sickle cell disease Flashcards
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
