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Haematology > sickle cell disease > Flashcards

sickle cell disease Flashcards

1
Q

what is the mutation that causes sickle cell disease *

A

a missensee mutation at codon 6 for the gene for the B globin chain

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2
Q

what is the effect of the mutation of sickle cell *

A

glutamic acid is replaced by valine

glutamic acid is polar = soluble

valine non-polar = insoluble

therefore deoxyhaemoglobin S is insoluble

HbS polymerises to form fibres - ‘tactoids’

intertetramic contacts stabalise the structure

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3
Q

what are the stages of sickling of red cells *

A

distortion: - reversible polymerisation initially with formation of oxyHbS, then irreversible

dehydration

increased adherenece to the vascular endothelium because of change in red cell membrane

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4
Q

how does the red cell affects contribute to the pathophysiology *

A

rigid, less deformable - so cant transverse the microvasculature

adherent - get stuck in vessels = ischemia and tissue injury

dehydrated = concentration of HbS in the red cell favouring polymerisation

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5
Q

what does sickle cell anamia refer to *

A

homozygous - ie 2 forms of BS genes - no normal B genes

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6
Q

what does sickle cell disease refer to *

A

general term that covers other conditions that cause sickling eg co-inheritance of HbS and HbC/B thalassaemia

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7
Q

what is teh epidemiology of sickle cell

A

widely distributed

across meditterainean

middle east asia

different haplotype indicates different multicentric orignin - gene has been selected for as protection against malaria on different occaisions

distribution matches the endemic of plasmodium falciparum malaria

25% africans and 10% caribbeans carry sickle cell gene

300000 births affected annually

number of migrants with gene increases the number of affected births

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8
Q

what is the epidemiology of sickle cell in the UK

A

12-15000 births

70% in greater london

most common monogenic disorder

detected by newborn screening

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9
Q

what is the inheritance pattern of the sickle gene *

A

autosomal recessive

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10
Q

how would you describe the inheritiance clinically *

A

heterogeneous - marked variability

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11
Q

describe teh pathogenesis of sickle cell *

A

shortened red cell lifespan because of haemolysis = anaemia, gall stones, aplastic crisis (Parvovirus B19) - increased turnover of red cells to compensate = low folic acid

anaemia also partly because of a reduced erythropoeitic drive because HbS has a lower affinity for O2 ie releases ox more efficiently (therefore tolerate low level of Hb)

blockage tto microvascularr circulation (vaso-occlusion) = tissue damage and necrosis (infarction), avute pain crisis because of ischemia in marrow, organ dysfunction

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12
Q

describe an aplastic pain crisis *

A

suseptible to normally innocuous virus - affects developing red cell in marrow = severe reduction in Hb

self limiting

may require transfusions

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13
Q

what are the consequences of tissue infarction *

A

hyposplenism - autoinfarction because of ischemia - suseptible to capsulated bacteria = pneumonococcal infection

dactylitis (inflammation of digit because of infarction and eventual shortening of digit), avascular necrosis (chronic joint damage) and osteomyelitis (bone infection, predisposed by dead tissue from infarction) all lead to acute pain crisis

chronic/recurrent leg ulcers

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14
Q

summarise the pathogenesis of vasoocclusion *

A

shape distorted -trapped in microvasculature

increased adherence to vessel wall

attracte white cells and platelets that are also adherent

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15
Q

how is NO related to sickle cell disease *

A

cell free Hb limits NO bioavailaibilty -> vasculopathy eg:

pul hypertension - correlates with the severity of haemolysis ie amount of cell free Hb = less NO = vasoconstriction - increased mortality

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16
Q

summarise the pathogenesis of sickle to different parts of the body *

A

lungs - acute chest syndrome (commonest cause of death), chronic damage, pul hypertension

urinary tract - haematuria (papillary necrosis), impaired conc of urine (hyposthenuria, lead to dehydration), renal failure, priapism

brain - stroke (middle cerebral artery), cognitive impairment

eyes - proliferative retinopathy

17
Q

what are teh early presentations of sickle disorders *

A

symptoms rare before 3 months - coincide with switch from HbF to HbB

manifestations:

dactylisis

splenic sequestation - enlargement because of pooling of blood, cause anaemia - fatal

infection - s. pneumoniae because of hyposplenism

18
Q

how does early diagnosis and prevention help sickle cell outcomes *

A

give penicillin prophylaxis

eductae parents to check for spleen enlargement

= significnat reduction in deaths from pneumococcal infection and splenic sequestation

life expectancy has improved but is still below age matched controls

life expenctancy increased by hyboxycarbimide and transfusion for stroke prevention

19
Q

what are sickle cell emergancies *

A

septic shock - BP <90/60

neuro signs/symptoms - stroke, ischemic in children, adults mix of ischemic and haemorrhagic

SpO2 <92% on air - hypoxic - set up vicious cycle = more sickling because of acute cough

symptoms/signs of anaemia with Hb <5 or fall >3g/dl from baseline

priapism >4hrs - erectile dysfunction

20
Q

describe acute chest syndrome *

A

when have new infiltration on chest x-ray and fever, cough, chest pain or tachypnoea

incidence SS>SC>SB+ thal

happens when there is a vaso-occlusive crisis, surgery or pregnancy

diagnosis delayed

mech ventilation 15%

mortality >18yr 9%

21
Q

describe effect of avascular necrosis of the femoral head *

A

may need joint replacement

causes significant disability

ball and socket is lost

22
Q

describe osteomyelitis in sickle cell *

A

because of salmonella infection or staphylococcus

multifocal

23
Q

describe stroke in sickle disease *

A

affects 8% SS

most common at 2-9yrs

involves major cerebral vessels - intercranial internal carotid

24
Q

describe gall stones in sickle *

A

by 25 years prevalence in SS = 50%

coinheritence of Gilbert syndrome gives increased risk (UGT 1A1 TA7/TA7 genotype) - increases risk - normally has TATA box with 6 TA repeats, in Gilbert syndrome - extra TA= reduced transcription

causes pain, papillary obstruction and gall stones in the pancreas

treated by lacroscopic cholecystemectomy

25
Q

what are lab features of sickle *

A

low HB - 6-8g/L

reticulocytes high (except in aplastic crisis) - bone marrow compensating

film: sickles, boat cells, target cells, Howell-Jolly bodies (due to hyposplenism)

26
Q

describe the diagnosis of sickle cell *

A

solubility test - in presence of reducing agent ocyHb -> deoxyHb = reduced sol, soln turbid (opaque) - however this doesnt differentiate from AS or SS

definite diagnosis by high performance liquid chromatography - separate proteins according to charge - on electrophoresis have A and A2 bands, and if AS - S band, A, A2 and F, if SS- no A band, some HbF, small amount HbA2. need solubilty test too because HbD and HbG run with HbS but are non-sickling.

blood count - low Hb 60-90g/L, raised reticulocyte count

blood film - sickles, howell jolly bodies, target cells

27
Q

describe general management of sickle cell disease *

A

folic acid for DNA synth to increase red cell production - 5mg/day

penicillin - prophylaxis

vaccination - capsulated bacteria and influenza

monitor spleen size

blood transfusion - exchange transfusion for acute anaemic events, chest syndrome and stroke / top up blood transfusion if aplastic/sequestation crisis

preg care - at greater risk of foetal loss and obs risks

exchange transfusion - stroke and acute chest syndrome

haematopoietic stem cell transplantation - <16yrs wiith severe disease, survival 90-95%, cure 85-90% - loss of fertility following myeloblative conditioning - results best when matched with HLA donor

induction of HbF - hydroxyurea (mean continue to make HbF = milder symptoms), butyrate

28
Q

describe management of a painful crisis *

A

pain relief as opiod

IV hydration

keep warm - cold is trigger for sickle crisis

oxygen if hypoxic - also treat cause eg pul emb/acute chest syndrome (consider exchhangee transfusion)

exclude infection by blood and urine cultures and chest x ray

29
Q

what triggers a painful crisis *

A

infection

exertion

dehydration

hypoxia

psychological stress

cold

30
Q

describe pain management in acute crisis *

A

opiods - marked individual variation in response, diamorphine most widely used, most children - oral

individual analgesia protocols

pt controlled analgesia - background level and bolus so pt can self admin- block after 20mins, usually results in lower doses

adjuvents - parcetamol (IV), NSAIDs, pregabalin/gabapentin (neuropathic pain)

31
Q

what are the current disease modifying therapies for SCD *

A

transfusion

hydroxyurea

haemopoietic stem cell transplantation

32
Q

describe hydroxyurea (hydroxycarbamide) as a treatment for sickle cell disease *

A

HbF inhibit polym of HbS = fewer complications

hydroxyurea increases production of HbF

decreases stickyness of red cells

reduces white cell production by bone marrow - cytotoxic so needs to be monitored, in SCD pts with higehr white cell counts have worse outcomes

improves hydratuion of red cells = dilute HbS = reduced sickling

generates NO - improves blood flow

no mortality in people who have been oin it for >15yrs

reductioin in crisis rate, hospiltilisation, acute chest syndrome, and transfusion

33
Q

describe stem cell transplantation as a treatment for SCD *

A

97% overall survival

reserved for severe disease- CNS disease, recurrent severe vaso-occlusive crisis and recurrent ACS

CNS:

stroke

abnormal TCD and silent infarct,

small infarcts with cognitive deficiency

abnormal MRA despite transfusions

abnormal TCD and red cell alloAb

CNS disease requiring transfusions with iron overload despite optimal care

34
Q

what are limitations for HSCT *

A

donor availabity

length of treatment - 2 month as inpatient, 4 month outpt

transplant related mortality

infertility

pubertal failure

chronic GvHD

organ toxicity

secondary malignancies

35
Q

gene therapy for SCD *

A

no sickle cell related adverse effects

change AA - mimic HbF

makes pt more like sickle trait than SS

36
Q

describe a P selectin inhibitor for SCD *

A

monoclonal Ab against P selectin- adhesion molecule involved in adherence of red cells

significant reduce in crisis rate

37
Q

describe sickle cell trait *

A

HbAS

normal life expectancy

normal blood count

asymptomatic usually

rarely painless haematuria - due to papillary necrosis

need to be cautious of: anaesthesia, high altitude (vaso-occlusive symptoms = splenic infarction), extreme exertion - especially in hot places because of dehydration

38
Q

what is a chest crisis *

A

hypoxia due to death of lung tissue

39
Q

effect of parvovirus *

A

infects red blood cell precursers, stops red cell production for a week

Hb fall drastically - aplastic crisis - reticulocyte count low

Haematology (11 decks)

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