acquired haemophilia a

1. Acquired Haemophilia A Dr Vanessa Manitta Haemostasis/Thrombosis Registrar 30/5/07

3. Mr MR Presenting Complaint Western Hospital: 2/52 painful right calf, 1/51 swelling; normal pulses, no paraesthesia, no erythema/signs of infection dog bite 4 weeks prior ? DVT : 1xdose of clexane US next day: spontaneous R calf Haematoma 8x10cm Rx � U/S guided drainage Drained 60-80 ml old blood APTT prolonged, no correction; ? Inhibitor Referred to Alfred Haemostasis/thrombosis unit

4. Mr MR Investigations APTT 78.7 INR 1.1 Fibrinogen 8.1 Mixing studies � no correction LAC, anti-cardiolipin Ab negative Factor assay : VIII 11%; Factor VIII inhibitor 5 BU FBE 118/8.5/289 Normal U&E, LFT, Weakly positive ANA

5. Mr MR Progress L leg Drain � 520 ml blood over 5 hours; Repeat Hb 104 Tranexamic acid iv 6/24 12 hours post admission: No drainage from left leg Increasing R calf pain and swelling; pain on passive movement of ankle T 38.1; CK 1170; Repeat U/S: complex collection 10 x 5 x5 cm Issue: ? Progression to compartment syndrome clinically good pulses, capillary return, no neurological deficit Concurrent constipation, vomiting, abdominal distension O/E distended abdomen, non tender, no masses

6. Mr MR Assessment: Acquired Haemophilia secondary to Clopixal Decanoate Mx: Commenced iv Cefepime and metronidazole CT abdomen: R iliopsoas muscle haematoma Methylprednisolone 1mg/kg IVIG (2x70g infusion) Haematoma evacuated/Fasciotomy that evening Novoseven 7.2mg iv 2hourly boluses

7. Mr MR Progress 2 hourly Novoseven boluses for 9/7; Total 21 days (total 100 doses) 2/7 post op HB 89 - 69 : Spherocytes, pos DAT, increased bilirubin, LDH, reticulocytes, free anti-A in serum Dx haemolysis secondary to intragam Commenced cyclophosphamide 150mg/d 10/7 post op (Steroids commenced weaned - total 3 week course) Psych RV: Clopixal changed to amisulpride D/C 23 days post presentation; factor VIII 58%, APTT 45.2s

8. Mr MR Follow Up Cyclophosphamide decreased to 100 mg/d at 2weeks post d/c (neutropenia 1.36) 3/52 post d/c: R lower leg cellulitis and deteriorating mental state (pt also ceased medications) Rx IV Antibiotics 2 weeks and transferred to psychiatry for treatment of relapsed schizophrenia Declining Factor VIII levels 27% ; Inhibitor titre rising 2 BU APTT prolonged 53 sec Cyclophosphamide recommenced 150mg

9. Mr MR Follow Up Factor VIII level continued to drop to 7%; no new episodes of bleeding or bruising prednisolone 50 mg o daily commenced D/c 1 month later - Factor VIII increased to 37% Prednisolone weaned completely over following two months Cleared of inhibitors 14 months post presentation � cyclophosphamide ceased

10. Mr MR Follow Up

11. Case 2 Mrs LU 21 y/o female Presented with 1/7 history painful swollen L calf and bruise US/ Doppler � no DVT; Tear of medial gastrocnemius muscle Past History No bleeding history Normal periods Caesarean section 10 months prior (G1P1) (no bleeding complications) No regular medications

12. Mrs LU Investigations APTT 61.2 INR 0.9 No correction with mixing Factor VIII level: 3% Inhibitor titre 26 IU Normal autoimmune screen BHCG negative FBE/U&E normal Assessment: Acquired Haemophilia A postpartum

13. Mrs LU Progress Commenced prednisolone 100 mg daily Calf bleed settled (3 weeks) without need for product replacement 4 week r/v: inhibitor titre increased 46 BU ; no change in Factor VIII level; no new bleeding events Commenced Rituximab x 4 doses weekly (375mg/m2); Prednisolone weaned

14. MRS LU Progress

15. Case 3 Mr ET 62 y/o male Past history Paroxysmal AF (had refused warfarin and aspirin) Partial Gastrectomy for PUD Presented in March 07 with L MCA territory embolic stroke Thrombolysed Cx 5x2.5 cm L frontal haemorrhage INR 1.0 APTT 33 Fibrinogen 3.3 Conservative management Cx Aspiration pneumonia; C difficile diarrhoea/colitis D/c Rehab 1 month later (28/3/07) on warfarin

16. Mr ET Management 24/4/07 2/7 Haematuria with clots; Transferred to Moorabbin INR 2.6 No APTT Vitamin K � INR 1.6 IDC inserted for washout Renal U/S: normal HB 121 - 99 - 66; CT abdomen � no bleed 27/4/07 Cystoscopy � filling defect L calyx of kidney ? TCC Ongoing haematuria; APTT 69 INR 1.1 fibrinogen 7.0 rapid AF - Haemodynamically unstable - HDU 29/4/07 developed R swollen leg Doppler � extensive proximal DVT Heparinised and IVC filter inserted

17. MR ET Progress 30/4/07 APTT on heparin 155 s � 228 s (APTT 94 s with heparin w/h) Ongoing haematuria (2-3 units in 2-3 days) 2/5/07 Retrospective testing 1:1 mix APTT 37; 1 hour incubation 51 (N = 23 � 34) LAC negative Factor VIII 0.06 APTT 85 (off heparin) FVIII inhibitor 1.4 BU Assessment : Acquired Haemophilia 4/5/07 Transferred to Monash Haematology

18. Mr ET

19. Acquired Haemophilia A Acquired Haemophilia A : autoantibody response to endogenous Factor VIII 1.48 cases per million per year (Collins et al Blood 2007) No genetic inheritance pattern Congenital Haemophilia A: alloantibody response to transfused Factor VIII 20-40% Congenital Haemophilia A patients

20. Pathophysiology Factor VIII structure: A1-a1-A2-a2-B-a3-A3-C1-C2 domain Undergoes proteolytic processing to form non-covalently linked heterodimers to associate with VWF heavy chain (variable lengths of A1, A2 and B domain) light chain (A3, C1, C2 domains) Inhibitors bind to the A2, A3 or C2 domain Non-complement fixing polyclonal IgG1 - IgG4 immunoglobulins Anti-C2 inhibitors disrupt the binding of FVIII to phospholipid and vWF Anti- A2 and A3 inhibitors interfere with FVIII binding to factor X and factor IXa respectively

21. Pathophysiology

22. Diagnosis Sudden onset of large haematomas or extensive ecchymoses in a pt without significant trauma or known bleeding disorder Prolonged APTT (normal PT/INR) which fails to correct with mixing studies Nonspecific inhibitors (eg heparin; LAC) ruled out Assessment Factor VIII activity - low Assess titre of the inhibitor (Bethesda assay)

23. Bethesda assay Measures residual FVIII activity after incubation of normal plasma with serial dilutions of patient plasma for 2 hours at 37 deg Inhibitor titre in Bethesda units = reciprocal dilution of patients plasma that leads to 50% inhibition of FVIII activity Inhibitor titre can be followed during treatment as a measure of efficacy

24. Clinical and Laboratory Features

25. Bleeding Characteristics Different bleeding pattern to congenital Haemophilia 2 year UK observational study identified 149 pts with AH whose bleeding symptoms known

26. Fatal Bleeding Outcomes

27. Natural History Green et al (Thromb Haemost 1981): survey of 215 nonhaemophilic patients 31 (14%) received no therapy other than supportive transfusions or factor concentrates (34% in recent UK study) the inhibitor disappeared spontaneously in 11 (36%) at an average duration of 14 months severe/ life threatening bleeding in 75 � 87% 11-22% mortality rate from complications directly or indirectly related to the inhibitor

28. Natural History Median time to CR is 4-6 weeks with immunosuppression Relapse rate after a first complete remission about 20%; median 7.5 months after stopping treatment 70% of such relapsing patients achieve a second complete remission Relapse of pregnancy-associated acquired factor VIII inhibitors rarely occur in subsequent pregnancies Collins et al Blood 2007

29. Disease Associations Majority idiopathic; disease association in up to 50% 17% autoimmune RA, SLE, UC, dermatomyositis, Sjogren�s, cryoglobulinemia 22% Malignancy (Collins et al Blood 2007) ALL, CLL, HCL, lymphoma, lung, colon, kidney, prostate, ovary 4% Postpartum state (Collins et al Blood 2007) Incidence of 1 case/350 000 births 3-6% Drug reaction (3-6%) Penicillins, sulphur drugs, case reports of depot thioxanthenes 2-5% Skin disorders psoriasis, pemphigus, erythema multiforme, Graft-vs.-Host after allogeneic BM transplant

30. Acquired Haemophilia and malignancy Sallah et al (Cancer 2001): Retrospective study of 41 patients with AH and cancer 64% of solid tumors were adenocarcinoma; most common sites prostate and lung. CLL most common haematologic malignancy

31. Acquired Haemophilia and Malignancy Sallah et al (Cancer 2001): treatment of the inhibitor led to a CR in 70% Responders had early stage tumors and a lower median inhibitor titre No statistical difference between terms of median FVIII level Overall survival higher in responders Treatment of the cancer with chemotherapy, surgery, hormonal manipulation led to the disappearance of the inhibitor in 25%

32. Acquired Haemophilia and Post Partum status Haeuser et al (Thromb Haemost 1995): Retrospective review of 51 cases The risk of developing an inhibitor was greatest after the first delivery. The median time to onset of the inhibitor after delivery was two months (range <1 month to 12 months) typically 1-4 months (up to 12 months in cases reports) Rarely during 3rd trimester (risk transplacental transfer)

33. Management Overview 1) initial treatment of bleeding and its complications RBC transfusions Avoid aspirin, Nsaids, clopidogrel, IM injections Agents that increase Factor VIII levels Factor VIII bypassing agents 2) inhibitor elimination Immunosuppression IVIG Rituximab

34. Haemostasis � increasing FVIII levels Haemostasis can be achieved if FVIII levels can be raised to 30 � 50% DDAVP Patients with very low inhibitor titre (<3 BU) and measurable baseline FVIII Case reports - FVIII >5% DDAVP induced rise in FVIII level between 16 - 140% (Mudad et al., Am J Haematol 1993) Response to DDAVP unpredictable Consider for minor bleeding episodes Issues with elderly and hyponatremia

35. Haemostasis � increasing FVIII levels FVIII infusion Patients with low inhibitor titre (<5 BU) Doses larger than used in congenital haemophilia required Often difficult to overcome due to kinetics (Second order kinetics) Monitor FVIII activity and clinical response during treatment

36. Haemostasis � increasing FVIII levels Porcine FVIII Inhibitor levels to porcine FVIII is 5-10% of the human titre Low chance of cross-reactivity except for congenital haemophilia A pts Good haemostatic efficacy in 78% of bleeds (partial response 11%; no response in 9%) (Morrison et al., Blood 1993) Adverse events: allergic reactions, thrombocytopenia, development of pFVIII antibodies Plasma derived porcine FVIII no longer available; Recombinant B-domain deleted porcine FVIII is undergoing phase II clinical trials in congenital haemophilia

37. Haemostasis � FVIII bypassing agents Use extrapolated from management of congenital haemophilic inhibitors Recombinant factor VIIa (Novoseven) Binds to surface of activated platelets supporting thrombin generation bypassing the need for FVIII Activated Prothrombin complex concentrate (aPCC) FEIBA (Factor Eight inhibitor bypassing activity) Plasma derived concentrate with activated clotting factors 50 -100 U/kg (max 24 hours of 200 units/kg) Risk of venous thromboembolism, MI, DIC (rare: 4-8 events per 105 infusions) No studies directly comparing the two agents

38. Feiba Negrier et al (Thromb Haemost 1997)- retrospective study on 60 inhibitor pts, 6 with acquired inhibitors - efficacy rated excellent in 81% of bleeding episodes. - FEIBA controlled bleeding effectively after 95% surgical procedures Sallah et al (Haemophilia 2004) Retrospective study 34 pts with AH 75 units/kg every 8 � 12 hours moderate bleeds: 100 % haemostatic efficacy at median 6 infusions in median 36 hours; severe bleeds: complete response rate of 76% with medium number of doses of 10 in median 48 hrs Overall CR rate 86%

39. Novoseven Hay et al (Thromb Haemost 1997) Analysis of 38 pts with AH 90 � 120 mcg/kg every 2-6 hours until bleeding stopped (median 28 doses over median 3.9 days) 100% excellent/good response rate with first-line therapy (14 pts) 92% good/partial response rate with salvage therapy

40. Plasmapheresis/immunoadsorption Used in severely bleeding/or presurgical pts with high inhibitor titres who failed to respond to bypassing agents FVIII replacement required post pheresis to achieve haemostasis immunoadsorption not available in many centres; technically difficult may be difficult to perform in acutely bleeding pts

41. Summary Haemostasis Management Choice of treatment dictated by severity of bleed, inhibitor titre, any previous clinical response, dosing schedule, use of plasma derived products and cost No validated laboratory assay available to monitor response to treatment (thrombin generation assays promising) Duration of treatment depends on clinical judgement Cannot extrapolate results from inhibitors in congenital haemophilia due to different inhibitor kinetics and bleeding phenotypes No convincing evidence that Novoseven or FEIBA is clinically more effective or more thrombogenic than the other If 1st line therapy fails, the alternative bypassing agent may be successful

42. Inhibitor elimination Immunosuppressive therapy to eradicate the inhibitor in AH should be undertaken as soon as the diagnosis is made Pt at risk of life threatening bleeds (spontaneously or with minor trauma) as long as inhibitor is present (irrespective of titre) Most pts with autoantibodies are elderly with co-morbid vascular disorders that typically managed with antithrombotic agents Need for emergent or elective surgery in pts with AH poses a major risk Most studies non-randomised and reported retrospectively

43. Steroids +/- cytotoxics Only one randomised prospective study (Green et al Thromb Haemost 1993): 31 pts treated with prednisolone 1 mg/kg/day for 3 weeks 30% achieved CR Patients randomly assigned prednisolone alone 75% CR (3 of 4 ) substitution cyclophosphamide (2mg/kg/d) 50% CR (3 of 6 ) addition cyclophosphamide to prednisolone 50% CR (5 of 10 ) Conclusion No statistical difference between treatment arms Not sufficient power to demonstrate a difference Did not continue treatment with prednisolone long enough to establish its effect

44. Steroids +/- cytotoxics

45. Other Cytotoxics Azathioprine, vincristine, Mycophenolate CVP Cyclosporin Used alone or with prednisolone as salvage therapy Especially effective in associated with SLE Conventional doses of 10-15 mg.kg/day to give therapeutic levels of 150-350ng/ml Increased immunosuppressant SE eg cytopenia, bacterial infections, hepatitis

46. IVIG Crenier et al (Br J Haematol 1996) : CR 12% with 26 pts treated with IVIG alone Dykes et al (Haemophilia 2001) Retrospective study with 6 pts treated with combination of steroids and IVIG overall response rate 66% Conclusion: Combination IVIG and Prednisolone appear to have better response than prednisolone or IVIG alone Similar to response with combination of prednisolone + cyclophosphamide

47. IVIG Collins et al (Blood 2007) - Largest study comparing non-randomised patients who either did or did not receive IVIG either with steroids or with cytotoxics (n = 79) IVIG no benefit in addition to other treatment regimens Literature review Delgado et al (Br J Haematol 2003) showed no benefit for IVIG Current evidence : IVIG as single agent or in combination with steroid or cytotoxics is not useful in inhibitor eradiation in AH

48. Rituximab Several studies have shown efficacy of rituximab in the treatment of AH Stasi et al (Blood 2004) - Largest series with 10 patients who received rituximab alone (375mg/m2 each week for 4 weeks)

49. Rituximab Stasi et al (Blood 2004) 8/10 pts achieved CR within 3-12 weeks 3 pts relapsed in median 28.5 weeks- rechallanged with rituximab a same dose and schedule with new sustained response in all three 2 non responders had titres >100 BU and responded to combination rituximab and cyclophosphamide

50. Rituximab + steroids/cytotoxics Adedayo et al (Thromb Haemost 2006) � Review of 6 pts treated with rituximab and steroid +/- cytotoxics 100% CR at similar times to previous studies of other immunosuppressive agents Field et al (Haemophilia 2007) 4 patients with inhibitor titres >100 who were resistant to initial therapy with cyclophosphamide, vincristine and prednisolone (CVP) 4 weekly infusion of rituximab 365mg/m2 +/- o/iv cyclophosphamide All 4 had a partial response; 3 relapsed Conclusion: rituximab is effective but not sufficient to achieve a sustained response in high titre inhibitors

51. Recommendations: Rituximab may lead to more rapid remission and control of bleeding than other therapies but no comparative patients to clarify Data do not support the assertion that rituximab is superior to other immunosuppressive agents Rituximab may provide a better result in the high titre population in combination with other therapies Consider in patients resistant to first line therapy or cannot tolerate standard immunosuppressive therapy New proposals Rituximab be included as first line therapy with prednisolone (titre >5 and <30) Rituximab be added to prednisolone and cyclophosphamide (titre > 30)

52. Key messages Clinical progress in AH is hampered by small numbers of patients and difficulties in performing randomised studies Correlation of clinical efficacy and assays for bypassing agents required No data supporting Novoseven or FIEBA is more superior than the other No clinical or laboratory features of the disease identifies the high risk pt (risk of fatal bleed) so all should be immunosuppressed as soon as the diagnosis is made

53. Recommendations No convincing date to suggest that one immunosuppressive regimen is superior to any other The choice of regimen should NOT be based on the inhibitor titre or FVIII level Immunosuppressive therapy should be initiated with prednisolone 1mg/kg/d +/- cyclophosphamide 1-2mg/kg/d (alternative Rituximab if issues regarding cytotoxicity) If pt does not respond to first line steroids + cytotoxic agent then rituximab can be added. No role for IVIG May need to consider multiple-modality regimens