thrombophilia liu 2014.pdf

Fellow Case Presentation
6/23/14
Kenneth Liu, M.D.

Outline
• Case
• Inherited thrombophilias
– Factor V Leiden
– Prothrombin gene mutation
– Protein C deficiency
– Protein S deficiency
– Antithrombin deficiency
– Hyperhomocysteinemia
– Hereditary Defects in Fibrinolytic Pathway
– Elevated factor VIII and other clotting factors
• Testing

HPI
• 32yo F G7P6 (1 molar pregnancy) who had a PE in
12/2009,diagnosed with V/Q scan, in the setting of
shellfish-induced anaphylaxis/NSTEMI. At the time, she
developed severe respiratory distress s/p “accidental”
shellfish consumption. As she is a allergic to IV contrast,
V/Q scan was performed, which was concerning for PE.
Since then, she had been on anticoagulation, with some
periods where she was lost to follow up. Workup
revealed elevated homocysteine. She has no other
PE/DVT. She is currently on warfarin.

• PMHx: asthma
• Meds: warfarin
• Allergies: shellfish, contrast
• FHx: mother – breast ca; father – CAD in the 40’s; no
family history of VTE
• SHx: lives with husband and 6 children. Tobacco use ½
ppd x 15 years. Occasional EtOH. Denies drugs

PE
• Gen: obese, NAD
• HEENT: PERRLA, anicteric
• Neck: no masses or lymphadenopathy
• Resp: CTAB
• Card: RRR, no m/g/r
• GI: +BS, S/NT/ND, no HSM
• Ext: no c/c/e, symmetric LE

Labs
• WBC 5.4k, Hgb 13.9, Hct 42.6, Plt 215, MCV 83
• Cr 1.0, normal LFTs
• 2014:
– Antithrombin III ftn/imm 94/320
– Protein C funct 106
– Protein S funct/immuno 94/104
– Factor VIII 110
– PAI-1 12; PAI-1 4G/5G positive for 1 copy of 4G variant
– Homocysteine 60.7
– D-dimer 0.2

Labs (con’t)
• 2012:
– MTHFR C677T homozygote
– Antiphospholipid panel negative
– D-dimer 2.0
• 2010:
– Factor V Leiden negative
– Prothrombin G20210A negative
• 2009
– D-dimer 1.65

Imaging
• V/Q scan 12/2009
– Perfusion images show a moderate sized defect in the superior
segment of the RLL that is mismatched on the ventilation images.
There is also a nonsegmentaldefect involving the anterior segment of
the RUL and medial segment of the RML that is matched on the
ventilation images
• Echo 12/2009
– Normal study. LVEF 65%. Normal sizes in all 4 chambers
• V/Q scan 4/2010
– Persistent (although overall improved) perfusion defects
• V/Q scan 4/2011
– No evidence of PE

History
• 1965: first description of hereditary thrombophilia described
by Egeberg – decreased antithrombin III levels inherited in an
autosomal dominant manner
• 1965: hereditary dysfibrinogenemia described by Beck et al.
• 1976: protein C deficiency described by Griffin et al.
• 1979: protein S deficiency described by Schwarz et al, Comp
et al.
• 1993: Dahlback et al. reported venous thrombosis often
associated with hereditary resistanceto activated protein C
• 1994: factor V leiden described
• 1996: prothrombin gene G20210A linked to familial venous
thromboembolism by Poort et al.
Williams Hematology 8th Edition. Chapter 131: Hereditary Thrombophilia. 2121-2143.
Plus other references in “References” section

Pathophysiology
• Thrombosis often is associated with defects in normal,
physiologic hemostaticmechanisms that are essential to avoid
bleeding
• Virchow’s triad: vascular wall abnormalities, reduced blood
flow (i.e. stasis), changes in blood components
• Thrombosis often is multifactorial, caused by inherited and
acquired risk factors

Thrombophilias and Predisposing Risk Factors
Thrombophilias Acquired Predisposing Risk Factors for Venous Thrombosis
Common
Factor V Leiden Increasing age
Prothrombin G20210A Surgery or trauma
Increased factor VIII level* Prolonged immobilization
Homozygous C677T polymorphism in
methylenetetrahydrofolate reductase†
Obesity
Smoking
Arteriosclerotic cardiovascular disease
Rare Malignant neoplasms
Protein C deficiency Long flights
Protein S deficiency Myeloproliferative diseases
Antithrombin deficiency Superficial vein thrombosis
Very rare Previous venous thrombosis
Dysfibrinogenemia Pregnancy and puerperium
Homozygous homocystinuria Use of female hormones
Antiphospholipid antibodies
Hyperhomocysteinemia
Activated protein C resistance unrelated to factor V Leiden
Varicose veins

Major Mechanisms of Inherited Thrombophilias

Annual Rates of VTE

Annual Rates of Recurrent VTE

Factor V Leiden Epidemiology
• The most common known inherited thrombophilia
• >90% of hereditary activated protein C resistance are due to
factor V Leiden, with an Arg506Gln substitution
• Ethnic distributions of FVL heterozygosity in the U.S.
– Caucasian Americans 5.3%
– Hispanic Americans 2.2%
– African Americans 1.2%
– Asian Americans 0.45%
– Native Americans 1.3%
– Carrier frequencies similar in Caucasian men and women (5.5% vs.
4.9%, P = 0.5)
• Analyses based on linkage disequilibria demonstratedthat the
mutation occurred in whites about 21,000 years ago
Ridker PM, et al. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous
thromboembolism screening. JAMA 1997;277(16):1305-7.
Zivelin A, et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites
approximately 24,000 years ago. Blood 2006;107:4666-8.

Jadaon MM. Epidemiology of activated protein C resistance and factor v
leiden mutation in the mediterranean region. Mediterr J Hematol Infect Dis.
2011;3:e2011037

Jadaon MM. Epidemiology of activated protein C resistance and factor v leiden mutation in the
mediterranean region. Mediterr J Hematol Infect Dis. 2011;3:e2011037

Factor V Leiden Mechanism
• Activated protein C (APC) inhibits the coagulation system by
cleaving the activated forms of factor V and VIII.
Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern
Med 1997;127(10):895-903.

Factor V Leiden Mechanism (con’t)
• In FVL, there is a point mutation in the factor V gene, G1691A,
which leads to Arg506Gln substitution
• This leads to partial resistance to proteolytic inactivation by
activated protein C
– Kinetic studies showed inactivation approx. 10 times slower
• However, despite being slower, cleavage does occur, which
explains why this is a rather mild risk factor for VTE
• Factor V also enhances inactivation of factor VIIIa by APC in
the presence of protein S … FVL reportedly defective in this
APC cofactor activity

Factor V Leiden Risk of Thrombosis
• FVL is mildly associated with increased risk of thrombosis
– Heterozygotes OR 4.9 (95% CI, 4.1-5.9)
– HomozygotesOR 9.85 (95% CI, 4.83-20.09)
• Systematicreview by Segal et al. 2009 showed that FVL
heterozygosity (OR 1.56, 95% CI 1.14-2.12) and homozygosity
(OR 2.65, 95% 1.2 -6.0) have mildly increased risk of recurrent
VTE
– Heterozygosityshould not alter AC treatment decisions
– Homozygositywith unprovoked VTE can be an argument for longer
term AC
Emmerich J, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism –
pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous
Thromboembolism. Thromb Haemost. 2001;86(3):809-16.
Segal JB, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with VTE and in family members of
those with a mutation: a systematic review. JAMA 2009;301:2472-85.

Factor V Leiden Risk of Thrombosis (con’t)

Factor V Leiden Risk of Thrombosis (con’t)
• Cerebral vein thrombosis
– Prevalence of factor V Leiden (14.5%)is higher in 55 patients with
cerebral vein thrombosis than 272 healthy controls (6.25%) (RR 2.55;
95% CI 1.04-6.26)
• Arterial thrombosis
– Meta-analysis showed a mild association between factor V Leiden and
arterial ischemic events (OR 1.21;95% CI 0.99-1.49)
– Association is stronger between mutation and stroke and MI in
younger patients
Ludemann P, et al. Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case-control study of 55 patients.
Stroke 1998;29(12):2507-10.
Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase
C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J
2003;146(6):948-57.

Other Factor V Mutations
• Reported to produce APC resistance phenotype:
– Factor V Cambridge (Arg306Thr)
– Factor V Nara (Trp1920Arg)
– Factor V Liverpool (Ile359Thr)
• Unclear clinical significance
– Factor V Hong Kong (Arg306Gly)
• Some of these mutated proteins may have preserved cofactor
activity towards cleavage of factor VIIIa by APC, which may
explain why some mutations do not increase risk of VTE
Williamson D, et al. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C.
Blood 1998;91(4):1140-4.
Nogami K, et al. Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC
resistance relative to FVLeiden. Blood 2014;123(15):2420-8.
Steen M, et al. Functional characterization of factor V-Ile359Thr: a novel mutation associated with thrombosis. Blood
2004;103(9):3381-7.
Chan WP, et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998;91(4):1135-9.

Prothrombin G20210A Substitution
Epidemiology
• Second most common inherited risk factor for VTE
• Mutation found largely in the white population
• More common in southern Europe and Middle East (3-5%)
compared to northern Europe (1.7%)
• In the U.S., the allele is present in 1.1% whites and 0.3%
blacks
• Analyses based on linkage disequilibria demonstratedthat the
mutation occurred in whites about 24,000 years ago
Zivelin A, et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000
years ago. Blood 2006;107:4666-8.

Mechanism
• A point mutation in the prothrombin (factor II) gene in the 3’-
untranslated region at nucleotide position 20210 from
guanine to adenine increases the stability and translation of
prothrombin mRNA
• This leads to increased synthesis of prothrombin by the liver
• Another proposed mechanism is that prothrombin can inhibit
APC’s inactivation of factor Va
• Heterozygotes have elevated level of plasma prothrombin
(mean of 132% compared to normal)
Poort SR, et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated
plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-703.

Risk of Thrombosis
• Prothrombin gene mutation is associated with VTE in all age
groups
– Prothrombin mutation heterozygotes OR 3.8
– Prothrombin mutation + FVL double heterozygotes OR 20.0
• Systematicreview by Segal et al. 2009 showed that
heterozygosity for prothrombin gene mutation is not
predictive of recurrent VTE (OR 1.45, 95% CI 0.96-2.2),
therefore its finding does not change decision of AC duration
• No data available for risk of recurrent VTE in homozygotes
Emmerich J, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism –
pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous
Thromboembolism. Thromb Haemost. 2001;86(3):809-16.

Risk of Thrombosis (con’t)
Segal JB, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with VTE and
in family members of those with a mutation: a systematic review. JAMA 2009;301:2472-85.

Risk of Thrombosis (con’t)
• Cerebral vein thrombosis
– Prevalence of prothrombin gene mutation (20%) is higher in 40
patients with cerebral vein thrombosis than 120 healthy controls (3%)
(OR 10.2; 95% CI 2.3-31.0)
– Odds ratio even higher (149.3;95% CI 31.0-711.0)in women taking
OCP and had prothrombin gene mutation
• Arterial thrombosis
– Meta-analysis showed a mild association between prothrombin gene
mutation and arterial ischemic events (OR 1.32; 95% CI 1.03-1.69)
– Association is stronger between mutation and stroke and MI in
younger patients
Martinelli I, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral
contraceptives. N Engl J Med. 1998;338(25):1793-7.
Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase
C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J
2003;146(6):948-57.

Protein C Deficiency
• Protein C is a vitamin-K dependent protein that is synthesized
in the liver
• It is activated by limited proteolysis by thrombin bound to
thrombomodulin. This is accelerated by endothelial protein C
receptor
• APC downregulates coagulation pathway by inactivating
factors Va and VIIIa with protein S as cofactor
• In addition, APC displays anti-inflammatory and anti-apoptotic
actions and stabilization of endothelium
• More than 150 mutations in the protein C gene have been
identified

Protein C Deficiency
http://practical-haemostasis.com/Thrombophilia%20Tests/ps_assays.html

Protein C Deficiency Epidemiology/Clinical Features
• Heterozygous protein C deficiency occurs in 0.2-0.4% of
normal individuals and 4-5% with objectively confirmed DVT
• Homozygousprotein C deficiency with protein C level <1% can
lead to neonatal purpura fulminans
• Patient with heterozygous protein C deficiency can result in
warfarin skin necrosis (large thrombotic skin necrosis) since
this leads to rapid fall in protein C activity due to short half-life
of protein C compared to that of prothrombin, factor IX, X
Goldenberg NA, Marco-Johnson MJ. Protein C deficiency. Haemophilia 2008;14(6):1214-21.

Protein C Deficiency Clinical Features (con’t)
Goldenberg NA, Marco-Johnson MJ. Protein C deficiency. Haemophilia 2008;14(6):1214-21.
Neonatal purpura fulminans Warfarin skin necrosis

Protein C Deficiency Diagnosis
• Protein C levels < 55% in the absence of AC, vitamin K
deficiency, liver disease suggests protein C deficiency
• Levels between 55-70% are borderline
• Warfarin should be discontinued at least 2 weeks before
testing
• Classification
– Type I: reduced antigen and activity; more common
– Type II: normal antigen, reduced activity

Protein S Deficiency
• Protein S is another vitamin K-dependent protein, mostly
synthesized in the liver, but also produced by endothelium,
kidney, testes,brain
• Approx. 60% protein S associate with plasma complement
factor C4b-binding protein (C4BP), while 40% are free – only
the free form can serve as cofactor for APC
• It acts as a cofactor for APC and helps downregulate thrombin
generation
• It also inhibits tissue factor activity by promoting interaction
between tissue factor pathway inhibitor and factor Xa
• More than 200 mutations in the protein S gene have been
described

Protein S Deficiency Epidemiology/Clinical Features
• Protein S deficiency has been found in approx 2-3% of
patients with VTE
• Most common inherited thrombophilia in Japan. Japanese
people have higher prevalence of protein S deficiency in both
VTE patients (12.7%) and general population (0.48-0.63%)
• DVT and PE are the most common forms of VTE
• Neonatal purpura fulminans and warfarin-induced skin
necrosis have been reported
Adachi T. Protein S and congenital protein S deficiency: the most frequent congenital thrombophilia in Japanese. Curr Drug
Targets 2005;6(5):585-92.

Protein S Deficiency Diagnosis
• Free protein S antigen and APC cofactor anticoagulant activity
are better parameters than total protein S for screening
• Lower limit of normal range for free protein S is lower in
females (55%) than in males (65%)
• Reduced free protein S can be seen in pregnancy, use of oral
contraceptives and hormone replacement therapy, nephrotic
syndrome, AC, vitamin K deficiency, liver disease
• Classification by measuring total, free protein S antigen and
protein S activity
– Type I: parallel reductions in both antigen and anticoagulant activity
– Type II: normal levels of antigen, but decreased anticoagulant activity
– Type III: decreased free protein S while total protein S antigen is low-
normal

Antithrombin Deficiency
• Antithrombin is a protease inhibitor that neutralizes thrombin and factors
Xa, IXa, XIa
• This reaction is accelerated by heparin
• More than 150 mutations in the antithrombin gene have been identified
Nachman RL, Silverstein R. Hypercoagulable states. Ann Intern Med 1993;119(8):819-27.

Antithrombin Deficiency Epidemiology/Clinical
Features
• AT deficiency found in approx 1-2% of patients with first
documentedVTE
• Complete deficiency is incompatible with life
• OR for thrombosis is approx. 20 and notably greater than
factor V Leiden heterozygotes
• Most common symptom is DVT in the lower extremities,
peaks at second decade of life
• Thromboses in unusual sites have been reported

Antithrombin Deficiency Diagnosis
• Classification:
– Type I: low levels of both antigen and activity; found in 1:5000 people
in Scotland
– Type II: normal levels of antigen; more common, found in 1:625
people
• IIa: mutations in the reactive site
• IIb: mutations in the heparin-binding site
• IIc: pleiotropic group of mutations

Relative Risk and Annual Incidence of Thromboses
for AT, Protein C, Protein S Deficiencies:
a study of 150 families
Martinelli I, et al. Different risks of thrombosis in four coagulation defects
associated with inherited thrombophilia: a study of 150 families. Blood
1998;92(7):2353-8..

Relative Risk and Annual Incidence of Thromboses
for AT, Protein C, Protein S Deficiencies:
a study of 2479 relatives of 877 probands
Lijfering WM, et al. Selective testing for thrombophilia in patients with first
venous thrombosis: results from a retrospective family cohort study on
absolute thrombotic risk for currently known thrombophilic defects in 2479
relatives. Blood 2009;113(21):5314-22.

Recurrent VTE free survival
Lijfering WM, et al. Selective testing for thrombophilia in patients with first
venous thrombosis: results from a retrospective family cohort study on
absolute thrombotic risk for currently known thrombophilic defects in 2479
relatives. Blood 2009;113(21):5314-22.

• Homocysteine is an intermediate in the metabolism of
methionine and cysteine
UpToDate. Overview of homocysteine. Last updated Nov 27, 2012.

• Severe hyperhomocysteinemia (> 100 μmol/L) occurs in 1 in
200,000-300,000 people and transmitted as autosomal
recessive trait
– Most common mutations are in cystathionine β-synthase(T833C and
G919A mostprevalent)
– Other mutations occur in MTHFR and methionine synthase
– Can be associated with neurologic abnormalities, ectopia lentis,
premature CVD, stroke, venous/arterial thrombosis
• Mild hyperhomocysteinemia
– Most common genetic cause is production of MTHFR with reduced
activity and increased thermolability (C677T)
– Homozygosityfor TT occurs in 10-20%healthy whites, 10% Asians, but
rare in Africans
– Low levels of folate, B12, B6 can also contribute
• Mechanism on thrombosis unclear

Hyperhomocysteinemia Risk of Thrombosis: meta-
analysis of 476 prospective and 3289 retrospective cases
Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR
and risk of venous thrombosis: a meta-analysis of published
epidemiological studies. J Thromb Haemostt2005;3(2):292-9.

MTHFR Risk of Thrombosis: meta-analysis of 8364 cases
Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR
and risk of venous thrombosis: a meta-analysis of published
epidemiological studies. J Thromb Haemostt2005;3(2):292-9.

Hereditary Defects in Fibrinolytic System
• Plasmin is responsible for cleavage of fibrin to fibrin
degradation products. Generation of plasmin from
plasminogen is mediated by tPA, which is inactivated by PAI-1
• Severe plasminogen deficiency with levels of 5-6% of normal
is rare but is manifested by pseudomembranous disease
affecting mucous membranes such as eyes, though clear
association with VTE
• Increased levels of PAI-1 is thought to cause decreased
fibrinolysis, and is thought to be related to the 4G/5G
insertion/deletion of the gene promoter
• Homozygotes for 4G have 25% high levels of PAI-1 than
homozygotes for 5G

Hereditary Defects in Fibrinolytic System (con’t)
• In a prospective population-based study of 308 patients with
VTE and 640 controls, no significant association between PAI-
1 4G/5G polymorphism and VTE
• Studies on association between PAI-1 and arterial thrombosis
had conflicting results
Folsom AR, et al. Prospective study of fibrinolytic markers and venous thromboembolism. J Clin Epidemiol. 2003;56(6):598-
603.
Meltzer ME, et al. Fibrinolysis and the risk of venous and arterial thrombosis. Curr Opin Hematol. 2007;14(3):242-8.

Elevated Factor VIII
• In the Leiden population-based case-controlstudy (301
patients), increased factor VIII levels is an independent
marker of thrombotic risk
– >150%: OR 4.8; 95% CI 2.3-10.0
– 100-125%:OR 2.3; 95% CI 1.3-3.8
• Clustering of increased factor VIII levels in families of patients
with VTE suggests heritability
• No gene mutation has so far been described
• Patients with non-O blood type have significantly higher levels
of factor VIII
• Unclear mechanism, but high factor VIII levels postulated to
enhance thrombin generation and/or decrease anticoagulant
effect of APC
Koster T, et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet
1995;345(8943):152-5.

Elevated Clotting Factors
UpToDate. Overview of the causes of venous thrombosis. Last updated April 1, 2014.

When to Test?
• This is debatable, but in general, patients who meet the
following:
– Unprovoked VTE
– Recurrent thrombotic events
– Provoked VTE in patients < 50 years old
– VTE provoked by pregnancy, OCP’s, or hormone replacement therapy
– Family history of VTE
– Cerebral or visceral vein thrombosis
– 3 or more consecutive unexplained fetal losses during 1st trimester, 1
or more fetal losses during 2nd or 3rd trimester, or 1 or more stillbirths

Acquired Conditions and Test Results
Tests* Acquired Conditions That Can Cause Abnormal Test Results
APCR (decreased ratio) Pregnancy, use of oral contraceptives, stroke, presence of lupus anticoagulant,† increased factor VIII
levels,† autoantibodies against activated protein C, use of oral anticoagulants†
Factor V Leiden —
Prothrombin G20210A —
Hyperhomocysteinemia Deficiencies of folate, vitamin B12, or vitamin B6, old age, renal failure, excessive consumption of coffee, smoking
Increased factor VIII levels Pregnancy, use of oral contraceptives, exercise, stress, older age, acute phase response, liver disease,
hyperthyroidism
Presence of lupus anticoagulant Systemic lupus erythematosus, antiphospholipid syndrome, autoimmune disease, liver disease, hyperthyroidism,
healthy subjects
Increased titer of
anticardiolipin antibody
Same as lupus anticoagulant, infectious diseases
Decreased level of protein C Liver disease, use of oral anticoagulants, vitamin K deficiency, childhood, disseminated intravascular coagulation,
presence of autoantibodies against protein C
Decreased level of free protein
S
Liver disease, use of oral anticoagulants, vitamin K deficiency, pregnancy, use of oral contraceptives, nephrotic
syndrome, childhood, presence of autoantibodies against protein S, disseminated intravascular coagulation
Decreased level of
antithrombin
Use of heparin, thrombosis, disseminated intravascular coagulation, liver disease, nephrotic syndrome
Increased level of factor IX —
Increased level of factor XI —
Homozygous MTHFR C677T —
Dysfibrinogenemia Neonates, liver disease

References
• Williams Hematology 8th
Edition. Chapter 131: Hereditary Thrombophilia. 2121-2143.
• Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh
1963;13:561-30.
• Beck EA, CharacheP, Jackson DP. A new inherited coagulation disorder caused by an abnormalfibrinogen
(“fibrinogen Baltimore”). Nature1965;208:143-45.
• Griffin JH, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest1981;68:1370-3.
• Comp PC, et al. Familial protein S deficiency is associated with recurrentthrombosis. J Clin Invest
1984;74:2082-88.
• Dahlback B, Carlsson M, Svensson PJ. Familialthrombophilia due to a previously unrecognized mechanism
characterized by poor anticoagulant responseto activated protein C: Prediction of a cofactor to activated
protein C. Proc Natl Acad Sci U S A 1993;90:1004-8.
• Bertina RM, et al. Mutation in blood coagulation factor V associated with resistanceto activated protein C.
Nature 1994;369:64-7.
• PoortSR, et al. A common genetic variation in the 3’-untranslated region of the prothrombin geneis
associated with elevated plasma prothrombin levels and an increasein venous thrombosis. Blood
1996;88:3698-703.
• Ridker PM, et al. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous
thromboembolism screening. JAMA 1997;277(16):1305-7.
• Jadaon MM. Epidemiology of activated protein C resistanceand factor v leiden mutation in the
mediterranean region. Mediterr J Hematol InfectDis. 2011;3:e2011037.
• Segal JB, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with VTE and in
family members of those with a mutation: a systematic review. JAMA 2009;301:2472-85.
• Zivelin A, et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites
approximately 24,000 years ago. Blood 2006;107:4666-8.

References (con’t)
• Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical
perspective. Ann Intern Med 1997;127(10):895-903.
• Emmerich J, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous
thromboembolism – pooled analysis of 8 case-controlstudies including 2310 cases and 3204 controls.
Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost. 2001;86(3):809-16.
• Ludemann P, et al. Factor V Leiden mutation is a risk factor for cerebralvenous thrombosis: a case-control
study of 55 patients. Stroke 1998;29(12):2507-10.
• Williamson D, et al. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistanceto
activated protein C. Blood 1998;91(4):1140-4.
• Nogami K, et al. Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and
morepotent APCresistancerelative to FVLeiden. Blood 2014;123(15):2420-8.
• Steen M, et al. Functional characterization of factor V-Ile359Thr: a novelmutation associated with
thrombosis. Blood 2004;103(9):3381-7.
• Chan WP, et al. A novelmutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998;91(4):1135-
9.
• Martinelli I, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-genemutation and in
users of oralcontraceptives. N Engl J Med. 1998;338(25):1793-7.
• Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and
methylenetetrahydrofolatereductaseC677Tmutations and events of the arterial circulatory system: a
meta-analysis of published studies. Am Heart J 2003;146(6):948-57.
• Goldenberg NA, Marco-Johnson MJ. Protein C deficiency. Haemophilia 2008;14(6):1214-21.
• Adachi T. Protein S and congenital protein S deficiency: the mostfrequent congenital thrombophilia in
Japanese. Curr Drug Targets 2005;6(5):585-92.

References (con’t)
• Nachman RL, Silverstein R. Hypercoagulablestates. Ann Intern Med 1993;119(8):819-27.
• Martinelli I, et al. Differentrisks of thrombosis in four coagulation defects associated with inherited
thrombophilia: a study of 150 families. Blood 1998;92(7):2353-8.
• Lijfering WM, et al. Selective testing for thrombophiliain patients with firstvenous thrombosis: results
froma retrospectivefamily cohortstudy on absolute thrombotic risk for currently known thrombophilic
defects in 2479 relatives. Blood 2009;113(21):5314-22.
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