슬라이드 1

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1 Biomarkers in VTE Soonchunhyang Univ. Hospital, Seoul, Korea Division of Respiratory Medicine / Thrombosis Clinic Yang-Ki Kim

2 Definition of Biological Markers Measurable and quantifiable biological parameters specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances Year introduced: 1989 MeSH database

hormone concentration, specific gene phenotype distribution in a

3 Table of contents Biomarkers in the diagnosis of VTE Biomarkers in predicting clinical outcomes of acute PE Biomarkers in predicting recurrence of VTE Biomarkers in indicating thrombotic potentials

acute PE Biomarkers in predicting recurrence of

4 Plasmin degradation of a fibrin clot D-dimer The presence of D- dimer is a telltale clue that blood clotting has been initiated. N Engl J Med 2003;349(13):1203-4

5 D-dimer Detection Methods 1. Enzyme-linked immunosorbent assay (VIDAS) : highly sensitive but not specific for DVT, quantitative results, technically time-consuming 2. Latex-agglutination assay (IL-Test) : inexpensive, rapid, quantitative, but 80% sensitivity 3. Whole-blood agglutination (SimpliRED) : qualitative, red-cell agglutination assays, monoclonal antibody specific for d-dimer operator-dependent N Engl J Med 2003;349(13):1203-4

6 D-dimer High Sensitivity & High NPV (negative predictive value) (~100%) Semin Vasc Med 2005;5(4):

7 폐색전증 진단을 위한 진료실에서의 예비검사 임상적 특징 High clinical likelihood of PE PE likely > 4 점 수 심부정맥혈전증의 임상적 증상 및 징후 3.0 폐색전증을 우선적 진단으로 고려하는 경우 3.0 심박수가 분당 100회를 초과 1.5 지난 4주 동안에 수술이나 3일 이상 거동이 안된 경우 1.5 심부정맥혈전증이나 폐색전증의 과거력 1.5 객혈 1.0 활동중인 암 (6개월 이내에 치료를 받았거나 보존적 치료) 1.0 Wells PS et al. Thromb Haemost 2000;83:416

0 심박수가 분당 100회를 초과 1.5 지난 4주 동안에 수술이나 3일 이상 거동이 안된 경우 1.

8 Incidence rate of PE using D-dimer and Wells score Score by model PE rate with -DD PE rate with +DD PE rate overall 4 1.7% [2/118] (0.2%-6.0%) 11.7% [7/60] (4.8%-22.6%) 5.1%[9/17] (2.3%-9.4%) > [3.29] (2.2%-27.4%) 60% [24/40] (43.3%-75.1%) 39.1%[27/69] 27.6%-51.6%) ( ) = 95% confidence interval: DD = D-dimer Thromb Haemost 2000;83:416

1%[9/17] (2.3%-9.4%) >4 10.3 [3.29] (2.2%-27.4%) 60% [24/40] (43.3%-75.1%) 39.

9 Diagnostic algorithm of PE using D-dimer 100 ER(outpatient) : 81.7% Inpatient : 18.3% Clinical decision rule 67, Unlikely (decision rule score 4) 33, Likely (decision rule score>4) D-dimer test 33, Normal D-dimer 34, Abormal D-dimer 67, CT indicated 45, PE excluded 20, PE confirmed 2, others JAMA 2006;295:172-9

3% Clinical decision rule 67, Unlikely (decision rule score 4) 33, Likely

10 Algorithm for Diagnostic Imaging Suspect DVT or PE Assess clinical likelihood DVT PE Low Not low Not high High D-dimer D-dimer Normal High Normal High Not DVT Imaging test needed Not PE Imaging test needed Harrison s Internal Medicine 17 th ed.

D-dimer Normal High Normal High Not DVT Imaging test needed

11 Summary of D-dimer D-dimer 는 체내에 혈전생성이 시작되었음을 의미 D-dimer 는VTE에서 증가하지만 기타 수술, 출혈, 외상, 악성종양, 패혈증, 고령, 임신(2기, 3기) 등과 관련해서도 증가할 수 있다. VTE를 진단에서 배제하는데 유용한 검사법 민감도가 높지만 VTE가 없는 환자의 90% 이상에서 정상으로 높은 NPV D-dimer 검사는 임상적 가능성(clinical probability)에 대한 평가와 함께 임상적으로 이용된다. 임상적 평가는 Wells score, Geneva score를 사용

VTE를 진단에서 배제하는데 유용한 검사법 민감도가 높지만 VTE가 없는 환자의 90% 이상에서 정상으로 높은 NPV D-dimer

12 Table of contents Biomarkers in the diagnosis of VTE Biomarkers in predicting clinical outcomes of acute PE Biomarkers in predicting recurrence of VTE Biomarkers in indicating thrombotic potentials

13 BNP(Brain Natriuretic peptide) N Engl J Med 2008;358:

14 BNP(Brain Natriuretic peptide) BNP(Brain natriuretic peptide)는 심근세포에서 합성되는 호르몬 전구물질인 pro-bnp는 심장의 용적확대(volume expansion)와 압력과부하 (pressure overload)로 인한 심근자극 후에 active BNP와 inactive NT-pro- BNP(N-terminal-proBNP)로 분해 급성 폐색전증에서 우심실의 전단응력(shear stress)이 높아지면 BNP 혹은 NT-pro-BNP가 상승하고 이는 우심실 기능이상(right ventricular dysfunction) 을 나타내는 표시자로 사용된다. 결과에 영향을 미치는 인자로는 환자의 나이, 체질량지수(body mass index, BMI), 신장기능이 있다.

BNP(N-terminal-proBNP)로 분해 급성 폐색전증에서 우심실의 전단응력(shear stress)이 높아지면 BNP 혹은 NT-pro-BNP가 상승하고 이는 우심실

15 BNP(Brain Natriuretic peptide) Overall mortality High BNP Normal BNP 6.52 [2.04, 20.86] Am J Respir Crit Care Med 2008;178(4):425-30

16 BNP(Brain Natriuretic peptide) Overall mortality NT-pro BNP elevated NT-pro BNP normal 8.72 [2.78, 27.40] 7.36 [3.35, 17.09] Am J Respir Crit Care Med 2008;178(4):425-30

17 BNP(Brain Natriuretic peptide) Adverse clinical outcome High BNP Normal BNP 6.30 [3.55, 11.16] Adverse clinical outcome defined as the occurrence of any of the following: death, CPR, mechanical ventilation, use of vasopressors, thrombolysis, thrombosuction, open surgical embolectomy, or admission to the ICU. Am J Respir Crit Care Med 2008;178(4):425-30

16] Adverse clinical outcome defined as the occurrence of any of the following: death,

18 BNP(Brain Natriuretic peptide) Adverse clinical outcome NT-pro BNP elevated NT-pro BNP normal 7.50 [3.79, 14.85] 6.77 [4.36, 10.49] Am J Respir Crit Care Med 2008;178(4):425-30

19 BNP(Brain Natriuretic peptide) Right ventricular dysfunction Elevated BNP Normal BNP [27.25, ] Am J Respir Crit Care Med 2008;178(4):425-30

20 BNP(Brain Natriuretic peptide) Right ventricular dysfunction NT-pro BNP elevated NT-pro BNP normal [5.73, 49.37] [16.71, 89.23] Am J Respir Crit Care Med 2008;178(4):425-30

NT-pro BNP normal 16.81 [5.73, 49.37] 38.

21 Troponin N Engl J Med 2002;346(26):

22 Troponin 심장 Troponin I(cTnT) 와 troponin T(cTnI)는 횡문근(striated muscle)에 있는 근육 단백질 심근괴사(myocardial necrosis)가 있는 경우 혈류로 유리 주로 심근경색증과 협심증에서 심근허혈로 인하여 증가되지만 폐색전증에서 도 중증의 우심실 압력 과부하(pressure overload) 혹은 우심실의 장기간의 압 력 과부하 후에 발생하는 경미한 심근손상에도 증가 폐색전증에서 troponin 의 상승은 우심실의 기능이상이나 확장과 관련 J Am Coll Cardiol 2000;36:1632-6

23 Troponin (+) Troponin (-) Troponin I Troponin Death based on serum Troponin I and T 4.01 [2.23, 7.23]

24 Troponin Death based on serum Troponin I and T Troponin T Troponin (+) Troponin (-) 4.01 [2.23, 7.23]

25 Troponin Death resulting from PE based on serum Troponin I and T Troponin (+) Troponin (-) Troponin I 7.11 [1.17, 43.37]

26 Troponin Death resulting from PE based on serum Troponin I and T Troponin T Troponin (+) Troponin (-) [4.03, 25.60] 9.44 [4.14, 21.49]

27 Pooled diagnostic indexes for various tests - RV dysfunction predicting death in PE showing stable haemodynamics Echocardio -graphy CT BNP Pro-BNP Cardiac troponin Sensitivity (%) (95% CI) Specificity (%) (95% CI) NPV (%) (95% CI) PPV (%) (95% CI) 70 (46 86) 65 (35 85) 88 (65 96) 93 (14 100) 81 (23 100) 57 (47 66) 56 (39 71) 70 (64 75) 58 (14 92) 84 (77 90) 60 (55 65) 58 (51 65) 76 (73 79) 81 (65 97) 73 (68 78) 58 (53 63) 57 (49 64) 67 (64 70) 63 (50 76) 75 (69 80) NPV : negative predictive value, PPV : positive predictive value Eur Heart J 2008;29:

28 Simplified PESI(Pulmonary Embolism Severity Index) Variable Points Age > 80 years 1 History of cancer 1 History of chronic cardiopulmonary disease 1 Pulse 110 beats/min 1 Systolic blood pressure <100 mmhg 1 Arterial oxyhemoglobin saturation (SaO2) <90% 1 A total point score for a given patient is obtained by summing the points. The score corresponds with the following risk classes: 0, low risk; 1, high risk. Am J Respir Crit Care Med 2005;172(8): Arch Intern Med 2010;170(15):1383-9

Testing and treatment algorithm for hemodynamically stable PE - acute symptomatic PE diagnosed in the ER or OPD setting PESI Very low & low risk strata Intermediate to high risk strata (-) Consider

29 Testing and treatment algorithm for hemodynamically stable PE - acute symptomatic PE diagnosed in the ER or OPD setting PESI Very low & low risk strata Intermediate to high risk strata (-) Consider outpatient treatment BNP testing (+) hospitaliza tion Troponin testing (-) hospitaliza tion (+) RV dysfunction (-) hospitaliza tion TTE (+) CCUS BMJ 2010;151: , Lancet 2011; 378: Proximal DVT?

30 Table of contents Biomarkers in the diagnosis of VTE Biomarkers in predicting clinical outcomes of acute PE Biomarkers in predicting recurrence of VTE Biomarkers in indicating thrombotic potentials

31 D-dimer D-dimer가 항응고치료 종료 후 증가한다는 것은 비정상적인 혈액응고 과정을 교정하기 위한 섬유소용해 과정이 활성화되었 다는 것을 의미

32 D-Dimer Testing to determine the duration of anticoagulation therapy (PROLONG study) New Engl J Med 2006; 355:

33 Usefulness of repeated D-dimer testing after stopping anticoagulation (PROLONG II) Group 1: Patients in whom D-d was normal at T90 and afterward (with D-d becoming abnormal only once). Group 2: Patients in whom D-d became abnormal at T90 and afterward remained altered persistently or at least twice. Group 3: Patients in whom D-d became abnormal after T90 and afterward remained abnormal persistently or at least twice. Blood 2010;115:

34 Annualized Risk for Recurrent VTE, by Timing of D-Dimer Testing After Anticoagulation Variable (-) D-Dimer Result (+) D-Dimer Result Timing of D-dimer testing after anticoagulation Annualized Risk for Recurrent VTE Per 100 Patient-Years (95% CI) < 3 weeks 2.0 ( ) 8.2 ( ) 3-5 weeks 4.2 ( ) 10.2 ( ) > 5 weeks 3.0 ( ) 7.4 ( ) D-Dimer result (positive vs. negative) HR 2.59 ( ) Ann Intern Med. 2010;153:

35 Table of contents Biomarkers in the diagnosis of VTE Biomarkers in predicting clinical outcomes of acute PE Biomarkers in predicting recurrence of VTE Biomarkers in indicating thrombotic potentials

36 Microparticles Microparticles은 0.1~1.0μm 크기의 작은 막소포(membranous vesicle)들 세포자멸(apoptosis) 혹은 세포활성(cellular activation)에 대한 반응으로 혈 소판, 백혈구, 적혈구 및 내피세포의 원형질막(plasma membrane)으로부터 유리 Microparticles은 염증(inflammation), 응고(coagulation) 및 혈관기능 (vascular function)에 역할을 할 것으로 추정 circulating tissue factor(tf)의 주된 운반자(carrier)이자 혈관내 혈전증 (intravascular thrombosis)의 중요한 개시자(initiator)의 역할 Thromb Res 2011;127:473-7

37 Response to vascular injury N Engl J Med 2008;359:938-49

38 Microparticles N Engl J Med 2008;359:938-49

39 Other biomarkers for thrombogenic potentials P-selectin Factor VIII Thrombin Generation Fibrin monomer

전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II)

전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II) 전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II) - i - - ii - - iii - - iv - - v - - vi - - vii - - viii - - ix - -