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

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

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 B RESULT A FACTOR LEVEL 20% aPTT 50 sec FACTOR LEVEL 50% aPTT 30 sec Correction No correction INHIBITOR 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 SPECIAL CONSIDERATION 2

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? 2

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.

Compassionate Use Program-Inhibitor Patients Summary of Efficacy (1988-1997) 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

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;79:1463-1467. 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;79:1463-1467.

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 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;352:777-785. Mayer SA et al. N Engl J Med. 2005;352:777-785.

What about Rituximab in Acquired Hemophilia? 2

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.

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 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.

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.