1. Acquired Inhibitors of Coagulation
September 30, 2006
B. GAIL MACIK, M.D.
Associate Clinical Professor of Internal Medicine and Pathology
Acquired Inhibitors of Coagulation

2. GOALS TODAY Review acquired inhibitors to clotting factors
Discuss basic diagnostic scheme for detecting and treating an inhibitor
2. Update treatment options for acquired FVIII inhibitors-Rituximab therapy and rFVIIa
GOALS TODAY 2

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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 B
RESULT A
FACTOR LEVEL
20%
aPTT
50 sec
FACTOR LEVEL
50%
aPTT
30 sec
Correction
No correction
INHIBITOR
FACTOR
DEFICIENCY

9. 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

10. 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

11. 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

12. 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%

13. 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
SPECIAL CONSIDERATION 2

14. Acquired Hemophilia Characteristics
Incidence 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 years of age

15. 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

16. 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

17. 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:

18. 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 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

19. 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

20. 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

21. How effective is rFVIIa in Acquired Hemophilia?2

22. 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
The compassionate use clinical program was developed to allow access to rFVIIa prior to licensure in patients with hemophilia A or B with inhibitors, patients with acquired inhibitors, and patients with FVII deficiency who had failed conventional therapies and interventions. Enrollment began in 1988 and included 211 individuals with hemophilia and inhibitors, 53 with acquired hemophilia, and 27 patients with factor VII deficiency. The recommended dosage for this program was 90 g/kg given every 2 hours in patients with inhibitors. Patients with FVII deficiency were treated with lower doses of rFVIIa (25 to 30 g/kg) as guided by the prothrombin time. As stated, inclusion in this program was granted only after other therapies failed.

23. Compassionate Use Program-Inhibitor Patients
Summary of Efficacy ( )
CNS or
Life-/Limb-
Threatening
Muscle/
Joint
Surgery/
Wound
Other
Total
Bleeds (N)
348
201
215
371
1,135
Bleeds
controlled (N)
Recombinant FVIIa showed a composite 93.9% control rate for bleeding episodes treated on this compassionate program. Approximately 96% of muscle/joint, 91% of surgery/wound, and 88% of CNS or life-/limb-threatening bleeds were controlled. These data are impressive given these patients were not entered into this program in a uniform, controlled, clinical condition, and they had failed prior interventions.
334
182
190
360
1,066
Controlled (%)
95.9
90.5
88.3 97
93.9
93.9% of bleeds controlled with rFVIIa

24. Compassionate Use: Acquired Inhibitors
Efficacy Results at End of Treatment With rFVIIa
100%
100 90
Good 80
75%
Partial 70
Bleeding
episodes (%)
Poor 60 50 40 30
Efficacy data were reported for 74 of 78 bleeding episodes treated with rFVIIa. Of interest and contrary to the protocol, rFVIIa was used as first-line therapy in 14 of 74 bleeding episodes in a total of 6 patients. It was used as salvage therapy in the remaining 60 episodes (29 patients). When rFVIIa was used after other therapies had failed, the response was judged as good or partial in 92% of cases at the end of treatment, specifically as good in 75% of the episodes, partial in 17%, and poor in 8%. The response to rFVIIa as first-line therapy was judged good in all 14 episodes (100%) at the end of treatment.
Hay CRM, et al. Thromb Haemost. 1997;79:
17% 20 8% 10
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:

25. 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
None of the patients receiving placebo experienced arterial thromboembolic SAEs, whereas the overall frequency of these events among the rFVIIa-treated patients was 5% (P = 0.01, Fisher’s exact test).
These events comprised 7 cases of myocardial ischemia and 9 cerebral infarctions, and all except 4 of these events occurred within 3 days of rFVIIa administration.
Of the patients who experienced cerebral infarctions, 2 were massive and fatal, 5 were moderately severe and disabling (of which 2 occurred 26 and 54 days after treatment and were not considered to be treatment related), and 2 were asymptomatic.
Thromboembolic events that were possibly or probably related to treatment and 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:
Mayer SA et al. N Engl J Med. 2005;352:

26. What about Rituximab in Acquired Hemophilia?2

27. 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 non-responder 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
The compassionate use clinical program was developed to allow access to rFVIIa prior to licensure in patients with hemophilia A or B with inhibitors, patients with acquired inhibitors, and patients with FVII deficiency who had failed conventional therapies and interventions. Enrollment began in 1988 and included 211 individuals with hemophilia and inhibitors, 53 with acquired hemophilia, and 27 patients with factor VII deficiency. The recommended dosage for this program was 90 g/kg given every 2 hours in patients with inhibitors. Patients with FVII deficiency were treated with lower doses of rFVIIa (25 to 30 g/kg) as guided by the prothrombin time. As stated, inclusion in this program was granted only after other therapies failed.

28. 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 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
The compassionate use clinical program was developed to allow access to rFVIIa prior to licensure in patients with hemophilia A or B with inhibitors, patients with acquired inhibitors, and patients with FVII deficiency who had failed conventional therapies and interventions. Enrollment began in 1988 and included 211 individuals with hemophilia and inhibitors, 53 with acquired hemophilia, and 27 patients with factor VII deficiency. The recommended dosage for this program was 90 g/kg given every 2 hours in patients with inhibitors. Patients with FVII deficiency were treated with lower doses of rFVIIa (25 to 30 g/kg) as guided by the prothrombin time. As stated, inclusion in this program was granted only after other therapies failed.

29. 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
The compassionate use clinical program was developed to allow access to rFVIIa prior to licensure in patients with hemophilia A or B with inhibitors, patients with acquired inhibitors, and patients with FVII deficiency who had failed conventional therapies and interventions. Enrollment began in 1988 and included 211 individuals with hemophilia and inhibitors, 53 with acquired hemophilia, and 27 patients with factor VII deficiency. The recommended dosage for this program was 90 g/kg given every 2 hours in patients with inhibitors. Patients with FVII deficiency were treated with lower doses of rFVIIa (25 to 30 g/kg) as guided by the prothrombin time. As stated, inclusion in this program was granted only after other therapies failed.