Acquired Inhibitors of Coagulation

Transcription

1 Acquired Inhibitors of Coagulation Christine L Kempton, MD, MSc Emory University

2 Disclosures for In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Novo Nordisk No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Novo Nordisk, Shire, Hoffman La Roche Presentation includes discussion of the following off-label use of a drug or medical device: Rituximab - 2 -

3 Outline Acquired Hemophilia (AH) Pathophysiology Epidemiology Diagnosis Management Promoting hemostasis Inhibitor eradication Acquired von Willebrand Disease Pathophysiology Diagnosis Management - 3 -

4 Case 80 year-old man with past history of cardiovascular disease presents to the ED with flank pain and bruising after a fall in the bathroom August- Dental extraction that led to large ecchymosis extending from his face to his chest September- Large ecchymosis on his inner left thigh Lab data K aptt 95.5 seconds PT 10.3 seconds - 4 -

5 Case: Imaging Anesthesiology. 2003;98(2):

6 Case: Laboratory Data Factor VIII (FVIII) < 0.25 IU/dl Von Willebrand Factor Antigen 202% Ristocetin cofactor activity 182% Inhibitor titer BU/ml aptt mixing study Immediate 50:50 mix 59.2 seconds Incubated 50:50 mix 91 seconds - 6 -

7 Case Factor VIII (FVIII) < 0.25% Von Willebrand Factor Antigen 202% Ristocetin cofactor activity 182% Inhibitor titer BU/ml aptt mixing study Immediate 50:50 mix 59.2 seconds Incubated 50:50 mix 91 seconds - 7 -

8 Pathophysiology IgG (subtype IgG1 and IgG4) antibodies that bind to FVIII and prevent it s action as a cofactor to Factor IX Antibody against self FVIII Autoimmune disease May be associated with other disorders of autoimmunity or disorders that may disorder the immune system Hofbauer et al. ; 2015: 125(7):

9 Pathophysiology Most cases are not associated with an underlying disorder 2% 15% 3% 17% 63% Idiopathic Autoimmune Pregnancy Malignancy Dermatological Collins et al. Blood 2007;108:

10 Pathophysiology In the absence of an underlying disorder, the reason for the loss of tolerance to FVIII is unclear Genetic predisposition Single nucleotide polymorphisms of CTLA-4 HLA Class II alleles DRB*16 and DQB1*0502 FVIII itself Age Increase in other autoimmune disorders with advanced age Increase in incidence of allo-antibodies to FVIII in patients with hemophilia in the 7 th and 8 th decade of life Oldenburg et al. Haemophilia 2010; 16(S3): 41 Hay et al. Blood. 2011;117(23):

11 Epidemiology Overall incidence 1.5 cases/million per year Incidence increases with age: Age years 0.29 per IM person years Age > 85 years per IM person years Median age at presentation ~78 years Collins et al. Blood 2007;108:1870 Knoebl et al. JTH 2012; 10:

12 Clinical Presentation Bleeding ~95% present with bleeding ~70% serious bleeding ~30% may not need hemostatic treatment FVIII level not predictive of bleeding Collins et al. Blood 2007;108:1870 Knoebl et al. JTH 2012; 10:

13 Clinical Presentation 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Subcutaneous Muscle GI GU Collins et al. Blood 2007;108:

14 Mortality Death attributable to inhibitor either directly or indirectly ~20% Death from bleeding ~3-9% Median of 19 days after presentation Death secondary to immune suppressive therapy ~4% Bitting RL et al. Blood Coagul Fibrinolysis. 2009;20:517 Knoebl et al. JTH 2012: 10; 622 Collins et al. Blood 2007:108;

15 Mortality Increased risk of death FVIII < 1 IU/dl Underlying malignancy Poor performance status Age > 65 years Tiede et al. Blood 2015;125:

16 Diagnosis First step to an accurate diagnosis is consideration of AH as a potential cause of the patient s signs or symptoms Diagnosis should be considered in patients with: Recent onset abnormal bleeding or, Have a prolonged aptt

17 Diagnosis

18 Treatment 1. HEMOSTASIS 2. INHIBITOR ERADICATION

19 Hemostasis Management Who Limb or life threatening bleeding Persistent bleeding particularly if ongoing transfusion Requires and invasive procedure (best to avoid if possible) What Depends on availability of medications and laboratory testing pfviii inhibitor titer - > 20 BU/ml, use bypassing agent FVIII levels- not able to monitor levels, use bypassing agent

20 Bypassing Agents Recombinant factor VIIa mcg/kg q 3 hours FEIBA U/kg q 8-12 hours Both pro-thrombotic Similar rates of efficacy (92-94%) Clinical monitoring only Baudo F et al. Blood. 2012;120:

21 Replacement Therapy DDAVP Low titer inhibitor (< 2 BU/ml) and FVIII > 5 IU/dl Minor bleeding Significant side effects in the elderly related to hyponatremia and cardiovascular disease Human FVIII Low titer (< 5-10 BU/ml) Dose high enough to overcome the inhibitor titer Requires monitoring

22 Replacement Therapy DDAVP Low titer inhibitor (< 2 BU/ml) and FVIII > 5 IU/dl Minor bleeding Significant side effects in the elderly related to hyponatremia and cardiovascular disease Human FVIII Low titer (< 5-10 BU/ml) Dose high enough to overcome the inhibitor titer Requires monitoring

23 Replacement Therapy: Recombinant Porcine FVIII Phase 2-3 study, n=28 Anti-porcine FVIII inhibitor titer < 20 BU/ml Treated with 200 U/kg as initial bolus and subsequent dosing based on FVIII peak and trough values Kruse-Jarres et al. Haemophilia, 2015; 21:

24 Recombinant Porcine FVIII Well tolerated No thrombocytopenia 2 subjects developed anti-porcine FVIII antibodies Kruse-Jarres et al. Haemophilia, 2015; 21:

25 Dosing Recombinant Porcine FVIII 200 U/kg more than is needed for many If no anti-porcine FVIII titer is present, dose IU/kg If detectable antiporcine FVIII titer: Severe bleeding dose 200 IU/kg Non-severe bleeding dose 100 IU/kg Kruse-Jarres et al. Haemophilia, 2015; 21:162 Tarantino et al. Haemophilia, 2016:1-25 -

26 Inhibitor Eradication Spontaneous resolution can occur (1/3 of patients), but occurs over months to years Spontaneous resolution more likely in patients with a peri-partum inhibitor There is no characteristic that is accurately predictive of bleeding risk IST should be started at presentation in all patients Lottenberg et al. Arch Intern Med 1987;147:1077 Green et al. Thromb Haemost 1981;45:200 Collins et al. Blood 2007:108;

27 First Line IST Corticosteroids Prednisone 1 mg/kg po daily Alternative: Pulse dexamethasone +/-Cyclophosphamide Oral 1-2 mg/kg daily Alternative 500 mg/m 2 or 1 g IV q 3-4 weeks +/-Rituximab 375 mg/m2 once weekly x 4 weeks Alternative: 100 mg IV weekly Not recommended as monotherapy Tiede et al. Blood 2015;125:

28 Choice of IST Corticosteroids alone best in setting of FVIII level > 1 IU/dl and low inhibitor titer Inhibitor titer > 20 BU/ml and FVIII > 1 IU/dl, chance of PR (FVIII activity > 50%) at 21 days was 53% Inhibitor titer > 100 BU/ml or FVIII level < 1 IU/dl, chance of PR at 21 days was 9% Tiede et al. Blood 2015;125:

29 Second Line IST Other immunosuppressive agents Calcineurin inhibitors Mycophenolate mofetil Bortezomib Case report Immune Tolerance Induction Limited role No role for IVIg McFadyen JD, et al. Br J Haematol Jul 19. doi: /bjh

30 Remission and Relapse Median time to: PR 31 days (IQR 19-51) CR 79 days (IQR ) Monitor FVIII and inhibitor titer frequently Relapse Occurs in up to 20% of patients Greatest risk of relapse early after withdrawal of IST The presence of high-titer IgA antibodies at greatest risk for relapse Collins P et al. Blood. 2012; 120: 47 Tiede A et al. Blood. 2016;127(19):

31 Outline Acquired Hemophilia A Pathophysiology Epidemiology Diagnosis Management Promoting hemostasis Inhibitor eradication Acquired von Willebrand Disease Pathophysiology Diagnosis Management

32 Acquired Von Willebrand Disease Pathophysiology Multiple mechanisms Autoantibodies (MGUS, lymphoproliferative disorders, autoimmune disorders) Decreased production (hypothyroidism) Shearing (cardiac disease) Binding to cancer cells (Wilm s tumor) Federici AB et al. Seminars in thrombosis and hemostasis. 2013; 39:

33 Acquired Von Willebrand Disease Pathophysiology Multiple mechanisms Autoantibodies (MGUS, lymphoproliferative disorders, autoimmune disorders) Decreased production (hypothyroidism) Shearing (cardiac disease) Binding to cancer cells (Wilm s tumor) Federici AB et al. Seminars in thrombosis and hemostasis. 2013; 39:

34 Acquired Von Willebrand Disease Diagnosis Based on demonstration of low von Willebrand Factor (VWF) antigen and/or low VWF activity New onset bleeding Lack of family history of von Willebrand disease Federici AB et al. Seminars in thrombosis and hemostasis. 2013; 39: 191 Tiede A et al. Blood. 2011; 117:

35 Acquired Von Willebrand Disease Laboratory Testing Type 2 pattern frequent Low VWF:Rco to VWF:Ag ratio Loss of high molecular weight multimers on multimer analysis Identification of inhibitory antibody difficult Lack of inhibition of VWF:Rco on mixing with normal pooled plasma does not exclude the presence of a antibody Tiede A et al. Blood. 2011; 117:

36 Acquired Von Willebrand Disease Management Half-life of VWF containing product shortened Treat the underlying disease if possible MGUS not typically treatable IgG MGUS responds well to IVIg IgM MGUS less responsive to IVIg, use plasmapharesis Tiede A et al. Blood. 2011; 117:

37 Conclusions Inhibitors to coagulation factors are rare, but serious disorders Delays in diagnosis lead to excess morbidity and mortality Acquired hemophilia should be considered in patients, particularly the elderly, with abnormal bleeding and a prolonged aptt Treatment to eradicate the inhibitor should be undertaken as soon as the diagnosis is made

38 Conclusions Acquired VWD should be suspected in patients with laboratory evidence of VWD but with new onset bleeding and no family history of VWD Treatment will depend on the associated underlying disorder