Download Thrombophilia: Practice Aspects

Thrombophilia: Practice Aspects
Ibrahim Alhijji, MB.BCh., FRCP
Head of Clinical Hematology
NCCCR
HMC
Feb. 2015
Contents
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•
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Introduction
Heritable Thrmbophilia
Effect on management
Summary
Contents
•
•
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Introduction
Heritable Thrmbophilia
Effect on management
Summary
Normal Hemostasis
• Vessel wall
– Endothelium
•
•
•
•
Platelets
Coagulation factors
Fibrinolytic system
Natural anticoagulants
X
TF VIIa
prothrombin
thrombin
VIIa TF
thrombin
prothrombin
IXa
VIIIa
Xa Va
TF-expressing cell
IX
VIII/vWF
V
XI
Va
XIa
platelet
X
IX
XIa
IXa
VIIIa
Xa Va
Activated platelet
Hoffman M et al. Blood Coagul Fibrinolysis. 1998; 9(suppl 1): S61-S65.
Bleeding or Thrombosis
• Any alterations in hemostatic mechanism may
lead to either bleeding or thrombosis
Incidence
• VTE is affecting 1-2 in 1000/year
• Leads to chronic post-thrombotic syndrome
(20%) and chronic thrombo-embolic
pulmonary hypertension (10%)
• 3rd most common cardiovascular disease after
MI and CVA
ACCP (Bates et al 2012, Kearon et al 2012)
NICE (2012)
Causes of death in Europe
• 543,454 due to VTE
• Exceeds combined deaths due to:
AIDS 5,860
BC 86,831
PC 63,636
Transport Accidents 53,599
T & H 2007
Circulation 1996
Contents
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Introduction
Heritable Thrmbophilia
Effect on management
Summary
Virchow’s Triad
• Pathogenesis of a Thrombus
Endothelial injury
Abnormal blood flow
Hypercoagulability
• Primary (genetic)
• Secondary (acquired)
Thrombophilias
• A heterogeneous group of conditions that
predispose individuals to VTE
Acquired
• Age: largest gradient of risk
• Malignancy: prevalence ranges from 3-18%
• Surgery:
– Orthopedic surgery:30 - 50%
– Abdominal surgery: 30%
– With anticoagulants: 18%
• Major trauma: 50-60%
• Immobilization
Acquired
• Oral contraceptives: 4 X increase in risk
• Hormonal replacement therapy: 2-4 X
increase
• Pregnancy and post-partum: 10 X increase
• Antiphospholipid antibodies: 10 X increase
Heritable Thrombophilia
1965 AT mutation identified
[Egeberg et al]
1967 Dysfunctional fibrinogen [Egeberg et al]
1981 Protein C
[Griffin et al]
1984 Protein S
[Comp et al]]
1993/4 APCr/FV L
[Dalhback/Bertina et al]
1996 Prothrombin mutation
[Poort et al]
Heritable Thrombophilia
• FVL and Prothrombin gene mutation are the
most common genetic abnormalities occurring
in patients with VTE (Seligsohn et al’ NEJM 2001)
• One or more of these abnormalities occur in
about 50% of patients with first VTE (Christiansen et
al, JAMA 2005)
Thrombophilia Prevalence
Risk factor
Subjects with
thrombosis (%)
General population
(%)
Relative Risk of
Thrombosis
Antithrombin
1
0.2
25-50
Protein C
3
0.3
10-15
Protein S
2-3
0.2
11
Factor V Leiden
Hetero
20-50
3-15
3-8/80 Homo
Prothrombin 3'
UTR mutation
Hetero
6
2
3
Multi-Casual Model
• The thrombotic event is the result of gene- gene interaction
and/or gene-environment interaction.
Variable
Normal
Hyperhomocysteinemia
Prothrombin G20210A
Oral contraceptives
Factor Leiden heterozygote
OCT and Factor Leiden
Factor Leiden homozygote
RR
1
2.5
2.8
4
7
35
80
Annual Incidence%
0.008
0.02
0.02
0.03
0.06
0.3
0.5-1
Thrombophilia screening: first-line tests
Coagulation screen
APTT, PT, TT
Antithrombin activity
Chromogenic assay
Protein C
Chromogenic assay
Protein S
Immunoreactive (free ± total)
Modified APC/SR
Predilution in FV-deficient plasma
Factor V Leiden
PCR
Prothrombin G20210A
PCR
APC/SR, activated Protein C sensitivity ratio; APTT, activated partial thromboplastin
time; prothrombin time;TT, thrombin time
Lab Evaluation
• Risks, benefits and limitations should be
discussed
• Patient should be consented
• It may has uncertain predictive value of
recurrence (anxiety)
• Negative test does not exclude an increased risk
of VTE (false reassurance)
• Repeat testing for identification of abnormality is
indicated
• Interpretation is difficult
Lab Evaluation
• Timing:
– Acute thrombotic event, chronic inflammatory
conditions, pregnancy, liver disease, DIC, OCP or
anticoagulant therapy will affect the results of
functional assays
– 14 days after the discontinuation of oral
anticoagulation therapy
Who Should we Test?
(NICE & BJH-2010)
• Do not offer testing to patients who have had
provoked VTE
• Do not offer thrombophilia testing to patients
during acute VTE or who are continuing
anticoagulation treatment
Who Should we Test?
(NICE & BJH-2010)
• Consider testing in patients (selected) who
have had unprovoked VTE, less than 40 yrs
and who have a first degree relative who has
had VTE if it is planned to stop anticoagulation
treatment
• Children with purpura fulminans
• Skin necrosis due to warfarin
Contents
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Introduction
Heritable Thrmbophilia
Effect on management
Summary
Treatment
• Initial management of acute thrombosis is the
same for patients with and without inherited
thrombophilia
– Anticoagulation with warfarin for 3-6 months
– There is no evidence that heritable thrombophilia
should influence the intensity of therapy (Schulman &
Tengborn, TH 1992; Kearon et al, Blood 2008)
Recurrent VTE
• The risk for recurrent VTE after major factor
related VTE is 1-3% patient per year
• Slightly higher for minor factor related VTE
• For unprovoked VTE the risk is 5-15% per year,
up to 30-35% after 5 years
(Iorio et al, AIM 2010; Douketis et al, AIM 2010; Eichinger et al, Circulation 2010;
Prandoni et al, Hematologica 2007)
Cambridge Venous Thromboembolism Study (CVTE) (2003)
• Two year Prospective Study:
– 570 patients
– Recurrence rate was 11%
• Lowest incidence after surgery related VTE (0%)
• Highest incidence with un-precipitated VTE
(19.4%)
Cambridge Venous Thromboembolism Study (CVTE) (2003)
– 85% of patients were tested for heritable
thrombophilic defects→ recurrence rates were
not related to presence or absence of heritable
thrombophilia.
– CONCLUSION: Thrombophilia testing had no
predictive value for reoccurrence
Baglin et al. The Lancet 2003.
Leiden Thrombophilia study (LETS) JAMA
2005
• Prospective follow up study of LETS pts
– 447 patients followed for a mean of 7.3 years
– Incidence rate of recurrence was highest during the first two
years: annual rate of 3.2%; cumulative recurrence of 12.4% at 5
years
• Risk of recurrence was 2.7 x higher in men than women (95% CI
, 1.8-4.2)
• Higher risk of recurrence with idiopathic initial VTE
• Lower risk of recurrence with provoked initial VTE
• OCT use during follow up had a higher recurrence rate (28 per
1000 pt-yrs vs 12.9 per 1000 pt-yrs)
Leiden Thrombophilia study (LETS) JAMA
2005
• Conclusion:
– Clinical factors (male sex, use of OCT’s, idiopathic
initial VTE) have a more significant role in risk of
reoccurrence than lab abnormalities
(Christiansen et al, JAMA 2005)
Thrombophilia and Recurrent VTE
• Retrospective analysis showed detection of
natural anticoagulants deficiency in selected
patients predicted a risk of recurrence of 6.2%
compared to 2.2% in patients with FVL or
Prothrombin gene mutation (Lijfering et al, Blood 2009)
• In general the risk of recurrence is uncertain
and it is low if first event was provoked (Cohn et al,
CDSR 2009)
Guidelines ACCP 2008
• The presence of hereditary thrombophilia has
not been used as major factor to guide
duration of anticoagulation for VTE because
evidence from prospective studies suggests
that these factors are not major determinants
of the risk of recurrence
Predicting Disease Recurrence- DASH
(Tosetto, JTH 2012)
• 1818 with unprovoked VTE treated with
warfarin for 3 months analyzed and followed
up for 5 years
Predicting Disease Recurrence- DASH
(Tosetto, JTH 2012)
Multivariate
Score
D-dimer-abnormal
2
Age-less than 50
1
Sex-man
1
Hormonal
associated VTE
-2
Predicting Disease Recurrence-DASH
(Tosetto, JTH 2012)
• May be useful to decide whether therapy
should be continued indefinitely (if score more
than 1) or stopped after 3 months (if score 1
or less)
• Independent validation is required in separate
population
D-dimer to guide the duration of
therapy (DULCIS, Blood 2014)
• Multicentre prospective study
• 1010 patients with unprovoked VTE
• 2 years follow up
D-dimer to guide the duration of
therapy (DULCIS, Blood 2014)
D-dimer to guide the duration of
therapy (DULCIS, Blood 2014)
• D-dimer can be considered as an independent
factor of VTE recurrence
• Serial measurement is suitable in clinical
practice
D-dimer
• Potential need for gender specific and age
specific D-dimer cut points (Legnani et al, IEM 2011)
• Additional research is needed
Men and HER DOO2
• Prospective cohort of patients with first
unprovoked VTE
• All men are considered at high risk of
recurrence
Men and HER DOO2
• For women >=2 factors (comprising lower
extremity hyperpigmentation, edema,
redness, D-dimer >=250 ng/ml [during
therapy], obesity [body mass index >=30
kg/m2] and age over 65 years) identifies
women at high risk for recurrent VTE
(Le Gal et al, TH 2010; Rodger et al, CMAJ 2008)
Residual Vein Occlusion
• Lack of a standard definition for RVO and the potential
for operator variability in the interpretation of US
findings
• Detected in at least 40% of patients at 3-6 months
treatment
• Poor predictor of VTE recurrence
JTH 2011
AJH 2011
TH 2011
EJVES 2010
Blood 2014
Risk Factors of VTE Recurrence
1.
2.
3.
4.
5.
Mode of initial presentation
Patient’s gender
D-dimers
Age
? Thrombophilia
Baglin et al, 2003; Douketis et al, BMJ 2011; DULCIS, Blood 2014
Duration of Therapy
• Depends on the presence or absence of risk
factors of VTE recurrence
• The benefit of continued therapy needs to be
balanced against the risk of therapy related
bleeding (Schulman et al, Chest 2008)
• Annual risk for therapy related bleeding is 13% with 0.3% associated with major
hemorrhage (Schulman et al, Chest 2008)
Factors that increase the risk of VKArelated bleeding (Scientifica 2012)
Treatment related
Patient related
First 3 months of therapy
Advanced age (>75 years)
Actual INR values > 4.5
Frequent falls
Low quality of anticoagulation monitoring
History of major bleeding
Uncontrolled hypertension
Renal or liver failure
Associated antiplatelet therapy
Drugs
Poor compliance
Absence of familial or social support
Recent surgery
Cancer
HAS-BLED score (Lip et al, JACC 2011)
Risk factors
Score for each risk
factor
Total score
Major bleeding
events (% patients)
in relation to the
total score
None
/
0
0.9
Hypertension
1
1
3.4
Abnormal renal or
liver function
1 each
2
4.1
Stroke
1
3
5.8
Bleeding history or
predisposition
1
4
8.9
Labile INR
1
5
9.1
Age > 65 years
1
6
/
Drugs/alcohol
concomitantly
1 each
/
/
HAS-BLED
• HAS-BLED score has been developed for
patients with AF who are generally elderly
(Pisters et al, Chest 2010)
• It needs to be studied in VTE patients
Guidelines ACCP 2012
• Recommend at least 3 months treatment for
unprovoked DVT
• Suggest to evaluate for the risk-benefit ratio of
extended therapy
Extended Therapy
• Periodic reassessment:
1. Patient’s bleeding risk
2. Patient’s values and preferences
3. New research findings
Contents
•
•
•
•
Introduction
Heritable Thrmbophilia
Effect on management
Summary
Summary
• Inherited thrombophilia can be found in up to
50% of VTE cases
• Only selected pts should be tested
• Laboratory testing should be done at right
time and results should be interpreted with
caution
Summary
• Initial management is not different from non
inherited thrombophilia
• Risk of recurrence should be identified for
unprovoked VTE
• Duration of therapy is determined largely by
clinical factors and patients preferences
Suggested management
Clinical condition
Management
Secondary* isolated distal DVT
6 weeks AC#
Unprovoked isolated distal DVT
3 months AC
Secondary proximal DVT and/or PE
3–6 months AC
Unprovoked first proximal DVT and/or PE 3–6 months AC, then stratify for
individual risk of recurrence
Life-threatening PE as index event
Consider extended£ AC
VTE associated to active cancer
AC until cancer is no longer active
Unprovoked VTE associated with
antiphospholipid syndrome or
antithrombin deficiency
Extended AC
Unprovoked VTE associated with other
Consider extended AC
major thrombophilic alteration (protein C
or S deficiency, homozygous factor V
Leiden or G20210A prothrombin
mutation or double heterozygous)
Second unprovoked VTE
Extended AC
Thank you