James Choi, MD
Hematology/Oncology
Arizona Center for Hematology/Oncology
Glendale, Arizona
Financial Disclosures
 Speaker for Bayer Healthcare.
Learning Objectives
 Overview of thrombophilia.
 Indication for initiating a workup.
 Risk stratification of thrombophilia.
 Duration of anticoagulation.
Venous Thromboembolism
 Most common presentation is DVT of the lower
extremity and PE
 A risk factor for thromboembolism is found in
80% of patients
 Often more than one factor at play
 Divided into hereditary and acquired
Risk Factors of Venous
Thrombosis
Acquired
Inherited
Mixed/Unknown
Advanced Age
Antithrombin Deficiency
Homocysteine
Immobilization
Protein C Deficiency
Factor 8
Major Surgery
Protein S Deficiency
Malignancy
Factor 5 Leiden mutation
Factor 9
Estrogen/Pregnancy
(OCP, HRT, SERMs)
Prothrombin G20210A mutation
Factor 11
APC resistance in absence of
FVL
Antiphospholipid antibody
syndrome
TAF1
MPD, PNH
Free TPI
IBD, Nephrotic syndrome,AAV
Fibrinolytic Activity
Heparin Induced
Thrombocytopenia
Obesity
Prolonged Air Travel
TPI: Tissue pathway inhibitor
Prevalence of Major Hypercoagulable
States
Inherited Thrombophilias
 Inherited hypercoaguable states

A genetic tendency for venous thromboembolism
 Should be suspected in anyone who:
◦ Presents with an unprovoked venous or arterial
thromboembolic disease at <45 yrs
◦ 2 or more thrombotic episodes in the absence of a risk
factor for thrombosis
◦ History of objectively confirmed idiopathic thrombosis in
first-degree relative
◦ Thrombosis in an unusual site

Mesenteric veins, dural sinus
◦ Neonatal thromobosis or stroke
◦ History of recurrent fetal loss
Inherited Thrombophilias
 In the recent past, a genetic cause for thrombophilia was detected in
only 5-15% of patients
 Limited to antithrombin gene deficiency, protein C+S deficiency,
dysfibrogenemia
 1993: Discovered Factor V gene mutation (Factor V Leiden)
 1996: Discovered the prothrombin G20210A gene mutation
 Inherited thrombophilias are most common in Caucasians, rare in
African or Asian
 In all comers with DVT, the incidence of inherited thrombophilias is
24-37%
 Of Caucasian patients who present with initial symptomatic DVT, 1220% are heterozygous for factor V Leiden and 6% heterozygous for
prothrombin G20210A mutation
Inherited thrombophilias
 More than 50% of cases, thrombosis is provoked by
surgery, pregnancy, immobilization, OCP, HRT, or old
age
 Recurrent venous thrombosis is highest in deficiency of
antithrombin, protein C, protein S, greater than one
inherited thrombophilia, homozygous for factor V Leiden
Major Mechanisms Involved in the Normal Control of Coagulation and Inherited
Thrombophilias
In inherited thrombophilias, thrombosis is most often caused
by impaired neutralization of thrombin or failure to control
the generation of thrombin
Seligsohn U and Lubetsky A. N Engl J Med
2001;344:1222-1231
Factor V Leiden
 Factor V is activated to Va, which acts as a
cofactor in the conversion of prothrombin to
thrombin
 Normally, Factor Va is degraded by APC and
limits prothrombin conversion to thrombin
 Arginine is replaced by Glutamine (Arg506Gln)
on the factor V gene, resulting in a protein called
factor V Leiden
 Factor V Leiden is less susceptible to inactivation
by APC and is now considered “resistant to APC”
 This results in a prothrombotic state
Factor V Leiden
 Most common - 40-50% of inherited thrombophilias
 Found in 5% of the Caucasian population
 Found in 10-20% of patients with first episode of
idiopathic DVT
 Found in 50% of patients with recurrent DVT
 90-95% of those with factor V Leiden are
heterozygous
 Homozygotes have a more severe course
 Acquired forms of APC resistance found in
pregnancy, use of OCPs, elevated Factor VIII or
those with antiphospholipid antibodies
Factor V Leiden
 Anticoagulation therapy
 Long term therapy not recommended in heterozygotes
 At no higher risk of recurrent thrombosis than those without the
mutation
 In homozygotes, should use prophylaxis in high risk
settings
 Heterozygous, pregnant women with no history of
thrombosis are at low risk for thrombosis


Anticoagulation is not recommended
Recommendations differ if have a history of thrombosis or
homozygous
Prothrombin G20210A Mutation
 A Vitamin K-dependant protein synthesized in
the liver
 Due to substitution of adenine for guanine
 Results in 30% higher prothrombin levels
 This promotes generation of thrombin and impairs inactivation of
Factor Va by APC
 Found in 2% of the Caucasian population
 Seen in 6-10% of patients presenting with first
episode of unprovoked DVT
 Like with factor V Leiden, there is no increased
risk of recurrent DVT in heterozygotes
Protein C deficiency
Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231
Protein C Deficiency
 Vitamin K dependent glycoprotein produced in the




liver
Thrombin binds to thrombomodulin, a protein on the
endothelial cell surface
This complex converts protein C to activated protein
C (APC) which degrades Factors Va and VIIIa,
limiting thrombin production
Thrombosis occurs when levels drop < 50%
Can be seen after surgery, trauma, pregnancy, OCP,
liver/renal failure, DIC, or warfarin use
Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231
Protein S Deficiency
 Vitamin K-dependant protein
 Circulates as both a free protein (40%) and bound C4b-
binding protein (60%), which is part of the classic
complement system
 Only free Protein S can act as a cofactor to APC for the inhibition
of Factors Va and VIIIa
 C4b is increased in acute phase reactions, causing free
Protein S to be decreased
 Like in Protein C deficiency, homozygous patients
present soon after birth with neonatal purpura fulminans
Protein S Deficiency
 Decreased levels of Protein S in
 Liver disease
 Renal disease
 Women – especially those on OCPs or pregnant
 IBD
 Neonates, infants
 50% of heterozygotes experience DVT by 35yrs
 May have atypical presentation: migraine headache,
mesenteric vein thrombosis
Antithrombin III Deficiency
 A vitamin K-independent protein that works
inhibit thrombin
 Prevalence: 1:2000-1:5000 persons
 30% of heterozygotes develop a thrombosis by
30yrs, 65% by age 50yrs
 Homozygous deficiency is almost always
incompatible with life
 60% will have recurrent thrombosis
 Risk of thrombosis is particularly high in pregnancy
 Heparin prophylaxis recommended throughout
pregnancy and coumadin for 6 weeks postpartum
Antiphospholipid Syndrome
 Defined by the occurrence of at least one clinical
feature AND the presence of at least one type of
autoantibody known as an aPL
Clinical Criteria:
- Arterial or venous thrombosis.
- Pregnancy morbidity.
Laboratory Criteria: confirmed on 2 or more
occasions
at least 12 weeks apart.
- IgG or IgM anticardiolipin antibody (med-high)
- Lupus anticoagulant
- Anti-Beta2 Glycoprotein antibodies
Plasma Homocysteine
 Measurement of fasting total plasma homocysteine
is no longer recommended
 There is no data supporting a change in the duration
or type of therapy for a patient with
hyperhomocysteinemia and a past history of a VTE
since homocysteine may be a marker for VTE rather
than a cause
 Results from the Leiden MEGA study indicate that
the presence of MTHFR mutation is not associated
with an increased risk for VTE
Testing for hypercoaguable states
 Acquired and genetic causes frequently overlap
 Who should be tested ?
 What tests should be ordered?
 When should they be ordered?
Who should be tested?






Idiopathic (i.e., spontaneous) VTE
VTE at young age (<45 years)
Recurrent VTE
VTE in unusual sites
VTE in the setting of a strong family history of VTE
Recurrent pregnancy loss (> 3 consecutive 1st trimester
pregnancy losses without an intercurrent term pregnancy)
 Testing should be strongly considered for patients who present with two or more of
these criteria. It may also be considered for select asymptomatic individuals,
particularly female relatives of patients with known inherited hypercoagulability,
provided that the results will affect their decision to begin oral contraceptive pill (OCP)
use or hormone replacement therapy (HRT).
Hypercoaguable workup
 APC resistance screen
 Clotting assay, then confirm with a genetic test
 Prothrombin G20210A mutation
 Genetic test (PCR)
 Functional assay for Protein C + S, antithrombin III deficiency
 Heterozygous deficiencies are from many different mutations and abnormalities
 Measure both free and total Protein S
 Affected by acute thrombosis and anticoagulation, so check levels at least 2
weeks after completing therapy
 Anticardiolipin and lupus anticoagulant clotting assay

Testing should be done at least 2 weeks after completion of anticoagulation
Hypercoaguable workup
 In the setting of acute clot or therapy:
 Coumadin reduces protein C and S levels
 Heparin can reduce antithrombin levels
 Heparin and coumadin make testing for lupus
anticoagulant and APC unreliable
 Sepsis is associated with reduction in levels of protein
C, protein S, antithrombin
DVT/PE
Without evidence of underlying
causative factors such as recent
surgery, trauma or known
malignancy.
1.
2.
3.
Obtain complete
medical history.
Perform physical
exam.
CBC, CMP.
Yes
Do findings suggest occult
malignancy?
Test for the most common
coagulation disorders:
1.Factor V Leiden mutation.
2.Prothrombin gene mutation.
3.Antiphospholipid antibody
syndrome.
Do test results confirm existence
of one of these disorders?
Consider testing for less common
coagulation disorders.
1.Protein C deficiency.
2.Protein S deficiency.
3.Antithrombin III deficiency.
Further workup as
indicated
No
Does any of the following
apply?
1.Less than 45 years old.
2.Family history of VTE.
3.Recurrent VTE.
4.Idiopathic or unusual site.
Factor V Leiden
Homozygous : longer
therapy
Prothrombin mutation
Antiphospholipid syndrome
Consider longer therapy
with higher INR.
Management of
thrombophilia
Risk Classification
Management
High Risk
Indefinite anticoagulation
2 or more spontaneous events
1 spontaneous life-threating event (near
fatal PE, cerebral, mesenteric, portal vein
thombosis)
1 spontaneous event in association with
antiphospholipid antibody syndrome,
antithrombin III deficiency, or more than 1
genetic defect
Moderate Risk
1 event with a known provocative
stimulus
Asymptomatic
Vigorous prophylaxis in high risk
setting
Recommendations Duration of Therapy
Patient
Characteristics
Risk of Recurrence
Duration of Therapy
Major transient risk
factor
3%
3 months
Minor risk factor; no
thrombophilia
< 10% if risk factor
avoided
6 months until factor
resolves
Idiopathic, no or low risk
thrombophilia
< 10%
6 months
Idiopathic, high risk
thrombophilia
> 10%
Indefinite
More than one
idiopathic event
> 10%
Indefinite
Cancer, other ongoing
risk factor
> 10%
Indefinite. Consider
LMWH for malignancy
References
 1. Lijfering. WM et al. Br J Haematol 2010; 149:824.
 2. FR Rosendaal - 2005 ASH educational handbook.
 3. Goldhaber SZ et al. J Am Coll Cardiol 2010;56:1.
 4. Kitchens CS et al. Semin Thromb Hemost. 1985, 11: 293-
315.
 5. Seligsohn U et al. N Engl J Med. 2001, 344: 1222-1231.
 6. Dickson BC et al. Univ Toronto Med J 2004; 81:166.
 7. Bertina RM. Genetic approach to thrombophilia. Thromb
Haemost 2001; 86:92.