haem 5 Flashcards
What is the sickle gene
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
What are tactoids
HbS polymerises due to insoluble deoxyhaemoglobin S
Stages in sickling of red cells
Distoriton (polymerisation reversible to due oxyHbS formation, then irreversible)
Dehydration
Increased adherence to vasc endothelium
RIGID, ADHERENT, DEHYDRATED
What does distribution of sickle cell anaemia match
Global distribution of beta gene
endemic Plasmodium falciparum malaria
Asia, West Africa and Central Africa and caribbeans
What is SS, SC ad Sbeta thalassaemia
Sickle cell anaemia (homozygous)
SC and Sbeta are heterozygous states
What does sickle cell diseases refer to
incorporates sickle cell anaemia and all other conditions that can lead to a disease syndrome due to sickling
Pathogenesis of sickle cell
- 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
- Blockage to microvascular circulation, esp. post capillary venules (vaso-occlusion)
- Tissue damage and necrosis (Infarction)
- Pain
- Dysfunction
Conseauences of tissue infarction in sickle cell diseases
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
Pathogenesis of vaso-occlusion in sickle cell disease
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.
Why there risk of pulmonary HTN in sickle cell disease
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
Effect of sickle cell disease on lungs, urinary tract, brain and eyes
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
When will presentation of sickle cell occur
Onset coincides with switch from fetal to adult Hb synthesis
(rare before 3-6 month)
Early manifestatins of sickle cell disorder
Dactylitis
Splenic sequestration*
Infection-S. pneumoniae*
Sickle emegergencies
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
What is acute chest syndrome
New pulmonary infiltrate on chest X-ray with Fever Cough Chest pain Tachypnoea
When does acute chest syndrome occur
SS>SC>Sbeta+ Thal
Develops in context of vaso-occlusive crisis
surgery pregnancy
Incidence of stroke in SS
8% (2-9 years).. in major cerebral vessels
Occurrence of gallstnes, and what can worsen this
50% in SS by age 25…
coinheritance of Gilbert (TATA for transcirption, 6 usually but 7 in gilbert)
Lab features in sickle cell disease
Low Hb,
Reticulocytes high (not apastic crisis as bone marrow shut down)
Blood film:
-sickled cells, boat cells, target cells, howell jolly body
How is sickle cell diagnosed
WIth a reducing agent, oxyHb will convert to deoxyHb,
Solubility will go down and solution becomes turbid
(doesn’t differentiated AS AND SS)
What is used for definitive diagnosis of sickle cell disease
Electrophoresis or high performance liquid
Chromatography (HPLC) separates proteins according to charge
look at the bands
Management of sickle cell disease generally
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
Management of painful crisis in sickle cell disease
Pain relief (opioids) Hydration Keep warm Oxygen if hypoxic Exclude infection: -Blood and urine cultures -CXR
What causes triggers painful crises in sickle cell disease
Infection, exertion, deydration, hypoxia and psychological stress
How is pain managed in sickle cell disease
Opioids (diamorphine, most children receive oral opioid)
- Individual analgesia protocols
- Patient controlled analgesia
- Adjuvants – paracetamol, NSAIDs, Pregabalin/Gabapentin
When are exchange transfusions used
Stroke
Acute chest syndrome
Other management
Haemopoietic stem cell transplantation
<16 yr with severe disease
Survival 90-95% Cure 85-90%
Induction of HbF
Hydroxyurea
Butyrate
What are the disease-modifying therapy for SCD
Transfusion
Hydroxycarbamide (Hydroxyurea)
Haemopoietic stem cell transplantation
How does HYDROXYUREA (HYDROXYCARBAMIDE) work
- Increases production of baby (fetal) haemoglobin (HbF). HbF INHIBITS polymerisation of HbS
- Decreases ‘stickiness’ of sickle red blood cells
- Reduces white blood cell production by the bone marrow
- Improves hydration of red blood cells
- Generates nitric oxide which improves blood flow
SIGNFICANTLY REDUCES NUMBER OF PAINFUL EPISODES
When is haematopoteitc stem cell transplant indicated
CNS disease
Recurrent severe VOC
or recurrent ACS if hydroxyurea fails
Limitations of HSCT
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
What is Crizanlizumab
P selectin inhibitor (less adhesion of sickle cells to vasc. endothelium)
Stabolise oxyhaemoglobin state
What is sickle cell trait
HbAS Normal life expectancy Normal blood count Usually asymptomatic Rarely painless haematuria
Caution: anaesthetic, high altitude, extreme exertion
Which types of vessels does SCA commonly affect
post capillary venules (vaso-occlusion)
Name a dangerous viral infection in those with sickle cell anaemia annd why
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
Why can patients with SCA have reduced erythropoietic drive
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
How is sequestration and aplastic crisis distinguished
In sequestration there will be reticulocytes, but none in aplastici crisis.
BOTH NEED URGENT TRANSFUSION
What increases risk of gall stones in sickle cellpatients
coinheritance of gilberts syndrome
Why are SCA patients at risk of some infections, and which infections are these
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.
Outline 2 types of gene editing as potential cures of sicklce cell
- Additive (add a gene which encodes normal HbA)
2. Knockout BCL11A (which is a gene which prevents transcritpion of gamma chain following birth).
