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Acquired Factor VIII deficiency

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Acquired Factor VIII deficiency Powered By Docstoc
					                Scenario
F/ 86
Autoimmune hypothyroidism
since 2001
Spontaneous bruising for 2
wks: neck, upper limbs, thigh,
flank
Increasing neck swelling with
respiratory arrest on day 1,
intubated and transferred to
ICU
                Scenario

APTT level – 77 second
PT, platelet level – normal
Hb 6.6 (prev Hb 12.4)

Mixing test
   APTT                    85.7 s
   APTT (1:1) mix          49.3 s
   APTT (1:1) mix 37C 1 hr 72.5 s
Cause of bleeding tendency?
 Ddx:
A.   Specimen contaminated by heparin
B.   Lupus anticoagulant
C.   Acquired inhibitors of the intrinsic factor
     pathway (VIII, IX, XI, XII)
D.   Acquired von Willebrand disease
               Scenario
Factor VIII inhibitor level: 40 Bethesda
Unit

Factor VIII level: 5 U/dL
(Normal: 50-200)


Dx: Acquired hemophilia A due to inhibitor
to factor VIII
               Scenario
Given recombinant factor VIIa (Novo-
seven) 4800mcg (90mcg/kg) iv bolus

for total 8 dose during first 1 week of
admission
                Prednisolone 40mg/d + MMF 1g bd since 12/6/07




Factor VIII inhibitor level   40 BU   14 BU
    Diagnostic tests – Mixing test
Identify whether inhibitor is present, but
not inhibitor’s specificity
Step 1: Establish whether a circulating
anticoagulant / inhibitor is present
   Mix equal amounts of the patient’s plasma
    (containing and normal plasma
   Measure APTT
      Immediately
      After incubation at 37 degrees for 1 to 2 hrs
Diagnostic tests – Mixing test
Immediate result
   Correction of the prolonged APTT  factor or
    vWF deficiency
   Persistent prolongation of APTT  inhibitor is
    present
Post-incubation result
   Some inhibitor has delayed reactivity: APTT
    corrected immediately after mixing, but
    prolong again after incubation
    Diagnostic tests – Mixing test
Step 2: Differentiate whether the
circulating anticoagulant is an autoAb
directed against a clotting factor / against
cell membrane phospholipids
   Add a source of phospholipid to the mixed
    plasma
      Correction of APTT  autoAb against
      phospholipid
      Persistent prolongation of APTT  autoAb against
      a clotting factor  perform the Bethesda assay
Diagnostic tests – Bethesda assay
Use: Quantifies the antibody titre
Method:
    Incubate serial dilutions of patient’s plasma
     with normal plasma at 37 degrees for 2 hrs
    Measure the residual FVIII activity
Definition: Number of dilution of patient’s
plasma that result in 50% decrease in
factor VIII activity
    Higher BU  more inhibitor
Acquired Haemophilia
       Acquired vs Congenital
No genetic inheritance pattern
M=F
Median age of presentation: 60 – 70 yrs
Bleeding pattern
   Congenital – haemathroses
   Acquired – soft tissue bleeding, muscle bleeding,
    haematuria, GI bleed
      May present with persistent bleeding after a surgical
      procedure
Increased mortality
       Acquired hemophilia
Most common is against factor VIII
Others: factor v, vii, ix, x, xi, xiii
Factor VIIIa as a cofactor to IXa
Forms a complex with factor X, IXa, phospholipid
surface
Increase the catalytic efficiency of factor IXa
toward factor X (X  Xa)




                                     Blood Reviews 2004;
                                     18:1-15
Anti FVIII Ab prevents F VIII from interaction with
its 4 partners –
phospholipid surface (PLs), vWF, factors IX, X




                               Thromb Haemost 2005; 94:760-9
172 patients identified in 2 yrs
Incidence: 1.48 per million per yr
Median age 78 yrs
Male 43% Female 57 %
      Presenting characteristics – Age




% with underlying diagnosis
     < 40 yrs – 100%
     40-59 yrs – 55%
     60-79 yrs – 42%
     > 80 yrs – 23%
Disease associations
                 No (%)
Presenting characteristics – Levels
             of FVIII
   Presenting characteristics – Bleeding




34% patients do not require haemostatic treatment
2 patients were asymptomatic
               Fatal bleeding
Bleeding is the cause of death in 9.1% at a
median of 19 days
Fatal bleeding can occur up to 5 mths after
presentation if the inhibitor is not eradicated.

Factor VIII and inhibitor titre at presentation were
not useful for predicting the severity of bleeding
events.
   Median inhibitor level was similar for those with fatal
    bleed and those who require no haemostatic therapy
Management options
            Goal of Treatment
Control bleeding
   Agents that increase F VIII levels
       DDAVP
       Factor VIII concentrates
   F VIII bypassing agents
       Activated prothrombin complex concentrates
       Recombinant factor VIIa
Eradication of the inhibitor
   Immunosuppression
   Biological therapy
         Increase F VIII levels
DDAVP
   Release endogenous FVIII protein
   Transient rise in factor VIII
   For patients with very low inhibitor titres <3 BU

Factor VIII concentrates
   Transient - High Ab titres rapidly inactivate FVIII
    concentrates
   For patients with low inhibitor titres <5 BU

FFP and cryoprecipitate do not contain sufficient
FVIII to overcome the inhibitor  rarely effective
F VIII bypassing agents - aPCC
For patients with severe bleeding or inhibitor titre > 5 BU
Each vial contains
    Factor IX, X, II
        F IXa generate additional F VIIa
    Antithrombin III
        Inactivates F Xa and thrombin
    Heparin
        Minimal amount, to forestall risks of thrombosis and DIC
    Low levels of factors V and VII

aPCC 75 units/kg every 8-12 hrs
Max dose of 200 units/kg within a 24 hr period
    Risk of thromboembolism, MI, DIC
       Recombinant factor VIIa
Brand-name: Novo-Seven
Mechanism
   Form a complex with tissue factor  local
    thrombin generation
   Activate F X (independent of tissue factor) on
    the surface of activated platelets

Dose
   90 – 120 microgram/kg every 3 hrs
   Short t ½ 2.7 hrs
   Bolus dose, given over 2-5 min
   Recombinant factor VIIa
At high dose, rFVIIa
binds activated
platelet independent
of TF
Localization activity
-> relative lack of
thrombotic
complication
                            rFVIIa
74 bleeding episodes in 38 patients with
acquired haemophilia
   Median dose 90 microgram/kg every 2-6 hrs
   Median no of doses: 28 per episode
   Median duration of treatment 3.9 days
   Response
      As initial therapy: 100% response rate
      Salvage therapy:
           75% good response rate
           17% partial response
           8% poor control of bleeding
   Those patients who did not respond within 24 hrs
    were unlikely to respond if rVIIa was continued.

                                    Thromb Haemost 1997; 78:1468-7
                  aPCC vs rVIIa
No direct comparison studies
APCC
   Adv of dosing every 8-12 hrs
   Cost $0.8/units. i.e. 70 units/kg q8hr = $ 2,800 q8hr
   Thrombosis risk

rVIIa
   Recombinent protein, less likely to be contaminated
    with infectious agents
   Infused every 2-3 hrs
   More costly
        $ 4,742.50 per vial (1.2 mg) -- $20,000 for each injection
          Inhibitor elimination
Prednisolone 1 mg/kg/day
   Inhibitor abolition in approx 30% of patients
+ Cyclophosphamide 1 to 2 mg/kg
   Increase response rate to 60-70%
   Slow response in 3-6 wks, some may have a
    prolonged response time of mths
   Relapse is not uncommon
Cyclosporin
   Use alone or with prednisolone
   Esp effective in patients with underlying SLE
        Outcome – UK study
Outcome between different treatment gps
   144/151 (95%) were treated with
    immunosuppression
      Steroid alone – 40 patients (26%)
      Concomitant steroids and cytotoxics – 48 patients
      (31%)
      The patient gp treated with steroids alone had a
      lower median inhibitor titre (p <0.01) and factor VIII
      level (not sig)
      But neither the inhibitor titre and factor VIII level
      were associated with outcome
Outcome – Inhibitor eradication
Complete remission – defined as
    Normal factor VIII level, undetectable inhibitor
     level
    Immunosuppression stopped or reduced to
     doses used before acquired haemophilia
     develop
    Without relapse
Outcome – Inhibitor eradication
102/144 patients (71%) achieve CR
    Mean time to remission
       All patients – 57 days
       Steroids alone – 49 days
       Steroids + cytotoxics – 39 days (P = 0.51)
No difference between steroid gp and
steroid + cytotoxic gp (irrespective of
treatment order)
    Outcome – Inhibitor relapse
18 / 90 patients (20%) had a relapse
Median time to relapse
   7.5 mths after stopping immunosuppression (range 1
    to 14 mths)

Out of the 18 patients
   10 patients (56%) achieve a second CR
   4 patients (22%) has inhibitor eradicated and factor
    VIII normalized, but immunosuppression could not be
    stopped without a relapse
   4 patients (22%) could not achieve a second
    remission
         Outcome – Survival
No difference between steroid gp and
steroid + cytotoxic gp (irrespective of
treatment order)
   Median survival time between presentation
    and death
      Steroid alone – 767 days
      Steroids + cytotoxics – 975 days
                  Outcome
-ve predictors of outcome
   Age
Not predictors
   Underlying diagnosis (except for postpartum)
   Factor VIII level, inhibitor titre at diagnosis
               Conclusions
Acquired Hemophilia A
   May not have bleeding, but fatal bleeding
    remains a risk if inhibitor not eradicated.
   No clinical or laboratory features identify the
    high-risk patients
   All patients advised immuno-suppressed once
    diagnosed
   Tx with steroid or steroid + cytotoxics
Thanks

				
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posted:9/14/2011
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