thrombophilia

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LONG TERM TREATMENT AFTER VENOUS
THROMBOEMBOLISM ERIC WATTS BASILDON THURROCK
UNIVERSITY HOSPITAL

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TO TREAT OR NOT TO TREAT? TO STOP OR
CONTINUE? TO DECIDE ON CLINICAL GROUNDS OR ON
THE BASIS OF INFORMATION WHICH CAN PREDICT
RECURRENCE? CAN WE DETERMINE THE RISK OF
STOPPING OR CONTINUING IN ORDER TO MAKE AN
INFORMED DECISION?
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Subsequent management following 1st spontaneous
thrombosis Risk of recurrence 20 at 2yrs 1
fatal if no AC Annual mortality approx. 0.2 On
warfarin risk of serious Hge 1 25 fatal Annual
mortality approx. 0.25
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How can we quantify the risk of
recurrence? Provoked vs unprovoked Past
history Family history ? Thrombo screen
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G S Aged 14 admitted with abdo pain Found to have
ileo femoral DVT Mother a long term
anticoagulant patient with recurrent DVT Thrombo
testing Mother - S deficiency Son S
deficiency FVL
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Thrombophilic families

• Recognised for decades
• Some associated with other genetic markers eg
  blood group AB
• In these families the age of onset of 1st
  thrombosis would often be less than 30 yrs
• Antithrombin III deficiency reported in such
  kindreds in 1965 a single gene defect

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THROMBOPHILIA CONFERENCE 1988
ATIII, S, C, LAC - defective fibrinolysis Abnor
malities are present in situations with
thrombotic risk detailed studies are required
to establish the nature of the relationships.
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Thrombosis is Multifactorial

• Most patients are elderly bedridden hospitalised
  post op or other illnesses IV cannulae etc
• How relevant are findings from such patients to
  fit young mobile relatives?

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Virchows Triad abnormalities in

• Vessel wall
• Composition of the blood
• Stasis
• The evidence is emerging through a fog

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The Assays

• Functional
• Antithrombin reliable test with tight normal
  range good QC
• Prot C results vary with technique lab overlap
  between normal heterozygotes
• Prot S more variable than Prot C
• APCR differing methods - a screening test

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Genetic Tests

• Factor V Leiden- reliable test takes time
• Prothrombin G20210A genetic test only no
  screening test
• Homocysteine- thermolabile tetrahydrofolate
  reductase variant can be identified but does not
  correlate with thrombosis

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Risk Factor gp VTE Ratio

• Antithrombin 0.02 1
  x50
• Prot C 0.2-0.4 3
  x10
• Prot S varies 0.1-0.4 1-2
  x5-10 -?co factors
• Factor V Leiden 5 20
  x4

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Risk Factor gp VTE Ratio

• Prothrombin G20210A 2 6 x3
• FVIII gt150 12 24
  x2
• Hyperhomocystein 5 10
  x2
• gt18.5umol/l
• Hyperhomocysteinaemia can be secondary to a wide
  range of chronic inflammatory Malignant disease
  renal failure poor diet etc

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Population based perspective

• Worcester DVT Study Anderson FA Arch
  Intern Med 1991 151(5)933-8
• Population of 380,000 served by 16 hospitals
  78-578 beds all cases of DVT PE documented for
  18/12 followed up for 4 years

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Worcester study

• Overall inc of DVT 48/100,000
• Overall inc of PE 23/100,000
• Average age 67 but exponential increase with age

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Worcester Study long term case fatality post
discharge

• 1yr 19
• 2yrs 25
• 3yrs 30

• Co morbid conditions
• Cancer 29
• CCF 23
• COPD 26
• Fractures 12
• MI 6

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FH of thrombosis

• The potential value value of testing families is
  in the possibility of preventing a first
  thrombosis - the EFECTIVENESS RISKS of this
  approach have not been formally assessed
• If there is a very strong FH prophylaxis may be
  justified should all tests be normal
• Large families with several affected members
  where the abnormality corresponds with thrombosis
  may informative

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Basildon Experience

• 8yrs 500 young patients
• All advised that they have an increased risk of
  thrombosis but that the absolute risk is small
• The risk of a second thrombosis overall is 20 in
  2 yrs
• Patients are advised to report early if they have
  any relevant symptoms- pain swelling
• Very few good FHs
• More married couples than parents and children

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A decision analysis based on epidemiological
data Risk of recurrent VTE (0-20 first 2-3
years then declines) Risk higher in spontaneous
VTE Incidence of major bleeding higher with age
Oral anticoagulation 90 successful in preventing
recurrences
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Baseline estimates and ranges
Recurrent VTE ( per 3 months) Time since initial
VTE (months) Spontaneous Secondary 4-6 5.60
2.78 7-12 2.70 1.35 13-24 2.30 1.15 25-
36 1.50 0.77 gt36 1.00 0.48 Case
fatality 9 Major bleeding ( per 3 months) Age
(years) lt40 0.16 40-49 0.25 50-59 0.37 60-69 0
.57 gt70 0.87 Case fatality 15 Relative risk
reduction achieved with treatment with vitamin K
antagonists 90
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Time since initial VTA (months) Time since initial VTA (months) Time since initial VTA (months) Time since initial VTA (months)
4-6 7-12 13-24 25-36 gt36
Age (years) Change in MB incidence Change in recurrent VTE incidence Change in recurrent VTE incidence Change in recurrent VTE incidence Change in recurrent VTE incidence
Age (years) Change in MB incidence -2.50 -1.21 -1.03 -0.70 -0.43
lt40 0.16 -0.20 498 -0.08 1178 -0.07 1453 -0.04 2596 -0.01 6710
40-49 0.25 -0.19 553 -0.07 1398 -0.06 1801 -0.03 3966 -0.002 62833
50-59 0.37 -0.17 590 -0.05 1868 -0.04 2666 -0.01 13861 0.02 -
60-69 0.57 -0.14 717 -0.02 4247 -0.01 13311 -0.02 - 0.05 -
gt70 0.87 -0.09 1059 0.02 - 0.04 - 0.07 - 0.09 -
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ISTH JULY 2003
Risk factors for recurrent VTE De Stefano
2003 205 patients medium age 36 36 had
thrombophilia markers Relative risk of recurrence
Tphil/Normal 1.1 CI 00.9-1.4
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Risk factors for recurrent VTE Leiden
Thrombophilia Study (LETS) S Christiansen
2003 474 consecutive patients with a first
episode of VTE Age 18-70 without known
malignancy 94 followed up for 7 years 87
recurrences (16)
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Hazard ratio Confidence interval (95)
Factor V Leiden 1.2 07.-1.9
PT 20210A 0.8 0.3-2.0
F.VIII elevation 1.1 0.7-1.8
F.IX elevation 1.0 0.5-1.8
F.XI elevation 0.6 0.3-1.1
PC/PS/AT-def 1.7 0.8-3.5
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Influence of Thrombophilia
Efficacy of warfarin for prevention of recurrent
VTE a randomised trial Kearon 2003 Objective to
determine if the risk of recurrence during
anticoagulation is increased by thrombophilia
markers 661 patients with spontaneous VTE 1600
patient years follow up Overall risk of
recurrence 3
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Marker RR C1
FVL 0.7 0.2-2.1
FVIII? 1.1 0.2-4.6
FXI 0.5 0.1-3.5
H Hcy 0.5 0.1-3.5
LAC 1.9 0.6-6.5
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Why? The new genetics and genome scanning Novel
family-based approaches to genetic risk in
Thrombosis J Blangero JT Williams L Almasy
Journal of Thrombosis and Haemostasis 2003 1,7
1391-1397 Few diseases are the result of a single
gene defect. The field of common complex disease
genetics has progressed through a major
paradigmatic change focussing on measurable
quantitative traits that correlate with disease
as against dichotomous disease traits. They
identify quantitative trait loci (QTL) works
best on extended families
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The bigger the pedigree, the more
information. Biggest is from Jirel, 2000
relatives gerome scanned and being assessed for
haemostasis related traits. The story so far
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Recommendations
Indefinite anticoagulation at a target of 2.0-3.0
is recommended only in these high risk
patients Bauer KA The Thrombophilias well
defined risk factors with uncertain therapeutic
implications Am.Int.Med. 2001 135 367-73 2 or
more spontaneous thromboses One spontaneous
thrombosis and LAC One spontaneous life
threatening thrombosis One spontaneous thrombosis
at an unusual site eg. mesenteric or cerebral One
spontaneous thrombosis with multiple
thrombophilic abnormalities
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CONCLUSION In spite of many years of
thrombophilia testing, the usefulness of this
approach is unproven. There are still differing
approaches in clinical practice. The main purpose
of thrombophilia testing is to generate data for
epidemiological research. Patient management is
determined largely by clinical factors
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Ximelagatran Overview

• Oral ximelagatran rapidly absorbed and
  biotransformed to the active form, melagatran
• Renal excretion
• Clinical studies demonstrate efficacywith bid
  dosing
• No coagulation monitoring required
• Low potential for drug/food/alcohol interaction
• Fixed dosing and predictable response

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The Dose-Linear Pharmacokinetics of Ximelagatran
y 0.0844 0.057x R2 0.95
y 0.0052 0.014x R2 0.94
AUC (µmolh/L)
Cmax (µmol/L)
Eriksson UG et al. Blood 199994(Suppl 1)26A.
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Extended secondaryprevention with the oral
direct THRombin Inhibitor ximelagatranin
patients with VEnous thromboembolism

• THRIVE III

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Study design
Initial VTEevent
ximelagatran 24 mg bid
n612
ITT
R
n611
placebo
INR lt1.5
Standard AC
2-week follow-up
18 months
61 months
Baseline
UltrasonographyPerfusion lung scan
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VTE events - DVT and/or PE
Estimated cumulative risk ()
12.6
plt0.0001 HR0.16 (95 CI 0.090.30) RRR78
9.8
placebo
ximelagatran
2.8
0
3
6
9
12
15
18
Months
40
Major and/or minor bleeding events
Estimated cumulative risk ()
30
p0.1703 HR1.19 (95 CI 0.931.53)
25
23.9
21.0
20
15
placebo
10
ximelagatran
5
0
18
3
6
9
12
15
0
Months
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Efficacy and safety of the oral direct thrombin
inhibitor ximelagatran for acute symptomatic
deep vein thrombosis with or without pulmonary
embolism

• THRIVE Treatment Study

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Study design
Double-blind, double-dummy design enoxaparin 5
- 20 days until INR ? 2.0 on warfarin
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Total VTE Estimated treatment differences at 182
dayswith 95 confidence intervals
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Total VTE Cumulative risk versus time after
randomisation
Cumulative risk ()
5
4
3
2
1
0
0
30
60
90
120
150
180
Days after randomisation
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Major bleeding Cumulative risk versus time after
randomisation
Cumulative risk ()
ximelagatran (14 events)
2.2
NS
1.3
0
30
60
90
120
150
180
Days after randomisation
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Stroke Prevention Using theORal Direct Thrombin
InhibitorXimelagatran in Patients With
Nonvalvular Atrial Fibrillation SPORTIF III
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Primary events stroke and SEEIntention-to-treat
analysis
Cumulativeevent rate ()
56 events (2.3/year)
warfarin
ximelagatran
40 events (1.6/year)
0
3
6
9
12
15
18
21
Duration (months)
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Primary events stroke and SEEIntention-to-treat
analysis
ximelagatranbetter
warfarinbetter
ximelagatran 1.6/year(40 events) warfarin2.3/y
ear(56 events)
Superiority
Non-inferiority
-3
-2
-1
0
1
2
3
Event rate difference ()
Difference per year 0.7 (95 CI 1.5, 0.1
p0.10)
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Adverse eventsHaemorrhage
Event rate( per year)
p0.007
29.8
25.8
1.8
1.3
0.4
0.2
Majorbleeding
Major minorbleeding
Intracranialhaemorrhage
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• Warfarin
• Decades of experience
• Vast quantities of data
• Patients and professionals familiar with the INR
• Cheap

• Ximelagatran
• Appears safe and effective
• No drug interactions
• No tests
• ? cost

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Risk of treatment

• Serious haemorrhage from warfarin
• 1 pa
• ¼ are fatal
• 70 in range is good control
• Many bleeds occur in control range

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Time since initial VTA (months) Time since initial VTA (months) Time since initial VTA (months) Time since initial VTA (months)
4-6 7-12 13-24 25-36 gt36
Age (years) Change in MB incidence Change in recurrent VTE incidence Change in recurrent VTE incidence Change in recurrent VTE incidence Change in recurrent VTE incidence
Age (years) Change in MB incidence -5.00 -2.42 -2.07 -1.39 -0.87
lt40 0.16 -0.43 235 -0.19 516 -0.16 618 -0.10 988 -0.05 1852
40-49 0.25 -0.41 242 -0.18 554 -0.15 673 -0.09 1137 -0.04 2458
50-59 0.37 -0.39 254 -0.16 615 -0.13 766 -0.07 1430 -0.02 4409
60-69 0.57 -0.36 274 -0.13 754 -0.10 995 -0.04 2504 0.01 -
gt70 0.87 -0.32 313 -0.09 1142 -0.06 1801 0.01 - 0.05 -