haemoglobin 3: sickle cell anaemia Flashcards
what genetic mutation causes sickle cell anaemia?
missense mutation at codon 6 of gene for B globin chain
what changes in the primary structure happen as a result of the mutation?
valine replaces glutamic acid (glu = polar & soluble, valine = non-polar & insoluble)
why are the cells sickle shaped?
HbS polymerises and forms fibres called tactoids -> intertetrameric contacts stabilise structure
what are some properties of sickle cells?
rigid, increased adherence to vascular endothelium, dehydrated
what is the epidemiology of SCD in the UK?
12-15k, most common monogenic disorder
what is the difference between sickle cell anaemia and sickle cell disease?
anaemia = SS homozygous genetic condition SCD = all conditions that lead to cell becoming sickled eg SC, SB-thalassaemia
how does the lifespan of a sickle cell differ from that of a normal cell?
very short (10-20 days)
what happens as a result of the changed lifespan of a sickle cell?
haemolysis causes: anaemia, gall stones, aplastic crisis (parvovirus B19 arrests development of red cells in bone marrow)
why does sickle cell result in anaemia?
increased haemolysis & lower affinity of HS for haemoglobin -> reduced erythropoietic drive
what happens as a result of the changed shape of a sickle cell?
vaso-occlusion -> tissue damage & necrosis (infarction), pain, dysfunction
what are the consequences of tissue infarction?
hyposplenism, dactylitis, avascular necrosis, osteomyelitis, chronic/reccurent leg ulcers
how does sickle cell cause pulmonary hypertension?
release of haemoglobin from haemolysis scavenges NO from endothelium -> causes vasoconstriction -> pulmonary hypertension
what is the overall pathogenesis of sickle cell anaemia?
lungs: acute chest syndrome, chronic lung damage, pulmonary hypertension
urinary tract: haematuria, hyposthenuria, renal failure, priapism
brain: stroke, cognitive impairment
eyes: proliferative retinopathy
what are the early presentations of sickle cell disorders?
dactylitis, splenic sequestration (increased size of spleen -> pooling of blood, anaemia), infection (s pneumoniae)
when do symptoms start to appear?
after 6 months (rare before 3-6 months) - onset coincides with switch from foetal to adult Hb synthesis
what are some examples of sickle emergencies?
septic shock (BP <90/60), neurological symptoms, SpO2 <92% (on air), acute anaemic event (with Hb <5 / fall >3mg/dl from baseline), priapism >4hr
what is a common cause of joint pain in SCD?
osteomyelitis caused by salmonella
stroke:
common in children 2-9, often arises from middle cerebral artery & intracranial internal carotid artery
gallstones:
by 25, 50% of SS patients have gallstones, coinheritance of gilbert syndrome increases risk 3-5x
what are the laboratory features of SCD?
low Hb (6-8g/dl)
increased reticulocytes
film: sickled cells, boat cells, target cells, howell-jolly bodies
how does a solubility test work?
in presence of reducing agent oxyHb -> deoxy Hb -> solubility decreases -> solution becomes turbid HOWEVER does not differentiate AS from SS
how can a definitive SS diagnosis be made?
electrophoresis & high performance liquid chromatography (HPLC) separates proteins by charge
what general measures can be taken to manage SCD?
folic acid, prophylactic penicillin, vaccination (against capsulated bacteria), spleen size monitoring, blood transfusion for acute events, pregnancy care
how can crises be managed?
pain relief (opioids), hydration, warmth, oxygen if hypoxic, exclude infection
how can pain be managed?
opioids (marked individual variation in response, diamorphine most widely used), patient controlled analgesia, adjuvants (paracetamol, NSAIDs, pregabalin/gabapentin)
what are the current disease-modifying therapies for SCD?
exchange transfusion, haemopoietic stem cell transplantation (<16yo with severe disease, survival 90-95%, cure 85-90%), induction of HbF (hydroxyurea, butyrate)
how can hydroxyurea be used to treat SCD?
increases production of HbF (which inhibits polymerisation of HbS), decreases stickiness of sickle cells, reduces WBC production by bone marrow, improves hydration of red cells, generates nitric oxide which improves blood flow
what are the indications for HSCT?
CNS disease, reccurent severe VOC, recurrent ACS
what are the limitations of HSCT?
donor availability (18%have unaffected sibling donor), length of treatment (2 months as inpatient, 4 months outpatient), transplant related mortality, long term effects (infertility, pubertal failure, chronic GvHD, organ toxicity, secondary malignancies)
overview of sickle trait:
HbAS, normal life expectancy, normal blood count, usually asymptomatic, rarely painless haematuria BUT caution: anaesthetic, high altitude, extreme exertion