Sickle cell disease. Fareed Omar 10 March 2018

Transcription

1 Sickle cell disease Fareed Omar 10 March 2018

2 Physiology

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4 Haemoglobin structure HbA2: 2α and 2δ chains (2-3%) HbF: 2α and 2γ chains (<1%) HbA: 2α and 2β chains (97%)

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7 Polymerization

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9 Sickle cell disease Inherited Autosomal recessive genetic disease Two copies of an abnormal gene must be present in order for the disease or trait to develop. If only one copy is present the patient is said to be a carrier or has sickle cell trait If both parents are carriers, the child may inherit both copies of the mutated genes from each parent and is said to be homozygous About 70 million people worldwide affected > infants are born with the disease worldwide

10 Distribution High Risk Medium Risk Low Risk Very Low Risk No Risk

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12 Diagnosis Hb-Electrophoresis Sickling test: high-performance liquid chromatography (HPLC) This test identifies which type of hemoglobin is present Usually sufficient to confirm diagnosis of both disease & trait Genetic test can be done to confirm Prenatal testing

13 Precipitating factors Oxygen (hypoxia) high altitude Osmolarity (dehydration) Temperature (vasoconstriction) ph Anxiety Exercise Trauma / surgery Folate deficiency Polymerization

14 Systemic Manifestations

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16 Bone Ischaemia / Infarction of the bone / bone marrow Severe pain Osteopenia Osteomyelitis Avascular necrosis Fat embolism -> Pulmonary embolism Acute aplastic crisis

17 Brain TIA, CVA -> strokes (2-11yrs) (10% before age 20) Cognitive impairment and learning difficulties Undetected microemboli (silent infarcts) Epilepsy: 10 fold increased risk Transcranial Doppler ultrasound

18 Transcranial Doppler (TCD) Annually Non invasive, non ionising, inexpensive, portable and safe technique that uses a pulsed Doppler transducer for assessment of intracerebral blood flow Velocity flow in the distal Internal Carotid Artery (dica) and the proximal Middle Cerebral Artery (MCA) Velocities of > 200 cm/sec increased risk of stroke Once identified, confirmed and treated with transfusion therapy, children with intracranial stenosis showed >90% reduction in stroke risk if haemoglobin S was less than 30%.

19 Lungs Acute chest syndrome (ACS) Fever, cough, chest pain, dyspnoea, wheeze Pulm infiltrates (CXR) Vaso-occlusion, fat embolism, pulmonary thromboembolism, infection Resp failure, CNS hypoxia, seizures Pulm oedema, multi-organ failure Bed rest, analgesia, hydration, Oxygen, ventilation, IV antibiotics, transfusion, Bronchodilators

20 Spleen Chronic infarcts over many years functional asplenia Higher risk for infection encapsulated organisms Acute crisis: massive splenic infarct splenic sequestration crisis rupture very high mortality Early urgent blood transfusion Splenectomy (after 4-6 years age)

21 Systemic manifestations Heart PHT, LV dysfunction, MI Kidneys Renal papillary necrosis, chronic renal insufficiency, Haematuria, Proteinuria GIT Ischaemia severe pain (Abdominal crisis) Skin ischaemia / infarcts pain and ulceration Priapism Liver fairly resilient relatively spared PAIN!! most painful disorder Don t underestimate pain

22 Management CURATIVE Genetic mutation in erythroid precursor cell erythropeoitic stem cell HSCT: removes the affected erythropeoitic stem cell and replaces it with normal donor stem cells Donor (sibling) who does not have sickle cell disease Risky mortality 7-20% from procedure Infections and GVHD In our setting often not practical and suitable donors not available Worldwide <18% have suitable donors

23 Management CHRONIC MANAGEMENT (AIMS) Preventing Veno-occlusive crisis (VOC) Treat crisis when it occurs Prevent infection (no.1 cause of mortality) Treat anaemia Manage complications (stroke, pulmonary HT)

24 Preventing VOC 1. Hydroxyurea (antisickling agent) Causes a shift in gene expression at the beta globin locus, such that expression from the gamma globin locus is increased relative to that from the beta globin locus Stimulates production of HbF Replaces some HbS with HbF Polymerization and therefore sickling Affects BM cells & can cause BM suppression - risk of infection (dose dependent)

25 N Engl J Med 1990: 322:

26 Am J Hematol. 2017;92:

27 Preventing VOC 2. Chronic transfusions the concentration of HbS For patients that are at increased risk for strokes Abnormal transcranial Doppler Previous strokes 8 10 transfusions / year Iron overload

28 Preventing VOC Avoid and manage conditions that may lead to acidosis Prevent dehydration or treat aggressively Avoid excessive cold Avoid or treat infections quickly and aggressively Vaccine boosters: encapsulated organisms Annual influenza vaccine Prophylactic Pen VK Folic acid (due to continuous haemolysis in these patients)

29 Treat crisis when they occur Goal: aggressive management Vigorous IV fluid management to prevent RBC from dehydration - Polymerization and to prevent acidosis Oxygen therapy to decrease the amount of deoxy Hb If infection suspected treat early Very aggressive pain management (within 30 min) Opioids Transfuse RCC if indicated

30 N Engl J Med 2017;376:848-55

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32 Summary Hydroxyurea Pen prophylaxis Folic acid Vaccinations Treat crisis aggressively

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34 Thank You