Genetic Tests for the Better Outcome of VTE? 서울대학교병원혈액종양내과윤성수

Transcription

1 Genetic Tests for the Better Outcome of VTE? 서울대학교병원혈액종양내과윤성수

2 Thrombophilia A hereditary or acquired disorder predisposing to thrombosis Questions Why should we test? Who should we test For what disorders? When? How should we alter patient management?

3 Survival after VTE Time DVT alone (%) PE (%) 0 d d d d d year Heit, Arch Intern Med 1999

4 Reasons to Test for Thrombophilia Risk of recurrence ~ 5%/year (~ 20%/1 st 2 yrs for idiopathic VTE) Standard VKAs with INR 2-3 Annual bleeding risk 0.25% for fatal bleeding 1.0% for life-threatening bleeding Hereditary thrombophilia and VTE risk Increase the risk of 1 st VTE But, increase the risk of recurrent VTE? Controversial! Semin Throm Hemost 2007

5 Hereditary Thrombophilia Clinical Features VTE at an early age Family history Recurrent VTE Unusual site: cerebral, mesenteric, renal Thrombosis during pregnancy Idiopathic venous thromboembolism

6 Hereditary Thrombophilia (HT) Genetic backgrounds of HT Deficiency of natural anticoagulants (NA) Antithrombin (AT) deficiency Protein C (PC) deficiency Protein S (PS) deficiency Increased pro-coagulant activity Activated protein C (APC) resistance (factor V Leiden mutation) Prothrombin G20210A mutation Impaired procoagulant downregulation Impaired fibrinolysis Altered innate immunity

7 Heterogeneity of HT Number of genetic variations leading to abnormal function of AT, PC and PS Quantitative dysfunction (type I deficiencies) Qualitative dysfunction (type II deficiencies) Different genetic disorders different levels of risk for thrombosis?

8 Who should be tested for thrombophilia? Indiscriminate screening of all pts with VTE (?) Selective screening for helping decision making Unprovoked 1 st VTE Age <50 with provoked VTE including VTE during OC use or hormone replacement tx Pregnancy-related VTE VTE after trauma or surgery Recurrent VTE (provoked or unprovoked) in noncancer VTE in unusual sites VTE in otherwise healthy children Semin Throm Hemost 2006

9 VTE Incidence by Ethnicity Ethnicity Incidence (± SD)/100,000 African-American 138 ± 6.5 White 103 ± 2.1 Hispanic 61 ± 2.8 Asian-American/Pacific Islanders 29 ± 2.4 Native American 33 White RH. Thromb Haemost 205 Hooper WC. Thromb Res 2003

10 Age-adjusted rates of PE, DVT, VTE Am J Med 2004;116:

11 Inter-ethnic Variations APC resistance and prothrombin mutations Commonly encountered in Caucasians Extremely rare in Asians Reinforces the importance of determining the prevalence and genetic background of HT in each ethnic group. Paucity of Korean data

12 Factor V Leiden Mutation Most common genetic disorder in Caucasians from Northern Europe: 5-7% Assoc with a 3-4 fold increase in the lifetime risk of developing VTE However, 80% of individuals with FVL never develop VTE!

13 Genetics of VTE A meta-analysis of 126,562 cases and 184,068 controls Electronic database search till Jan case-control studies: 21 genes (28 polymorphisms) 25,083 manuscripts identified 257 potentially relevant studies 207 studies with genotype frequencies- 115 polymorphisms in 52 genes 170 studies for meta-analysis - 28 polymorphisms in 21 genes - 48,870 cases and 71,394 controls 50 articles excluded (Failed to meet inclusion criteria) 37 articles excluded (2 or more studies required) Thromb Haemost 2009;102:

14 Genetics of VTE Statistically Significant Associations with VTE Genes OR CI p value Race/effect Factor V G1691A < Caucasians Factor V A4070G Caucasians Prothrombin 20210A < Caucasians Prothrombin G11991A Caucasians PAI-1 4G/5G Caucasians alpha-fibrinogen Thr312Ala Caucasians MTHFR/ C677T Chinese/Thai populations ACE I/D African American populations Factor XIII Val34Leu Protective effect beta-fibrinogen 455 G/A Protective effect Thromb Haemost 2009;102:

15 Genetics of VTE Conclusion Largest genetic meta-analysis of hemostatic genes in VTE Sporadic VTE: frequently encountered problem Evidence of inherited component suggested Relative risk for each gene: undetermined because of small number of subset Thromb Haemost 2009;102:

16 Warfarin Pharmacogenomics Genes associated with warfarin dose requirements cytochrome P450 (CYP)2C9 vitamin K epoxide reductase complex 1 (VKORC1) genes Clinical aspects Reduced doses required with the variant CYP2C9*2, CYP2C9*3, or VKORC1-1639A allele. Explains 50 to 60% of the variance in warfarin dose requirements in Caucasians and Asians, but only 25 to 40% among African Americans Also influences the time required to attain therapeutic anticoagulation and the risk for over-anticoagulation and hemorrhage Clinical importance Improves the accuracy of dose prediction However, an improvement in anticoagulation control or a reduction in hemorrhagic complications has not been demonstrated. the routine use of CYP2C9 and VKORC1 genotyping is not supported by currently available evidence. Curr Opin Mol Ther 2009;11(3);243-51

17 Executive Summary Screening for thrombophilia in high-risk situations Assess risks in 3 high-risk group pts (electronic database from 1966 to 2003) Medline, EMBAE, CINAHL, Cochrane, DARE, Kings Fund UK 4 screening scenarios assessing the effectiveness of prophylactic treatment in preventing VTE 1. Women prior to OC: restrict VTE prevention on negative tests 2. Women prior to HRT: restrict VTE prevention on negative tests 3. Women at the onset of pregnancy: VTE prevention on positive tests 4. All pts prior to major elective orthopedic surgery: VTE prevention on positive tests Health Technology Assessment 2006;vol 10: no 11

18 Executive Summary Screening for thrombophilia in high-risk situations Risk of clinical complications Highest risk in factor V Leiden in all 4 groups tested Effectiveness of prophylaxis Preventing pregnancy loss: insufficient data for statistically significant associations Orthopedic surgery: insufficient data for the relative effectiveness of different thromboprophylaxis in preventing VTE Health Technology Assessment 2006;vol 10: no 11

19 Executive Summary Screening for thrombophilia in high-risk situations Cost-effectiveness analysis on 10,000 hypothetical subjects Without screening, number of adverse complications 7 women on combined OC 104 women on HRT 2,921 pregnant women 1,265 orthopedic surgery With screening Universal screening prior to HRT: prevent 42 VTE events (most costeffective) Prior to OC: prevent 3 VTE events (least cost-effective) Irrespective of pt groups, selective screening based on the presence of previous personal or family history of VTE was most cost-effective than universal screening! Health Technology Assessment 2006;vol 10: no 11

20 2 goals of long-term therapy To complete treatment of the acute episode of VTE (ie, first 3 months) To prevent new episodes of VTE that are not directly related to the acute event (ie, after the first 3 months) Kearon C. et al. Chest 2008;133:454S-545S

21 Estimated Relative Risk of VTE Recurrence in Pts with Thrombophilia Type of thrombophilia Natural anticoagulant def FLV Prothrombin 20210A Elevated FVIII:c Elevated FIX 1.2 Elevated FXI 0.6 Mild hyperhomocysteinemia Antiphospholipid syndrome 2-6 Relative risk Semin Throm Hemost 2007

22 Adjustment of anticoagulation after a 1 st VTE Not beneficial regardless of thrombophilia VKA < 2.0 Recurrence risk (1.9 vs 0.6%) Major bleeding risk not different between a low- intensity and regular-intensity treatment (0.96 vs 0.93%) Higher intensity VKA in APL No reduction in the risk of recurrence Increase in the bleeding risk! Semin Throm Hemost 2007

23 Absolute Risk of VTE in Asymptomatic Carriers Type Overall Risk (%/year) Surgery, Trauma, Immobilization (%/episode) Pregnancy (%/Pregnancy) OC (%/year of use) Natural anticoagulant deficiencies FLV Prothrombin 20210A Elevated FVIII:c Mild hyperhomocysteinemia Semin Throm Hemost 2007

24 Reviews on Korean Data No large-scale population data are available Data are restricted to thrombotic patients Usually based on a single episodic observation of NA decrease many were thought to be acquired or transient deficiency A few studies performed genetic analysis AT: two large deletions PC: Arg211Trp, Val339Met, Asp297His, Met406Ile, Pro210Leu PS: large duplications

25 Prevalence in thrombophilic population Korean (%) Western (%) Protein C deficiency Protein S deficiency Antithrombin deficiency 0.9 <1 Factor V Leiden Prothrombin G20210A Hyperhomocysteinemia Increased coagulation factors Dysfibrinogenemia 1.5? Lupus anticoagulant 의협종합학술대회. Courtesy of Pf. Kim HK from SNUH

26 Paradigm Change in Korea Recent studies that challenged the old belief - SMART study The rates of postop. venous T. in Asians including Korea were 13% after general Sx. 16 ~ 50% after orthopedic Sx - AIDA study The rates of venous T. after orthopedic Sx in Asians including Korea were 26%~58% Courtesy of Pf. Kim HJ from SMC

27 Population vs Patients (SMC experience) Distribution of genetic defects Population (N=3,033) PC def (35%) Patients (N=46) PC def (50%) AT def (56%) AT def (33%) PS def PS def def (17%) Courtesy of Pf. Kim HJ from SMC

28 ACCP guideline 1986 : first consensus statement on antithrombotic therapy 2008 : 8 th edition Evidence-based clinical practice guideline Korea Incidence? Treatment guideline? Kearon C. et al. Chest 2008;133:454S-545S

29 Major determinant factors Risk factors for recurrent DVT Bleeding risk Stability of INR Residual cardiopulmonary function status Patients preference Kearon C. et al. J Thromb Haemost 2009;7(suppl. 1):

30 3 groups for recurrent VTE 1. Reversible risk factors Major reversible risk (recurrence rate 3% in the 1 st year) Surgery within 1 month Hospitalization Immobilization due to cast Minor reversible risk (~5% in the 1 st year) Pregnancy Estrogen therapy Air travel more than 8 hours Previous major reversible risk within 1 to 3 month 2. Idiopathic (10% at 1 year, 30% at 5 years, 50% at 10 years) 3. Cancer ( 15% in the 1 st year)

31 Duration of anticoagulant therapy for DVT Risk group DVT secondary to a reversible risk Unprovoked DVT (1 st event) Unprovoked DVT (2 nd event) Proximal DVT DVT and cancer Asymptomatic DVT Spontaneous spf v. thrombosis Infusion thrombophlebitis for 3 months Duration At least 3 months, and then re-evaluate the risk Long-term anticoagulation Long-term anticoagulation LMWH 3-6 mo., and then indefinite anticoagulation Same as symptomatic DVT Intermediate dose of LMWH or UFH or VKA for 4 weeks NSAID or topical drug for 2 weeks, not recommend systemic anticoagulation Same treatment for acute PE except life-threatening PE If a 1 st unprovoked episode of VTE that is a PE, recommend long-term treatment ACCP guideline 8 th edition. Chest 2008;133:299S-339S

32 Balancing risks and benefits of extended anticoagulant therapy for idiopathic VTE Factors that favor stopping anticoagulant therapy due to higher risk of bleeding History of bleeding without a reversible cause Chronic renal or hepatic failure Requirement for antiplatelet therapy History of non-cardioembolic stroke Persistently poor anticoagulant control Older than 75 years when VTE diagnosed Factors that are expected to add to the benefits of indefinite anticoagulant therapy Second or subsequent idiopathic event Positive D-dimer after withdrawing therapy Pulmonary embolism Persistent pulmonary hypertension Male gender Established postthrombotic syndrome Hereditary or acquired thrombophilia Residual DVT Kearon C. et al. J Thromb Haemost 2009;7(suppl. 1):

33 Summary Initial and subsequent management of VTE not affected by identification of thrombophilic conditions with few exceptions! routine testing for thrombophilia causes unexpected consequences (misinterpretation of the results, false impression, insurance etc.) Observed clinical VTE phenotype >>> genotype Recommended workup! Measure functional level of AT in heparin resistance APS testing in idiopathic VTE acl + anti-beta-2gpi (not affected by warfarin, heparin) White RH. Mount Sinai J Med 76; , 2009

34 VTE giants Physicians Patients Thank you!