sickle cell disease Flashcards
(22 cards)
what happens in sickle cell disease?
Missense mutation at codon 6 of the gene for
b globin chain
Glutamic acid replaced by Valine
GLU= polar, soluble
VALINE = nonpolar and insoluble
Deoxyhaemoglobin S is insoluble
HbS polymerises to form fibres - “tactoids”
Intertetrameric contacts stabilise structure
what are the stages in sickling of RBCs?
RIGID, ADHERENT, DEHYDRATED
Distortion
- Polymerisation initially reversible with formation of oxyHbS - Subsequently irreversible
Dehydration
Increased adherence to vascular endothelium
Sickle cell disease =
sickle cell anaemia and also incorporates all the other conditions that lead to a disease syndrome due to sickling of RBCs.
what are the characteristics of sickle cell anaemia and compound heterozygous states eg SC, Sb thalassaemia
Genetically simple – Autosomal recessive
Clinically heterogeneous
pathogenesis:
shortened red cell lifespan leads to?
leads to haemolysis
o Anaemia – partly due to reduced erythropoietin drive as HbS is a low affinity Hb.
o Gallstones – co-inheritance of Gilbert syndrome further increases risk.
o Aplastic crisis – Parvovirus B19
pathogenesis:
blockage to microvascular circulation leads to?
Infarction.
§ Spleen – hyposplenism (leads to infection).
§ Bones/joints – dactylitis (inflammation of bone), avascular necrosis and osteomyelitis (infection of bone).
§ Skin – ulcerations.
Pain and dysfunction.
what are the different pathogenesis that could occur due to SC/where?
shortened red cell lifespan blockage to microvascular circulation lungs urinary tract brain eyes
pathogenesis:
lungs
o Acute: Acute chest syndrome.
o Chronic: Pulmonary hypertension.
§ Correlates with severity of haemolysis.
§ Free plasma haemoglobin from haemolysis scavenges NO and causes vasoconstriction.
pathogenesis:
effect on the urinary tract
o Haematuria – due to papillary necrosis.
o Renal failure and Hyposthenuria – impaired concentration of urine.
o Priapism.
pathogenesis:
effect on the brain
Stroke and cognitive impairment – affects 8% of SS, most common 2-9yrs.
pathogenesis:
effect on the eyes
Proliferative retinopathy.
what are the clinical presentation for SCD
§ Symptoms are rare before 3-6 months (as the switch to adult HbA synthesis hasn’t occurred yet). § Early manifestations are: o Dactylitis – most common in children. o Splenic sequestration. o Infection (pneumococcal normally)
Painful crises can also be triggered by – infection, exertion, dehydration, hypoxia and psychological stress.
Management
generally :
o Folic acid – anaemia.
o Penicillin – splenic dysfunction.
o Vaccination – splenic dysfunction.
o Monitor spleen size – splenic dysfunction.
§ Acute splenic sequestration can mean you get an enlarged spleen and often requires prophylactic therapy (against pneumococcal infection), transfusions to correct anaemia and maybe splenectomy.
o Blood transfusion for acute anaemic events, chest syndrome and stroke.
o Pregnancy care.
how would you deal with a painful crisis?
Painful crises – must exclude infection as cause with blood/urine cultures and chest x-ray. o Pain relief – opioids. o Hydration. o Keep warm. o Oxygen if hypoxic.
other management options
exchange transfusion (stroke and acute chest syndrome) haematopoietic stem cell transplantation- from sibling HLA or other haplo-identical donors -induction of HbF
what is the laboratory features of SCD?
§ Hb is low – 6-8g/dL. § Reticulocytes (immature RBCs) high – except in aplastic crisis. § Film (shown on left bottom): o Sickled cells. o Boat cells. o Target cells. o Howell-Jolly bodies.
how can you diagnose SCD?
solubility test
solubility test
§ In presence of reducing agent, oxyHb is converted to deoxyHb.
§ Solubility decreases and solution becomes turbid.
§ Doesn’t differentiate AS from SS though – so only checks to see if you have one or more sickle traits.
how would you diagnose SCD?
electrophoresis
§ Separates proteins according to charge.
§ You can see homozygous sickle patients have NO HbA and only HbS and a little HbA2.
§ Heterozygous sickle patients have both HbS and HbA
what are the features of sickle cell trait- HbAS
§ Normal life expectancy.
§ Normal blood count.
§ Asymptomatic usually – rarely painless haematuria.
§ Caution taken with – anaesthetic, high altitude and extreme exertion.
what can a painful crisis be triggered by?
infection exertion dehydration hypoxia psychological stress
how is the pain managed?
Opioids
- Marked individual variation in response
- Diamorphine most widely used
- Most children receive oral opioid
Individual analgesia protocols
Patient controlled analgesia
Adjuvants – paracetamol, NSAIDs, Pregabalin/Gabapentin
how can hydroxyurea be used for the treatment of SCD?
Increases production of baby (fetal) haemoglobin (HbF)
Decreases ‘stickiness’ of sickle red blood cells
Reduces white blood cell production by the bone marrow
Improves hydration of red blood cells
Generates nitric oxide which improves blood flow
