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
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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
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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
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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:
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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
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Recombinant FVIIa (90 g/kg q 2-6 hrs) (94% effective)
(common doses 90-200 g/kg q 2-6 hrs-not studied)
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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
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Arterial thromboembolic SAEs occurred significantly (P =
0.01) more frequently with rFVIIa treatment (5%) than
with placebo (0%)
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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