hemophilia Flashcards
(33 cards)
normal physiology
- Process of preventing blood loss should occur as soon as the wound is created
- Should be a tightly regulated process (turn on/off)
- Process should only happen at the site of the wound
- Clot should dissolve when no longer needed
describe hemophilia
rare inherited bleeding diathesis that results in unusual susceptivity to bleeding
define hemophilia A
deficiency in FVIII = reduced/absent FVIIIa = reduced catalytic efficiency of FIXa = limited activation of FX
define hemophilia B
deficiency in FIX = reduced catalytic efficiency of FIXa = limited activation of FX
what causes hemophilia (what is not activated) ?
- coagulation cascade cannot function properly =
- intrinsic pathway not activated, not enough fibrin produced, above normal bleeding
what is necessary to diagnose hemophilia?
less than 50% of normal protein
how do we classify the severity of hemophilia?
what are the classifications?
- based on the levels of FVIII or FIX (as predicts risk of furture bleeding events)
- mild, moderate, severe
protein levels used to define mild hemophilia are:
levels of 5-50% of normal
protein levels used to define moderate hemophilia are:
levels of 1-5% of normal
protein levels used to define severe hemophilia are:
levels less than 1% of normal
hemophilia A and B are what type of genetic disease? what does this mean?
- monogenetic
- means mutation in one single gene is implicated in the disease process
where is the mutation responsible for hemophilia?
what type of mutation is most common?
other types?
- mutation in the F8/F9 gene on the X chromosome
- point mutations are most common
- others = large or small deletions, insertions
in what pattern are mutations for hemophilia inherited?
what does this lead to?
- via X-linked recessive patterns
- leads to deficiency of the functional FVIII or FIX proteins
explain male inheritance of hemophilia
one altered gene is enough to cause hemophilia
explain female inheritance of hemophilia
- rare as its unlikely for a female to have 2 mutated versions of the gene
- females who are carriers are generally asymptomatic (only 20-30% show signs of bleeding)
who’s more likely to have hemophilia men or women?
men bc only one X chromosome
would it be practical to asses hemophilia patients mrna for mutations? why or why not?
- no
- mRNA transcripts are large, also,
- only cells that produce the protein (liver cells) will express the mRNA
- thus, FVIII and FIX mRNA won’t be present in the blood
- would have to do a liver biopsy instead which is very invasive
would it be practical to use a dna sample to detect molecular mutations in a hemophilia patient? why or why not?
- yes
- dna can be obtained from simple blood draw (extracted from peripheral blood mononuclear cells)
- could then use PCR & next gen sequencing to determine the sequence of the F8 or F9 genes and compare them to a reference
F8 gene codes for? smaller or bigger than F9 gene?
- FVIII protein
- 26 exons (bigger)
F9 gene codes for? smaller or bigger than F8 gene?
- FIX protien
- 8 exons (smaller)
what mutation presents for the majority of severe hemophilia cases? why?
- F8 intron inversion
- F8 found at the end of X chromosome so its more succeptible to inversion
- F8 also large
- most happen at intron 22 - largest intronic region in the gene
what is the mechanism for detecting inversions? (4)
(1) isolate dna from wbcs in blood draw
(2) incubate dna w restriction enezyme (cuts dna into smaller peices)
(3) run fragments through electrophoresis gel
(4) reference dna to healthy dna
what are the clinical applications of hemophilia? (major symptoms) (2)
- spontaneous bleeding - localized to joints and soft tissue
- provoked bleeding - can be result of trauma or surgery
what is the goal of treatment for hemophilia patients?
to maintain therapeutic levels of FVIII and FIX for sustained periods of time - to ensure coagulation cascade can function properly
