Thrombophilia

Dr Galila Zaher
MRCPath
Consultant Hematologist
Thrombophilia
A disorder of the haemostatic mechanism
with a predisposition towards thrombosis
BUT Many patients with defects remain
asymptomatic despite multiple challenges
AND >50% patients with TED will have no
identifiable laboratory abnormality
AND proven thrombophilic defect and a
family history of TED are at greater risk
of TED than individuals with no family
history but a similar defect
Thrombophilia
Patients with spontaneous venous
thromboses, or of a severity that is out of
proportion to a recognised stimulus


Venous Thromboembolic
Disease
Common , associated with considerable morbidity
and mortality
USA:
1:1,000 pa clinically significant DVTs
250,000 hospitalisations annually due
to VTED

Complications
Risk of recurrence: 2 years 17.5%
5 years 24.6%
Fatal PE: 1:50,000 pa
20-30% PM
Commonest cause of death in pregnancy
Post-phlebitic syndrome up to 20%

Who to test?
Thrombosis at an unusual site
Recurrent thromboses
Family history of thrombosis
Age less than 40
Recurrent miscarriages

Inherited 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]

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
Other Inherited Risk Factors
Hyperhomocysteineaemia
Dysfibrinogenaemias
Factor VII /
Heparin Cofactor II
Factor XII deficiency
Disordered fibrinolysis
Elevated PAI-1
Plasminogen deficiency
Thrombin Activatable Fibrinolytic Inhibitor
(TAFI)
Anti-phospholipid antibodies

Risk factor Subjects with
VTE (%)
General
population (%)

RR of
Thrombosis

Lupus
anticoagulant
3-10 4 11
Anti-cardiolipin
antibodies

3-10 4 3.2
OCP

21 6 4.2
Pregnancy


6.2 2.3 2.8
Previous VTED

14 2 8
Acquired
Obesity
Immobility (surgery/trauma)
OCP/HRT
Pregnancy/puerperium
Haemoglobinopathies
Myeloproliferative syndromes
Hyperviscosity syndromes
Cardiac failure
Acquired
Chronic inflammatory disorders
Klinefelters syndrome
Behets syndrome
Malignancy
Drug induced (e.g. HIT)
TTP/HUS
Nephrotic syndrome
Protein S deficiency
Inflammatory bowel disease

Thrombophilia and Laboratory
Testing
Diagnostic accuracy
Clinical value of the tests
Interpretation of results

Tests frequently requested (and
interpreted) by individuals who are not
specialists in this area
Laboratories frequently have no clinical
information relating to the patient

Genetic Testing
Reliable and reasonably robust
National External Quality Assurance Schemes
(NEQAS)
Some incorrectly identified samples

APCr low: Factor V Leiden mutation confirms
APCr normal: No further testing

Risk of VTED modest
Do we seek informed consent for genetic testing?
Phenotypic Testing Accuracy
Enormous variability in results:
NEQAS/ECAT data supports this
Oral anticoagulants : Protein C/S
Inappropriate to base a diagnosis on a
single result but how many times ?
Incorrect information to patients
may be falsely reassuring or result in
inappropriate treatment
Antithrombin deficiency
24 patients with genotypically proven AT
deficiency
Heparin co-factor assay
IIa substrate:Correctly identified all mutations
Xa substrate:Correctly diagnosed only 50% cases
NEQAS thrombophilia Survey March 2000
Functional AT assays showed significant differences
depending upon substrate
Laboratory Tests

Heterozygotes
Normal
relatives





15% heterozygous PC
deficient patients had
normal PC activity and
5% normal relatives
had low PC activity
Immediate Management
No evidence that anticoagulation is less efficient
with prothrombotic abnormalities
Antithrombin deficiency : Heparin resistance is
rare type I :can be efficiently anticoagulated ,
antithrombin concentrates is not usually indicated
PC and PS deficiency:Warfarin induced skin
necrosis is rare
Screening prior to initiating OAC therapy
inappropriate
LA,severe FXII deficiency&elevated Factor VIII
levels difficult monitoring UFH
Intensity Or Duration Of
Anticoagulation
No randomised prospective studies:Current data/experience
standard oral anticoagulant protocols
No evidence that more intensive regimes or extended
periods of anticoagulation are required
BUT - APL/multiple inherited abnormalities including
may be exceptions
Risk of recurrence may be increased and extended
periods of treatment may be required
OACs: Mortality 0.3-0.4%
Major bleed 2-3%
Aggressive Thromboprophylaxis?
RR increased but the absolute risk is small
Thromboprophylaxis :
Asymptomatic :No indication
At-risk individuals & high risk periods:
should be given
Economy Class syndrome 90% have >2 risk
factors for thrombosis
Prothrombotic Abnormality & OCP
Thrombosis in women with inherited
prothrombotic & OCP is increased
Family studies may be of value in
establishing the risk of thrombosis if a
genetic risk factor has been identified
POP or progestagen-containing IUDs no
increased risk of VTED
Factor V Leiden + OCP
RR VTED 35/50-fold increase
Prothrombotic Abnormality & OCP
Avoid
In women with history of TED
1st-degree relative with TED
in women with multiple genetic defects
Asymptomatic women with identified genetic
risk factors - not absolute
contraindication OCP

Prothrombotic Abnormality & HRT
HRT increases risk of TED ~3-fold
Risk highest in the initial 12 ms of treatment
Synergy between HRT and thrombophilia
Use with caution in women with a PMH of TED
EVTET study HRT: 10.7% incidence of VTED
Placebo: 2.3%
Asymptomatic women with identified genetic risk
factors - not an absolute contraindication to HRT
Thromboprophylaxis In Pregnancy
Risk of VTED increased in pregnancy
Genetic risk factor
Multiple pregnancy
Advanced maternal age
Prolonged bed-rest
Previous thrombotic history
Recurrent miscarriages
Routine thromboprophylaxis is not
indicated in all women with thrombophilia

Thrombophilia & Arterial
Disease
No good evidence
Anti-phospholipid syndrome
Hyperhomocysteineaemia
Factor V Leiden/Prothrombin mutation -
Possible synergistic interaction with other
risk factors

Summary
Increasing enthusiasm for thrombophilia testing
Concerns about accuracy and interpretation
Lack of evidence-based data to aid management
Are we providing patients and clinicians with
inaccurate information that leads to false
reassurance or alternatively creates panic and
results in inappropriate treatment?

Genetic defect NO TED
TED 50% No lab abnormality
Lab abnormality +FH >lab with NO FH

Other Inherited Risk Factors
Histidine rich glycoprotein
Elevated FVIII/FX/FXI
Thrombomodulin mutations
EPCR mutations
Tissue Factor Pathway Inhibitor (TFPI)
Factor V Cambridge
Factor XIII (Val234Leu)
Platelet glycoprotein receptor polymorphisms

Thrombophilia
Thrombosis is a multi-factorial disease
Multiple genetic risk factors increase the
risk of TED
In the majority: screen for only the
common inherited/acquired prothrombotic
abnormalities
50% of patients with TED have no evidence
of prothrombotic abnormalities

Management of
thrombophilia
Dr Galila Zaher
MRCPath
Consultant Hematologist


BLOOD CLOTTING
Blood clotting interactions

Plasma protein clotting factors




Vascular endothelium
Platelets

Hemostasis
Subendothelial matrix
Platelets
Hemostatic plug
Fibrin
Endothelial cell
RBC
WBC
WBC
Hemostasis
Subendothelial matrix
Platelets
Hemostatic plug
Fibrin
Endothelial cell
RBC
WBC
WBC
COAGULOPATHIES

Bleeding Thrombosis


Clotting factors Natural anticoagulant
platelets



Clot formation
Platelet activation Primary
hemostasis
No &count (immediate)
Fibrin generation
plasma clotting Secondary
hemostasis
factors (delayed)





Adhesion

GpIIb/IIIa
Platelet Activation
GpIIb/IIIa GpIIb/IIIa Aggregation
ADP
Adrenaline
Platelet
Exposed Collagen
Endothelium
vWF
COLLAGEN
GpIIb/IIIa GpIIb/IIIa Aggregation GpIIb/IIIa
GpIIb/IIIa
Aggregation
Adhesion Adhesion
ADP
Adrenaline
THROMBIN
Clotting factor production
Liver: source of plasma clotting factors
except VWF

Factor VIII: produced by liver &
endothelium

VWF: endothelial cells & megakaryocytes

Vitamin K dependent clotting factors are:
II, VII, IX, X

COAGULATION PATHWAYS
Intrinsic & extrinsic pathways
conclude in the common pathway

Intrinsic pathway clotting factors

Extrinsic pathway clotting factors

Common pathway clotting factors

Intrinsic pathway
XII ---> XIIa

XI---------XIa

IX --------> IXa
+ VIII APC PC +PS
Ca +PL
X----------------------> Xa [Common pathway]

V+Ca+PL
Prothrombin -------------> thrombin AT
v
fibrinogen--------------> fibrin
Extrinsic pathway
VII + TF ----->VIIa/TF


Activation of fibrinolysis

plasminogen
thrombin
plasmin
damaged cells
t-PA
PAI
cross-linked fibrin
fibrinogen
FDP
(X,Y,D,E)
X-FDP
(D-Dimer, cross-linked oligomers, DD/E ...)
antiplasmin
extrinsic pathway
inflammation
trauma
mental/physical stress
Generation Of Fibrin and D-Dimer
D
E
D
E
D D
E E
F XIIIa
fibrin
fibrin polymer
D D
E
D
E
D
E
D D
E
cross-linked
fibrin (clot)
fibrinogen
E
D D
E
thrombin
FpA, FpB
D-dimer cross-
linkage
E
D
E
D
E
D
E
D
E
D
E
D
E
E
D D
E
E
D
E
D
E
E
D D
E
D-Dimer
D-Dimer is a synonym for a variety
of cross-linked fibrin degradation
products.
Indicative for dissolution of an
existing thrombus.
Evidence of a previous thrombotic
event
Clinical Application Of D-Dimer
Exclusion of deep vein thrombosis (DVT)
Exclusion of pulmonary embolism (PE)
Supports diagnosis and monitoring of DIC

Incidence Of Venous Thromboembolism
Annual frequency per 100,000 :
Deep vein thrombosis 160

Symptomatic, non-fatal PE 20

Fatal, autopsy-detected PE 50
250,000 hospitalisations annually due to VTED

Int Angiol 1997
Complications
Risk of recurrence: 2 years 17.5%
5 years 24.6%
Fatal PE: 1:50,000 pa
20-30% PM
Commonest cause of death in pregnancy
Post-phlebitic syndrome
3 years after DVT 35- 69%
5-10 years after DVT 49-100%
Venous ulcers
Mortality From Pulmonary Embolism
About 1/10 hospital deaths is due to PE

PE is still the leading cause of maternal
mortality

Diagnosis Of DVT
Compression ultrasound (CUS)
Sensitivity ~97%;
Specificity ~94%
Problems:
Calf vein thrombosis sensitivity
Previous thrombosis specificity
Combine with D-Dimer and PTP
Clinical Prediction Rule
Entire leg tenderness along deep veins
collateral superficial veins

Entire leg swelling
Calf swelling >3 cm difference
Dilated superficial veins
Pitting edema
Clinical Prediction Rule
Recent bed ridden >3 days

Major surgery within last 3 ms.
Active cancer within last 6 mo.
Plaster
Paralysis
Presence of alternative Diagnosis
-2

Diagnostic Strategies for First Attack
proximal Deep Venous Thrombosis
High probability Moderate-Low
probability
(>3) (1-2) (0)

Doppler US D-Dimers


Abnormal Normal Normal High
Doppler US

Venography Normal Abnormal

Normal Abnormal Save to withhold treatment

Treat with heparin

Diagnostic Strategies for First Attack
Distal Deep Venous Thrombosis

High probability Moderate-Low
probability
(>3) (1-2) (0)

Doppler US D-Dimers


Abnormal Normal High Normal
Doppler US

Repeat in W or venography Normal abnormal



Abnormal Normal

Save to withhold treatment withhold treatment


Treat with heparin
Acute VTE
The usual management consists of UFH
or LMWH followed by warfarin.
Heparin is continued for at least 5 days
or untill INR is in the therapeutic range.
Warfarin can be started within the first
24h.



Heparin
Mechanism of action :augments anti-thrombin
action AT:T 1:1
Heparin
AT:T 1:1000
T : 90m
Dose :loading: 80U/Kg IV
:maintenance :18U/Kg/h
Route of administration: IV/SC
Duration :3-5d DVT
7-10d PE
Heparin
Monitoring :APTT:1.5-2.5 X control
4-6 h
Reversal :stop heparin
protamine sulphate :1U neutralize
100 IU heparin
No FFP
Side effects: Bleeding
osteoporosis
HIT
Heparin
Contraindications :congenital bleeding
disorders
HIT
Recent eye or CNS operation
LMWH
Dose :brand dependent
Mechanism of action :anti-X > anti-II
Route of administration :IV or S/C
Monitoring : not indicated
Indication for monitoring : pregnancy ,morbid obesity
, sever renal or liver derangement
Duration :3-5 d DVT
7-10 d PE
Reversal :stop heparin
protamine sulphate :un-predictable response
LMWH
Contra-indications :PMH :HIT
CNS eye operations
Inherited bleeding disorders
Side effect : less HIT , bleeding &
osteoporosis.
Warfarin
Mechanism of action : Vit K antagonist
Vit K :gamma carboxylation as a post
translation modification
Pro-coagulant :X,IX,VII&II(1972)
Natural anticoagulant PC &PS
T
1/2
PC is shorter than FVII temporary
hyper-coagulable state
Dose :5 mg P.O
Route of administration: P.O
Warfarin
Monitoring :INR
INR: (PT patient/PT control )
ISI
Desired target INR:2.5
INR 3.5 : mechanical heart valve , recurrent
VTE despite proper anti-caogulation ,+/- APL
Side effect : bleeding 1/100/y
ICH 2.5/1000/y
Warfarin induced skin necrosis
Contra-indications: pregnancy (first &last
trimester),Inhetited bleeding disorders
,acute stage HIT
Thrombophilia
A disorder of the haemostatic mechanism with
a predisposition towards thrombosis
BUT Many patients with defects remain
asymptomatic despite multiple challenges
AND >50% patients with TED will have no
identifiable laboratory abnormality
AND proven thrombophilic defect and a family
history of TED are at greater risk of TED than
individuals with no family history but a similar
defect
Thrombophilia
Thrombosis is a multi-factorial disease
Multiple genetic risk factors increase the risk of TED
In the majority: screen for only the common
inherited/acquired prothrombotic abnormalities
Patients with spontaneous venous thromboses, or of
a severity that is out of proportion to a recognised
stimulus

50% of patients with TED have no evidence of
prothrombotic abnormalities

Thrombophilia
Definition : abnormal tendency towards excessive thrombosis .
Indications :
VTE below 35-40 Y
Unprovoked VTE
VTE at unusual sites
Life threatening VTE
Recurrent fetal lose syndrome
Recurrent first trimester abortions
Investigating SLE patients
Recurrent thromboses
Family history of thrombosis
Whom to test?
Thrombosis at an unusual site
Unprovoked VTE
Life threatening VTE
Age less than 40
Recurrent thromboses
Family history of thrombosis
Recurrent miscarriagesVTE below 35Y
Recurrent fetal lose syndrome
Recurrent first trimester abortions
Investigating SLE patients
Inherited 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]

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
Other Inherited Risk Factors
Hyperhomocysteineaemia
Dysfibrinogenaemias
Factor VII /
Heparin Cofactor II
Factor XII deficiency
Disordered fibrinolysis
Elevated PAI-1
Plasminogen deficiency
Thrombin Activatable Fibrinolytic Inhibitor (TAFI)
Acquired
Obesity
Immobility (surgery/trauma)
OCP/HRT
Pregnancy/puerperium
Haemoglobinopathies
Myeloproliferative syndromes
Hyperviscosity syndromes
Cardiac failure
Acquired
Chronic inflammatory disorders
Klinefelters syndrome
Behets syndrome
Malignancy
Drug induced (e.g. HIT)
TTP/HUS
Nephrotic syndrome
Protein S deficiency
Inflammatory bowel disease

Anti-phospholipid antibodies

Risk factor Subjects with
VTE (%)
General
population (%)

RR of
Thrombosis

Lupus
anticoagulant
3-10 4 11
Anti-cardiolipin
antibodies

3-10 4 3.2
OCP

21 6 4.2
Pregnancy


6.2 2.3 2.8
Previous VTED

14 2 8
Thrombophilia and Laboratory
Testing
Diagnostic accuracy
Clinical value of the tests
Interpretation of results

Tests frequently requested (and interpreted) by
individuals who are not specialists in this area
Laboratories frequently have no clinical
information relating to the patient

Thrombophilia screen
PC level : Functional assay
PS level : Functional assay
AT level : Functional assay
APCR ratio :functional assay correlates with
genetic study: FVL
Prothrombin gene mutation
MTHFR
APS: LA: functional assay
Anti-cardilipin antibodies

Genetic Testing
Reliable and reasonably robust
National External Quality Assurance Schemes (NEQAS)
Some incorrectly identified samples
APCr low: Factor V Leiden mutation confirms
APCr normal: No further testing

Risk of VTED modest
Do we seek informed consent for genetic testing?
Phenotypic Testing Accuracy
Enormous variability in results:
NEQAS/ECAT data supports this
Oral anticoagulants : Protein C/S
Inappropriate to base a diagnosis on a
single result but how many times ?
Incorrect information to patients may
be falsely reassuring or result in
inappropriate treatment
Antithrombin deficiency
24 patients with genotypically proven
AT deficiency
Heparin co-factor assay
IIa substrate:Correctly identified all mutations
Xa substrate:Correctly diagnosed only 50%
cases
NEQAS thrombophilia Survey March 2000
Functional AT assays showed significant
differences depending upon substrate
Laboratory Tests

Heterozygotes
Normal
relatives





15% heterozygous PC
deficient patients had
normal PC activity and
5% normal relatives
had low PC activity
Timing Of Thrombophilia
Avoid acute presentation:
consumption of the natural anticoagulant
Heparin & warfarin therapy interfere with
the assay
Best time after D/C of warfarin therapy by
2-4 W
Any abnormal results should be repeated 4-
6W apart before labeling patient as
thrombophilia

Interpretation
Life threatening episode
40-50% of selected patients with
VTE have normal results despite
extensive testing
APS & AT are highly thrombogenic &
associated with high recurrence
rate.
Double heterozygosity :high
incidence of VTE
Immediate Management
No evidence that anticoagulation is less efficient with
prothrombotic abnormalities
Antithrombin deficiency : Heparin resistance is rare
type I :can be efficiently anticoagulated ,
antithrombin concentrates is not usually indicated
PC and PS deficiency:Warfarin induced skin necrosis
is rare
Screening prior to initiating OAC therapy
inappropriate
LA,severe FXII deficiency&elevated Factor VIII levels
difficult monitoring UFH
Intensity Or Duration Of
Anticoagulation
No randomised prospective studies:Current data/experience
standard oral anticoagulant protocols
No evidence that more intensive regimes or extended periods of
anticoagulation are required
BUT - APL/multiple inherited abnormalities including may be
exceptions
Risk of recurrence may be increased and extended periods
of treatment may be required
OACs: Mortality 0.3-0.4%
Major bleed 2-3%
Aggressive Thromboprophylaxis?
RR increased but the absolute risk is
small
Thromboprophylaxis :
Asymptomatic :No indication
At-risk individuals & high risk periods:
should be given
Economy Class syndrome 90% have
>2 risk factors for thrombosis
Prothrombotic Abnormality & OCP
Thrombosis in women with inherited
prothrombotic & OCP is increased
Family studies may be of value in establishing
the risk of thrombosis if a genetic risk factor
has been identified
POP or progestagen-containing IUDs no
increased risk of VTED
Factor V Leiden + OCP
RR VTED 35/50-fold increase
Prothrombotic Abnormality & OCP
Avoid
In women with history of TED
1st-degree relative with TED
in women with multiple genetic defects
Asymptomatic women with identified
genetic risk factors - not absolute
contraindication OCP

Prothrombotic Abnormality & HRT
HRT increases risk of TED ~3-fold
Risk highest in the initial 12 ms of treatment
Synergy between HRT and thrombophilia
Use with caution in women with a PMH of TED
EVTET study HRT: 10.7% incidence of VTED
Placebo: 2.3%
Asymptomatic women with identified genetic risk
factors - not an absolute contraindication to HRT
Thromboprophylaxis In Pregnancy
Risk of VTED increased in pregnancy
Genetic risk factor
Multiple pregnancy
Advanced maternal age
Prolonged bed-rest
Previous thrombotic history
Recurrent miscarriages
Routine thromboprophylaxis is not indicated
in all women with thrombophilia

Thrombophilia & Arterial
Disease
No good evidence
Anti-phospholipid syndrome
Hyperhomocysteineaemia
Factor V Leiden/Prothrombin mutation -
Possible synergistic interaction with other risk
factors

Summary
Increasing enthusiasm for thrombophilia testing
Concerns about accuracy and interpretation
Lack of evidence-based data to aid management
Are we providing patients and clinicians with
inaccurate information that leads to false reassurance
or alternatively creates panic and results in
inappropriate treatment?

Genetic defect NO TED
TED 50% No lab abnormality
Lab abnormality +FH >lab with NO FH

Other Inherited Risk Factors
Histidine rich glycoprotein
Elevated FVIII/FX/FXI
Thrombomodulin mutations
EPCR mutations
Tissue Factor Pathway Inhibitor (TFPI)
Factor V Cambridge
Factor XIII (Val234Leu)
Platelet glycoprotein receptor polymorphisms

Diagnosis Of DVT/PE
Development and validation of structured
clinical assessment for estimating pre-test
probability (PTP)
Advances in availability of sensitive and
rapid turnaround assays for D-Dimer

Integration of the two above advances into
a diagnostic, safe algorithm for non-invasive
objective testing, reducing the need for
invasive procedures

Pre-test probability (PTP) for PE
according to Wells 1997
score
clinical symptoms / signs of DVT 3.0
active cancer treated within last 6 months 1.0
heart rate > 100/min 1.5
immobilization / surgery in last 4 weeks 1.5
previous history of DVT or PE 1.5
hemoptysis 1.0
no alternative diagnosis (more) likely than PE 3.0

>6 = high PTP; 2-6 = moderate PTP; <1.5 = low PTP
_ _
Strategy in diagnosis of PE
low pre-test probability (PTP) and negative
D-Dimer, VQ scan negative or non-diagnostic
PE excluded

high PTP and diagnostic VQ scan
PE confirmed

in any other case
further testing by CUS and /or angiography
SD Chunial, JS Ginsberg Throm Res 2000

Anti-thrombin deficiency
Resistant to heparin.
Heparin lower AT level by 30%.
AT conc is safe & effective.
Recommended:
1. Difficult to achieve adequate anticoagulation .
2. Recurrent thrombosis despite adequate
anticoagulation.
3. Thromboprphylaxis when anticoagulation is
contraindicated.

Anti-thrombin deficiency
AT conc: pooled normal human plasma.
recombinant AT .
Dose : 50 units /Kg .
Plasma monitoring : plasma level >80%.
Repeat 60% of the initial dose 24h.
The biological t1/2 2-4 days.

Protein C deficiency
Warfarin induced skin necrosis rare.
Warfarin reduce PC by 50%.
Routine measurement of plasma PC before
starting OAC is not recommended.
Known cases of PC deficiency should receive
OAC under heparin &increased gradually.
PC conc or FFP can provide protection against
recurrent skin necrosis until a stable level of
anticoagulation is achieved.

Long term therapy to prevent
recurrence
Recurrence in the first year is 27%.Kearon 3m
Vs extended anticoagulation favours extended
The lowest recurrence found after 6-12 m of initial
therapy .
Long term warfarin is highly effective in preventing
recurrence as compared with 6 m
therapy(2.6Vs21%) this benefit is partially
counterbalanced by a trend towered an increased
incidence of major bleeding (8 %Vs3% )&no
difference in mortality .


The cumulative incidence of recurrence
after of cessation OAC

0
5
10
15
20
25
30
First year 5 years 8 years
Recurrace
Prandoni.
Risk of recurrence
FVL &PG mutation heterozygosity :conflicting reports.
Number of major bleeding would exceed the number
of clinically PE that would be prevented
Combined heterozygosity for FVL &PG20210 :the
recurrence rate is significantly high .
important risk factors : homozygous FVL, APS &
cancer.
PC&PS deficiency Low frequency to draw firm
conclusion.


The decision to continue
anticoagulation
Risk of recurrence.
Risk of major bleeding .
Patient compliance &preference.
Life expectancy.
Quality of life.
Recommendations .
Indefinite anticoagulation at target INR 2-3 is
recommended only in the following high risk patients:
Two or more spontaneous thrombosis.
One spontaneous thrombosis in case of AT
deficiency or APS.
One spontaneous life threatening thrombosis (near
fatal PE ,cerebral, mesenteric ,or portal vein
thrombosis).
One spontaneous thrombosis at an unusual site
(mesenteric ,cerebral).
One Spontaneous thrombosis in the presence of
more than a single genetic defect.
Future approaches
Extended low intensity warfarin at INR 1.5-2.
The PREVENT study :low intensity warfarin
reduce the rate of recurrence by more than
60% compared with placebo without an
increased in major bleeding.
Ximelagatran :was compared to placebo
&was shwoen to be highly effective in
preventing recurrent VTE.
surgery
Inherited thrombophilia& surgery :
Are high risk group .
Prophylactic perioperative anti-
coagulation &LMWH.