Sickle cell anemia

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Dr. Kalpana MallaMD Pediatrics

Manipal Teaching Hospital

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.

Genetics of Sickle Cell

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

There will be different forms of Hemoglobin when there is a mutation in the beta subunit.

Hemoglobin A

Alpha Alpha Beta Beta

A carrier for Sickle Cell Will have…

•An S mutation in one copy of the hemoglobin beta gene. •Half of the beta subunits are replaced with Beta S. •This person has the Sickle Cell trait.

Hemoglobin

Alpha Alpha Beta Beta S

When a person is a carrier, they will have:

25 % normal HbA 50 % HbS

25 % HbSS

alpha

betabeta

alpha alpha alpha

Beta S beta

alpha alpha

Beta S

Beta S

Sickle Cell Disease: HbSS

•This results when both copies of the hemoglobin beta gene have an S mutation. •All of this person’s beta subunits are replaced by beta S.

Hemoglobin

Alpha Alpha Beta S Beta S

RELATION TO MALARIA1. It is Unknown why people with the Sickle Cell Trait are 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 factorG6PDHLA-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 β0 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

CRISES EPISODES

• 1. HAND FOOT SYNDROME• 2. ACUTE PAINFUL CRISIS• 3. ACUTE CHEST SYNDROME• 4. ACUTE SPLENIC SEQUESTRATION• 5. STROKE

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

INFARCTS

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 MANIFESTATIONSRENALProgressive deteriorationGlomerular and tubular fibrosisPolyuria >5yrsRenal papillary necrosis -> hematuriaNephrotic syndrome

PRIAPISMPooling 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

BONE NECROSIS

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%

PAPPENHEIMER BODIES

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 strokesevere anemiaacute splenic sequestration

• BT doesn’t reverse ischemic damage• Can continue to have CVD and AVN• Preferably give leuco-poor packed cell

transfusion

DRUG THERAPYHydroxyurea : 15-30 mg/kg/dayIncreases Hb F

BONE MARROW TRANSPLANT

<16 yr with HLA matched siblingOnly cure

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