Acquired Inhibitors of Coagulation
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Transcript Acquired Inhibitors of Coagulation
Acquired Inhibitors of Coagulation
September 30, 2006
B. GAIL MACIK, M.D.
Associate Clinical Professor of Internal Medicine and Pathology
GOALS TODAY
1. Review acquired inhibitors to clotting factors
2. Discuss basic diagnostic scheme for detecting and
treating an inhibitor
2. Update treatment options for acquired FVIII inhibitorsRituximab therapy and rFVIIa
Definition of a Coagulation
Inhibitor
AN ANTIBODY THAT NEUTRALIZES THE
FUNCTION OR REMOVES A CLOTTING
FACTOR FROM CIRCULATION
Usually presents as spontaneous or excessive
bleeding
May present as laboratory abnormality; ie,
prolonged PTT/PT
Types of Inhibitors
Alloantibodies – occur in patients with a
congenital clotting factor deficiency
Autoantibodies – arise de novo in people without
a history of a clotting factor deficiency
May occur with other autoimmune disorders
May be seen with lymphoproliferative disorders
Occur any age but increase incidence of
spontaneous inhibitors in the elderly
Incidence of Clotting Factor
Inhibitors
ALL AUTOANTIBODIES ARE UNCOMMON
Most frequent – Factor VIII, VWF, Factor II (APS?)
Less common – Factor V, IX, XI, XIII
Rare but reported – Fibrinogen, VII, X
Clotting Factor Acquired Inhibitors
Special associations
FV with topical thrombin products – cross reaction to
Bovine FV in some preps
FV with aminoglycosides or cephlosporins
FII or thrombin with topical thrombin preps
FII or thrombin with Antiphospholipid antibodies
FVIII with penicillin derivatives
FXIII with Isoniazid
FX with amyloidosis
FXI with genital urinary defects/cancers
FVIII, FIX, fibrinogen with pregnancy
Incidence of Clotting Factor Inhibitors
Special associations – more
Cancers are associated with acquired inhibitors
FV with Waldenstroms macroglobulinemia
FXI with Bladder/prostate cancers
Lymphoproliferative disorders / MGUS with
VWF/VIII particularly but also with other factors
Other autoimmune disorders are associated with
clotting factor inhibitors-SLE, RA, etc
Diagnosis of Clotting Factor Inhibitors
PATIENT BLOOD:
NORMAL BLOOD:
FACTOR LEVEL 0%
aPTT 80 sec
FACTOR LEVEL 100%
aPTT 28 sec
MIXING
STUDY
NOTE: ONLY 30-40% FACTOR
REQUIRED FOR NORMAL aPTT
50% PATIENT : 50% NORMAL
RESULT A
No correction
INHIBITOR
FACTOR LEVEL
20%
aPTT
50 sec
RESULT B
FACTOR LEVEL
50%
aPTT
30 sec
Correction
FACTOR
DEFICIENCY
Diagnosis of Clotting Factor Inhibitors
The PT and PTT are the screening studies
Prolonged PT +/- PTT that CORRECTS PLUS low
factor level = “clearing” antibody that does not interfere
with protein function
Prolonged PT +/- PTT that FAILS to correct =
“neutralizing” antibody that prevents protein function and
may or may not accelerate clearance
Diagnosis of Clotting Factor Inhibitors
The PT and PTT are the screening studies:
PT + PTT that initially corrects on mix but then prolongs
with 1-2 hour incubation = FV inhibitor
PTT that initially corrects on mix but then prolongs =
FVIII inhibitor
Normal PT + PTT with new hematomas/bleeding = FXIII
inhibitor
Treatment of Clotting Factor Inhibitors
FACTOR REPLACEMENT
Platelet transfusion may help with FV, fibrinogen, VWF, or
FXIII replacement - factor “hidden” from antibody
FFP, cryoprecipitate, or clotting factor concentrate,
depending on factor involved have limited success
rVIIa reported to be used with FII, FV, FVIII, FIX, VWF,
FXIII and FXI antibodies ( approved for FVIII and FIX)
Plasmapheresis/exchange tried with limited success to
decrease antibody titer to allow replacement to work
May NOT need replacement if no active bleeding
particularly with FV or FII antibodies
Treatment of Clotting Factor Inhibitors
ERADICATION OF THE INHIBITOR
Prednisone is mainstay of treatment with variable results
IVIg may work with any inhibitors - particularly with VWF
inhibitors
Rituximab has been increasingly tried - limited data
Immunosuppressive drugs are often used cyclophosphamide and azothiaprine most commonly
No treatment is an option if no clinical bleeding
Spontaneous remission or remission with treatment of
underlying disorder occurs ~ 30-80%
SPECIAL CONSIDERATION
Factor VIII autoantibodies are the most common
acquired inhibitor. Acquired hemophilia is
much better characterized than other factor
inhibitors and special treatments more actively
studied
Acquired Hemophilia 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
Acquired Hemophilia Characteristics
Most individuals are previously healthy-idiopathic
Some have defined or evolving associations:
Autoimmune (SLE, RA)
Lymphoproliferative disease
Multiple Sclerosis
Graft-vs.-Host after allogeneic BM transplant
Asthma, Inflammatory Bowel Disease, Pempigus
Severe allergic reactions to:antibiotics, interferon-,
BCG vaccine
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
FVIII Inhibitors Inactivate FVIII
Autoantibody Inactivation
Kinetics
• Display type II kinetics
• Clearance is not linear
• Difficult to “overwhelm”
with clotting factor
replacement
Boggio, LN, Green D. Rev Clin Exp Hematol. 2001;5:389-404
Treatment of Bleeding in Factor VIII
Autoantibodies
Human Factor VIII Concentrates (if < 5 BU)
Porcine Factor VIII (90 U/kg q 12 hrs) (80%
effective) NOT CURRENTLY AVAILABLE
Bypassing agents
Recombinant FVIIa (90 g/kg q 2-6 hrs) (94% effective)
(common doses 90-200 g/kg q 2-6 hrs-not studied)
FEIBA (70 U/kg q 8-12 hrs) (81% effective)
Autoplex (>50 U/kg) (75-80% effective) NOT AVAILABLE
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
Management of Autoantibody to Factor VIII
Immunosuppressive Medications
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, rituximab, interferon ,
Induction of immune tolerance does not work
How effective is rFVIIa
in Acquired
Hemophilia?
Compassionate Use Program
Objective: Provide rFVIIa as salvage therapy
Enrollment began in 1988
211 persons with hemophilia A or B
53 persons with acquired inhibitors
27 persons with FVII deficiency
Recommended dosages
Inhibitor: 90 µg/kg q2h
Use of rFVIIa granted only after other therapies
failed
Compassionate Use Program-Inhibitor Patients
Summary of Efficacy (1988-1997)
Muscle/
Joint
Surgery/
Wound
CNS or
Life-/LimbThreatening
Other
Total
Bleeds (N)
348
201
215
371
1,135
Bleeds
controlled (N)
334
182
190
360
1,066
Controlled (%)
95.9
90.5
88.3
97
93.9
93.9% of bleeds controlled with rFVIIa
Compassionate Use: Acquired Inhibitors
Efficacy Results at End of Treatment With rFVIIa
100
90
80
70
Bleeding
episodes (%) 60
50
40
30
20
10
0
100%
Good
Partial
Poor
75%
17%
8%
Salvage
1st Line
92% good/partial response rate with salvage therapy
100% excellent/good response rate with first-line therapy
Hay CRM, et al. Thromb Haemost. 1997;79:1463-1467.
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.
What about Rituximab in
Acquired Hemophilia?
Rituximab in Acquired Hemophilia
14 published reports (review 6/2006, Ann Pharmacotherapy)
Dose - 375mg/m2 weekly X 4 most common (same as lymphoma)
Case reports - 5 single case and 3 with 2 patients=11pt
Ages 28-81, duration of ab 22d-10yrs, all failed previous tx
Normalized hemostasis in 9/11 patients reported (one nonresponder died of airway hematoma after 2nd dose)
8 pts required 1-4 doses / 1 pt received 11 doses over 21mon
Small series 3 pts-all complete response to 4 wk therapy
Small series 4 pts-all rapid complete response within 2-3 weeks
Small series 4 pts-3/3 “autos” responded, 1 allo less effect
Small series 4 pts-4/4 responded but duration 3.5/8.5 months with
response to additional course of rituximab
Rituximab in Acquired Hemophilia
1 small open label trial in 10 patients
Co-morbidities prostate cancer, NHL, pregnancy, RA in 4 pts
4pts received prior therapy for inhibitor – pred+CTN, or COP
Titers range 4-250 BU, all FVIII levels < 1%
Rituximab given once weekly X 4
Results
8 pts with rapid resolution of bleeding
Normalized FVIII in 8/10 pts; 2 had 50% decrease in titer
2 partial responders completely normalized with
cyclophosphamide 1 gm/m2 + rituximab
Therapy well tolerated with mild reactions in 4/10 pts
Relapse occurred in 3 pts (10, 14, 20 weeks) and all responded
to second course of rituximab
Key Articles
Stachnik JM. Rituximab in the treatment of acquire hemophilia.
Ann Pharmacother 2006 vol 40:1151.
Franchini M and Veneri D. Acquired coagulation inhibitor
associated bleeding disorders: An update. Hematology 2005 vol
10:443.
Macik BG and Crow P. Acquired autoantibodies to coagulation
factors. Curr Opin Hematol 1999 vol 6:323
Pruthi RK, Nichols WL. Autoimmune factor VIII inhibitors. Curr
Opin Hematol 1999 vol 6:314
Hay CRM, Negrier C, Ludlam CA. The treatment of bleeding in
acquired hemophilia with recombinant factor VIIa: A multicenter
study. Thromb Haemost 1997 vol 78:3