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(1)

Thrombophilia

Moon Ju Jang, M.D.

Division of Hematology and Oncology, Department of Internal Medicine School of Medicine, CHA University

2011 혈액종양내과 분과전문의 연수강좌

(2)

What is “thrombophilia”?

• Nygaard KK (1937)1

Patients with an unexplained tendency for, mainly arterial, thrombotic events.

• Egeberg O (1965)2

Norwegian family that had a remarkable tendency to VTE, and discovered that this was based on an inherited deficiency of AT.

• 1980s3,4

Inherited deficiencies of protein C and protein S were described.

1. Arch Intern Med 1937;59:82–106

2. Thromb Diath Haemorrh 1965;13:516–530 3. J Clin Invest 68(5):1370–1373

4. N Eng J Med 311(24):1525–1528

(3)

What is “thrombophilia”?

Thrombophilia

Inherited or acquired clinical phenotype manifesting in selected individuals as a greater risk to develop recurrent thrombosis at a younger age than the

general population

Hypercoagulability

Laboratory phenotype whereby in vivo activation of clotting, fibrinolysis, endothelial cells and platelets is identified in vitro by specialized clotting techniques and by specific antibodies directed at biomarkers of clotting activation and damaged vasculature.

J Thromb Thrombolysis 2011;31:275–281

(4)

Thrombophilia

Inherited

Common G1691A mutation in the factor V gene (factor V Leiden) G20210A mutation in the prothrombin (factor II) gene Rare Antithrombin deficiency

Protein C deficiency Protein S deficiency Very rare Dysfibrinogenemia

Increased levels of F VIII, IX, XI, or fibrinogen

Acquired

Common Anti-phospholipid syndrome

(5)

Contents

1. Epidemiology 2. Thrombotic risk

3. Overview of various thrombophilias

4. Thrombophilia testing for patients with VTE

5. Thrombophilia testing to modify the risk of a first VTE

6. Summary

(6)

Incidence of Thrombophilia

General

Population (%) Unselected VTE

Patients (%) Selected VTE Patients (%)*

AT deficiency 0.15-0.2 1 3-5

PC deficiency 0.13-0.5 3 1.4-8.6

PS deficiency 0.16-0.2 2 1.4-7.5

Factor V Leiden 2-15 21 10-64

Prothrombin G20210A mutation 2-3 6 18

Hyperhomocyteinemia 5-10 10-25 -

Antiphospholipid antibodies 0-5 5-15 -

* age < 45 years and/or recurrent thrombosis

(7)

Thrombophilia in Korea?

Population data at SMC (Kim HJ et al) - Study subjects

: 3,129 individuals from Health Promotion Center at SMC : 1,873 men and 1,256 women (M:F = 1.5:1)

: Mean age 52.5 yr; range 18~86 yr - Coagulation test screening

: AT activity, PC activity, free PS Ag - Confirmation by molecular genetic test

: Direct sequencing for SERPINC1 (AT def), PROC (PC def) and PROS1 (PS def)

(8)

Incidence of AT Deficiency in Korea

Study population Strategies and criteria Frequency Ref

Scottish blood donors (N=9,669)

Persistently decreased AT activity (<2SD)

 family study and mutation analysis

0.17~0.18% Tait et al, 1994

Canadian blood donors

(N=2,491) Persistently decreased AT activity (Xa-

based assay, <2SD) 0.2% Wells et al, 1994 Japanese blood donors

(N=2,690) Decreased PS activity (<2SD) &

high AT/PS ratio (>2SD) 0.15% Sakata et al, 2004 Korean individuals

visiting for routine heakth checkup

(N=3,046)

Decreased AT activity (<1-percentile)

 mutation analysis 0.42~0.48%

(9)

Incidence of PC Deficiency in Korea

Study population Strategies and criteria Frequency Ref US blood donors

(N=5,422) Decreased PC antigen

(<2.1 ug/ml; 3.5SD ) 0.33~0.5% Mietich et al, 1987

Scottish blood donors (N=9,648)

Persistently decreased PC activity (<2SD)  family study and mutation

analysis 0.14~0.17% Tait et al, 1995

Japanese blood donors

(N=2,690) Decreased PC activity (<3SD) &

high AT/PC ratio (> 3SD) 0.13% Sakata et al, 2004

Korean individuals visiting for routine

health checkup (N=2,953)

Decreased PC activity (<1-percentile)  mutation

analysis

0.27~0.40%

(10)

Incidence of PS Deficiency in Korea

Study population Strategies and criteria Frequency Ref

Scottish blood donors (N=3,788)

Persistently decreased total and free PS levels (< 1 percentile)

 mutation analysis 0.16~0.21% Dykes et al, 2001

Japanese blood donors (N=2,690)

Decreased PS activity (<2SD) &

high AT/PS ratio (>2SD) 1.12% Sakata et al, 2004

Korean individuals visiting for routine

health checkup (N=3,033)

Decreased free PS antigen (<1-percentile)  mutation

analysis

0.066~0.16%

(11)

Incidence of Thrombophilia in Korea

Study population AT def PC def PS def Combined

Scottish blood donors

(N=3,788~9,669) 0.17~0.18% 0.14~0.17% 0.16~0.21% 0.47~0.56%

Japanese blood donors

(N=2,690) 0.15% 0.13% 1.12% 1.40%

Korean individuals visiting for routine

health checkup (N=2,953~3,046)

0.42~0.48% 0.27~0.42% 0.065~0.17% 0.76~1.6%

(12)

Distribution of genetic defects

Population vs Patients

def PS (17%)

PS def

PC def (50%) PC def (35%)

AT def (33%) AT def (56%)

VTE Patients with thrombophilia

Population

(13)

Contents

1. Epidemiology

2. Thrombotic risk

3. Overview of various thrombophilias

4. Thrombophilia testing for patients with VTE

5. Thrombophilia testing to modify the risk of a first VTE

6. Summary

(14)

Thrombotic risk of thrombophilia

Crit Rev Clin Lab Sci. 2006;4393:249-290.

0 5 10 15 20 25

Hyperhomocysteinemia PT gene mutation Elevated FVIII levels Factor V Leiden PS deficiency PC deficiency AT deficiency

Number of times Relative to General Population

(15)

No thrombophilic defects

FV Leiden High FVIII

Prothrombin G20210A

Antithrombin deficiency Protein C deficiency Protein S deficiency

Blood. 2009;113:5314-5322

Event-free survival of first VTE

in relatives with thrombophilic defects

25%

55%

(16)

Contents

1. Epidemiology 2. Thrombotic risk

3. Overview of thrombophilia

4. Thrombophilia testing for patients with VTE

5. Thrombophilia testing to modify the risk of a first VTE

6. Summary

(17)

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

(18)

Endothelium Xa Va

Prothrombin Thrombin

Fibrinogen

Fibrin

“Thrombus”

Regulation of Thrombin Formation by the AT & Protein C System

APC

APC inhibits further thrombin generation

Activated protein C is generated by thrombin-TM

Protein C

Protein S

Thrombomodulin

Thrombin

AT

(19)

1. AT Deficiency

• About 0.2% of the general population

• About 3-5% of VTE patients (before the age of 40-45)

• Autosomal dominant

• Most cases are heterozygous.

• Over two hundred different SERPINC1 mutations have been identified.

• AT activity levels in the range of 40–60%

• Thrombotic risk: x 20

• Classification: quantitative (Type I), qualitative (Type II) deficiency

• Diagnosis: AT activity, AT antigen

(20)

2. PC Deficiency

• Protein C deficiency cause thrombosis when levels drop to <50%.

• Autosomal dominant

• Most cases are heterozygous.

• Over two hundred different PROC mutations have been identified.

• Thrombotic risk: x 10

• Neonatal fulminance or skin necrosis and DIC in homozyous neonate

• Warfarin-induced skin necrosis: rare but serious complication

• Classification: quantitative (Type I), qualitative (Type II) deficiency

• Diagnosis: PC activity, PC antigen

(21)

3. PS Deficiency

• Protein S exists in a free and bound state

• 60-70% of protein S circulates bound to C4b binding protein

• Free PS, is the functionally active form of protein S

• Autosomal dominant, heterozygous

• Over two hundred different PROC mutations have been identified.

• Thrombotic risk: x 10

• Classification: quantitative (Type I), qualitative (Type II)

Type III: mild quantitative deficiency (shift total/free S antigen level)

• Warfarin-induced skin necrosis

• Diagnosis: PS & free PS antigen, PS activity

(22)

4. Factor V Leiden Mutation

• 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”

• Most cases are heterozygous (90-95%)

• 40-50% of inherited thrombophilias (m/c)

• Found in 5% of the Caucasian population

• Found in 10-20% of patients with first episode of idiopathic DVT

(23)

Distribution of the Factor V Leiden mutation

in the world population

(24)

5. Prothrombin G20210A Variant

• Substitution of adenine for guanine in nucleotide position 20210

• 30% increase in prothrombin levels.

• Most cases are heterozygous.

• Found in 2% of the Caucasian population

• 5-10% of familial thrombosis in Caucasian

• Thrombotic risk: x 5

(25)

6. Hyperhomocysteinemia

• Inherited or nutrient-related disturbances

• Inherited deficiencies is associated with alterations in enzymes such as cystathionine β-synthase, methionine synthase, and methylenetetrahydrofolate reductase (MTHFR).

• Activates FV, PC activation↓, inactivates cofactor activity of TM

• Thrombotic risk: x 3

• MTHFR 677TT genotype: 20% higher risk of VTE

(26)

Homocysteine metabolic pathway

S-adenosyl methionine methionine

Homocysteine

Cysteine SO4 -

S-adenosyl homocysteine 3. MTHFR

Methyl THF THF

B12

Cystathionine

Remethylation

Transsulfuration

1. Cystathionine synthase

2. MS

Food

(27)

Homocysteine-Lowering Therapy and Risk for VTE

Secondary analysis of HOPE-2 trial : Primary prevention

Ann Intern Med. 2007;146:761-767

The Vitamins and Thrombosis (VITRO) : Secondary prevention

Blood. 2007;109:139-144 p = ns

p = ns

(28)

7. Antiphospholipid Syndrome

• aPL is 1~5% in general populations

• 16~50% in autoimmune diseases such as SLE

• 5~20% in patients with thrombosis

• Diagnosis: 1 Clinical Criteria + 1 Laboratory Criteria - Clinical Criteria(thrombosis, Pregnancy morbidity)

- Laboratory Criteria: anticardiolipin Ab, LA, Anti-β2gp1 Ab

• Recurrent thromboses tend to occur in same site

• Unusual events: superficial thrombophlebitis, SVC syndrome, renal vein/artery thrombosis, adrenal infarction, Budd-Chiari syndrome, central retinal vein/artery occlusion

(29)

Treatment recommendations

The American College of Chest Physicians (ACCP) guidelines

1. For patients with unprovoked DVT, we recommend treatment with a VKA for at least 3months.

2. For patients with a first unprovoked VTE that is a proximal DVT, and in whom risk factors for bleeding are absent and for whom good anticoagulant monitoring is achievable, we recommend long-term treatment.

3. For patients with a second episode of unprovoked VTE, we recommend long-term treatment.

ACCP guideline 8th edition. Chest 2008;133:299S-339S

(30)

Contents

1. Epidemiology 2. Thrombotic risk

3. Overview of various thrombophilias

4. Thrombophilia testing for patients with VTE

5. Thrombophilia testing to modify the risk of a first VTE

6. Summary

(31)

When to suspect ?

• VTE at young age ( <45 years old)

• Recurrent VTE

• VTE in unusual sites

• VTE in the setting of a strong family history of VTE

(32)

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

(33)

Diagnostic Tests for Thrombophilias

Priority Thrombophilia

High priority Factor V Leiden

Prothrombin G20210A variant Homocystein level

Lupus anticoagulant Intermediate priority AT activity

PC activity Free S antigen

Anticardiolipin antibodies

Low priority Fibrinogen

Factor IX, XI activity MTHFR

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

(34)

Testing for Hereditary Defects in Patients With Thrombosis

Pro

Improve understanding of pathogenesis of thrombosis Identify and counsel affected family members

Obviate expensive diagnostic testing (e.g. CT scans) looking for a malignancy

Con

Infrequent identification of patients with defects whose management would change

Potential for overaggressive management Cost of testing

(35)

Cost of thrombophilic testing

Test Approximate Cost

USA($)

(36)

Lancet 2003 JAMA 2005 Haematologica 2006

Cambridge Leiden study Italian cohort

The risk of recurrent VTE in

patients with inherited thrombophilia

Lancet 362:523–526.

JAMA 293(19):2352–2361.

Haematologica 91(5):695–698.

p = ns p = ns

p = ns

(37)

Ho et al, Arch Intern Med 2006

Factor V Leiden

PT G20210A mutation

(38)

Risk of recurrent VTE in patients with

hereditary deficiency of either PS, PC or AT

Relative risk of recurrence with concomitant defects

: 1.4 (0.7-2.6) (1 defect) and 1.4 (0.8-2.7) (> or =2 defects)

Thromb Haemost 2009;101:93-9.

(39)

Summary of clinical studies

Risk of Recurrent VTE in Thrombophilia

Cambridge

(Lancet 2003) Leiden study

(JAMA 2005) Italian cohort

(Heamatologica 2006) Brouwer et al.

(Thromb Haemost 2009) AT deficiency

1.50

(95% CI 0.82-2.77)

(95% CI 0.9-3.7) 1.8

(95% CI 1.0-3.9) 1.9

1.4 (95% CI 0.7-2.6) PC deficiency

(95% CI 0.9-2.2) 1.4 PS deficiency

Factor V Leiden NS -

Prothrombin

G20210A variant NS -

Lancet 2003;362:523–526.

JAMA 2005;293:2352–2361.

Haematologica 2006;91(5):695–698.

Thromb Haemost 2009;101:93-9

(40)

Thrombophilic testing in patients with thrombosis

Routine screening of patients with VTE for an underlying thrombophilic defect “is not justified”

However, the risk of subsequent thrombosis over 5 years in patient with thrombophilia is 50%.

The AT, PC and PS def. patients have a high absolute risk of recurrence.

In selected situations (recurrent, unusual site, younger age, family history),

thrombophilic testing might guide therapeutic decision-making and long-term patient care.

(41)

Contents

1. Epidemiology 2. Thrombotic risk

3. Overview of various thrombophilias

4. Thrombophilia testing for patients with VTE

5. Thrombophilia testing to modify the risk of a first VTE

6. Summary

(42)

Risk of a first VTE in carriers of a familial thrombophilic defect

Sanson BJ et al.

(1999 Blood) EPCOT

(2005 JTH) GIRTE

(1999 ATVB)

Carrier, No N=208 N=575 N=233

Annual incidence Annual incidence Annual incidence

AT 1.6% 1.7% 1.07%

PC 1.0% 0.7% 0.54%

PS 0.4% 0.8% 0.50%

Factor V Leiden 0.1%

APCR 0.30%

1.5% 0.8% 0.52%

Blood 1999; 94:3702–3706

J Thromb Haemost 2005; 3: 459–64.

Arterioscler Thromb Vasc Biol 1999;19:1026–1033.

(43)

Retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic

defects in 2479 relatives

Carrier N Annual incidence

(95% CI) Adjusted RR (95% CI)

AT 60 1.7%

(1.14-2.60) 28.2

(13.5-58.6)

PC 91 1.52%

(1.06-2.11) 24.1

(13.7-42.4)

PS 94 1.90%

(1.32-2.64) 30.6

(26.9-55.3)

Factor V Leiden 652 0.49%

(0.39-0.60) 7.5

(4.4-12.6)

Prothrombin G20210A variant 288 0.34%

(0.22-0.49) 5.2

(2.8-9.7)

High FVIII 776 0.49%

(0.41-0.51) 7.1

(4.3-11.8)

Blood. 2009;113:5314-5322

(44)

It is clear that the 2% annual major bleeding risk associated with

continuous anticoagulant treatment

outweighs the risk of VTE.

(45)

Age

ThrombosisRisk

Inherited Thrombophilia (1.5%/year)

Interaction between Inherited and Acquired Risk Factors

Bleeding risk (2.0%/year)

Acquired risk factors

Surgery, trauma, immobilization, pregnancy, oral contraceptive use,

severe medical illness, stroke…

(46)

Estimated incidence of a first episode of VTE in carriers of various thrombophilic defects

AT, PC, PS def. Factor V Leiden Prothrombin G20210A variant

Overall

(%/year, 95% CI) 1.5 (0.7–2.8) 0.5 (0.1–1.3) 0.4 (0.1–1.1)

Surgery, trauma, or immobilization

(%/episode, 95% CI) 8.1 (4.5–13.2) 1.8 (0.7–4.0) 1.6 (0.5–3.8)

Pregnancy

(%/pregnancy, 95% CI) 4.1 (1.7–8.3) 2.1 (0.7–4.9) 2.3 (0.8–5.3)

Oral contraceptive use

(%/year of use, 95% CI) 4.3 (1.4–9.7) 0.5 (0.1–1.4) 0.2 (0.0–0.9)

Blood 2009;113:5314-5322

Thromb Haemost 1999;81:198–202 Blood 1999;94:3702–3706.

Ann Int Med 1996;125:955–960.

Arterioscler Thromb Vasc Biol 1999;19:1026–1033

(47)

Frequency of pregnancy-related VTE in anticoagulant factor-deficient women

: implications for prophylaxis

Ann Intern Med 1996;125:955-60.

• Retrospective cohort study

• 129 otherwise asymptomatic female family members of patients with a history of VTE and an established deficiency of AT, PC, or PS.

: 60 had anticoagulant factor deficiency VS 69 did not.

• In the nondeficient group, 198 pregnancies occurred; VTE - 0.5%

• In the deficient group, 169 pregnancies occurred; VTE - 4.1%

• Hazard ratio: 8.0 [95% CI 1.2 to 184]

(48)

1. Pregnant women with no prior history of VTE but AT deficiency : Suggest both antepartum and postpartum prophylaxis (Grade 2C)

2. For all other pregnant women with thrombophilia but no prior VTE

: suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C).

ACCP guideline 8th edition. Chest 2008;133:844S-886S

Prevention of Pregnancy-Related VTE in Women With Thrombophilia

The American College of Chest Physicians (ACCP) guidelines

(49)

Screening of asymptomatic individuals for thrombophilia in thrombophilic family

Might be useful for asymptomatic carriers.

- To reduce exposition to other risk factors

- To offer appropriate prophylaxis in high-risk situations

- but only if associated with appropriate counseling!!!

(50)

Contets

(51)

Summary (1)

• The frequency of confirmed thrombophilia in Korea was estimated to be 0.76~1.6% in general population.

• Thrombotic risk high in patients with AT, PC, and PS deficiency, moderate in patients with FV Leiden and high FVIII, low in patient with Prothrombin G20210A variant and hyperhomocysteinemia.

• For patients with unprovoked VTE, we recommend treatment with a VKA for at least 3months.

• For patients with a second episode of unprovoked VTE, we recommend long-term treatment.

(52)

Summary (2)

Routine screening of patients with VTE for an underlying thrombophilic defect

“is not justified”.

• In selected situations (recurrent, unusual site, younger age, family history), thrombophilic testing might guide therapeutic decision-making and long- term patient care for high-risk thrombophilic patients.

• Screening of asymptomatic individuals for thrombophilia might be useful to offer appropriate prophylaxis in high-risk situations.

These guidelines need to be updated based on results from well controlled studies conducted in Korea.

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