Haem 5 - Sickle Cell disease Flashcards
What causes sickle cell disease from a genetic perspective
Missense mutation at codon 6 for Beta-globin chain.
Glutamic acid replaced by valine
- Valine is insoluble (unlike glutamine) —> so deoxyhaemoglobin S is insoluble —> HbS polymerises to form “tactoid” fibres —> distort shape of RBC —> distorted structure stabilised by intertetrameric contacts
Describe the stages in sickling of RBC
- Distortion - polymerisation occurs but initially reversible with formation of oxyHbS. Subsequently irreversible.
- Dehydration - further concentrates Hb in cell —> favours polymerisation
- Increased adherence to vascular endothelium
RIGID, ADHERENT, DEHYDRATED
Sickle cell anaemia is homozygous (SS) but may also involve compound heterozygous states e.g. SC, SB thalassaemia. escribe its genetic and clinical features
Genetically simple - autosomal recessive
Clinically heterogeneous
Sickle cell disease leads to shortened RBC lifespan due to haemolysis. What effects does this have
- Anaemia
- Gall stones
- Aplastic crisis due to Parvovirus B19 (blocks maturation of developing RBCs)
Anaemia is partly due to a reduced erythropoietic drive - HbS has lower affinity than HbA
Sickle cell disease can also cause microvascular blockage (vast-occlusion). This can cause?
- Tissue damage and necrosis (infarction)
- Pain
- Dysfunction
What are the consequences of tissue necrosis and infarction (as a result of SCD)
- Spleen - hyposplenism
- Bones/joints - dactylitis, avascular necrosis, osteomyelitis
- Skin - chronic, recurrent leg ulcers
How can SCD vasculopathy and NO cause pulmonary hypertension
Intravascular haemolysis releases free Hb into plasma —> this free Hb scavenges NO —> causing vasoconstriction
Pulmonary hypertension = quite common in SCD. Pulmonary hypertension correlates directly with severity of haemolysis
Associated with increased mortality
How can SCD affect lungs, urinary tract, brain and eyes?
Lungs - acute chest syndrome, chronic damage, pulmonary hypertension
Urinary tract - haematuria (papillary necrosis), impaired urine conc (hyposthenuria), renal failure, priapism
Brain - stroke, cognitive impairment
Eyes - proliferative retinopathy
SCD has a high variable and unpredictable course even within the same family
Y
The onset of SCD symptoms coincides with?
Switch from foetal to adult Hb synthesis
Symptoms rare before 3-6 months
Early manifestations include: dactylitis, splenic sequestration, infection (S. pneumoniae - can be fatal)
What are the SCD emergencies
- Septic shock / sepsis (BP < 90/60)
- Neurological signs/symptoms
- SpO2 < 92% on air
- Symptoms/signs of anaemia with Hb < 50 or fall >3g/dl from baseline
- Priapism > 4hrs
Describe acute chest syndrome
New pulmonary infiltrate on CXR
With: fever/chest pain/cough/tachypnoea
Incidence SS>SC>SB+ thalassaemia
Develops in context of vaso-occlusive crisis, surgery, pregnancy
Often a delayed diagnosis
Treated by emergency exchange transfusion
Where is a common site of avascular necrosis from SCD
Femoral head
Why might osteomyelitis occur from SCD
Osteomyelitis due to salmonella
Coinheritance of what syndrome further increases risk of gallstones?
Gilbert syndrome
What are the lab features of homozygous SCD
- Low Hb (typically 6-8g/dl)
- Reticulocytes high (except in aplastic crisis)
- Film shows sickled cells, boat cells target cells, Howell Jolly bodies
How can SCD be diagnosed
Solubility test: incubate with reducing agent —> oxyHb converted to deoxyHb —> solubility decreases —> solution becomes turbid and opaque (if HbS present)
Solubility test doesn’t differentiate AS from SS
Definitive diagnosis = electrophoresis or HPLC used to separate proteins according to charge
What are the general measures used to manage SCD
- Folic acid
- Penicillin
- Vaccination
- Monitor spleen size
- Blood transfusion - for acute anaemic events, chest syndrome and stroke
- Pregnancy care
How are painful crises of SCD managed
- Pain relief - variation in response. Diamorphine most widely used. Kids get oral opioid. Adjuvants = paracetamol, NSAIDs, pregabalin/gabapentin
- Hydration
- Keep warm
- Oxygen if hypoxic
- Exclude infection - blood and urine cultures and CXR
What are the triggers of painful crises
- Infection
- Exertion
- Dehydration
- Hypoxia
- Psychological stress
When is an exchange transfusion used
In stroke or acute chest syndrome
What are the current disease-modifying therapies for SCD?
- Transfusion
- Hydroxycarbamide (hydroxyurea)
- Haemopoietic stem cell transplantation
Describe the use of haemopoietic stem cell transplantation
- Used in <16 y/o w/ severe disease, if hydroxyurea fails
- Disease free survival = 90-95%, cure 85-90%.
Limitations:
- Major limitation = low availability of HLA-matched donors
- Length of treatment - 2 months (inpatient) and 4 months (outpatient).
- Transplant related mortality
- Long term effects = infertility, pubertal failure, chronic GvHD, Organ toxicity, secondary malignancies
What is used to induce HbF production
- Hydroxyurea
2. Butyrate
