Acquired Hemophilia A

1. ACQUIRED
HEMOPHILIA A

2. ACQUIRED HEMOPHILIA A
CHARACTERISTICS
Incidence 0.2-1.0 case per million per year – is
incidence increasing???
80-90% present with major hemorrhages
10-22% mortality attributed to inhibitor
Biphasic age distribution
 Small peak in young postpartum women
 Major peak in 60-80 years of age

3. ACQUIRED HEMOPHILIA A
CHARACTERISTICS
 Most individuals are
previously healthy-idiopathic.
 Some have defined
or evolving
associations.

4. CLINICAL MANIFESTATIONS OF ACQUIRED
HEMOPHILIA
 Overt bleeding -most frequently bruising, muscle
hematomas, GI bleeding, hematuria
 Iatrogenic - IV lines, bladder catheterization or post
surgical bleeding
 Acute complications - compartment syndromes, airway
compression 2nd to subglottic bleeding
 Values of more than 5 BU/ml are defined as high
titer inhibitors and are generally associated with
more aggressive bleeding and delayed responses
to treatment .

5. FVIII INHIBITORS INACTIVATE
FVIII
AAuuttooaannttiibbooddyy IInnaaccttiivvaattiioonn
KKiinneettiiccss
• DDiissppllaayy ttyyppee IIII kkiinneettiiccss
• CClleeaarraannccee iiss nnoott lliinneeaarr
• DDiiffffiiccuulltt ttoo ““oovveerrwwhheellmm””
wwiitthh cclloottttiinngg ffaaccttoorr
rreeppllaacceemmeenntt
Boggio, LN, Green D. Rev Clin Exp Hematol. 2001;5:389-404

6. LABORATORY EVALUATION IN
A BLEEDING PATIENT
 PLATELET COUNT
 BLEEDING TIME (BT)
 PROTHROMBIN TIME (PT)
 PARTIAL THROMBOPLASTIN TIME
(PTT)
 THROMBIN TIME (TT)

7. CLINICAL FEATURES OF
BLEEDING DISORDERS
Platelet Factor
Disorders
Coagulation
disorders
Site of bleeding Skin, Mucous
membranes (epistaxis,
gum, vaginal, GI tract)
Deep in soft tissues
(joints, muscles)
Petechiae Yes No
Ecchymoses (“bruises”) Small, superficial Large, deep
Hemarthrosis / muscle
bleeding
Extremely rare Common
Bleeding after cuts &
scratches
Yes No
Bleeding after surgery
or trauma
Immediate Delayed (1-2 days)

8. Platelet Coagulation
Purpura
Ecchymoses
Petechiae

9. THE CLOTTING MECHANISM
Collagen Tissue Thromboplastin
aPTT PT
X
V
VII
XII
XI
IX
VIII
PROTHROMBIN THROMBIN
FIBRINOGEN
(I)
(II) (III) FIBRIN

10. Look at Thrombin
Time!!!

11. When you see isolated PROLONGED
aPTT, the next test to order is……
aPTT MIXING STUDY!!!!

12. PTT MIXING STUDIES:
 Mixing studies are tests performed on blood
plasma used to distinguish factor deficiencies
from factor inhibitors, such as lupus
anticoagulant (LA), or specific factor inhibitors,
such as antibodies directed against factor VIII.

13. PTT MIXING STUDIES:
 Mixing studies take advantage of the fact that
factor levels that are 50 percent of normal
should give a normal Prothrombin time (PT)
or Partial Thromboplastin time.

14. PTT MIXING STUDIES:
 Mixing studies can help determine the
appropriate next steps to take to diagnose
the cause of an abnormal APTT or PT.

15. TEST METHOD
 The patient plasma is mixed
1:1 with Normal pooled
plasma that contains 100%
of the normal factor level
results in a level ≥ 50% in
the mixture (say the patient
has an activity of 0%; the
average of 100% + 0% =
50%).
 Therefore, correction with
mixing indicates factor
deficiency; failure to correct
indicates an inhibitor.

16. TEST METHOD
 Some inhibitors are time dependent. The clotting test
performed immediately after the specimens are mixed
may show correction because the antibody has not
had time to inactivate the added factor (false positive).
A test performed after the mixture is incubated for 2
hours at 37°C will show prolongation.
 Nonspecific inhibitors like the lupus anticoagulant
usually are not time dependent; the immediate
mixture will show prolongation.
 Many specific factor inhibitors are time dependent,
and the inhibitor will not be detected unless the test
is repeated after incubation (factor VIII inhibitors are
notorious for this).

18. INTERPRETATION
Differentiation of Factor Deficiency and Inhibitors By Mixing Studies
1:1 Mixing Study Results
Not incubated Incubated
Factor deficiency Correction Correction
Immediate acting inhibitor No correction No correction
Time/temperature
dependent inhibitor
Correction
(Falsely) No correction
Table adapted from McKenzie, S.,, Clinical l Laboratory Hematology, 2004, p. 790.

19. VALUES EXPECTED

20. THE BETHESDA UNIT
One Bethesda Unit:
The amount of antibody that
inhibits half of the factor VIII
activity in a 1 to 1 mixture of
patient plasma and normal
plasma incubated at 37°C
for 2 hours
Kasper, 1975

21. Treatment of Bleeding in Factor VIII
Autoantibodies-Control Bleeding and
Eliminate Inhibitors
For patients with non life-threatening
bleeding and low inhibitor titers, DDAVP
at a dose of 0.3 mcg/kg SQ per day given
for three to five days may be sufficient for
control of bleeding or for hemostatic
coverage of invasive procedures .

22. Treatment of Bleeding in Factor VIII
Autoantibodies-Control Bleeding and
Eliminate Inhibitors
Most bleeding associated with low titer
inhibitors (ie, <5 Bethesda units) may be
treated with human factor VIII
concentrates at high doses (eg, 20 IU/kg
for each Bethesda unit of the inhibitor plus
an additional 40 IU/kg, with monitoring of
factor VIII activity 10 minutes following
bolus injection, and repeat IV bolus
dosing if the incremental recovery is not
adequate).

23. Treatment of Bleeding in Factor VIII Autoantibodies-
Control Bleeding and Eliminate Inhibitors
 For patients with higher titer factor VIII inhibitors (>5
BU) or severe bleeding, treatment with activated
prothrombin complex (eg, factor VIII inhibitor
bypassing activity [FEIBA]) or human recombinant
human factor VIIIa (rfVIIa) can be employed.
 Bypassing agents achieve an 86% control in all
bleeding types and a 76% control in severe
bleedings.
 Recommended doses are similar to those employed
in hemophilia patients with inhibitors (eg, typical
FEIBA dose 75 units/kg; rfVIIa median starting dose
90.4 mcg/kg, range 45 to 181 mcg/kg).

24. NovoSeven® (rFVIIa) controls bleeding at the site of
vascular injury only1
rFVIIa works locally at the site
of vascular injury, where tissue
factor (TF) is exposed and
activated platelets are found1
Binding of factor VIIa or rFVIIa
to TF initiates the coagulation
generating small amounts of
thrombin2 
At pharmacological doses
rFVIIa directly activates factor
X on the surface of activated
platelets resulting in a
“thrombin burst”3,4 
The thrombin burst leads to
the formation of a stable
haemostatic plug which
controls the bleeding3 
Haemostasis and NovoSeven® – mode
of action; Feb 2006
Adapted from Hoffman M et al., 2001.1

25. Side Effects of Treatment of Bleeding in
Autoantibodies
Recombinant FVIIa - Thrombosis (< 2%)
FEIBA and Autoplex
Thrombosis
Allergic Reactions
Low risk for transmission of infectious agents

26. Arterial and Fatal Thromboembolic SAEs
DATA from ICH Study
 Arterial thromboembolic SAEs occurred significantly
(P = 0.01) more frequently with rFVIIa treatment (5%)
than with placebo (0%)
These events manifested in the form of myocardial ischemic
events (7) and cerebral infarction (9)
 Thromboembolic SAEs that were fatal or disabling
occurred in 2% of rFVIIa-treated patients compared
with 2% in the placebo group
Mayer SA et al. N Engl J Med. 2005;352:777-785.

27. Management of Autoantibody to Factor VIII
 Immunosuppressive Medications
 Immediate initiation of immunosuppressive therapy after
confirmation of AHA diagnosis is recommended.
Prednisone 60 mg/day x 3-6 wks
Work better in low titer, new inhibitors with no
associated disease
 Others
Combined Rx - prednisone plus cyclophosphamide
Cyclosporine, tacrolimus, azathioprine, mycophenolate
mofetil, interferon a.
Rituximab has been used in refractory cases in a dose
of 375 mg/m2 every week for 4 weeks.

28. Management of Autoantibody to Factor
VIII
 The above therapies have been shown to achieve a
complete remission (CR) rate of inhibitor eradication
between 52- 82%.
 Complete remission is defined as normal Factor VIII
activity (70%-140%) without factor substitution and
undetectable inhibitor titer levels.
 Partial remission can be defined as attaining a
minimum of FVIII recoveries of 30% and/or a
reduction of the inhibitor titer to less than 5 BU
without further bleeding events.

29. TREATMENT
There is no evidence that one
immunosuppressive therapy is clinically
superior to all others in treating AHA or that a
certain therapy should be chosen depending
on inhibitor titer or the hemorrhagic status.
Therefore, first-line treatment is determined
by evaluation of disease condition and
consideration of possible adverse effects.

30. MANAGEMENT OF AUTOANTIBODY
TO FACTOR VIII
Physical removal of inhibitors by plasma
exchange therapy or protein A
adsorption column is effective for
transient removal of inhibitors in patients
with acute, severe bleeding.

31. MODIFIED BONN MALMÖ
PROTOCOL (MBMP)
1. Large-volume immunoadsorption (IA) (2.5-3x total plasma
volume on days 1-5)
2. I.v. IgG substitution (0.3 g/kg body weight (BW)/d, on days 5-
7)
3. Immunosuppression with cyclophosphamide (1-2 mg/kg BW/d)
and prednisolone (1 mg/kg BW/d) from day 1 until remission
(dose reduction),
4. Administration of FVIII, typically 100 IU/kg BW every 6 hours.
Zeitler H et al. Atheroscler Suppl. 2009 Dec 29;10(5):122-5.

32. MONITORING RESPONSE TO
TREATMENT
 Primary goal of treatment is cessation of bleeding,
followed ultimately by a decrease in the titer of the
inhibitor.
 The former is monitored via the usual clinical and
laboratory observations (eg, observable blood loss,
blood in urine or stool, repeated blood counts).
 Since inhibitor titers drop very slowly following
successful treatment, it is neither necessary nor
advisable to check the patient’s aPTT or inhibitor titer
more often than every two to four weeks once
immunosuppressive therapy has been started.

33. SUMMARY
 When encountered with a bleeding elderly patient with isolated
prolonged PTT-think coagulation factor inhibitors vs acquired
VWD vs Lupus Anticoagulant (associated more with
thrombosis).
 If thrombin time is normal, heparin as the etiology for prolonged
PTT less likely.
 Call the lab and expedite PTT Mixing study.
 Make sure the lab does the delayed phase of the PTT Mixing
Study.
 Treat bleeding aggressively with bypass agents and
immunosuppressives simultaneously.
 Immunoadsorption is a safe and highly effective alternative with
a high potential to cure severe AH.