Sickle Cell Disease Flashcards
What is the sickle gene
missense mutation at codon 6 of the gene for beta globin chains (glutamic acid -> valine)
How does the sickle gene affect the overall cell
Glutamine (polar and soluble) -> Valine (non polar insoluble) HbS polymerises to form tactoid fibres deoxyHbS Is insoluble Distortion of cells
Describe the structure of sickle cells
Rigid
Adherent
Dehydrated
What are the stages in the sickling of red cells
Distortion (polymerisation is initially reversible with formation of oxyHbS, then irreversible)
Dehydration
Increased adherence to the vascular endothelium
Distinguish between sickle cell anaemia, sickle cell disease, and sickle cells trait
Sickle Cell Anaemia = homozygous state (SS)
Sickle Cell Disease = anything that causes disease due to sickling (generic)
trait = HbAS (almost normal)
Describe the sickle cell trait
Normal life expectancy and blood count
Usually Asymptomatic
Under conditions of hypoxia they may have some complications due to sickling cells e.g. anaesthesia, high altitude, extreme exertion
Summarise the pathogenesis of sickle cell disorders
Shortened lifespan (20 days) -> haemolysis
What are the consequences of sickle cell disease
Anaemia
Gallstones
Aplastic crisis
Explain how sickle cell disease causes anaemia
Removal of short-lifespan RBCs
Reduced erythropoietic drive as haemoglobin S has a low affinity for oxygen so it delivers oxygen
more effectively to tissues
So hypoxia doesn’t stimulate the erythropoietin release from the kidneys as much.
Explain how sickle cell disease causes gallstones
Increased haemolysis means an increase in the release of bilirubin and other red cell breakdown products
Excretion through the gallbladder
Explain how sickle cell disease causes an aplastic crisis
Parvovirus B19 - infects developing red cells in marrow to arrest development
Parvovirus switches off RBC production until the virus clears, and won’t have an effect in healthy people (120days)
Due to the 20 day life span of sickled cells, a parvovirus infection can lead to a steep drop in haemoglobin (ANAEMIA)
What are the consequences of microvascular blockage
tissue damage and necrosis (infarction)
Pain
Dysfunction
What are the consequences of tissue infarction
Spleen - hyposplenism
Bones/joints - dactylitis, avascular necrosis, osteomyelitis
Skin - chronic/recurrent leg ulcers
How is pulmonary hypertension associated with haemolysis
Correlates with severity of haemolysis
Free plasma Hb resulting from intravascular haemolysis scavenges NO and causes vasoconstriction
Associated with increased mortality
Describe the early presentation of sickle cell disorders
Symptoms rare before 3-6 months
onset coincides with the switch from HbF to HbA
Dactylitis (digit inflammation)
Splenic sequestration
Infection - S. pneumoniae
Why does splenic sequestration occur in SCD
Spleen holds onto RBC, gets bigger and damaged and doesn’t protect from infection
Could be aplastic crisis.
Look for reticulocytes, if none found = aplastic crisis
How is SCD diagnosed
Films and GBC
Solubility test and electrophoresis
What are the hematological features of SCD
Low Hb 6-8g/dL Reticulocytes Sickled cells Boat cells Target cells Howell Jolly Bodies
Describe the solubility test and explain why it should be used with other diagnostic methods
- In the presence of a reducing agent, oxyHb -> deoxyHb
- Solubility decreases
- Solution becomes turbid
Does not differentiate sickle cell trait from sickle cell disease
Describe electrophoresis
Separates proteins according to charge
Glutamate is positively charged and valine is not charge
Therefore, the normal A chains will travel further towards the negative pole
Sickle cell trait - two bars and somebody
Sickle cell disease - one bar lower down
What is the clinical presentation of sickle cell disease
Dactylitis
Splenic sequestration
Pneumococcal infection
Painful crisis
What is the most common clinical manifestation of sickle cell disease
Vaso-occlusive crisis
Occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and resultant pain
Pain crises constitute the most distinguishing clinical feature of SCD
What may a painful crisis in sickle cell disease be triggered by
Infection Exertion Dehydration Hypoxia Psychological stress
How is SCD managed generally
Folic acid Penicillin Vaccination Hydroxycabimade (hydroxyurea) Monitor spleen size Blood transfusion Pregnancy care Haemapoietic stem cell transplant
What is the treatment for a SCD painful crisis
Opioids
Hydration
Keep Warm
Oxygen
What is the significance of HbF in SCD
HbF inhibits polymerisation of HbS
Infants with SCD do not usually develop symptoms until > 3 months
Patients with higher HbF levels have fewer complications and improved survival
Why may hydroxycabimade be used for SCD management
increases HbF to prevent painful crises, acute chest syndrome and need for transfusions
(CI when planning a family/pregnant)
What are the indications to have a haematopoietic stem cell transplant (HSCT) for SCD
CNS disease
Recurrent severe vaso-occlusive crisis*
Recurrent ACS*
*if hydroxyurea fails
