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Y2 MCD Haematology > haemoglobin > Flashcards

haemoglobin Flashcards

sickle cell anaemia: explain the genetic basis, clinical features, haematological features and management principles of sickle cell anaemia and sickle cell trait

1
Q

what genetic change causes sickle cell disease

A

missense mutation at codon 6 of gene for B-globin chain (short arm of chromosome 11), where polar and soluble glutamic acid is replaced by non-polar and insoluble valine

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2
Q

what is the resulting haemoglobin in sickle cell disease

A

deoxyhaemoglobin S (HbS)

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3
Q

features of HbS

A

insoluble, polymerises to form fibres (tactoids), intertetrameric contacts stabilise structure

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4
Q

3 stages in sickling of red cells

A

distortion, dehydration, increased adherence to vascular endothelium

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5
Q

effect of distortion on polymerisation

A

polymerisation is initially reversible with formation of oxyHbS, but is subequently irreversible

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6
Q

3 features of sickle red cells

A

rigid (can’t traverse microvascular circulation), adherent (cause ischaemia), dehydrated (further concentrates HbS in red cells)

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7
Q

distribution of sickle cell disease and malaria

A

match

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8
Q

sickle cell disorders

A

sickle cell anaemia (homozygous HbSS), compound heterozygous states (e.g. HbSC, HbSB-thalassaemia - coinheritance)

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9
Q

sickle cell disorders: genetic and clinical inheritance pattern, and impact on clinical course

A

genetically autosomal recessive, clinically heterogenous (varying severity); clinical course variable and unpredictable even within same family

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10
Q

what does sickle cell disease incorporate

A

sickle cell anaemia, all other conditions that can lead to a disease syndrome due to sickling

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11
Q

2 pathogenesis of sickle cell disease

A

shortened red cell lifespan due to haemolysis, blockage to microvascular circulation (vaso-occlusion)

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12
Q

pathogenesis of sickle cell disease: 3 consequences of haemolysis

A

anaemia, gall stones, aplastic crisis (parvovirus B19)

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13
Q

pathogenesis of sickle cell disease: what is anaemia partly due to, as well as haemolysis

A

reduced erythropoietic drive, as HbS is low affinity so releases O2 more efficiently

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14
Q

pathogenesis of sickle cell disease: 3 consequences of vaso-occlusion

A

tissue damage and necrosis (infarction), pain (due to ischaemia within bone marrow), dysfunction

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15
Q

pathogenesis of sickle cell disease: 3 locations with consequences of tissue infarction

A

spleen, bones/joints, skin

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16
Q

pathogenesis of sickle cell disease: consequence of infarction of spleen

A

hyposplenism, increasing susceptibility to encapsulated bacteria

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17
Q

pathogenesis of sickle cell disease: 3 consequences of infarction of bones/joints

A

dactylitis, avascular necrosis (e.g. of femoral head), osteomyelitis (infection of bone e.g. due to Salmonella infection)

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18
Q

pathogenesis of sickle cell disease: consequence of infarction of skin

A

chronic/recurrent leg ulcers

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19
Q

pathogenesis of sickle cell disease: pathogenesis of vaso-occlusion

A

starts with HbS polyermisation -> poikilocytosis -> entrapped in micro-circulation (rigid and adherent)

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20
Q

pathogenesis of sickle cell disease: effect of intravascular haemolysis on NO

A

cell-free Hb in vaso-occlusion limits NO bioavailability by scavenging in sickle cell disease

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21
Q

pathogenesis of sickle cell disease: what does vaso-occlusion cause which correlates with severity of haemolysis

A

pulmonary hypertension (associated with increased mortality)

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22
Q

4 locations of complications of sickle cell disease

A

lungs, urinary tract, brain, eyes

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23
Q

3 complications of sickle cell disease in lungs

A

acute chest syndrome, chronic damage, pulmonary hypertension

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24
Q

4 complications of sickle cell disease in urinary tract

A

haematuria (papillary necrosis), impaired concentration of urine (hyposthenuria), renal failure, priapism

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25
Q

2 complications of sickle cell disease in brain

A

stroke (8% of SS; involves major cerebral vessels), cognitive impairment

26
Q

complication of sickle cell disease in eyes

A

proliferative retinopathy

27
Q

when do symptoms of sickle cell disorders present and why

A

rare before 3-6 months, with onset coinciding with switch from foetal to adult Hb synthesis

28
Q

3 early manifestations of sickle cell disorders

A

dactylitis, splenic sequestration (applies to all populations), infection by S. pneumoniae (due to hyposplenism; applies to all populations)

29
Q

what can be done to prevent infection in sickle cell disorders

A

penicillin prophylaxis, parental education

30
Q

what 5 things constitute a sickle emergency

A

septic shock (BP <90/60), neurological signs/symptoms, SpO2 <92% on air (hypoxia, due to acute chest syndrome) may create vicious cycle), symptoms/signs of anaemia with Hb <5 or fall >3g/dl from baseline, priapism >4 hours

31
Q

5 clinical features of acute chest syndrome

A

new pulmonary infiltrate on chest x-ray with fever, cough, chest pain and tachypnoea

32
Q

relative incidence of acute chest syndrome in sickle cell disorders

A

SS>SC>Sb+ thalassaemia (more common in homozygous)

33
Q

when does acute chest syndrome develop

A

vaso-occlusive crisis, surgery or pregnancy

34
Q

what furthers risk of gall stones in sickle cell disorders

A

coinheritance of Gilbert syndrome (extra TATA repeat on promoter, reducing protein activity and bilirubin conjugation)

35
Q

2 laboratory features of sickle cell disorders

A

low Hb, high reticulocytes (attempt to compensate for anaemia)

36
Q

when would reticulocytes not be high in sickle cell disorders

A

aplastic crisis

37
Q

4 red cells present on blood film in sickle cell disorders

A

sickled cells, boat cells, target cells, Howell Jolly bodies

38
Q

how are sickle cell disorders diagnoses

A

solubility test

39
Q

what happens in a solubility test if sickle cell disorder

A

in presence of reducing agent oxyHb converted to deoxyHb, decreasing solubility and causing solution to become opaque

40
Q

limitation of solubility test when diagnosing sickle cell disorders

A

doesn’t differentiate AS from SS (can’t tell if homozygous or heterozygous)

41
Q

2 techniques for definitive diagnosis of sickle cell disorder

A

electrophoresis or high performance liquid chromatography (HPLC) separate proteins according to charge, so HbA2 furthest, then HbS, then HbA; can tell if homozygous or heterozygous by number of bands of HbS

42
Q

6 general measures to manage sickle cell disorders

A

folic acid (required for DNA synthesis); penicillin (prophylaxis); vaccination (especially vs encapsulated bacteria and influenza); monitor spleen size; blood transfusion for acute anaemia events, chest syndrome and stroke; pregnancy care

43
Q

4 ways to manage a painful sickle cell disorder crisis

A

pain relief (opioids), hydration, keep warm, oxygen if hypoxic (treat cause also)

44
Q

2 methods to exclude infection in painful sickle cell disorder crisis

A

blood and urine cultures, chest x-ray

45
Q

what 6 things trigger a painful sickle cell disorder crisis

A

infection, exertion, cold, dehydration, hypoxia, psychological stress

46
Q

painful sickle cell disorder crisis: how are opioids administered in children

A

oral

47
Q

painful sickle cell disorder crisis: most widely used opioid and limitation

A

diamorphine, but marked individual variation in response

48
Q

painful sickle cell disorder crisis: examples of adjuvants

A

paracetamol, NSAIDs, pregabalin/gabapentin

49
Q

3 disease-modifying therapies for sickle cell disorders

A

exchange transfusion, haemopoietic stem cell transplantation, induction of HbF

50
Q

disease-modifying therapies for sickle cell disorders: when would an exchange transfusion be conducted

A

stroke, acute chest syndrome

51
Q

disease-modifying therapies for sickle cell disorders: patients suitable for haemopoietic stem cell transplantation

A

<16 years with severe disease and with compatible HLA

52
Q

disease-modifying therapies for sickle cell disorders: how to induce HbF

A

hydroxyurea (hydroxycarbamide), butyrate

53
Q

disease-modifying therapies for sickle cell disorders: why is HbF induced

A

inhibits polymerisation of HbS (proof: patients don’t usually develop symptoms until >3 months as contains a- and y-globin chains), causing fewer complications and improved survival

54
Q

disease-modifying therapies for sickle cell disorders: 5 beneficial effects of hydroxyurea

A

increases HbF production, inhibits polymerisation of HbS, reduces white cell production by bone marrow, improves hydration of red cells, generates NO which improves blood flow

55
Q

disease-modifying therapies for sickle cell disorders: 3 indications for requiring a haemopoietic stem cell transplantation

A

CNS disease, recurrent severe vaso-occlusive crisis if hydroxyurea fails, recurrent acute chest syndrome if hydroxyurea fails

56
Q

disease-modifying therapies for sickle cell disorders: 6 features of CNS disease indicating need for haemopoietic stem cell transplantation

A

stroke, abnormal TCD and silent infarct, silent infarcts with cognitive deficiency, abnormal MRA despire transfusions, abnormal TCD and RBC alloantibodies, CNS disease requiring transfusions with iron overload despite optimal care

57
Q

disease-modifying therapies for sickle cell disorders: 4 limitations of haemopoietic stem cell transplantations

A

donor availability (HLA typing), length of treatment, transplant related mortality, long term effects

58
Q

disease-modifying therapies for sickle cell disorders: 5 long term effects of haemopoietic stem cell transplantation

A

infertility, pubertal failure, chronic GvHD, organ toxicity, secondary malignancies

59
Q

2 gene therapies in treating sickle cell diseases

A

genetically correct stem cells to repopulate bone marrow; inhibit P-selectin which causes adherence to vessels, preventing crisis

60
Q

5 features of sickle cell trait (genetics and clinical presentation)

A

HbAS, normal life expectancy, normal blood count, usually asymptomatic, rarely painless haematuria

61
Q

3 cautions for sickle cell trait

A

anaesthetic, high altitude, extreme exertion

Y2 MCD Haematology (20 decks)

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