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haem 5 Flashcards

1
Q

What is the sickle gene

A

Point mutation in codon 6 of beta globin chain which is on chromosome 11, as are the other beta clusters (glutamate to valine)

Glu –> soluble
Val–> insoluble

DEOXYHAMOGLOBIN S insoluble

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2
Q

What are tactoids

A

HbS polymerises due to insoluble deoxyhaemoglobin S

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3
Q

Stages in sickling of red cells

A

Distoriton (polymerisation reversible to due oxyHbS formation, then irreversible)

Dehydration

Increased adherence to vasc endothelium

RIGID, ADHERENT, DEHYDRATED

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4
Q

What does distribution of sickle cell anaemia match

Global distribution of beta gene

A

endemic Plasmodium falciparum malaria

Asia, West Africa and Central Africa and caribbeans

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5
Q

What is SS, SC ad Sbeta thalassaemia

A

Sickle cell anaemia (homozygous)

SC and Sbeta are heterozygous states

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6
Q

What does sickle cell diseases refer to

A

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

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7
Q

Pathogenesis of sickle cell

A
  1. Shortened red cell lifespan- haemolysis, leading to:
    - Anaemia
    - Gall Stones
    - Aplastic Crisis (Parvovirus B19)–> i..e if erythropoiesis is stopped because of this, the patient will become profoundly anaemic within a couple of days because of the reduced lifespan of the red cells

Anaemia partly due to a reduced erythropoietic drive as haemoglobin S is a low affinity haemoglobin for O2

  1. Blockage to microvascular circulation, esp. post capillary venules (vaso-occlusion)
    - Tissue damage and necrosis (Infarction)
    - Pain
    - Dysfunction
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8
Q

Conseauences of tissue infarction in sickle cell diseases

A

Spleen
- hyposplenism (spleen can become engorged and act as reservoir of blood, which needs transufsion, and in older age, the spleen shrinks which causes patients to become at risk of death from pneumococcal sepsis)

Bones/Joints 
    - dactylitis
    - avascular necrosis
    - osteomyelitis
Skin		
    - chronic/recurrent leg ulcers
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9
Q

Pathogenesis of vaso-occlusion in sickle cell disease

A

Basically the sickle shaped cells due to polymerised HbS get physically trapped in the microcirculation, and also have upregulated cell adhesion molecules which adheres them to the vascular endothelium. Additionally, activated leukocytes become entrapped too.

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10
Q

Why there risk of pulmonary HTN in sickle cell disease

A

correlates with the severity of haemolysis

The likely mechanism is that the free plasma haemoglobin resulting from intravascular haemolysis scavenges NO and causes vasoconstriction

Associated with increased mortality

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11
Q

Effect of sickle cell disease on lungs, urinary tract, brain and eyes

A

Lungs
Acute chest syndrome
Chronic damage
Pulmonary hypertension

Urinary tract     
Haematuria (papillary necrosis)
Impaired concentration of urine (hyposthenuria)
Renal failure
Priapism

Brain
Stroke
Cognitive impairment

Eyes
Proliferative retinopathy

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12
Q

When will presentation of sickle cell occur

A

Onset coincides with switch from fetal to adult Hb synthesis

(rare before 3-6 month)

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13
Q

Early manifestatins of sickle cell disorder

A

Dactylitis
Splenic sequestration*
Infection-S. pneumoniae*

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14
Q

Sickle emegergencies

A

septic shock (bp less than 90/60)

Neurological signs or symptoms

SpO2 <92% on air

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

Priapism >4 hours

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15
Q

What is acute chest syndrome

A 
New pulmonary infiltrate on chest X-ray
 with   
Fever
Cough
Chest pain
Tachypnoea
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16
Q

When does acute chest syndrome occur

A

SS>SC>Sbeta+ Thal

Develops in context of vaso-occlusive crisis
surgery pregnancy

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17
Q

Incidence of stroke in SS

A

8% (2-9 years).. in major cerebral vessels

18
Q

Occurrence of gallstnes, and what can worsen this

A

50% in SS by age 25…

coinheritance of Gilbert (TATA for transcirption, 6 usually but 7 in gilbert)

19
Q

Lab features in sickle cell disease

A

Low Hb,

Reticulocytes high (not apastic crisis as bone marrow shut down)

Blood film:
-sickled cells, boat cells, target cells, howell jolly body

20
Q

How is sickle cell diagnosed

A

WIth a reducing agent, oxyHb will convert to deoxyHb,

Solubility will go down and solution becomes turbid

(doesn’t differentiated AS AND SS)

21
Q

What is used for definitive diagnosis of sickle cell disease

A

Electrophoresis or high performance liquid
Chromatography (HPLC) separates proteins according to charge

look at the bands

22
Q

Management of sickle cell disease generally

A

Folic acid (it is proposed that folate in anemia raises hemoglobin levels and helps provide a healthy reticulocyte response)

Penicillin (for pneumococcal disease)

Vaccination (for pneumococcus)

Monitor spleen size

Blood transfusion for acute anaemic events, chest syndrome and stroke

Pregnancy care

23
Q

Management of painful crisis in sickle cell disease

A 
Pain relief (opioids)
Hydration
Keep warm
Oxygen if hypoxic
Exclude infection: 
-Blood and urine cultures
-CXR
24
Q

What causes triggers painful crises in sickle cell disease

A

Infection, exertion, deydration, hypoxia and psychological stress

25
Q

How is pain managed in sickle cell disease

A

Opioids (diamorphine, most children receive oral opioid)

  • Individual analgesia protocols
  • Patient controlled analgesia
  • Adjuvants – paracetamol, NSAIDs, Pregabalin/Gabapentin
26
Q

When are exchange transfusions used

A

Stroke

Acute chest syndrome

27
Q

Other management

A

Haemopoietic stem cell transplantation
<16 yr with severe disease
Survival 90-95% Cure 85-90%

Induction of HbF
Hydroxyurea
Butyrate

28
Q

What are the disease-modifying therapy for SCD

A

Transfusion
Hydroxycarbamide (Hydroxyurea)
Haemopoietic stem cell transplantation

29
Q

How does HYDROXYUREA (HYDROXYCARBAMIDE) work

A
  1. Increases production of baby (fetal) haemoglobin (HbF). HbF INHIBITS polymerisation of HbS
  2. Decreases ‘stickiness’ of sickle red blood cells
  3. Reduces white blood cell production by the bone marrow
  4. Improves hydration of red blood cells
  5. Generates nitric oxide which improves blood flow

SIGNFICANTLY REDUCES NUMBER OF PAINFUL EPISODES

30
Q

When is haematopoteitc stem cell transplant indicated

A

CNS disease
Recurrent severe VOC
or recurrent ACS if hydroxyurea fails

31
Q

Limitations of HSCT

A

Donor availability is at 20% (i.e. only 20% of SCA sufferers have HLA match)…- 1-2% with SCD qualify..

Length of treatment- 2 monts as inpatient snad 4 months of outpatient

Long terms effects include infertility and pubertal failure, chronic GvHD, secondary malignancies

32
Q

What is Crizanlizumab

A

P selectin inhibitor (less adhesion of sickle cells to vasc. endothelium)

Stabolise oxyhaemoglobin state

33
Q

What is sickle cell trait

A 
HbAS 
Normal life expectancy
Normal blood count
Usually asymptomatic
Rarely painless haematuria

Caution: anaesthetic, high altitude, extreme exertion

34
Q

Which types of vessels does SCA commonly affect

A

post capillary venules (vaso-occlusion)

35
Q

Name a dangerous viral infection in those with sickle cell anaemia annd why

A

Parvovirus B19—- because this virus always arrests bone marrow eryhrocyte maturation.

In normal people this is fine as RBCs last 120 days but in SCA patients who have RBC with rofoundly reduced lifespan, this is problematic and results in sever anaemia –> APLASTIC CRISIS

36
Q

Why can patients with SCA have reduced erythropoietic drive

A

Because the HbS has low affinity for oxygen, so it gives up oxygen easily.

Therefore kidney doesn’t realise there is hypoxia so there is low erythropoietin released

37
Q

How is sequestration and aplastic crisis distinguished

A

In sequestration there will be reticulocytes, but none in aplastici crisis.

BOTH NEED URGENT TRANSFUSION

38
Q

What increases risk of gall stones in sickle cellpatients

A

coinheritance of gilberts syndrome

39
Q

Why are SCA patients at risk of some infections, and which infections are these

A

As the patients gets older the spleen shrinks and the patients become at risk of death from infections which are normally held in check by splenic activity such as malaria or pneumococcal sepsis.

40
Q

Outline 2 types of gene editing as potential cures of sicklce cell

A
  1. Additive (add a gene which encodes normal HbA)

2. Knockout BCL11A (which is a gene which prevents transcritpion of gamma chain following birth).

Blood (12 decks)

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