haem 5

Question 1

What is the sickle gene

Answer 1

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

Question 2

What are tactoids

Answer 2

HbS polymerises due to insoluble deoxyhaemoglobin S

Question 3

Stages in sickling of red cells

Answer 3

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

Dehydration

Increased adherence to vasc endothelium

RIGID, ADHERENT, DEHYDRATED

Question 4

What does distribution of sickle cell anaemia match

Global distribution of beta gene

Answer 4

endemic Plasmodium falciparum malaria

Asia, West Africa and Central Africa and caribbeans

Question 5

What is SS, SC ad Sbeta thalassaemia

Answer 5

Sickle cell anaemia (homozygous)

SC and Sbeta are heterozygous states

Question 6

What does sickle cell diseases refer to

Answer 6

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

Question 7

Pathogenesis of sickle cell

Answer 7

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

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

Question 8

Conseauences of tissue infarction in sickle cell diseases

Answer 8

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

Question 9

Pathogenesis of vaso-occlusion in sickle cell disease

Answer 9

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.

Question 10

Why there risk of pulmonary HTN in sickle cell disease

Answer 10

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

Question 11

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

Answer 11

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

Question 12

When will presentation of sickle cell occur

Answer 12

Onset coincides with switch from fetal to adult Hb synthesis

(rare before 3-6 month)

Question 13

Early manifestatins of sickle cell disorder

Answer 13

Dactylitis
Splenic sequestration*
Infection-S. pneumoniae*

Question 14

Sickle emegergencies

Answer 14

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

Question 15

What is acute chest syndrome

Answer 15

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

Question 16

When does acute chest syndrome occur

Answer 16

SS>SC>Sbeta+ Thal

Develops in context of vaso-occlusive crisis
surgery pregnancy

Question 17

Incidence of stroke in SS

Answer 17

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

Question 18

Occurrence of gallstnes, and what can worsen this

Answer 18

50% in SS by age 25…

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

Question 19

Lab features in sickle cell disease

Answer 19

Low Hb,

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

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

Question 20

How is sickle cell diagnosed

Answer 20

WIth a reducing agent, oxyHb will convert to deoxyHb,

Solubility will go down and solution becomes turbid

(doesn’t differentiated AS AND SS)

Question 21

What is used for definitive diagnosis of sickle cell disease

Answer 21

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

look at the bands

Question 22

Management of sickle cell disease generally

Answer 22

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

Question 23

Management of painful crisis in sickle cell disease

Answer 23

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

Question 24

What causes triggers painful crises in sickle cell disease

Answer 24

Infection, exertion, deydration, hypoxia and psychological stress

Question 25

How is pain managed in sickle cell disease

Answer 25

Opioids (diamorphine, most children receive oral opioid) - Individual analgesia protocols - Patient controlled analgesia - Adjuvants – paracetamol, NSAIDs, Pregabalin/Gabapentin

Question 26

When are exchange transfusions used

Answer 26

Stroke | Acute chest syndrome

Question 27

Other management

Answer 27

Haemopoietic stem cell transplantation <16 yr with severe disease Survival 90-95% Cure 85-90% Induction of HbF Hydroxyurea Butyrate

Question 28

What are the disease-modifying therapy for SCD

Answer 28

Transfusion Hydroxycarbamide (Hydroxyurea) Haemopoietic stem cell transplantation

Question 29

How does HYDROXYUREA (HYDROXYCARBAMIDE) work

Answer 29

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

Question 30

When is haematopoteitc stem cell transplant indicated

Answer 30

CNS disease Recurrent severe VOC or recurrent ACS if hydroxyurea fails

Question 31

Limitations of HSCT

Answer 31

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

Question 32

What is Crizanlizumab

Answer 32

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

Question 33

What is sickle cell trait

Answer 33

``` HbAS Normal life expectancy Normal blood count Usually asymptomatic Rarely painless haematuria ``` Caution: anaesthetic, high altitude, extreme exertion

Question 34

Which types of vessels does SCA commonly affect

Answer 34

post capillary venules (vaso-occlusion)

Question 35

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

Answer 35

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

Question 36

Why can patients with SCA have reduced erythropoietic drive

Answer 36

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

Question 37

How is sequestration and aplastic crisis distinguished

Answer 37

In sequestration there will be reticulocytes, but none in aplastici crisis. BOTH NEED URGENT TRANSFUSION

Question 38

What increases risk of gall stones in sickle cellpatients

Answer 38

coinheritance of gilberts syndrome

Question 39

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

Answer 39

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.

Question 40

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

Answer 40

1. Additive (add a gene which encodes normal HbA) | 2. Knockout BCL11A (which is a gene which prevents transcritpion of gamma chain following birth).