Download Thrombophilia

INHERITED THROMBOPHILIA
INHERITED THROMBOPHILIA
Defects in physiologic anticoagulant pathways
•Antithrombin deficiency
•Protein C deficiency
•Protein S deficiency
•Factor V Leiden
Increased production of procoagulant
•Prothrombin G20210A gene mutation
 Many other genes affect coagulation – the contribution
of mutations in these genes to thrombotic risk is
presently impossible to quantify
INHERITED CONDITIONS NOT ASSOCIATED WITH
CLINICALLY SIGNIFICANT RISK OF THROMBOSIS
• MTHFR mutations
• Plasminogen deficiency and other defects in
fibrinolysis
THROMBOPHILIA DUE TO DEFICIENCY
OF ANTICOAGULANT PROTEIN
Antithrombin, Protein C, Protein S
• Typically 30-60% of normal plasma activity of
•
•
affected protein
Dominant inheritance
Genetically heterogeneous



Type 1: low antigen and activity
Type 2: normal antigen, low activity (missense
mutations)
Type 3 (Protein S): Increased binding to C4b binding
protein, decreased free protein S level/activity
• Thrombotic risk varies from family to family
• Together account for approximately 10-15% of
cases of inherited thrombophilia
Plasma levels of anticoagulant proteins are
poor predictors of inherited deficiency
Likelihood that a gene mutation is present if
measured protein activity is 50% of normal:
– Antithrombin = 75%
– Protein C =60%
– Protein S = 25%
Thromb Haemost 2012; 108: 247
FACTOR V LEIDEN
A highly prevalent inherited risk factor for thrombosis
• Polymorphism eliminates a preferred protein C
cleavage site, slows inactivation of factor Va by
protein C
• Factor Va procoagulant activity not affected

Not a “deficiency”
• Same genotype responsible for all cases

Diagnosed by DNA testing
• Very common


About 5% of US population heterozygous, 0.05%
homozygous
High allele frequency implies evolutionary advantage
FACTOR V LEIDEN
Prevalence in different ethnic groups
Group
Allele
frequency
Heterozygote
frequency
Homozygote
frequency
European
4.4%
8.6%
0.2%
Asia Minor
0.6
1.2
0.004
African
0
0
0
SE Asian
0
0
0
Native
American
0
0
0
Lancet 1995;346:1133
FACTOR V LEIDEN INCREASES RISK OF
VENOUS, BUT NOT ARTERIAL, THROMBOSIS
Physicians' Health Study (15,000 subjects)
Ridker et al, NEJM 1995;332:912
P = 0.02
12
% Heterozygotes
10
8
P = 0.9
6
P = 0.7
P = 0.4
4
2
None
MI
Stroke
MI
or
Stroke
0
Type of thrombosis
DVT
or
PE
PROTHROMBIN G20210A GENE POLYMORPHISM
• Polymorphism in 3' untranslated (noncoding) part of prothrombin gene
• No effect on prothrombin structure or
function
• Heterozygotes have 5-10% higher plasma
levels of prothrombin, 2-3 fold relative risk
of venous thromboembolism
• About 1-2% of population heterozygous
• Diagnosis: DNA testing
CLINICAL FEATURES OF
INHERITED THROMBOPHILIA
INHERITED THROMBOPHILIA
Clinical findings in homozygous state
Antithrombin III deficiency
CLINICAL FINDINGS IN
HOMOZYGOTES
lethal?
Protein C deficiency
neonatal purpural fulminans
Protein S deficiency
neonatal purpural fulminans
(? - rare)
FVL
Prothrombin mutation
Premature thrombosis in
many (most?) - some
asymptomatic
CONDITION
HOMOZYGOUS PROTEIN C DEFICIENCY WITH
NEONATAL PURPURA FULMINANS
INHERITED THROMBOPHILIA
Clinical Features in Heterozygotes
• Venous thromboembolism
 No
convincing evidence of increased risk of
arterial thrombosis
• Onset often in 20s and 30s
 Many
carriers asymptomatic throughout life
• About half of VTE episodes unprovoked
• Increased risk of pregnancy loss
Thrombotic risk varies with type of thrombophilia
Proportion of individuals from thrombphilic families
who have an episode of VTE by age 50:
• Protein C, protein S or antithrombin deficiency:
40-50%
• Factor V Leiden or prothrombin polymorphism:
10-15%
Blood 2009;113:5314
Relative risk of VTE in individuals with low
plasma protein S vs protein S mutation
Relative risk of
thrombosis
95% CI
Low plasma protein S
(general population)
0.7
0.3-1.8
Protein S mutation in
thrombophilic family
11.5
4.3-30.6
Koster et al, Blood 1995;85:2756
Simmonds et al, Ann Intern Med 1998;128:8
Family history predicts thrombotic risk just as well
as laboratory testing for thrombophilia
A case-control study
Fam Hx VTE
Odds ratio for
thrombosis
(95% CI)
Negative
1 (reference)
Any relative
2.2 (1.9-2.6)
Relative < 50
2.7 (2.2-3.4)
> 1 Relative
3.9 (2.7-5.7)
Event
OR for event with
positive FH
OR for event with
positive test for
thrombophilia
Unprovoked VTE
2.5
2.3
Provoked VTE
16.4
21.2
Arch Intern Med 2009;169:610
The presence of thrombophilia does not predict
thrombotic risk in the absence of a family hx of VTE
Event in proband leading to
diagnosis of thrombophilia
Incidence of VTE in relatives
per 1000 patient-yrs (95% CI)
Carriers
Non-carriers
VTE
1.6 (1.2-2.2)
0.5 (0.3-1.0)
Arterial thrombosis
0.5 (0.1-2.8)
0.8 (0.2-3.0)
Obstetric complication
0.6 (0.2-1.6)
0.0 (0-0.8)
Asymptomatic
0.3 (0.1-1.2)
0.0 (0-0.7)
Thromb Haemost 2011;106:646
RISK OF THROMBOSIS IN
THROMBOPHILIA
EFFECT OF GENE DOSE
Relative risk of thrombosis in heterozygous
and homozygous factor V Leiden
Genotype
Relative Risk
Normal
1
Heterozygous
7
Homozygous
80
Rosendaal et al, Blood 1995;85:1504
EFFECT OF GENE INTERACTIONS
Co-inheritance of protein C deficiency and
factor V Leiden within a family
Gene Mutation
Thrombosis present Thrombosis absent
(%)
(%)
Protein C and
Factor V
16 (73)
6 (27)
Protein C
5 (31)
11 (69)
Factor V
2 (13)
11 (87)
None
0
11 (100)
Koeleman et al, Blood 1994;84:1031
INTERACTION WITH ACQUIRED RISK FACTORS
Oral contraceptive
RISK FACTOR
RELATIVE RISK OF
THROMBOSIS
Oral contraceptive
4
Factor V Leiden
8
Both
35
Vandenbroucke et al, Lancet 1994;344:1453
INTERACTION WITH ACQUIRED RISK FACTORS
Estrogen replacement
RISK FACTOR
RELATIVE RISK OF
THROMBOSIS
Estrogen replacement
3.5
Factor V Leiden
4.6
Both
11
Rosendaal, 2001
WHAT ARE THE IMPLICATIONS OF
A POSITIVE TEST FOR
THROMBOPHILIA IN AN
ASYMPTOMATIC PERSON?
RELATIVE RISK OF VENOUS EVENTS IN RELATIVES OF PATIENTS
WITH THROMBOPHILIA
Vossen et al, J Thromb Haemost 2004;2:1526
THE ABSOLUTE RISK OF VENOUS EVENTS IN ASYMPTOMATIC
RELATIVES OF THROMBOPHILIC PATIENTS IS LOW
Vossen et al, J Thrombos Haemost 2005;3:459
Bleeding risk with long term anticoagulation estimated at 1-3%/year
INCIDENCE OF FIRST VTE EVENTS IN SPECIFIC RISK
SITUATIONS IN THROMBOPHILIC INDIVIDUALS
Vossen et al, J Thrombos Haemost 2005;3:459
THROMBOPHILIC
INDIVIDUALS
CONTROLS
Travel > 8h
0% (0/504)
0% (0/1244)
Surgery or
immobilization > 2 w
2% (3/176)
0.04% (2/407)
Plaster cast
0% (0/33)
0% (0/71)
Cancer
10% (1/10)
6% (1/17)
Pregnancy
7% (2/28)
0% (0/75)
RISK SITUATION
Analysis restricted to individuals not given prophylaxis
SHOULD ORAL CONTRACEPTIVES ROUTINELY BE
WITHHELD FROM WOMEN WITH FACTOR V LEIDEN?
PREDICTED OUTCOMES WITH ALTERNATIVE CONTRACEPTIVE METHODS
Oral
contraceptive
Levonorgesterol
-IUD
Copper IUD
Condom
1st VTE/100
pregancy-yr
0.55
0.25
0.25
0.25
VTE/100,000
pregnancy-yr
550
250
250
250
Unintended
pregnancies/
100,000 p-y
200
700
1400
12,000
Additional
cases of VTE
6
20
40
336
Total # VTE
556
270
290
586
Blood 2011;118:2055
MANAGEMENT OF ASYMPTOMATIC
INDIVIDUALS WITH INHERITED
THROMBOPHILIA
•
•
•
Counseling/reassurance
Prophylaxis in high-risk situations
Carefully consider risk/benefit ratio and
alternatives when prescribing oral
contraceptives or HRT
IS THE MANAGEMENT OF
PATIENTS WITH VTE AFFECTED
BY THE RESULTS OF
THROMBOPHILIA TESTING?
The risk of recurrent venous thromboembolism is higher
in patients with idiopathic events
Lancet 2003; 362: 523–26
Idiopathic VTE
Other risk factor
Postop VTE
The risk of recurrent VTE is not significantly affected by
the presence of inherited thrombophilia
Lancet 2003; 362: 523–26
Hazard ratio 1.50
(95% CI = 0.82-2.77)
p=0.187
The presence of inherited thrombophilia does not
usually affect treatment of patients with VTE
•
•
Idiopathic VTE is a strong independent
predictor of recurrence risk, and so is a
potential indication for long-term
anticoagulation
The presence of inherited thrombophilia is not a
good predictor of VTE recurrence risk and so
should not be used as the basis for prolonging
therapy
Warfarin-induced skin necrosis in a
protein C-deficient patient
Compound heterozygote for FVL and protein C deficiency
Day 5 of warfarin treatment, on heparin
Concomitant bilateral adrenal hemorrhagic infarction
WARFARIN LOWERS LEVELS OF PROTEIN C FASTER THAN
LEVELS OF PROCOAGULANT VITAMIN K-DEPENDENT PROTEINS
Prothrombin
Protein C
Transient hypercoagulability?
THROMBOPHILIA AND
PREGNANCY
INCREASED RISK OF FETAL LOSS IN WOMEN WITH
HERITABLE THROMBOPHILIA
European Prospective Cohort on Thrombophilia (1384 women)
Lancet 1996;348:913
CONDITION
RR OF
STILLBIRTH
95% CI
RR OF
MISCARRIAGE
95% CI
ANTITHROMBIN
DEFICIENCY
5.2
1.5-18.1
1.7
1.0-2.8
PROTEIN C
DEFICIENCY
2.3
0.6-8.3
1.4
0.9-2.2
PROTEIN S
DEFICIENCY
3.3
1.0-11.3
1.2
0.7-1.9
FACTOR V LEIDEN
2
0.5-7.7
0.9
0.5-1.5
COMBINED DEFECTS
14.3
2.4-86.0
0.8
0.2-3.6
ALL THROMBOPHILIA
3.6
1.4-9.4
1.27
0.94-1.71
BUT…
There is no evidence that
anticoagulant (LMWH) or
antiplatelet (ASA) prophylaxis
improves pregnancy outcomes
in women with inherited
thrombophilia
WHO TO TEST?
Inherited thrombophilia is more likely if a patient
with VTE




Is young
Has a family history of VTE
Had unprovoked VTE
Had warfarin-induced skin necrosis (protein C)
 Test results rarely affect patient management!
WHEN TO TEST?
•
•
•
•
FVL, prothrombin polymorphism: any time (DNA test not
informative after liver transplantation)
Antithrombin:
 Not during acute thrombosis
 Not during pregnancy or estrogen/OCP use
 Off heparin/LMWH at least 2 weeks
Protein C:
 Off warfarin (preferable), or on stable warfarin dose at least 2
weeks
 Preferably not during acute thrombosis
Protein S:
 As for protein C
 Not during pregnancy, OCP use or acute inflammation
Neonatal period, DIC, liver disease, asparaginase Rx can all cause
acquired deficiency of AT, PC, PS
 Testing should usually be done in the outpatient setting
ACQUIRED THROMBOPHILIA
• Antiphospholipid syndrome
• Hyperhomocysteinemia (may be inherited)
• Inflammatory bowel disease
• Cancer
• Nephrotic syndrome
• Myeloproliferative disorders
• Pregnancy
• Oral contraceptive/estrogen
• Hyperviscosity
HOMOCYSTEINE
CAUSES OF HYPERHOMOCYSTEINEMIA
SEVERE
• homozygous cystathione beta-synthase deficiency
(1:250,000)
• homozygous methylenetetrahydrofolate reductase
deficiency
MILD OR MODERATE
• heterozygous CBS deficiency (0.3-1.4% of population)
• C677T polymorphism in MTHFR (10% of population
homogyzous)
• B12, folate or B6 deficiency
• Aging
• Chronic renal failure
HIGHER HOMOCYSTEINE LEVELS ARE
ASSOCIATED WITH VASCULAR RISK
Meta-analysis
Condition
Increase in risk per 5 micromole
increase in plasma HC (95% CI)
Ischemic heart disease
1.32 (1.19-1.45)
Stroke
1.59 (1.29-1.96)
VTE
1.60 (1.15-2.22)
BMJ 2002;325:1202
BUT…
LOWERING HOMOCYSTEINE DOES NOT
DECREASE VASCULAR RISK
• VISP trial (JAMA 2004): Moderate reduction in HC
•
•
•
had no effect on vascular risk during 2 yr followup
HOPE 2 trial (NEJM 2006): Vitamin supplements
lowered HC levels but had no effect on vascular
risk
NORVIT trial (NEJM 2006): More aggressive
vitamin supplementation associated with
increased vascular risk
VITRO study (Blood 2007): Lowering HC did not
prevent recurrent VTE
ANTIPHOSPHOLIPID
ANTIBODIES
ANTIPHOSPHOLIPID ANTIBODIES
• Lupus anticoagulant
• Cardiolipin antibodies (IgG, IgM)
• Beta-2 glycoprotein I antibodies (IgG, IgM)
• Thrombotic risk associated with higher
antibody levels, positive tests for more than
one type of antibody
INCIDENCE OF ANTIPHOSPHOLIPID
ANTIBODIES
PATIENT GROUP
ANTIBODY TYPE
APPROX
INCIDENCE
SLE
LAC
30%
SLE
aCL
40%
Blood donors
aCL
2%
Healthy elderly
aCL
52%
Love and Santoro, Ann Intern Med 1990
CLINICAL CONDITIONS ASSOCIATED
WITH ANTIPHOSPHOLIPID ANTIBODIES
The “antiphospholipid syndrome”
• Thrombosis (arterial and venous)
• Recurrent fetal loss
• Hematologic abnormalities:


Immune thrombocytopenia
Immune hemolytic anemia
Arthritis & Rheumatism 2002;46:1019-27
CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME
(Asherson, 1992)
• 1% or less of APL patients
• Generalized vasculopathy (?thrombotic or
•
•
•
•
inflammatory)
Livedo reticularis
Multiple organ system involvement
 Renal failure
 Hypertension
 ARDS
 CNS
Rapid progression; sudden death in some patients
Treatment: anticoagulation, plasma exchange,
immunosuppresion (sirolimus?)
“Although a positive APLA test
appears to predict an increased risk
of recurrence in patients with a first
VTE, the strength of this association
is uncertain because the available
evidence is of very low quality”
Blood 2013;122:817-824
ANTIPHOSPHOLIPID SYNDROME
CLINICAL CRITERIA
1.
One or more documented episodes of arterial, venous, or small vessel
thrombosis (other than superficial venous thrombosis) in any tissue or organ
–
–
2.
Thrombosis must be confirmed by objective validated criteria
For histopathologic confirmation, thrombosis should be present without significant evidence of
inflammation in the vessel wall
Pregnancy morbidity
a.
b.
c.
One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week
of gestation, with normal fetal morphology documented by ultrasound or by direct examination
of the fetus, or
One or more premature births of a morphologically normal neonate before the 34th week of
gestation because of: (i) eclampsia or severe pre-eclampsia defined according to standard
definitions, or (ii) recognized features of placental insufficiency, or
Three or more unexplained consecutive spontaneous abortions before the 10th week of
gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal
chromosomal causes excluded
J Thromb Haemost 2006;4:295
ANTIPHOSPHOLIPID SYNDROME
LABORATORY CRITERIA
1.
2.
3.

Lupus anticoagulant (LAC) present in plasma, on two or more occasions at
least 12 weeks apart, detected according to the guidelines of the
International Society on Thrombosis and Haemostasis (Scientific
Subcommittee on LACs/phospholipid- dependent antibodies)
Anticardiolipin antibody (aCL) of IgG and/or IgM isotype in serum or plasma,
present in medium or high titer (i.e., > 40 GPL or MPL, or > the 99th
percentile), on two or more occasions at least 12 weeks apart, measured by a
standardized ELISA
Anti-ß2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma
(in titer >the 99th percentile), present on two or more occasions at least 12
weeks apart, measured by a standardized ELISA, according to recommended
procedures
APL syndrome considered present if at least one of the clinical and
one of the laboratory criteria are present
J Thromb Haemost 2006;4:295
TREATMENT OF PATIENTS WITH
ANTIPHOSPHOLIPID ANTIBODIES
Asymptomatic: no treatment
History of thrombosis:
– Consider prolonged treatment in selected patients
• Recurrent or unprovoked thrombosis (arterial or
venous)
• Persistently high antibody levels
• More than 1 APL antibody test positive
– Most patients can be treated with standard
anticoagulant regimen
• Two RCTs have shown inferior outcomes with high
intensity warfarin treatment
• A few patients exhibit warfarin failure – consider long
term LMWH treatment (no data yet on newer oral
anticoagulants)
ANTIPHOSPHOLIPID ANTIBODIES AND
FETAL LOSS
• Antiphospholipid antibodies associated with lower
live birth rates in unselected “low-risk”
pregnancies
• Live birth rates in untreated women with APL and
at least one fetal loss have ranged from 10-85% in
published studies
• Aspirin and heparin have been associated with
higher live-birth rates in several studies, but most
of these did not include a placebo-treated arm
Arth Rheum 2004;50:1028
ANTIPHOSPHOLIPID ANTIBODIES AND
FETAL LOSS
• Testing for APL should be restricted to women
with at least three consecutive miscarriages
• Other causes of pregnancy loss (especially
abnormal karyotypes) should be ruled out
• If criteria for obstetric APL syndrome met, treat
with aspirin and/or LMWH during pregnancy and
postpartum period
Arth Rheum 2004;50:1028
ANTICOAGULATION IN WOMEN WITH APLA
AND RECURRENT PREGNANCY LOSS
2012 ACCP CONSENSUS RECOMMENDATIONS
• Women who meet lab and clinical criteria for
obstetric APLA:
Antepartum prophylactic or intermediatedose LMWH plus low dose ASA
CHEST 2012; 141:e691S