDEMIOLOGY• Endemic malarial areas• Central India, Sub-Saharan Africa, Mediterranean, North Africa, Middle East• South America, Carribean, US: African descent…slave trade• Incidence 1:625 in African Americans
The Proteins of Hemoglobin A• There are 4 protein subunits of Hemoglobin A Hemoglobin A Alpha Alpha Beta Beta There will be different forms of Hemoglobin when there is a mutation in the beta subunit.
A carrier for Sickle Cell Will have…•An S mutationin one copy of Hemoglobinthe hemoglobinbeta gene.•Half of the beta Alpha Alpha Beta Beta Ssubunits arereplaced withBeta S.•This person hasthe Sickle Celltrait.
When a person is a carrier, they will have: 25 % normal HbA 50 % HbS 25 % HbSS
Sickle Cell Disease:•This results HbSSwhen bothcopies of the Hemoglobinhemoglobin betagene have an Smutation. Alpha Alpha Beta S Beta S•All of thisperson’s betasubunits arereplaced by betaS.
1. It is Unknown why people with the Sickle Cell Trait are RELATION TO MALARIA resistant to Malaria, but there are several theories…2. The carriers of Sickle Cell have some abnormal Hemoglobin, and when they come in contact with the Malaria parasite they become sickled. Then those cells go through the spleen, which eliminates the cells because of their sickle shape, so the Malaria would be eliminated as well.3. The Sickle Cell trait causes the malaria to stay in the body for an extended period of time, so it is able to build up a defense to it.
3. Because oxygen concentration is low in the spleen, and because infected cells often get trapped in the spleen, it is possible that they are destroyed in the spleen• 4. The Malaria parasite produces an acid when it is inside of the red blood cells. This causes the red blood cells to polymerize, and the cells will sickle. These sickled cells are then destroyed when the blood cells go through the spleen.
RELATION TO MALARIASickle cell “trait” (heterozygote Hb AS) have:• 1. lower levels of Pl. falciparum parasitemia• 2. higher hemoglobin counts• 3. less severe reinfections than normal pplWhy?• 1. confounding factors in these areas that confer immunity/ resistance: Duffy chemokine factor G6PD HLA-B53, HLA-DRB1• 2. actual mechanism not known
TYPES• Hb SS (Homozygous S)- Sickle Cell Anemia• Hb AS (Heterozygous S) - Sickle Cell Trait• Sickle β0 Thalassemia (functions exactly like Sickle Cell Anemia)• Sickle β+ Thalassemia• Hb SC ( mutation for Hb C occurs same site as HbS. Instead of valine, lysine is exchanged for glutamine)
SEVERITY OF DISEASE Hb SS ≥ Sickle β 0 Thal >>Hb SC >> Sickle β + Thal>> HbAS
PATHOPHYSIOLOGY • Single base pair exchange • Thymine for adenine in 6th codon of β gene • Encodes Valine instead of Glutamine • Charge at that site altered • Allows polymerization of Hb under hypoxia and acidosis • Inc 2,3-DPG and dec pH increases O2 affinity -> hypoxia
PATHOPHYSIOLOGY (CONTD…)• Amount of polymerisation is dependant upon the other Hb (extent of homology with HbS)• Copolymerization in this desc.order (S, C, D, O...so on and so forth)• Polymerization -> RBC membrane alters-> sickling -> incr.adhesiveness -> capillaries blocked -> local anoxia -> infarction of organs• Infarction of liver, kidney, spleen, brain, bones, joints• Thrombotic coagulopathy• If resp infections -> hypoxia worsens -> more sickling• Sickle cells seq in spleen. So splenomegaly• Paradoxically spleen undergoes rptd infarction -> autosplenectomy• Long standing hemolysis -> biliary pigment stones• Long standidng hypoxia -> clubbing, leg ulcers, growth retardation• Long standing anemia -> compensatory hyperactivity of BM
CLINICAL FEATURES• Newborns: do not manifest as there is high HbF• By 5-6mo: many have functional asplenia. Hence bacterial sepsis• By 5yr: 95 % functional asplenia• Universally anemia and jaundice• Thereafter CRISES EPISODES
HAND FOOT SYNDROME• Acute sickle dactylitis• Painful, symmetric swelling of hand and feet• Ischemic necrosis of small bones• Blood supply choked off due to rapidly expanding bone marrow• Xray: extensive bone destr. and repair
ACUTE PAINFUL CRISIS• Young children: mostly extremities• Older patients: abdomen, back, chest• Assoc with intercurrent illness• Vaso occlusive event• Abdominal organ infarctions
ACUTE CHEST SYNDROME• Pulmonary infarction• Associated with pneumonia or microscopic fat emboli from BM infarction• Acute chest pain• Hemopytsis• Cyanosis• May lead to death
ACUTE SPLENIC SEQUESTRATION• In infants and young children (6mo-3yrs)• Distinct and episodic event• Foll acute febrile illness• For unknown reasons large amounts of blood become acutely pooled in spleen• Massive enlargement of spleen• Circulatory collapse
STROKE• Catastrophic event• >5yrs• Hemiplegia• 10% of patients affected• 25-30% have occult strokes- school performance affected• Trancranial doppler studies
OTHER MANIFESTATIONSRENAL Progressive deterioration Glomerular and tubular fibrosis Polyuria >5yrs Renal papillary necrosis -> hematuria Nephrotic syndromePRIAPISM Pooling of blood into corpora cavernosa obstructing venous bloodflow
COMPLICATIONS• Bacterial sepsis – H. influenzae, pneumococci• Parvovirus B19 infection -> aplastic episodes• Acute chest syndrome –> pulmonary infarction• Chronic splenic sequestration• Severe anemia• Stroke -> hemiplegia• Priapism -> impotence• Chronic renal failure• Skin ulcers• Gall stones• Avascular necrosis -> hip pain• Retinopathy and Hyphema (more in HbSC d/s)• Salmonella osteomyelitis• UTI• Growth retardation , delay in puberty• Assoc Zn deficiency• Sickle cell cardiomyopathy
INVESTIGATIONS• Mild to moderate anemia (5-9gm/dl)• Inc. retics• Inc. TLC with sometimes Inc neutrophils• Normal to inc. platelets• Normal MCV (unless thalassemic Hb)• PS: sickle cells, nucl RBCS, target cells, HJ bodies• BM: hyperplastic marrow with erythroid predominance• Xray:Osteoporosis, sclerosis of long bones• Renal conc capacity decreased• Hb electrophoresis• Genetic / mutational analysis• Prenatal diagnosis• Transcranial doppler (TCD). If blood velocity >200cm/sec in brain, then transfuse to keep Hb S <30%
SICKLE THALASSEMIA• Presentation is same as Hb SS (SCA) if Sickle β0 Thalassemia• If Sickle β+ Thalassemia, then C/F are blunted• Doubt if Hb electrophoresis shows HbSS• But MCV <78fl or microcytosis in PS
SICKLE CELL TRAIT• Assoc with α thalassemia• Life span normal• Complications rare• Sudden death due to rigorous exercise• Splenic infarcts at high altitude• Hematuria• Hyphema with IO bleed and blindness• Renal medullary Ca predisposition
MANAGEMENT OF SCD• General• Prophylaxis• Febrile episodes• Analgesia• Blood transfusion• Drugs• Bone marrow transplant• Surgeries – splenectomy, cholecystectomy
GENERAL MANAGEMENT• Vaccines• Penicillin V prophylaxis• Caretakers taught : temp, assess illness, spleen, anemia, stroke…and bring to hosp urgently• Folic acid supplementation due to high red cell turnover
MANAGEMENT OF FEBRILE EPISODES• Hospitalise. Not OPD management <3yrs• Look for occult bacteremia• CBC, Blood culture, Urine culture, CXR• Monitor for Acute splenic sequestration crisis• Empirical Ceftriaxone (75-100mg/kg)
MANAGEMENT OF PAIN• Paracetamol intially• Later if relenteless pain : limited opiates – codeine• Wean off opiates in 3-4days• Avoid masking of disease progression with opiates• >7-10 yr PCA (patient controlled analgesia) pump• Look for cause of pain
BLOOD TRANSFUSION• Indications: acute chest syndrome stroke severe anemia acute splenic sequestration• BT doesn’t reverse ischemic damage• Can continue to have CVD and AVN• Preferably give leuco-poor packed cell
DRUG THERAPY Hydroxyurea : 15-30 mg/kg/day Increases Hb F BONE MARROW TRANSPLANT <16 yr with HLA matched sibling Only cure
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