SICKLE CELL ANAEMIA

PRESENTED BY

DR. OHIAERI’S UNIT

(TEAM A)

DR. EKE EGHOSASERE PAUL; DR IGBOELI ELOCHUKWU

Introduction

Pathogenesis

Presentation

Complications

Diagnosis

Differential diagnoses

Investigations

Management/Treatment

Conclusion

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INTRODUCTION Sickle cell disease (SCD) is a potentially devastating

condition that is caused by an autosomal recessive inherited haemoglobinopathy which results in the vaso-occlusive phenomena and haemolysis.

The severity of the complications that occur with this disorder are widely variable, but overall mortality is increased and life expectancy decreased when compared to the general population.

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Introduction… HbS is a haemoglobin tetramer (α2/βS2) that is poorly

soluble and polymerizes when deoxygenated.

It is seen worldwide but occurs most frequently in Africans, and less commonly in those of Mediterranean and Arab descent. It is also seen in the Middle East, Southern Europe, some parts of Eastern Europe and the Indian subcontinent.

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Introduction

1st described in 1910 by Herrick

SCA denotes the genotype having 2 abnormal Hb both of which are HbS (i.e. homozygous for HbS)

SCD denotes all genotypes containing at least one HbSand another abnormal Hb, in which HbS makes up at least 50% of the Hb present.

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Introduction… Inherited as an autosomal recessive (single gene)

disorder

HbS arises from a mutation substituting thymine for adenine in the 6th codon of the β-chain gene, GAG to GTG. This causes coding of valine (fat soluble) instead of glutamate (water soluble) in position 6 of the Hb β-chain

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Introduction… SCD usually manifests early in childhood usually soon

after 6 months of age when HbF levels start to fall

Epidemiology: In Nigeria, the frequency is 3% of the general population

In this centre the total number of patients registered in the SCA clinic b/w June 2011-January 2013 is 162 patients (age 1-14 yrs)

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PATHOGENESIS

Results from deoxygenation-dependent polymerization of HbS, with formation of spindle-shaped liquid crystalline bodies (tactoids), deforming the RBC , with increased mechanical fragility and haemolysis, predominantly at extra-vascular sites.

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Pathogenesis…

Affected RBCs can undergo repeated cycles of “sickling and unsickling’’ (when exposed to low & high O2 levels in the venous & arterial circulation, respectively)

Over time some lose the capacity to return to normal shape →Irreversibly Sickled Cells (ISC) seen in peripheral blood film

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Pathogenesis…

Factors that promote sickling:

Often no precipitating cause is found

Hypoxaemia

Decreased pH

Extremes of temperature (fever, cold)

Advanced cell age

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Pathogenesis… Increased intracellular HbS

Dehydration

Physical Exertion

Infection

Hyperleukocytosis

Low intracellular HbF

Low 2,3-DPG levels

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PRESENTATIONSCA has a diverse symptomatology

Any organ or system in the body can be affected

Most HbSS patient do not show any sign of disease in early infancy due to the predominant presence of HbF

When HbF levels begin to fall at about age 6mths most patients manifest signs of dx

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Presentation…6mo to 2yrs

Dactylitis. – due to ischaemic necrosis of the small bones, believed to be caused by a choking off of the blood supply as a result of the rapidly enlarging bone marrow.

Tender,warm,non-pitting swelling of dorsa of hands and feet.—Hand-foot syndrome.

Failure to thrive, anaemia, jaundice, infections, crises.

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Presentation after 2yrs

Failure to thrive

Anaemia, jaundice

Infections

Crises

Sickle cell habitus….long, thin limbs,protuberant abd, gnathopathy, peculiar facies.

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Presentation…

Crises – recurrent episodes of acute illness experienced by SCA patients

Steady State – the condition in which the SCA patient is free of all acute symptoms and is deemed well

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Presentation…

SCA Crises

Vaso-occlusive

Acute anaemic

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Presentation…Vaso-occlusive

Pain or thrombotic crisis

Commonest clinical manifestation

Caused by occlusion of blood vessels leading to ischaemic injury

Can affect any part of the body (but especially the long bones, abdomen, chest and back)

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Presentation…

About 50% of individuals with SCA experience VOC

Frequency of crisis is extremely variable. Some have up to 6+ episodes/yr. Others may have episodes only at great intervals or none at all. But each individual typically has a consistent pattern for crisis frequency.

Acute onset and may last several hours to days and terminate as abruptly as it began.

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Presentation…

Infancy – VOC manifests as hand and foot syndrome. May present with refusal to walk, irritability; fever; localized swelling, tenderness or warmth

May mimick acute osteomyelitis, septic arthritis; appendicitis, pancreatitis, cholecystitis, urinary tract infection, pelvic inflammatory disease

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Presentation…Acute Anaemic Crises

Hyperhaemolytic

Aplastic

Sequestration

Megaloblastic

Iron deficiency

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Presentation…Hyperhaemolysis – acute exacerbation of the

chronic haemolysis by infectious processes. Lab shows fall in haematocrit, Hb levels; and reticulocytosis

Aplastic – acute failure of erythropoiesis. May be due to Parvovirus infection; folatedeficiency or severe bone infarction. Lab shows fall in haemotocrit, Hb; and low or absent reticulocytes. Usually self-limiting –bone marrow recovers in 7-10 days

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Presentation…

Sequestration – sudden onset progressive anaemia, splenomegaly, and signs of peripheral shock due to trapping of significant portion of RBC mass in the spleen.

Megaloblastic changes – due to higher folate requirements from the chronic haemolytic state

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Presentation…

Iron deficiency – is uncommon bcosof increased dietary Fe absorption and frequent blood transfusions.

May occur as a result of infestations or poor dietary intake

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COMPLICATIONSCNS – most severe CNS complication is CVA

(stroke). Others include sensorineuralhearing loss, retinopathy and blindness.

They may also present with convulsions

Pulmonary – Acute Chest Syndrome (ACS).

Is a medical emergency

Characterized by chest pain, fever, cough, tachypnoea, prostration, leukocytosis, and pulmonary infiltrates in the upper lobes.

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Complications…

ACS is usually due to infection. Other causes: pulmonary infarction, fat embolism from bone marrow infarction

Also recurrent sickling episodes in pulmonary vasculature→formation of microthrombi→ infarction and damage to the alveoli. This can result in pulmonary hypertension

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Complications…CVS - The heart is affected by the chronic

anemia, and microinfarcts. Haemolysis and blood transfusion lead to hemosiderindeposition in the myocardium. Both ventricles and the left atrium are all dilated

Liver – 40-80% have hepatomegaly. Usually due to sinusoidal obstruction (& dilatation) by sickled RBC, and engorgement of Kupffercells ff. phagocytosis of effete RBCs.

Intrahepatic stasis can result in elevated conj. bilirubin.

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Complications…

Gallbladder – cholelithiasis; cholecystitis(Rt upper quadrant pain assoc. with fatty foods)

Uncommon in Nigeria due to low fat/high fibre diet

Acute cholecystitis may require surgery

Common bile duct blockage (Rt upper quadrant pain + elevated conj. hyperbilirubinaemia)

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Complications…Spleen

Splenomegaly in the 1st 2yrs of life due to extramedullary haemopoiesis, congestion and sequestration

Autosplenectomy by 10yrs of age (especially in temperate regions) as a result of repeated infarction causing splenic fibrosis and regression in size

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In Nigeria many SCD children above 10yrs have splenomegaly probably due to recurrent malaria infection. However there is a Functional Asplenia

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Complications…

Immune System

Impaired immunity & susceptibility to infections by encapsulated organisms e.g. H. influenzae, S. pneumoniae. Other organisms include Salmonella, N. meningitidis, Mycoplasma, S. aureus, E. coli and S. pyogenes.

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Underlying factors: Splenic hypofunction, defective opsonization and abnormal leukocyte phagocytic action. Recurrent vaso-occlusion with tissue necrosis, and elevated serum Fe levels may also be contributory

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Complications…

Renal:

Hyposthenuria: inability to concentrate urine. Presents as polyuria, nocturia and even enuresis

Haematuria: from papillary necrosis and sloughing.

Nephrotic syndrome has been reported

CKD is also a common cause of morbidity & mortality in older patients

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Complications…UGS:

Priapism: sustained, painful, and unwanted erection which may be spontaneous or follow sexual intercourse or masturbation.

Prolonged episodes may lead to impotence

“Stuttering episodes are managed with oral stilboestrol while major cases require sedation and appropriate analgesics

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Complications…

MSS:

Frontal bossing; gnathopathy (protrusion of upper teeth; malocclusion)

Hand/Foot Syndrome (Dactylitis)

Avascular necrosis of femoral/humeral head

Osteomyelitis (frequently Salmonella)

Leg ulceration (usually affects the malleolar areas)

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Complications…Endocrine:

Delayed physical and sexual development

Due to chronic anaemia and low endocrine production

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DIAGNOSISClinical - 80% of cases.

Screening Tests – indicate presence of HbSbut do not define the Hb genotype e.g. Solubility test

4 drops of blood + 2ml of freshly prepared Na dithionite + K2P04 in a test tube.

Read against a bright light

Clear soln…..HbA, CC, DD

Ppt above, clear soln beneath…….HbSS

Ppt above, pink soln beneath……HbAS

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Hb Electrophoresis – most common for definitive diagnosis. Based on differential protein mobility in an electrical field. Uses cellulose acetate or citrate agar buffers

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Isoelectric Focusing – also a form of electrophoresis. Superior to the above. Method of choice for newborn screening

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Diagnosis…Prenatal Diagnosis – usually in the first

trimester of pregnancy. Samples are taken from amniotic cells or chorionic villus and DNA analysis done by PCR and DNA sequencing.

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LABORATORY FINDINGS

Full Blood Count

Increased retic count of 5-15%

WBC 12-20,000

Normal MCV

Hb 5-9g/dl

Normal or slightly increase platelet count.

Normal differential or preponderance of neutrophils

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Lab Findings…

Nucleated RBC indicates severe anaemia

Target cells, poikilocytosis, anisocytosis, hypochromic cells, sickled RBC

Howell-Jolly bodies

Markedly hyperplastic bone marrow with erythroid predominance.

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DIFFERENTIAL DIAGNOSIS 1. Leukaemia

2. Rheumatic fever

3. Juvenile rheumatoid arthritis

4. Osteomyelitis

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MANAGEMENTEarly Diagnosis & good follow up

Determine and record physical, haematological parameters

Avoid factors that encourage sickling

Folic acid supplementation

Malaria prophylaxis (routine proguanil)/prevention of other infections (oral pen V NB-2yrs)

Immunization: pneumococcal; Hib (@2yrs)

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Health Education & Counselling

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Management of Acute Illnesses & ComplicationsObjectives of Mgt

To relieve pain promptly

To treat precipitating cause e.g. infection, dehydration

To prevent or delay recurrence

To correct fluid and electrolyte imbalance

To relieve anxiety

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Management of VOC

Mild to moderate:

Bed rest at home.

Liberal oral fluids.

Analgesics.

Identify and treat cause.

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Admit

Administer analgesics commensurate with degree of pain.

I.V. fluids are usually given at 1.5x maintenance

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Management of Hyperhaemolytic crisis

Admit

Give O2

Transfuse in presence of:

1. Anaemic heart failure.

2. PCV below 15%.

3. Significant fall in pcv below steady state value.

4. Overwhelming infection.

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Acute Sequestration Crisis

Treat shock; elevate foot of bed, give parenteral steroids (methylpred or hydroc.)

Packed cell transfusion, 5-10 ml/kg.

N.B. Some sequestered cells will return to the circulation.

Partial E.B.T.

Splenectomy

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Aplastic Crisis

Intermittent oxygen.

Whole blood transfusions

Steroid therapy.

?Bone marrow transplantation.

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Management of Infections

Common organisms…….H. infl., pneumococcus, salmonella spp., S. aureus.

Choice of antibiotics:

Chloramphenicol + Erythromycin

Xtalline pen + Chloramphenicol

Chloramphenicol + Cloxacillin

Cephalosporins

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Priapism

Sedatives/anxiolytics.

Analgesics.

Intracavernous injection of adrenergic agonists…e.g. Etilefrine.

E.B.T

Surgery, if ICI fails: caverno-spongiosumanastomosis.

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Haematuria

Usually stops spontaneously

Conservative treatment:

Liberal fluids, to reduce clot formation

Correct anaemia

Epsilon amino caproic acid, an antifibrinolytic agent, is useful in mgt

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Other Approaches Induction of HbF synthesis

Hydroxyurea - 15mg/kg/24 hrs. MOA – increases HbFlevels, decreases expression of adhesive molecules on RBCs and so prevents VOC. Gradually increase to max of 30mg/kg/24hrs. Monitor FBC, LFT and HbF. Increase in HbF is usually 10-15%

Recombinant human erythropoietin (rhEPO)

Resveratrol, a natural dietary polyphenol

Butyric acid

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Bone Marrow Transplantation

Has curative potential

Problems:

1. GVHD

2. Acute effects of total body irradiation

2. Lack of suitable stem cell donors.

3. Limited access to normal HLA identical

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Stem cell

Originally, stem cells were procured from the bone marrow by direct puncture and aspiration of bone marrow and re-infused intravenously

An improvement on bone marrow transplantation

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CONCLUSION

SCA is a debilitating genetic disease but symptoms can be alleviated with early diagnosis, and with general improvement of health status through health education, regular medical follow up and which can be prevented with pre-marital counselling.

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THANK YOU

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