Acquired Haemophilia A

1
Acquired Haemophilia A

• Dr Vanessa Manitta
• Haemostasis/Thrombosis Registrar
• 30/5/07

2
Case 1 Mr MR

• 34 y/o male
• Past history
• Schizophrenia
• Tonsillectomy as child
• Circumcision 9 years age
• L leg 10 years prior internal fixation
• No past history bleeding or excessive bruising
• No family history
• Medications
• Clopixal 250mg IM fortnightly for 3 years (last
  dose 11/7 prior to presentation)

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 UE, 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/UE 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

• No inhibitor 3 years later
• No recurrence/ bleeding post second pregnancy
• Currently in her 3rd pregnancy

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
• 11 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

• Haematuria settled spontaneously
• HB 103 57 CT abdomen large L
  retroperitoneal haematoma and hydronephrosis
• Patient not offered haemostatic products due to
  poor co-morbid condition
• Progressive ARF
• Palliated
• d/c home and died within 1 week.

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

• Type 1 alloantibodies inactivate FVIII via 1st
  order kinetics
• Type 2 acquired autoantibodies show non-linear
  inactivation pattern (second order kinetics)
• Type 2 inhibitors usually do not totally
  inactivate factor VIII in vitro however the
  measurable factor activity offers little or no
  protection against haemorrhage in vivo

(Alice et al ASH 2006)
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
Collins et al (Blood 2007) 2 year national
surveillance study by the United Kingdom
Haemophilia Centre Doctors Organisation
identified and characterised the presenting
features and outcome of all pts with AH in the UK
( n 154)
25
Bleeding Characteristics

• Different bleeding pattern to congenital
  Haemophilia
• 2 year UK observational study identified 149 pts
  with AH whose bleeding symptoms known

(Collins et al, Blood 2007)
26
Fatal Bleeding Outcomes
Collins et al., Blood 2007

• Median inhibitor titre (7.2 BU) and Factor VIII
  level similar in pts requiring no haemostatic
  treatment and those with fatal bleeds
• Conclusion No correlation between inhibitor
  titre, factor VIII level, and fatal bleeding

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, Sjogrens,
  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 lt1 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 (lt3 BU)
  and measurable baseline FVIII
• Case reports - FVIII gt5 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 (lt5 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

10
9
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
Collins et al., Blood 2007

• 76 CR in median time of 57 days irrespective
  of treatment group
• Similar number of deaths from any cause
• Conclusion No statistical difference in
  inhibitor eradication or mortality between pts
  treated with steroids alone or steroid
  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 gt100 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 gt100 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 gt5 and lt30)
• Rituximab be added to prednisolone and
  cyclophosphamide (titre gt 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