Inherited Bleeding Disorders, ASPHO Flashcards
most common SHA mutation?
intron 22 inversion of F8 gene
mild-mod HA mutations tend to be?
point mutations…
mod: a lot of missense mutations
mild: mostly pt muations
hemophilia b types of mutations?
severe: small and large deletions
mild-mod: missense mutations
mild hemophilia factor level?
5-40%
when does SHA prsent?
birth-3 yrs
mod hemophilia presents when? mild?
mod: 2-10
mild: 5-21
prese of SHA?
- fam hx
- circumcision bleeding
- heel stick bleeding
- bruising
- vaccine related bleeding
- mucosal bleeding
- jt bleeding
pres of mild HA?
often after surgery or trauma
rate of inhibitor development in SHA vs. SHB?
SHA 25%; SHB 5%
moderate HA :inhibior risk?
1-2%
risk for arhtopathy is ___ ___ ___ in SHA, ___ ___ ___ ___ in mod, __ in mild
universal without ppx; very common without ppx; rare
once out of first yr of life, most common area for bleeding in hemophilia?
joints! esp elbows, knees, ankles
retroperitoneal hemorrahge usually results from what in hemophilia? symptoms?
- iliopsoas muscle
- pain in flank, groin, or rarely thigh (referred pain)
- pain exacerebated and localized to RLQ by extending leg (stretching the muscle)
- difficulty walking (typically walk hunched over to relax the iliopsoas)
other than PTT and F8/F9 other test you can do at diagnosis?
geentic testing
3 ways to do prenatal testing?
- amiocentesis
- percutaneous umb blood sampling
- chorionic villous sampling
can you test factor levels prenatally?
not reliable… F9 levels are physiologically low in fetuses…F8 levels can be falsely high
carriers for HA can be symptomatic due to? what is this? level would fall in what range? need to be sure to rule out what?
lyonization…non-random x-chrom inactivation…mild HA range…vWD
most reliable way to diagnose a hemophilia carrier?
genotyping (first find molec defect in the index case)
meds for HA?
factor replacement
DDAVP
antifibrinolytic therapy
tertiary ppx in hemophilia =?
after onset of joint disease
secondary ppx in hemophilia?
after 2nd joint bleed
primary ppx in hemophilia?
before 2nd joint bleed, for all pts with severe and about 20% of pts iwth moderate
ppx dosing for HA?
25-40 u/kg/dose 3x per week
ppx dosing for HB?
50-100 u/kg/dose 2x per week
on demand therpay appropraite for whom?
mild hemophilia pts, most mod pts
chronci arthopathy develops when?
-can develop even after one jt bleed though generally takes several bleeds in same joint
what’s a target joint?
multiple bleeds in the same joint…3 bleeds in 6months or 4 in one year
management of chronic arthropathy?
- initiation of secondary ppx
- surgery…synovectomy
- pain managenemtn
- physio
- walking aids, orthotics
**tx intracranial bleed how?
keep factor level at 100% for at least 2 weeks, continue tx with ppx dosing indefinitiely
retroperitoneal bleed: tx how?
80% correction x at lesat a few days…follow up with short-term ppx (weeks)
muscle bleed: tx how?
40-60% correction, at least until can use muscle with no pain
**joint bleed: tx how?
40-60% correction, generally 1-3 dose suffices
tx mucosal bleed how?
30-50% correction, add antifibrinolytics
tx: sc hematoma?
observation! unless in “bad” location like buttocks, give factor
**pre-op tx for srugery?
100% correction pre-op and maintain trough of 50% until risk of bleeding is over
factor 8: 1 u/kg increaes factor level by how much?
2%
factor 9: 1 u/kg raises factor by how much?
1%…however, for recombinant products taht raise factor level by 0.7/kg (eg: benefix)
is ddavp = vasopressin analog used in hemophilia b?
no, only HA
ddavp indication in hemophilia?
mucocutaneous bleeds, minor procedures (dental)
AEs of DDAVP?
hypotension, flushing (hyponatremia esp in <3 yrs)…first dose should be given in clinic
pros of f8 therapy?
- immediate effect
- level sustained..half life of 6-12 hours
- highly effective
- safe
cons of f8 therapy?
- IV admin
- availability
- cost
- inhibitor development
ddavp pros?
- IN, IV, SC routes
- works for mild bleeds
- generally safe
- relatively cheap
ddavp cons?
- levels don’t peak high enough for serious bleeds (jt, muscle, etc)
- levels return to baseline in ~ 4hours
- not all pts respond
- some responsive pts have hypotension/flushing
half life of f9 therapy?
12-18 hours
issue with inhibitors in hemophilia b?
immune tolerance induction can –> anaphylaxis
management for hemophilia A pt undergoing surgery
-ensure pt doesn’t have inhibitor
-replace factor to 100% immediately prior to procedure (give 50 u/kg)
-repeat bolus doses to maintain a trough >50% until bleeding risk has passed (50 iu/kg q12h, for example and adjust as needed…or continuous infusion of 3 IU/kg/hr to maintain trough>50%)
(major surgery: consider contin infusion)
-antifibrinolytics esp if mucous membrane surgery
specifically for hemophilia B, surgical management?
120-140 u/kg of recombinant f9 (or 100 u/kg of plasma-derived f9) immediately before procedure to raise level to 100%…continue SAME dose q12-24h or can give continuous infusion of 6 iU/kg/hr to maintain trough >50%
for dental procedures, how high do you want to correct for procedures? also give what?
- 80-100%
- antifibrinolytic (aminocaproic acid or TXA)
- pressure gauze
- consdier DDAVP
managament of hematuria in hemophilia?
- correct to 80-100%
- IV fluids: 1.5-2x maintenance
- antifibronlytic agents are CONTRAINDICATED (unless you know for sure that the source is the lower urinary tract= bladder/urethra…but for exam just say no)
- don’t give ddavp (not reliable enough)
- glucocorticoids? limited data
pt bleeding more than expected with factor tx…2 causes?
- insufficient dose
- inhibitor
if suspect inhibitor, manage how?
- test for inhibitor immediately
- for bleeding, tx with bypassing agent
- for pts on ppx, therpay should be suspended
RFs for inhibitor?
- severe hemophila
- fam hx of inhibitors
- large deletion >nonsense>inversion>missense
- african american higher
- less risk if plasma-derived
- short burst of needing a lot of factor therapy
- cumulative exposure days (usually first 20 exp days)
test for inhibitors?
bethesda assay
how does bethesda assay work?
patient plasma, mix with normal plasma so each are 50%. tehn, measure f8 activity…if the pt sample alone has less factor 8 activity than the control mixture, then you know there’s an inhibitor.
1 bethesda unit=?
amount of inhibitor that results in 50% residual FVIII:C activity of a defined test mixture.
transient inhibitors are __ ___ and only picked up __ ___
clinically insignficant; on surveillance
what constitues a high titer inhibitor?
> 5 BU…must use bypassing agents to treat and/or prevent bleeding
for low titer inhibitors, do what?
can be treated with factor replacemnt at higher than usual doses
manage inhibitors with?
immune tolerance therapy= regular (usually daily or q2 days) infsuions or factor to educate the immune system to become tolerant…takes 6-18 months
when in tolerance achieved iwth ITI?
pt has recover of >66% adn half life of >6 hours
what if someone with low titre inhibitor bleeds?
give higher dose of factor…multiply the inhibitor titre by the IU/kg that you would normally give for that bleed…recheck inhibitor titre after to make sure not rising
what if someone with high titre inhibitor bleeds?
give aPCC or rFVIIIa
rf7a dose for bleed in hemophilia?
90-120 mcg/kg
uses for rF7a in hemphilia other than acute bleed with inhibitor?
surgical and regular ppx (same as for aPCC)
what does aPCC contain?
Fs 2,7,9,10
aPCC dose. for bleeding in hemophilia with inhibitor? for ppx?
bleed: 50-100 IU/kg/dose q8-12 (max 200 iu/kg/day)
ppx: 75 iu/kg q2 days
you ___ tx high titre patients with factor
CANNOT
does ddavp work for inhbitor pts?
no!
what’s the most common bleeding d/o?
VWD (1% by lab…real = 1 in 500)
types of bleeding in vwd?
epistaxis easy bruising oral bleeding post-surg menorrhagia post-partum bleeding
2 roles of vwf?
plt binding
carrier molec for f8
vwf is an __ __ __; what increases it?
acute phase reactant; phgy stress, DDAVP, estogen, preg
vwf circulates as a __ __ protein then binds to __ in ___ and will __. __ then stick to it via ___ ___. plts get activated and more __ gets __ ___
circular globular; collagen subendothelium; unfurl; plts; GP1b receptor. vwf; laid down
describe vwd 2a
AD; multimerization defect with ABSENT large/intermediate size multimers
describe vwd 2b
AD; gain of function mutaionin VWF; too adherent to plts, so large multimers are attached to plts and not circulating
describe vwd 2m
AD; OPPOSITE of 2b…loss of function mutation and does NOT bind well to plts
describe type 2n
AR; pateints are compound heterozygotes with type 1….loss of VWF binding function to F8
inehrtiance of type 3 vwd?
AR…absence of vwf!
Is PTT always high in vwd?
no, only if f8 is low
is bleeding time, pfa-100 a good screening test for vwd?
no, not sensitive enough
dx tests for vwd?
VWF antigen
ristocetin cofactor activity
FVIII
-also, may later do vWF multimer analysis (agarose gel)
for which types of vwd is f8 normal ONLY
2m
for which type of vwd is f8 absent?
3
for which type of vwd is f8 LOW always?
2N
for which types of vwd can f8 be normal or low?
1, 2a, 2b
vwf antigen could be normal or low in which type of vwd?
2m
vwf antigen absent in which type of vwd?
3
ristocetin cofactor absent in which type of vwd?
3
ristocetin cofactor VERY low in which two types of vwd?
2a, 2m
in which type of vwd is there increased aggregation to low dose ristocetin?
2B
in which type of vwd are multimers absent?
3
in which type of vwd are large AND intermediate MW mutliemers decreased?
2a
in which type of VWD are large MW multimers decreased only?
2b
way to dx vwd type 2n?
vwd 2n-f8 binding assay
blood types with lowest to highest vwf ag levels?
O<a></a>
lower limit of normal for vwf ag for o blood group? ab?
35.6, 63.8…a=48…b=56.8
tx for VWD?
DDAVP VWF cocnentrate antifibrolytic estrogen (increases vwf, f8) topical antifibrinolutic topical thrombin for oral or nose bleeds cellulose or collagen embedded gauze
ddavp works for which types of vwd?
type 1, and maybe (?) 2a
major surgery vwd: give what?q
vwf replacmenet; antifibrionlytics
afibrinogenmia can present how?
splenic rupture
preg loss
f10 def can present how?
ICH
f11 def typically bleed when? population?
after surg or trauma; Ashkenazi jewish population
f13 def often presnts how?
umbilical stump bleed, ICH
rare hemophilia inheritance?
AR for all
