September 30, 2006September 30, 2006

B. GAIL MACIK, M.D.Associate Clinical Professor of Internal Medicine and Pathology

Acquired Inhibitors of Coagulation Acquired Inhibitors of Coagulation Acquired Inhibitors of Coagulation Acquired Inhibitors of Coagulation

1.1. Review acquired inhibitors to clotting factorsReview acquired inhibitors to clotting factors

2.2. Discuss basic diagnostic scheme for detecting and Discuss basic diagnostic scheme for detecting and treating an inhibitortreating an inhibitor

2. Update treatment options for acquired FVIII 2. Update treatment options for acquired FVIII inhibitors-Rituximab therapy and rFVIIainhibitors-Rituximab therapy and rFVIIa

GOALS TODAYGOALS TODAY

Definition of a Coagulation Definition of a Coagulation InhibitorInhibitor

AN ANTIBODY THAT NEUTRALIZES THE AN ANTIBODY THAT NEUTRALIZES THE FUNCTION OR REMOVES A CLOTTING FUNCTION OR REMOVES A CLOTTING

FACTOR FROM CIRCULATIONFACTOR FROM CIRCULATION

Usually presents as spontaneous or excessive Usually presents as spontaneous or excessive bleedingbleeding

May present as laboratory abnormality; ie, May present as laboratory abnormality; ie, prolonged PTT/PTprolonged PTT/PT

Types of InhibitorsTypes of Inhibitors

Alloantibodies – occur in patients with a Alloantibodies – occur in patients with a congenital clotting factor deficiencycongenital clotting factor deficiency

Autoantibodies – arise de novo in people without Autoantibodies – arise de novo in people without a history of a clotting factor deficiencya history of a clotting factor deficiency

May occur with other autoimmune disordersMay occur with other autoimmune disorders May be seen with lymphoproliferative disordersMay be seen with lymphoproliferative disorders Occur any age but increase incidence of Occur any age but increase incidence of

spontaneous inhibitors in the elderlyspontaneous inhibitors in the elderly

Incidence of Clotting Factor Incidence of Clotting Factor InhibitorsInhibitors

ALL AUTOANTIBODIES ARE UNCOMMONALL AUTOANTIBODIES ARE UNCOMMON

Most frequent – Factor VIII, VWF, Factor II Most frequent – Factor VIII, VWF, Factor II (APS?)(APS?)

Less common – Factor V, IX, XI, XIIILess common – Factor V, IX, XI, XIII

Rare but reported – Fibrinogen, VII, XRare but reported – Fibrinogen, VII, X

Clotting Factor Acquired InhibitorsClotting Factor Acquired InhibitorsSpecial associationsSpecial associations

FV with topical thrombin products – cross reaction to Bovine FV in FV with topical thrombin products – cross reaction to Bovine FV in some prepssome preps

FV with aminoglycosides or cephlosporinsFV with aminoglycosides or cephlosporins FII or thrombin with topical thrombin prepsFII or thrombin with topical thrombin preps FII or thrombin with Antiphospholipid antibodiesFII or thrombin with Antiphospholipid antibodies FVIII with penicillin derivativesFVIII with penicillin derivatives FXIII with Isoniazid FXIII with Isoniazid FX with amyloidosisFX with amyloidosis FXI with genital urinary defects/cancersFXI with genital urinary defects/cancers FVIII, FIX, fibrinogen with pregnancyFVIII, FIX, fibrinogen with pregnancy

Incidence of Clotting Factor InhibitorsIncidence of Clotting Factor Inhibitors

Special associations – moreSpecial associations – more

Cancers are associated with acquired inhibitors Cancers are associated with acquired inhibitors FV with Waldenstroms macroglobulinemiaFV with Waldenstroms macroglobulinemia FXI with Bladder/prostate cancersFXI with Bladder/prostate cancers Lymphoproliferative disorders / MGUS with Lymphoproliferative disorders / MGUS with

VWF/VIII particularly but also with other factorsVWF/VIII particularly but also with other factors

Other autoimmune disorders are associated with Other autoimmune disorders are associated with clotting factor inhibitors-SLE, RA, etcclotting factor inhibitors-SLE, RA, etc

MIXING MIXING STUDYSTUDY

NORMAL BLOOD:FACTOR LEVEL 100%

aPTT 28 sec

PATIENT BLOOD:FACTOR LEVEL 0%

aPTT 80 sec

NOTE: ONLY 30-40% FACTOR NOTE: ONLY 30-40% FACTOR REQUIRED FOR NORMAL aPTTREQUIRED FOR NORMAL aPTT

50% PATIENT : 50% NORMAL

FACTOR LEVEL 50%

aPTT 30 sec

FACTOR LEVEL 20%

aPTT 50 sec

INHIBITORFACTOR DEFICIENCY

CorrectionNo correction

RESULT A RESULT B

Diagnosis of Clotting Factor InhibitorsDiagnosis of Clotting Factor Inhibitors

Diagnosis of Clotting Factor InhibitorsDiagnosis of Clotting Factor Inhibitors

The PT and PTT are the screening studiesThe PT and PTT are the screening studies

Prolonged PT +/- PTT that CORRECTS Prolonged PT +/- PTT that CORRECTS PLUSPLUS low factor low factor level = “clearing” antibody that does not interfere with level = “clearing” antibody that does not interfere with protein function protein function

Prolonged PT +/- PTT that FAILS to correct = Prolonged PT +/- PTT that FAILS to correct = “neutralizing” antibody that prevents protein function and “neutralizing” antibody that prevents protein function and may or may not accelerate clearancemay or may not accelerate clearance

Diagnosis of Clotting Factor InhibitorsDiagnosis of Clotting Factor Inhibitors

The PT and PTT are the screening studies:The PT and PTT are the screening studies:

PT + PTT that initially corrects on mix but then prolongs PT + PTT that initially corrects on mix but then prolongs with 1-2 hour incubation = FV inhibitorwith 1-2 hour incubation = FV inhibitor

PTT that initially corrects on mix but then prolongs = PTT that initially corrects on mix but then prolongs = FVIII inhibitorFVIII inhibitor

Normal PT + PTT with new hematomas/bleeding = FXIII Normal PT + PTT with new hematomas/bleeding = FXIII inhibitorinhibitor

Treatment of Clotting Factor InhibitorsTreatment of Clotting Factor Inhibitors

FACTOR REPLACEMENTFACTOR REPLACEMENTPlatelet transfusion may help with FV, fibrinogen, VWF, or Platelet transfusion may help with FV, fibrinogen, VWF, or

FXIII replacement - factor “hidden” from antibodyFXIII replacement - factor “hidden” from antibodyFFP, cryoprecipitate, or clotting factor concentrate, FFP, cryoprecipitate, or clotting factor concentrate,

depending on factor involved have limited successdepending on factor involved have limited successrVIIa reported to be used with FII, FV, FVIII, FIX, VWF, FXIII rVIIa reported to be used with FII, FV, FVIII, FIX, VWF, FXIII

and FXI antibodies ( approved for FVIII and FIX)and FXI antibodies ( approved for FVIII and FIX)Plasmapheresis/exchange tried with limited success to Plasmapheresis/exchange tried with limited success to

decrease antibody titer to allow replacement to workdecrease antibody titer to allow replacement to workMay NOT need replacement if no active bleeding May NOT need replacement if no active bleeding

particularly with FV or FII antibodiesparticularly with FV or FII antibodies

Treatment of Clotting Factor InhibitorsTreatment of Clotting Factor Inhibitors

ERADICATION OF THE INHIBITORERADICATION OF THE INHIBITORPrednisone is mainstay of treatment with variable results Prednisone is mainstay of treatment with variable results IVIg may work with any inhibitors - particularly with VWF IVIg may work with any inhibitors - particularly with VWF

inhibitorsinhibitorsRituximab has been increasingly tried - limited dataRituximab has been increasingly tried - limited dataImmunosuppressive drugs are often used - Immunosuppressive drugs are often used -

cyclophosphamide and azothiaprine most commonly cyclophosphamide and azothiaprine most commonly No treatment is an option if no clinical bleedingNo treatment is an option if no clinical bleedingSpontaneous remission or remission with treatment of Spontaneous remission or remission with treatment of

underlying disorder occurs ~ 30-80%underlying disorder occurs ~ 30-80%

Factor VIII autoantibodies are the most common Factor VIII autoantibodies are the most common acquired inhibitor. Acquired hemophilia is acquired inhibitor. Acquired hemophilia is

much better characterized than other factor much better characterized than other factor inhibitors and special treatments more inhibitors and special treatments more

actively studiedactively studied

SPECIAL CONSIDERATIONSPECIAL CONSIDERATION

Acquired Hemophilia CharacteristicsAcquired Hemophilia Characteristics

Incidence 0.2-1.0 case per million per year – is Incidence 0.2-1.0 case per million per year – is incidence increasing???incidence increasing???

80-90% present with major hemorrhages80-90% present with major hemorrhages10-22% mortality attributed to inhibitor10-22% mortality attributed to inhibitorBiphasic age distributionBiphasic age distribution

Small peak in young postpartum womenSmall peak in young postpartum women Major peak in 60-80 years of ageMajor peak in 60-80 years of age

Most individuals are previously healthy-idiopathicMost individuals are previously healthy-idiopathicSome have defined or evolving associations:Some have defined or evolving associations:

Autoimmune (SLE, RA)Autoimmune (SLE, RA) Lymphoproliferative disease Lymphoproliferative disease Multiple SclerosisMultiple Sclerosis Graft-vs.-Host after allogeneic BM transplant Asthma, Inflammatory Bowel Disease, Pempigus Severe allergic reactions to:antibiotics, interferon-,

BCG vaccine

Acquired Hemophilia CharacteristicsAcquired Hemophilia Characteristics

Clinical Manifestations of Acquired Clinical Manifestations of Acquired HemophiliaHemophilia

Overt bleeding -most frequently bruising, Overt bleeding -most frequently bruising, muscle hematomas, GI bleeding, hematuriamuscle hematomas, GI bleeding, hematuria

Iatrogenic - IV lines, bladder catheterization Iatrogenic - IV lines, bladder catheterization or post surgical bleedingor post surgical bleeding

Acute complications - compartment Acute complications - compartment syndromes, airway compression 2nd to syndromes, airway compression 2nd to subglottic bleedingsubglottic bleeding

FVIII Inhibitors Inactivate FVIIIFVIII Inhibitors Inactivate FVIII

Boggio, LN, Green D. Rev Clin Exp Hematol. 2001;5:389-404

Autoantibody Inactivation Autoantibody Inactivation KineticsKinetics

• Display type II kineticsDisplay type II kinetics• Clearance is not linearClearance is not linear• Difficult to “overwhelm” Difficult to “overwhelm”

with clotting factor with clotting factor replacementreplacement

Treatment of Bleeding in Factor VIII Treatment of Bleeding in Factor VIII AutoantibodiesAutoantibodies

Human Factor VIII Concentrates (if < 5 BU)Human Factor VIII Concentrates (if < 5 BU)Porcine Factor VIII (90 U/kg q 12 hrs) Porcine Factor VIII (90 U/kg q 12 hrs) (80% (80%

effective) NOT CURRENTLY AVAILABLEeffective) NOT CURRENTLY AVAILABLEBypassing agentsBypassing agents

Recombinant FVIIa (90 Recombinant FVIIa (90 g/kg q 2-6 hrs)g/kg q 2-6 hrs) (94% effective) (94% effective)

(common doses 90-200 (common doses 90-200 g/kg q 2-6 hrs-not studied)g/kg q 2-6 hrs-not studied) FEIBA (70 U/kg q 8-12 hrs) FEIBA (70 U/kg q 8-12 hrs) (81% effective)(81% effective) Autoplex (Autoplex (>>50 U/kg) 50 U/kg) (75-80% effective) NOT AVAILABLE(75-80% effective) NOT AVAILABLE

Side Effects of Treatment of Bleeding in Side Effects of Treatment of Bleeding in AutoantibodiesAutoantibodies

Recombinant FVIIa - Thrombosis (< 2%?) Recombinant FVIIa - Thrombosis (< 2%?) FEIBA and AutoplexFEIBA and Autoplex

ThrombosisThrombosis Allergic ReactionsAllergic Reactions Low risk for transmission of infectious agentsLow risk for transmission of infectious agents

Management of Autoantibody to Factor VIIIManagement of Autoantibody to Factor VIII

Immunosuppressive MedicationsImmunosuppressive Medications Prednisone 60 mg/day x 3-6 wksPrednisone 60 mg/day x 3-6 wks Work better in low titer, new inhibitors with no Work better in low titer, new inhibitors with no

associated diseaseassociated disease

OthersOthers Combined Rx - prednisone plus Combined Rx - prednisone plus cyclophosphamide cyclophosphamide Cyclosporine, tacrolimus, azathioprine, mycophenolate Cyclosporine, tacrolimus, azathioprine, mycophenolate

mofetil, rituximab, interferon mofetil, rituximab, interferon , ,

Induction of immune tolerance Induction of immune tolerance does not workdoes not work

How effective is How effective is rFVIIa in Acquired rFVIIa in Acquired

Hemophilia?Hemophilia?

Compassionate Use ProgramCompassionate Use Program

Objective: Provide rFVIIa as salvage therapyObjective: Provide rFVIIa as salvage therapyEnrollment began in 1988Enrollment began in 1988

211 persons with hemophilia A or B211 persons with hemophilia A or B 53 persons with acquired inhibitors53 persons with acquired inhibitors 27 persons with FVII deficiency27 persons with FVII deficiency

Recommended dosagesRecommended dosages Inhibitor: 90 µg/kg q2hInhibitor: 90 µg/kg q2h

Use of rFVIIa granted only after other therapies failedUse of rFVIIa granted only after other therapies failed

93.9% of bleeds controlled with rFVIIa93.9% of bleeds controlled with rFVIIa93.9% of bleeds controlled with rFVIIa93.9% of bleeds controlled with rFVIIa

Muscle/Muscle/JointJoint

Muscle/Muscle/JointJoint

Surgery/Surgery/WoundWound

Surgery/Surgery/WoundWound OtherOtherOtherOther TotalTotalTotalTotal

CNS orCNS orLife-/Limb-Life-/Limb-

ThreateningThreatening

CNS orCNS orLife-/Limb-Life-/Limb-

ThreateningThreatening

Bleeds (N)Bleeds (N)Bleeds (N)Bleeds (N)

BleedsBleedscontrolled (N)controlled (N)BleedsBleedscontrolled (N)controlled (N)

Controlled (%)Controlled (%)Controlled (%)Controlled (%)

348348348348 201201201201 215215215215 371371371371 1,1351,1351,1351,135

334334334334 182182182182 190190190190 360360360360 1,0661,0661,0661,066

95.995.995.995.9 90.590.590.590.5 88.388.388.388.3 97979797 93.993.993.993.9

Summary of Efficacy (1988-1997)Summary of Efficacy (1988-1997)

Compassionate Use Program-Inhibitor PatientsCompassionate Use Program-Inhibitor PatientsCompassionate Use Program-Inhibitor PatientsCompassionate Use Program-Inhibitor Patients

Efficacy Results at End of Treatment With rFVIIaEfficacy Results at End of Treatment With rFVIIa

92% good/partial response rate with salvage therapy92% good/partial response rate with salvage therapy100% excellent/good response rate with first-line therapy100% excellent/good response rate with first-line therapy

Compassionate Use: Acquired InhibitorsCompassionate Use: Acquired Inhibitors

Hay CRM, et al. Hay CRM, et al. Thromb Haemost. Thromb Haemost. 1997;79:1463-1467.1997;79:1463-1467.

GoodGood

PartialPartial

PoorPoorBleedingBleedingepisodes (%)episodes (%)

1st Line1st LineSalvageSalvage00

101020203030404050506060707080809090

100100 100%100%

75%75%

17%17%8%8%

Arterial and Fatal Thromboembolic SAEsArterial and Fatal Thromboembolic SAEsData from ICH StudyData from ICH Study

Arterial and Fatal Thromboembolic SAEsArterial and Fatal Thromboembolic SAEsData from ICH StudyData from ICH Study

ArterialArterial thromboembolic SAEs occurred significantly ( thromboembolic SAEs occurred significantly (PP = = 0.01) more frequently with rFVIIa treatment (5%) than with 0.01) more frequently with rFVIIa treatment (5%) than with placebo (0%)placebo (0%) These events manifested in the form of myocardial ischemic These events manifested in the form of myocardial ischemic

events (7) and cerebral infarction (9)events (7) and cerebral infarction (9) Thromboembolic SAEs that were Thromboembolic SAEs that were fatalfatal or or disablingdisabling

occurred in 2% of rFVIIa-treated patients compared with occurred in 2% of rFVIIa-treated patients compared with 2% in the placebo group2% in the placebo group

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

What about Rituximab in What about Rituximab in Acquired Hemophilia?Acquired Hemophilia?

Rituximab in Acquired HemophiliaRituximab in Acquired Hemophilia

14 published reports 14 published reports (review 6/2006, Ann Pharmacotherapy)(review 6/2006, Ann Pharmacotherapy) Dose - 375mg/m2 weekly X 4 most common (same as lymphoma)Dose - 375mg/m2 weekly X 4 most common (same as lymphoma) Case reports - 5 single case and 3 with 2 patients=11ptCase reports - 5 single case and 3 with 2 patients=11pt

Ages 28-81, duration of ab 22d-10yrs, all failed previous txAges 28-81, duration of ab 22d-10yrs, all failed previous tx Normalized hemostasis in 9/11 patients reported (one non-responder Normalized hemostasis in 9/11 patients reported (one non-responder

died of airway hematoma after 2died of airway hematoma after 2ndnd dose) dose) 8 pts required 1-4 doses / 1 pt received 11 doses over 21mon8 pts required 1-4 doses / 1 pt received 11 doses over 21mon

Small series 3 pts-all complete response to 4 wk therapySmall series 3 pts-all complete response to 4 wk therapy Small series 4 pts-all rapid complete response within 2-3 weeksSmall series 4 pts-all rapid complete response within 2-3 weeks Small series 4 pts-3/3 “autos” responded, 1 allo less effectSmall 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 Small series 4 pts-4/4 responded but duration 3.5/8.5 months with

response to additional course of rituximabresponse to additional course of rituximab

Rituximab in Acquired HemophiliaRituximab in Acquired Hemophilia

1 small open label trial in 10 patients1 small open label trial in 10 patients Co-morbidities prostate cancer, NHL, pregnancy, RA in 4 ptsCo-morbidities prostate cancer, NHL, pregnancy, RA in 4 pts 4pts received prior therapy for inhibitor – pred+CTN, or COP4pts received prior therapy for inhibitor – pred+CTN, or COP Titers range 4-250 BU, all FVIII levels < 1%Titers range 4-250 BU, all FVIII levels < 1% Rituximab given once weekly X 4Rituximab given once weekly X 4 ResultsResults

8 pts with rapid resolution of bleeding8 pts with rapid resolution of bleeding Normalized FVIII in 8/10 pts; 2 had 50% decrease in titerNormalized FVIII in 8/10 pts; 2 had 50% decrease in titer 2 partial responders completely normalized with cyclophosphamide 1 gm/m2 2 partial responders completely normalized with cyclophosphamide 1 gm/m2

+ rituximab+ rituximab Therapy well tolerated with mild reactions in 4/10 ptsTherapy well tolerated with mild reactions in 4/10 pts Relapse occurred in 3 pts (10, 14, 20 weeks) and all responded to second Relapse occurred in 3 pts (10, 14, 20 weeks) and all responded to second

course of rituximabcourse of rituximab

Key ArticlesKey Articles

Stachnik JM. Rituximab in the treatment of acquire hemophilia. Stachnik JM. Rituximab in the treatment of acquire hemophilia. Ann Ann PharmacotherPharmacother 2006 vol 40:1151. 2006 vol 40:1151.

Franchini M and Veneri D. Acquired coagulation inhibitor associated Franchini M and Veneri D. Acquired coagulation inhibitor associated bleeding disorders: An update. bleeding disorders: An update. HematologyHematology 2005 vol 10:443. 2005 vol 10:443.

Macik BG and Crow P. Acquired autoantibodies to coagulation factors. Macik BG and Crow P. Acquired autoantibodies to coagulation factors. Curr Curr Opin HematolOpin Hematol 1999 vol 6:323 1999 vol 6:323

Pruthi RK, Nichols WL. Autoimmune factor VIII inhibitors. Pruthi RK, Nichols WL. Autoimmune factor VIII inhibitors. Curr Opin Curr Opin HematolHematol 1999 vol 6:314 1999 vol 6:314

Hay CRM, Negrier C, Ludlam CA. The treatment of bleeding in acquired Hay CRM, Negrier C, Ludlam CA. The treatment of bleeding in acquired hemophilia with recombinant factor VIIa: A multicenter study. hemophilia with recombinant factor VIIa: A multicenter study. Thromb Thromb HaemostHaemost 1997 vol 78:3 1997 vol 78:3