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Bleeding disorders (Haemophilia A (Clinical features (unexplained and…
Bleeding disorders
Haemophilia A
common mutation effecting 30-100 per million
Sex linked
up to 33% of patients
Its defect is an absence or low concentrations of factor VIII
approximately 50% patients present with missense or frameshift mutations
others have an inversion at the end of the x chromosome which leads to a severe clinical form
Clinical features
unexplained and excessive bleeding from cuts or injuries
large or deep bruises
unusual bleeding after vaccinations
pain in joints
blood in stools
Diagnosis
extended activated partial thromboplastin time
low plasma factor VIIIc concentration
Treatment
recombinant VII preparations heat or solvent treated
DDAVP-vasopressin –milder forms of hameohpiia only
raises circulating plasma FVIII
Von Willebrand disease
Reduced or abnormal protein function of through point mutation or major deletion
produced in endothelial cells and platelets
encoded on chromosome 12- pattern is autosomal dominant
excessive blood loss from superficial cuts
main roles
Stabilise factor VIIIc in the plasma.
Acts as an adapter protein for platelets
to bind to collagen
Classification
TYPE 1
Quantitative partial deficiency
TYPE 2
Functional abnormality
TYPE 3
Complete deficiency
Haemophilia B (christmas disease)
inheritance and clinical features are very similar to that of haemophilia A
deficiency in factor IX - coded by a gene very close to factor VII on X chromosome
bleeding episodes treated with high purity factor IX concentrates
Function of factor V
co-factor in coagulation cascade - when activated (FVa) stabilises factor V (FVa)
Regulation of FVa activation
activated protein c has serine protease activity which is enhanced by protein S
cleaves FVa at 3 sites - R = arginine
R506
R306
R679
FV Leiden
point mutation at position 1691
results in arginine replaced by glutamine
Results in
10-20x slower inactivation of factor Va
5 fold increase in risk of DVT in heterozygotes
80 fold increase risk of dvt in homozygotes