1 / 29

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

September 30, 2006 B. GAIL MACIK, M.D. Associate Clinical Professor of Internal Medicine and Pathology. Acquired Inhibitors of Coagulation . Review acquired inhibitors to clotting factors Discuss basic diagnostic scheme for detecting and treating an inhibitor

Jimmy
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. 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

  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. INHIBITOR RESULT A RESULT B Diagnosis of Clotting Factor Inhibitors MIXING STUDY PATIENT BLOOD: NORMAL BLOOD: FACTOR LEVEL 0% aPTT 80 sec FACTOR LEVEL 100% aPTT 28 sec NOTE: ONLY 30-40% FACTOR REQUIRED FOR NORMAL aPTT 50% PATIENT : 50% NORMAL • FACTOR LEVEL • 20% • aPTT • 50 sec • FACTOR LEVEL • 50% • aPTT • 30 sec Correction No correction 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. 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

  14. 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

  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;5:389-404

  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 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

  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?

  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

  23. Compassionate Use Program-Inhibitor Patients Summary of Efficacy (1988-1997) CNS or Life-/Limb- Threatening Muscle/ Joint Surgery/ Wound Total Other Bleeds (N) 348 201 215 371 1,135 Bleeds controlled (N) 334 182 190 360 1,066 Controlled (%) 95.9 90.5 88.3 93.9 97 93.9% of bleeds controlled with rFVIIa

  24. Compassionate Use: Acquired Inhibitors Efficacy Results at End of Treatment With rFVIIa 100% 100 90 Good 75% 80 Partial 70 Bleeding episodes (%) Poor 60 50 40 30 17% 20 8% 10 0 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.

  25. Arterial and Fatal Thromboembolic SAEsData 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 disablingoccurred 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.

  26. What about Rituximab in Acquired Hemophilia?

  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

  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 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

  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

More Related