VIIa

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HEMOSTASIS
VIIa
TF
INITIATION OF HEMOSTASIS
TF-BEARING CELL
PROPAGATION OF HEMOSTASIS
ACTIVATED PLATELET
THROMBIN
FIBRIN HEMOSTATIC PLUG
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Normal Hemostasis
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Thrombin
FV FVIII
IIa (THROMBIN)
FVa FVIIa
FIBRINOGEN
FIBRIN (SOLUBLE FIBRIN MONOMERS)
FXIIIa
STABILIZED, CROSS-LINKED FIBRIN (HEMOSTATIC PLUG)
FIBRINOLYSIS
TAFI
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Fibrin Structure
Thrombin
(a)

• 0.60 U/mL

(b)
0.10 U/mL
(c)
0.05 U/mL
(d)
0.03 U/mL
Blomback et al. 1994
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Thrombin Activity
0.05
With FVIII present
0.045
(- FXI)
0.04
FVIII-deficiency
0.035
50 nM FVIIa
0.03
Thrombin activity (dA405/min)
0.025
150 nM FVIIa
0.02
0.015
0.01
0.005
0
0
20
40
60
80
100
120
140
Time (min)
Kjalke et al. 1999
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FACILITATE HEMOSTASIS

• Enhance thrombin generation
• Inhibit fibrinolysis
• WHY FVIIa?
• FVIIa not enzymatically active unless in complex
  with TF
• FVIIa not immediately inhibited by AT
• FVII present in plasma
• FVIIa added to hemophilia plasma with inhibitors
  normalized APTT

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Potential Use of rFVIIa

• Increases thrombin generation
• Hemophilia (FVIII/FIX deficiency)
• Platelet disorders
• Diffuse bleeding triggered by surgery and trauma
• Impaired initial hemostasis
• FVII-deficiency
• Liver disease (low levels of FVII)
• OAC therapy (low levels of FVII)

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Hemophilia
II
VIII/vWF
VIIIa
X
V
Va
Xa
VIIa
Va
TF
IIa
XI
XIa
TF-bearing cell
VIIa
TF
platelet
II
X
IIa
VIIa
Va
Xa
activated platelet
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Haemophilia

• FDA-approved Hemophilia with inhibitors
• Efficacy in major surgery 90-100 (90-100 µg/kg
  q2 for first 48 hs, q4 hours on D3-D4then to q6
  hours for another week (Shapiro et al 1998
  Ingerslev et al 1997)
• Efficacy in serious bleedings 83-95 (Lusher et
  al 1998)
• Efficacy in home treatment 92 (Key et al 1998)
• Acute bleeds in hemophilia gt5 BU
• No good laboratory markers for monitoring
  efficacy
• TEG or Trend of quantitative D-dimer levels as a
  blood counts and fibrinogen level

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COST-EFFECTIVENESS in mild-mod HA bleeding UK
study

• Clinical effectiveness
• rFVIIa mean 2.3 doses of 90 ug/kg controlled 92
  of all minor bleeds within 24 hrs (Key et al
  1998).
• FEIBA (aPCC) mena 3 doses of 75 units/kg
  controlled 79 of minor bleeds within 36 hrs
  (Hilgartner)

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COST EVALUATION MILD-MOD BLEEDINGS IN
HAEMOPHILIA
Average cost Time to resolve Mean number doses/episode Mean time to resolution Effectiveness OVERALL COST
rFVIIa 11,794 30 hrs 3.6 17.3 hrs 89.3 9,113 US
FEIBA 20,46 58 hrs 4.8 43.6 66.7 12,542
rFVIIa is safe and has a higher efficacy relative
to other treatment options.
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The FENOC study

• FEIBA (activated prothrombin complex concentrate
  (aPCC).
• Test equivalence of products in treatment of
  ankle, knee, and elbow joint bleeding.
• A prospective, open-label, randomized,crossover
• Data for 96 bleeding episodes contributed by 48
  participants were analyzed.
• FEIBA and NovoSeven appear to exhibit a similar
  effect on joint bleeds, although the efficacy
  between products is rated differently by a
  substantial proportion of patients.
  2007 ASH

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FVII-DEFICIENCY

• Autosomal recessive 1/500 000 persons
• Genetic clinical heterogeneity
• FVII activity lt1 severe
• Prolonged PT normal APTT
• There is only small number of patients available
  (case series)
• FDA-approved dose 15 -30µ g per kg, q6 -12 hs
• Monitored by PT its correction correlate well
  with achievement of clinical hemostasis

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USE OF rFVIIa IN FVII-DEFICIENCY

• N32 treated in Compassionate and ER between
  1988- 1999.
• Treated at 28 sites in 6 countries (AUS, DK,
  I,Malaysia, USA)
• Non-surgical episodes 43 joint bleeds
• EFFECTIVE in 37/43 (86) episodes independent on
  location of bleed.
• Surgical episodes 26
• EFFECTIVE in 25/26 (96) episodes.
• 10 adverse events 2 pt developed Abs against
  FVII
• FDA-approved dose 15 to 30µ g per kg q 6-12 hours
• Monitored by the PT.

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Preliminary guidelines for off-label use
proposed in 2004

• The consensus panel related use of rFVIIa as
  appropriate in
• Cardiac, thoracic, aortic, and spinal surgery
• Hepatic resection
• Hysterectomy postpartum bleeding
• Severe, multiple trauma substantial blood
  replacement ineffective.
• Non traumatic ICH lt4 hours since onset of
  symptoms
• Anti-coagulated patients with expanding
  hematomas.
• Doses of 41 to 90 µg / kg recommended in adults
  for all scenarios.
• Correction of the pH value gt7.2
• Multitrauma patients is 100 - 140 µg/ kg repeat
  dose

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European Recommendations on the use of rFVIIa as
an adjunctive treatment for massive bleeding
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Trauma.

• Uncontrolled massive hemorrhage is 2nd cause of
  death
• Massive hemorrhage surgical / vascular and a
  coagulopathic component.
• Lethal triad consumption , dilution and
  metabolic disorders
• In cases of injury, TF is brought into contact
  with naturally occurring FVIIa, to initiate
  thrombin
• Pharmacological doses, rFVIIa bind activated
  platelets at the site of injury and activate FIX
  and X directly, leading to a thrombin burst

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BluntTrauma

• Successful report for trauma in an Israeli
  soldier
• Case series of 36 patients stopped bleeding in
  72 of cases
• Several case studies ,case series , retrospective
  cohort
• Conventional hemostatic measures have failed.
• Promising addition to thrapeutic armamentarium
• Multicenter, randomized, double-blind, placebo
  controlled study by Boffard
• Initial dose of 200 µg/kg , then 100 µg/kg, at 1
  and 3 hours
• Produced a significant reduction in the primary
  endpoint RBC transfusion requirements , need for
  massive transfusion, and incidence of respiratory
  failure Grade B
• Penetrating trauma are uncertain, no
  recommendations can be made for this indication.
  Grade B

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Penetrating
Boffard et al. J Trauma 2005
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Recommendations on the use of rFVIIa as an
adjunctive treatment for massive bleeding a
European perspective

• Not be used in prophylactically in elective
  surgery (grade A)
• Use of rFVIIa in blunt trauma (grade B).
• Not be recommended for use in penetrating trauma
  (grade B)
• Not be recommended for use in liver surgery
  (grade B)
• Not be recommended for use in or in bleeding
  episodes in patients with ChildPugh A cirrhosis
  (grade B). Bleeding after cardiac surgery (grade
  D).
• Postpartum hemorrhage (grade E)
• Uncontrolled bleeding in surgical patients (grade
  E)
• Monitoring of rFVIIa efficacy should be performed
  visually and by assessment of transfusion
  requirements (grade E),
• Critical Care 2006, 10R120

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Warfarin Reversal

• Dramatic increase in number of patients
  receiving OAC
• Interindividual variation (environmental and
  genetic)
• Incidence of fatal haemorrhage 1/Y.
• Increased risk of ICH gt 50 y compared with
  non-anticoagulated 10x
• Reversal seriousness of bleeding , thrombotic
  risk and speed and completeness of reversal
• Options dose omission ,vit K factors
  replacement
• FFP or PCCs

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Warfarin Reversal PCCs

• Intermediate purity plasma products
• Only HTDEFIX is licensed in UK for warfarin
  reversal
• PCCs, (4 factor concentrates), OR low VII
  (3 )
• Amounts of protein C and S
• Optimum dose not established.
• Thrombogenicity, exacerbation of DIC are dose
  related
• Current cost in UK (single treatment for a 70 kg
  individual 437 -875).
• More expensive gt FFP. ( unit of produced from UK
  plasma costs about 30).
• FFP that is methylene blue treated or produced
  from non-UK plasma is more expensive.)

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Warfarin Reversal rFVIIa

• Advocated in the management of bleeding
• Studied in a small number of studies
• Normalises the INR in anticoagulated
• Dose range, 1590 mg/kg
• Small numbers of patients with ICH successfully
  treated with rFVIIa have been reported
  recently.5456
• Lin J, J Neurosurg 20039873740.
• Sorensen B, Blood Coagul Fibrinolysis
  20031446977
• On the basis of this limited data, the role of
  rFVIIa in warfarin reversal remains unclear.

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Use in intracranial hemorrhage.

• A recent report in ICH in adults
• Control the expansion of intracranial hematomas
  in elderly patients, improving neurologic
  outcome and significantly decreasing mortality.
• Serious thromboembolic events were higher in the
  treated groups (7 vs. 2 for placebo).
• Bijsterveld NR, Circulation 20021062550-4.

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SAFETY PROFILE

• Theoretical increased risk of thrombotic events
• rFVIIa bind to active PLTs , hemostatic activity
  should be restricted to vessel injury (TF is
  exposed PLTs are locally activated)
• Experimental evidence for localized effect in
  rabbit model
• Dec 1995 -Jan 2005,total amount of rFVIIa
  released 680,245 standard doses approved or
  off-label use,
• Over this postmarketing period, 123 thrombotic
  corresponding to a mean of 1/10000 thrombotic
• Review in patients with acquired and congenital
  hemophilia with inhibitors, incidence of
  thrombotic events was low

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SAFETY PROFILE

• Review of 13 controlled clinical trials, 1178
  patients with coagulopathy No significant
  association was found between exposure to rFVIIa
  and incidence of thrombotic events????.
• No inhibitors reported neither in HA nor
  off-label use.
• Two patients with FVII-DEFICIENCY (no FVII
  protein) developed transient inhibitors against
  FVII.
• Thrombotic complication elderly with existing
  atherosclerotic disease.
• FDA report Arterial and venous thromboembolic
  events .Half occurred in first 24 hours after
  last rFVIIa dose.
• Underlying medical conditions existed in some.
• Lack sufficient information dosage ,concomitant
  medications, pre-existing medical conditions and
  the confounding indication

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Advantages Disadvantages

• Advantages
• Rapid onset of action
• Low-volume dosing
• Recombinant nature alleviating infectious
  disease transmission
• Low risk of thrombogenicity increasing cases
  being reported of thromboembolic manifestations
• Disadvantages
• Substantial cost 1000 per milligram
• Risk of thrombosis
• Variability of current recommended dose and
  dosing intervals
• Short half-life
• Limited data pertaining to safety and efficacy,
• Problems with monitoring its efficacy.

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SUMMARY

• Great potential in achieving hemostasis in
  patients refractory to traditional treatments.
• Significant cost and uncertain benefit in many
  clinical situations, it should not be used
  indiscriminately.
• Transfusion service , pharmacy OR content expert
  in hemostasis are appropriate gatekeepers
• The ordering physician must demonstrate to a
  gatekeeper that the patient meets established
  criteria
• For off-label use a maximum of two doses
• Further doses given only after additional expert
  consultation.
• FDA-approved indication Hemophilia patients
  with inhibitors Congenital FVII deficiency

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• Thanks

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Hemostatic Defects

• Most common are
• Low platelet counts
• Low levels of vit K-depandent coagulation factors
  (FVII, FX, FIX, FII, ProtC)
• lowered fibrinogen
• lowered FVIII and FV
• - increased fibrinolysis

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Use in qualitative PLT disorders.

• Ability of pharmacologic doses to enhance rate of
  thrombin generation on activated PLTs
• Midlevel evidence and case reports exist.
• Glanzmanns thrombasthenia reports with good
  results.
• A report of 33 episodes in 7children 60
  excellent response if treated within 12 hours of
  onset of bleeding.
• Surgical prophylaxis and excessive menstrual
  bleeding
• Doses of 90 to 120µ g per kg
• Approved for use in Europe
• Poon MC, international survey. J Thromb Haemost
  200421096-103.