hemophilia Flashcards
clinical features
- hemarthrosis
*muscle bleeding
coags in hemophilia A and B
prolonged PTT w/ correction in mixing study
severe hemophilia criteria
<1% factor activity
moderate hemophilia criteria
1-5% baseline factor activity
mild hemophilia criteria
5-50% baseline factor activity
Factor dosing in hemophilia A
1 unit/kg, which will raise factor VIII level by 2%
(1 to 2)
50 units/kg raises factor level to 100%
*Factor VIII has a binding partner (VWF) to enable it to remain in blood for longer than Factor IX
Maintenance factor dosing in hemophilia A
25 u/kg at 12h often given as maintenance dose
emicuzumab mechanism
binds to both the activated coagulation factor IX and to factor X, mediating the activation of the latter. This is normally the function of coagulation factor VIII, which is missing in haemophilia A patients (so it’s a factor VIII mimetic)
Breakthrough drug for hemophilia A
emicizumab
Factor dosing in hemophilia B
1 unit/kg, which will raise factor VIII level by 1%
(1 to 1)
Goal factor levels perioperatively for minor surgeries
Above 50% for 3-5 days
Goal factor levels perioperatively for major surgeries
Above 80% for 10-14 days
Other drug that can be used in mild hemophilia A for mild bleeds
DDAVP
Management of life threatening bleed in patient with possible but unknown inhibitor
bypass with recombinant factor seven
How to test for an inhibitor
bethesda assay
Bethesda assay interpretation
IF >5 bethesda units, you can’t treat with factor replacement (1 bethesda unit = 50% decline in factor 8 or 9).
*Give bypassing agent
Drug contraindicated with novoseven
emicizumab (VTE)
acquired hemophilia A management
- immunosuppression with steroids
- treat underlying cause
Hemophilia A genetics most commonly
Most commonly due to Intron 22 or intron 1 inversion
Hemophilia B genetics most commonly
Missense mutation
Can female carriers ahve a bleeding phenotype?
Yes substantial variability in baseline factor levels among female carriers
How can women be affected with heomphilia?
- skewed X inactivation
- de novo new mutation in woman who is a carrier
- 2 new de novo mutations
- compound heterozygote
- turner syndrome (missing x chromosome)
- vWD 2N (low levels of factor VIII)
Goal nadir factor levels for CNS trauma/hemorrhage or major surgery
Greater than 80%
Goal nadir factor levels for joint, muscle, GI tract, epistaxis, hematuria
30-50%
How frequently hemophilia A pts need prophylaxis with new long acting product
Once weekly
Primary ancillary treatments for hemophilia
- DDAVP
- fibrinolytics
Hemophilia subtype more with higher incidence of inhibitors
Hemophilia A
RF’s for inhibitor development - 1) genetic 2) ethnic 3) recombinant vs. plasma derived factor VIII
- larger gene deletions and nonsense mutations
- African American, hispanic
- Recombinant Factor 8
What is a high titer bethesda unit
Greater than 5
Options for preventing bleeding in hemophilia patients with inhbitors
- immune tolerance induction (expose pt to factor daily and they develop tolerance)
- re balancing therapies
- prevent bleeding with emicizumab
Treatment of bleeding in hemophilia patients with inhibitors
1) rFVIIa
2) bypassing agents (eg FEIBA)
3) rPorcine Factor VIII if no cross-reactivity
4) r(human) factor VIII if B.U. titer low
*emicizumab is only used for prophylaxis
Breakthrough drug for pts with inhibitors
emicizumab
Contraindication to emicizumab use
FEIBA (VTE + TMA)
Re-balancing therapy drugs for hemophilia
- fitusiran
- concizumab
- reduction in protein C and S levels
Fitusiran mechanism
small RNA targeting antithrombin
concizumab mechanism
Antibody to tissue factor inhibitor
Obstacles to gene therapy for hemophilia
- neutralizing antibodies
- FVIII misfolding
- hepatotoxicity
Treatment of hepatotoxicity from gene therapy
steroids
Drug often used for oral surgery in hemophilia patients
Tranexamic acid
How can a boy inherit hemophilia?
Mother has to be a carrier (boy receives Y chromosome from father)
