Acquired Factor VIII deficiency

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

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?
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
Factor VIII inhibitor level: 40 Bethesda

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

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

for total 8 dose during first 1 week of
                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
      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
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
      Correction of APTT  autoAb against
      Persistent prolongation of APTT  autoAb against
      a clotting factor  perform the Bethesda assay
Diagnostic tests – Bethesda assay
Use: Quantifies the antibody titre
    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
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
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
Increase the catalytic efficiency of factor IXa
toward factor X (X  Xa)

                                     Blood Reviews 2004;
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
   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
       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
   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
   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
   Form a complex with tissue factor  local
    thrombin generation
   Activate F X (independent of tissue factor) on
    the surface of activated platelets

   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
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
   Adv of dosing every 8-12 hrs
   Cost $0.8/units. i.e. 70 units/kg q8hr = $ 2,800 q8hr
   Thrombosis risk

   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
   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
      Steroid alone – 40 patients (26%)
      Concomitant steroids and cytotoxics – 48 patients
      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
    Immunosuppression stopped or reduced to
     doses used before acquired haemophilia
    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
         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
-ve predictors of outcome
   Age
Not predictors
   Underlying diagnosis (except for postpartum)
   Factor VIII level, inhibitor titre at diagnosis
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
   Tx with steroid or steroid + cytotoxics

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