Case Presentation

1
Case Presentation

• Pt is a 60 y.o. white male with severe hemophilia
  A with a known inhibitor who bit his tongue and
  developed swelling of his tongue. He came to BJH
  for care of his bleeding episode

2
PMH

• 1957 at age 13 had a CNS hematoma that compressed
  his optic nerve resulting in blindness
• 1971 at age 27 patient was first known to have an
  inhibitor
• 1997 Left flank hematoma treated with high doses
  of Factor VIII with increase in Inhibitor titer
  to 641 BU/ml

3
PMH

• Obesity with 287 lb
• Joint contractures and difficulty walking
• Chronic hepatitis C
• HTN
• HIV negative

4
Medications

• No factor use for 7 years
• None listed on admission record

5
Family History
HIV Dead Inhibitor
Patient No HIV
Nephew
6
Labs On Admission

• PTT 73 seconds
• PT 16.1 seconds
• INR 1.31
• Fibrinogen 111 mg/dl
• D dimer 0.23
• FVIII activity 3 (was lt1 previously)
• Hb 15.7
• WBC 6.7
• Platelets 174

7
Additional Labs

• Alk phos 82
• AST 41
• ALT 18
• Albumin 3.2
• Bilirubin 1.3
• Hepatitic C antibody positive
• Hepatitis C PCR 1,240,000 IU/ml
• Factor VIII inhibitor 0.7 BU/ml (0-0.5)

8
Chest X-Ray on Admission

• There is marked soft tissue swelling of the neck
  and tongue with complete obliteration of the
  upper airway.

9
Treatment

• Tracheostomy placement for airway obstruction
• Placement of 3 leeches on the tongue
• Novoseven

10
Treatment

• Gave 90 ug/kg VIIa q2 hours for 8 hours
• 90 ug/kg every 4 hours for 24 hours
• 90 ug/kg every 2 hours for 24 hours
• VIIa every 4 to 6 hours for 24 hours
• FFP intermittently (4 units)
• Human Factor VIII 60 U/kg given at 2 days after
  admission, and then once a day for 3 days
• 7 days after admission the patient was found
  without respiration in his room and expired

11
Post-mortem Analysis

• Pulmonary hemorrhage
• Airway was open

12
Coagulation Assays

• Date PTT 5050 Mix BU/ml FVIII
• 1997 642
• 4-15-98 67.7 39.6
• 8-13-98 63.2 35.5
• 4-15-99 9.1 lt1
• 4-12-00 1.7 lt1
• 9-16-04 73
• 9-17-04 59.5/49 0.7 3
• 9-18-04 60.9/32 130
• 9-19-04 30 45/119
• 9-20-04 30.3/36.7 130
• 9-21-04 40.2/37.8 61
• 9-22-04 60.2/33 68
• 9-23-04 88.5/38.1 63

13
Inhibitors in Hemophilia A

• More common in patients with deletions,
  truncations, or inversions (35)
• Risk low with missense mutations (5)
• If brother has an inhibitor, 50 chance of
  developing an inhibitor
• Occur after an average of 8 to 12 exposure dates
• Average age on onset is 1.7 to 3.3 years

14
Treatment of Inhibitors

• Management of acute bleeding episodes
• Eradication of inhibitor
• Immune tolerance induction
• High and frequent doses of factor reduces the
  inhibitor in 80
• Costs about 1 million per year
• Maintenance regimen of ITI unclear

15
Immune Tolerance Induction
From Nigel Key, British Journal of
Hematolgy127379, 2004
16
Management of Acute Bleeding Episodes

• High dose human FVIII (if lt5 to 10 BU/ml) can
  use immunoadsorption with protein A
• Porcine FVIII
• Factor VIIa
• Activated prothrombin complex concentrates
• FEIBA
• Autoplex no longer available

17
Porcine FVIII

• 15 of anti-human FVIII antibodies cross-react
  with porcine FVIII (85 do not)
• Recombinant B domain-deleted porcine FVIII made
  by Octagon being evaluated (parvovirus concerns
  in plasma-derived)
• Treatment with porcine FVIII will induce
  inhibitors in 35 of patients over time
• Costs 1.83 per unit in 2003 dose similar for
  human FVIII (50 U/kg loading and 25 U/kg
  maintenance, for 6000 per day for 60 kg

18
Homology Porcine and Human FVIII (Healey Blood
884209, 1996)
19
Amino Acid Alignment in C2 Domain
20
Factor VIIa NovoSeven

• FVIIa is injected, which is the active form of
  Factor VII
• This probably associates with tissue factor at
  the site of injury and activates IX and X
• Normal FVII levels are 0.5 ug/ml (10 nM) and
  normal FVIIa levels are 0.1 nM
• Inject 90 ug/kg and achieve 3 to 20 nM FVIIa
  half life 2.7 hours

21
FVIIa

• Minor bleeds
• 2 to 3 doses of 90 ug/kg every 2 hours good
  outcome in 84 to 88
• 1 dose of 200 to 350 ug/kg good outcome in 97
• Surgery
• 90 ug/kg every 2 to 6 hours was better than 35
  ug/kg

22
Infusion of FVIIa at 20 ug/kg/hour Tranexamic
acid 4 gm/day Mauser-Bunschoten et al
Haemophilia 8649, 2002
23
Schedule for Surgery or Major Bleed

• 90 ug/kg to achieve hemostasis for 1-2 days
• Give higher dose (200-300 ug/mg) if ineffective
• Lengthen interval to every 3 hours and then up to
  every 6 hours
• Cover for 7 to 10 days

24
Cost of NovoSeven

• 0.85 per mg
• Dose of 9.6 mg is 8160 (purchase cost from the
  company cost in hospital?)
• Cost of NovoSeven during the hospitalization of
  this patient for 230 mg is 195,500

25
FEIBA

• Factor Eight Inhibitor bypassing agent
• Purify the vitamin K dependent factors that
  undergo contact activation at some point
• Contains FVIIa and Xa in addition to
  non-activated factors (amounts unclear)
• 1 unit shortens the aPTT of an inhibitor plasma
  by 50
• Give 50 to 100 U/kg up to twice a day cost is
  0.82/unit, or 9,840 per day for 200 mg/kg
• 50-65 effective for a minor bleed vs. 25 placebo

26
Summary of Costs
27
Adverse Effects

• Thrombosis
• FVIIa or FEIBA may increase the risk of
  thrombosis
• Giving both at the same time is contraindicated

28
Neonatal Gene Therapy for Hemophilia A

• Achieved 100 of normal canine Factor VIII
  activity in Hemophilia A dogs and prevents
  bleeding
• Induces tolerance to human FVIII in mice

29
Neonatal Gene Transfer can Prevent Inhibitor
Formation in Mice
30
Conclusions

• Inhibitor formation is a serious and common
  problem in patients with hemophilia A
• ITI with high doses of FVIII can reduce the
  inhibitors, but maintenance schedule is unclear
• Treatment with porcine FVIII is reasonable but
  not currently available
• VIIa is effective but extremely expensive
• FEIBA is a reasonable alternative that is less
  expensive
• Perhaps ITI at birth will induce tolerance

31
From Nigel Key, British Journal of
Hematolgy127379, 2004