Transcript THROMBIN

TF VIIa
HEMOSTASIS
TF-BEARING CELL
ACTIVATED PLATELET
THROMBIN
FIBRIN HEMOSTATIC PLUG
INITIATION
OF HEMOSTASIS
PROPAGATION
OF HEMOSTASIS
Normal Hemostasis
II
X
TF
IX
IX
IIa
II
X
VIIIa
IXa
Xa
VIIIa
V
Xa Va
TF-bearing
VIIa TF cell
IXa
XIa
VIIa
VIII/vWF
XI
platelet
Va
activated platelet
IIa
Va
XIa
Thrombin
IIa (THROMBIN)
FV
FVIII
FVa FVIIa
FIBRINOGEN
FIBRIN
(SOLUBLE
FIBRIN MONOMERS)
FXIIIa
FIBRINOLYSIS
TAFI
STABILIZED,
CROSS-LINKED
FIBRIN
(HEMOSTATIC
PLUG)
Thrombin:
Fibrin Structure
0.60 U/mL (a)
0.10 U/mL (b)
0.05 U/mL (c)
0.03 U/mL (d)
Blomback et al. 1994
Thrombin Activity
0.05
With FVIII present
(- FXI)
0.045
Thrombin activity
(dA405/min)
0.04
FVIII-deficiency
0.035
+ 50 nM FVIIa
0.03
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
FACILITATE HEMOSTASIS
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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
Potential Use of rFVIIa
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Increases thrombin generation
Hemophilia (FVIII/FIX deficiency)
Platelet disorders
Diffuse bleeding triggered by surgery and
trauma
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Impaired initial hemostasis
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FVII-deficiency
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Liver disease (low levels of FVII)
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OAC therapy (low levels of FVII)
Hemophilia
II
X
VIIa
TF
VIII/vWF
Xa Va
IIa
TF-bearing
cell
VIIIa
V
Va
XI
XIa
VIIa TF
X
VIIa
platelet
II
Xa Va
activated platelet
IIa
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 >5 BU
• No good laboratory markers for monitoring efficacy
• TEG or Trend of quantitative D-dimer levels as a blood
counts and fibrinogen level
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)
COST EVALUATION
MILD-MOD BLEEDINGS IN HAEMOPHILIA
Average
cost
Mean
number
doses/epi
sode
Mean
Effective
time to
ness:
resolution
OVERALL
COST
rFVIIa £11,79 30 hrs
4
3.6
17.3
hrs
89.3%
9,113
US$
£20,46 58 hrs
4.8
43.6
66.7%
12,542
FEIBA
Time to
resolve
rFVIIa is safe and has a higher efficacy relative to other treatment options”.
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
FVII-DEFICIENCY
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Autosomal recessive 1/500 000 persons
Genetic & clinical heterogeneity
FVII activity <1% 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
USE OF rFVIIa IN FVII-DEFICIENCY
• N=32 treated in Compassionate and ER between 19881999.
• 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 <4 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 >7.2
Multitrauma patients is 100 - 140 µg/ kg repeat dose
European Recommendations on the use of rFVIIa
as an adjunctive treatment for massive bleeding –
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
Trauma: % Patients Requiring > 20 Units RBC
35
rFVIIa
Placebo
30
25
%
Pts 20
P=0.03
15
P=0.08
10
5
0
Blunt
Boffard et al.: J Trauma 2005
Penentrating
Penetrating
Recommendations on the use of rFVIIa as an adjunctive
treatment for massive bleeding – a European perspective
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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 Child–Pugh 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, 10:R120
Warfarin Reversal
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Dramatic increase in number of patients receiving OAC
Interindividual variation (environmental and genetic)
Incidence of fatal haemorrhage :1%/Y.
Increased risk of ICH > 50 y compared with nonanticoagulated 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 > 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, 15–90 mg/kg
Small numbers of patients with ICH successfully treated
with rFVIIa have been reported recently.54–56
• Lin J, J Neurosurg 2003;98:737–40.
• Sorensen B, Blood Coagul Fibrinolysis 2003;14:469–77
• On the basis of this limited data, the role of rFVIIa in
warfarin reversal remains unclear.
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 2002;106:2550-4.
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
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;
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.
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
Thanks
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
Use in qualitative PLT disorders.
• Ability of pharmacologic doses to enhance rate of
thrombin generation on activated PLTs
• Midlevel evidence and case reports exist.
• Glanzmann’s 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 2004;2:1096-103.