CLINICAL & EXPERIMENTAL THROMBOSIS and HEMOSTASIS Original Article Clin Exp Thromb Hemost 2014;1(1):5-9 일시적위험인자가

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1 Original Article Clin Exp Thromb Hemost 2014;1(1):59 일시적위험인자가없는폐색전증에서혈액응고관련인자들의변화 이진욱, 정혜인, 김현중, 최원일 * 계명대학교의과대학내과학교실 Alteration of Factors Associated with Coagulation in Provoked Pulmonary Embolism Jin Wook Lee, Hye In Jung, Hyun Jung Kim, WonIl Choi* Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea Received: 12 January 2014 Revised: 5 March 2014 Accepted: 16 March 2014 *Corresponding author: WonIl Choi, MD Department of Internal Medicine, Keimyung University School of Medicine, 56 Dalseongro, Junggu, Daegu , Korea Tel: Fax: wichoi@dsmc.or.kr Copyright Korean Society on Thrombosis and Hemostasis. All rights reserved. Purpose: Pulmonary embolism (PE) is regarded as a form of deep vein thrombosis. Although the recurrence rate of venous thrombosis in provoked embolism is lower than it is in unprovoked vein thrombosis, proteins associated with coagulation have not been well studied in provoked PE. This study sought to evaluate factors associated with coagulation between provoked and unprovoked PE. Methods: This retrospective cohort study included 207 PE patients. Patients that had transient risk factors at diagnosis were included in the provoked PE group, while all others were classified as unprovoked PE. Evaluation of proteins associated with coagulation included protein C, protein C activity, protein S, protein S free form, protein S activity, antithrombin III, factor VIII, and factor IX. Results: Among 207 PE cases, 65 (31.4%) cases were diagnosed as provoked PE. Clinical characteristics were not significantly different between provoked and unprovoked PE. However, RV/LV ratio was significantly higher in provoked PE than it was in unprovoked PE. Proteins and activity associated with coagulation were significantly lower in provoked PE than in unprovoked PE: protein C antigen (33% vs. 54%, P= 0.01), protein S antigen (31% vs. 53%, P= 0.001), protein S activity (55% vs. 71%, P< 0.001), antithrombin III antigen (61% vs. 79%, P< 0.001), and factor VIII (160% vs. 184%, P= 0.01). Conclusion: Provoked PE had significantly lower anticoagulation protein levels and activity than unprovoked PE. Keywords: Pulmonary embolism, Coagulation, Deep vein thrombosis 서론 정맥혈전증은진단시항응고제치료중단후의재발위험도에따라분류되고이에따라치료기간이달라지게된다. 1 재발위험도는유발인자유무에따라달라일시적인위험인자가있는정맥혈전증 (provoked VTE) 과일시적위험인자가없는정맥혈전증 (unprovoked VTE) 으로나뉜다. 1 일시적유발인자가있는정맥혈전증 (provoked VTE) 은수술후발생한경우와수술과관련이없는경우에서재발위험도가다르게나타나며, 최근 1 개월이내수술을받았던위험인자가있었던경우는유발인자가있는정맥혈전증 (provoked VTE by surgery), 에스트로겐치료, 임신, 다리외상, 8 시간이상의비행과같은일시적인비수술적유발인자가있었던경우는비수술적유발인자가있는정맥혈전증 (provoked VTE by a nonsurgical reversible risk factor) 으로분류된다. 2 폐색전증 (pulmonary embolism, PE) 은정맥혈전증의연장으로간주되고분류도정맥혈전과같다. Virchow 에따르면정맥혈전증은혈류의정체 (stasis), 응고항진성 (hypercoagulability), 혈관내피손상 (endothelial dysfunction) 으로설명할수있다. 3 하지정맥의경우정맥혈류가근육의수축에따라정맥이수축되어혈류가생성되지만, 폐동맥의경우이러한근육수축에따른혈류의변화 가없다. 말초정맥압력이중심정맥압과거의압력이일치하는것으로본다면, 4 폐동맥압은중심정맥압에비해 23배이상높으며따라서혈류도빠른것으로바꾸어생각할수있다. 또한폐동맥은하지정맥과는달리근육에의해서펌프작용에의해순환하는작용이없다. 폐순환에서폐동맥은전체폐순환저항의 46% 를차지하고있다. 5 이러한관점에서본다면정맥혈류의정체 (stasis) 는하지정맥과폐동맥에서는다르다고볼수있다. 혈류의차이가있다면동맥혈에서혈액응고인자가혈관내에머무르고있는시간이짧아상대적인농도가낮듯이, 하지정맥에비해서폐동맥내에서혈액응고인자의노출강도가낮을것으로추측할수있다. 또한외부의압력이나상처및기타외인성손상에영향이거의없을것으로생각되는폐동맥의경우상대적으로혈관손상의기회가거의없을것으로보인다. 이에폐동맥혈전증 ( 폐색전증 ) 이발생했다면다른곳에서발생한정맥혈전증이이동한것으로유추하여, 일반적으로폐동맥혈전증은정맥혈전증의연장으로고려된다. 그러나만성폐색전증등의예로보아폐동맥혈전증의경우하지정맥혈전증과일부다른병태생리를가질것으로판단된다. 6 일시적위험인자라함은 Virchow가언급한세가지위험인자가일시적으로발생한경우로해석할수있는데, 하지정맥혈전증과는달리폐동맥혈전증의경우이러한일시적위험인자가있는군과없는군사이의임상 This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 5

2 Lee JW, et al. 양상의차이가있는지, 그리고혈액응고와관련된인자의변화가있는지등에대해서는연구가많지않다. 또한혈장응고인자들과정맥혈전질환과의연구가많이이루어져있지만, 유발인자가있으면서발생한정맥혈전과유발인자가없는경우에발생한경우를비교한연구는잘되어있지않다. 이에이연구는폐색전증에서유발인자유무에따라응고인자의차이가있는지를확인하고자하였다. 방법 연구대상본연구는의학연구윤리심의위원회의승인을받아시행되었다 년 1 월부터 2011 년 12 월까지입원및외래환자혹은응급실방문환자중에서컴퓨터단층촬영폐혈관조영술 (Computed Tomography Pulmonary Angiography, CTPA) 을시행한후폐색전증으로확진받은환자 667 명의환자중에서혈전성향증 (thrombophilia) 조사를위해혈액응고와관련된인자를측정한 207 예를대상으로하였다. 모든환자는폐색전증이처음진단된환자를대상으로하였으며, 만성폐색전증환자는제외하였다. 연구방법본원에서폐색전증의진단은임상적으로폐색전증이의심되는환자에서는 Siemens 사의 16 또는 64 개의검출기를가진스캐너를이용하여 CTPA 를시행하고, CTPA 에서폐색전증의소견이관찰되지않은경우폐색전증이없는것으로해석하였다. 환자가심부정맥혈전을가지고있으면서호흡기증상이동반된경우다시 CTPA 로폐색전증유무를평가하였다. 신부전이있거나조영제에부작용의병력이있는경우폐환기관류스캔을시행하였다. CTPA 판독은폐동맥중심부혹은주변부의충만결손 (filling defect) 이있을때폐색전증으로진단하였다. NT probnp (Nterminal prohormone of brain natriuretic peptide) 는 207 명의환자중 128 명에서측정이되었으며흉부전산화단층촬영이나폐혈관전산화단층촬영을시행한 198 명의환자에서우심실 / 좌심실직경비를측정하였다. 응고억제인자및응고인자의측정폐색전증의진단후혈액을 3.7% sodium citrate 채혈관에채취하여분석하였다. C 단백활성도와 S 단백활성도는응고인자 5 번 (factor V, FV) 을기질로사용하여응고기능을평가하여측정하였다 (Diagnostica Stago, Asnieres, France). 혈장의 C 단백, 총 S 단백 (total protein S), 유리단백 S (free protein S) 는방사면역확산 (radial immunodiffusion) 법으로측정하였다. 항트롬빈 III, 응고인자 8 번 (factor VIII, FVIII), 응고인자 9 번 (factor IX, FIX) 은자동화혈액응고분석기 (ACL Top 500, Intstrumentation Labroratry, Bedford, USA) 를이용하여측정하였다. 응고억제인자결핍증의분류응고억제인자결핍증의유형은다음과같이분류하였다. 단백결핍과활성도감소의기준은 50% 이상감소한경우로정의하였다. 7,8 C 단백결핍의경우 1 형 (type 1) 은기능적활성도 (functional activity) 와항원량이같이감소된경우이고, 2 형 (type 2) 은기능적활성도는감소되어있으나항원의농도는정상인경우로하였다. S 단백결핍의경우기능적활성도는감소되고 S 단백의유리형항원과총항원량이같이감소된경우를 1 형 (type 1), 기능적활성도는감소되고 S 단백의유리형항원과총항원량이정상인경우를 2 형 (type 2), 기능적활성도가감소되고 S 단백의유리형항원은감소되었지만총항원량은정상인경우를 3 형 (type 3) 으로하였다. 통계연속변수는평균과표준편차로표시하였다. 양군의비교에서연속변수는 Student ttest 로비연속변수의비교는 Chisquare test 로유의수준 0.05 미만일때통계적으로유의한것으로판정하였다. 통계프로그램은 SPSS 20.0 (SPSS Inc., Chicago, IL, USA) 을사용하였다. 결과 일시적위험인자를가진환자중에서수술과관련된예는 25 예이었고, 61 예에서고정 (immobilization) 과연관되었고, 수술과고정두가지위험인자를모두가진환자는 21 예였다. 일시적위험인자가없는경우는 142 예였다. 폐색전증으로진단된 207 명의환자중입원 30 일이내에사망한환자는 9 명 (4.3%) 이었다 (Table 1). 일시적인위험인자 (provoked) 를가진폐색전증군과일시적인위험인자를가지지않은 (unprovoked) 환자군을비교했을때, 나이, 성별및비만도에서는유의한차이를보이지않았다. 진단받은당시환자가가지고있는기저질환을비교하여심부전, 신기능이상유무, 활동성암의유무및이전심부정맥혈전증이나폐색전증의병력에서두군간의유의한차이는보이지않았다. 내원당시두군간의임상증상및활력징후를비교하여객혈이나흉통의유무는두군간의유의한차이가없었다. 수축기평균혈압은양군에차이가없었으며쇼크의빈도도두군간유의한차이를보이지않았으나, 일시적인위험인자를가진폐색전증환자에서쇼크의빈도가높은경향을보였다. 두군에서입원당시측정한 NT probnp 와말초혈액백혈구는유의한차이를보이지않았지만, 우심실 / 좌심실직경비는일시적인위험인자를가진폐색전증군에서일시적인위험인자를가지지않은폐색전증군에비해 24% 정도더증가되었다. 혈장 C 단백의참고범위는항원량 72160%, 활성도 70130% 이었고, 혈장 S 단백의참고범위는총항원량 60150%, 유리형항원량 50150%, 활성도 % 이였다. 혈액응고인자분석에서 C 단백항원, S 단백항원, S 단백활성도, 항트롬빈 III, FVIII 등이일시적인위험인자를가진폐색전증군에서유의하게낮았다 (Table 2). C 단백의경우일시적인위험인자를가진폐색전증군이일시적인위험인자를가지지않은폐색전증군에비해 40% 정도유의하게낮았으나 C 단백의활성도는유의한차이가관찰되지않았다. S 단백의경우에서도일시적인위험인자를가진폐색전증군이일시적인위험인자를가지지않은폐색전증군에비해 42% 낮았고, S 단백활성도는 23% 정도유의하게낮았으나 S 단백유리형항원은유의한차이가관찰되지않았다. 항트롬빈 III 는일시적인위험인자를가진폐색전증군에서일시적위험인자를가지지않은군에비해평균 18% 낮았고, FVIII 의경우일시적인위험인자를가진폐색전증군에서일시적위험인자를가지지않은군에비해평균 24% 낮았다. S 단백응고억제인자결핍의유형은일시적인위험인자를가진폐색전증에서 C 단백의활성도와항원량이같이감소한 1 형 (type 1) 의빈도가일시적위험인자를가지지않은폐색전증에비해유의하게높았다 (Table 3). C 단백응고억제인자결핍의유형은일시적인위험인자를가진폐색전증에서 S 단백활성도와 S 단백유리형항원량이같이감소한 3 형 (type 3) 의빈도가일시적위험인자를가지지않은폐색전증에비해유의하게높았다. 고찰 본연구에서응고억제에관여하는 C 단백과 S 단백항원, S 단백활성도, 6

3 Coagulation Factors in Pulmonary Embolism Table 1. Clinical characteristics at diagnosis for the 207 patients Variable Overall (n = 207) Unprovoked PE (n = 142) Provoked PE (n = 65) Pvalue Age in years 66.2 ± ± ± Male, n (%) 78 (37.6) 56 (39.4) 22 (33.8) 0.44 BMI 24.0 ± ± ± Comorbidity, n (%) Heart failure Renal dysfunction Cancer Previous DVT or PE Infection Clinical finding, n (%) Hemoptysis Chest pain Altered mental state* Systolic blood pressure, mmhg Shock Positive spiral CT, n (%) Main pulmonary artery Lobar artery Segmental artery Subsegmental artery Cardiac chamber ratio and cardiac biomarker, mean RV/LV ratio (n = 198) NT ProBNP, ng/l (n = 128) WBC, cells/μl Outcome, n (%) 30 day mortality PESI Lower extremity DVT, n (%) 28 (12.7) 30 (14.5) 12 (5.7) 10 (4.8) 57 (27.5) 11 (5.3) 27 (13.0) 17 (8.2) ± (6.2) 198 (95) 94 (48) 62 (31) 34 (17) 8 (4) 1.30 ± 0.5 2,658 ± 4,795 9,498 ± 4, (16.9) 95.9 ± (29) 18 (12.7) 18 (12.7) 11 (7.7) 8 (5.6) 33 (23.9) 7 (4.9) 19 (13.4) 10 (8.0) ± (4.2) 136 (95) 63 (46) 44 (32) 23 (17) 6 (5) 1.20 ± 0.4 2,058 ± 4,092 9,212 ± 4,325 4 (2.8) 85.8 ± (31) 10 (15.4) 12 (18.5) 1 (1.50) 2 (3.1) 23 (35.3) 4 (6.2) 8 (12.3) 7 (10.7) ± (10.8) 62 (95) 30 (48) 19 (31) 11 (18) 2 (3) 1.49 ± 0.6 4,227 ± 6,092 10,124 ± 4,629 5 (7.7) 86 ± (26) Data are presented as mean ± standard deviation. *Altered mental status was defined as disorientation, stupor, or coma; Shock was defined as systolic blood pressure < 90 mmhg; Most proximal anatomic level of pulmonary embolism shown by spiral computed tomography. SD, standard deviation; DVT, deep vein thrombosis; PE, pulmonary embolism; NT probnp, Nterminal prohormone of brain natriuretic peptide; RV, right ventricle; LV, left ventricle; WBC, white blood cell; PESI, pulmonary embolism severity index Table 2. Factors associated with coagulation between uprovoked and provoked pulmonary embolism Coagulation profile Overall (n = 207) Unprovoked PE (n = 142) Provoked PE (n = 65) Pvalue Protein C antigen, % 48.0 ± ± ± Protein C activity, % 81.8 ± ± ± Protein S antigen, % 47.0 ± ± ± Protein S antigen, free form, % 52.0 ± ± ± Protein S activity, % 66.0 ± ± ± 21.7 < Antithrombin III antigen, % 73.0 ± ± ± 33.3 < Factor VIII, % ± ± ± Factor IX, % 91.0 ± ± ± Data are presented as mean ± standard deviation. 항트롬빈 III 등이일시적인위험인자를가진폐색전증에서일시적인위험인자를가지지않은폐색전증에비해유의하게낮았다. 또한 FVIII 의농도도일시적인위험인자를가진폐색전증군에서일시적인위험인자를가지지않은폐색전증군에비해유의하게낮았다. C 단백결핍증의경우정맥혈전의위험성을 810 배정도높인다. 9 C 단백과 S 단백결핍의역학은대상환자군에따라차이가있는데, 건강인에서 는결핍의빈도가매우낮지만, 50 세미만의재발성심부정맥혈전증혹은가족력이있는환자군에서는 C 단백결핍의빈도가 4.8%, S 단백결핍의빈도가 4.3% 로높게관찰된다. 10 심부정맥혈전증환자에서 C 단백결핍은 113 예중 10 예 (9%), S 단백결핍은 113 예중 21 예 (19%) 로높게관찰된바있다. 11 국내에서는정맥혈전증에서 C 단백결핍증은 10.3%, S 단백결핍증은 6.9% 로관찰되었고, 12 폐색전증연구에서는 C 단백결핍은 9.5%, S 단백결 7

4 Lee JW, et al. Table 3. Frequency of protein C and proteins S deficiency between unprovoked and provoked pulmonary embolism Type of deficiency Ptotein C deficiency Type 1 Type 2 Total Protein S deficiency Type 1 Type 2 Type 3 Total Overall (n = 207) 24 (11.5) 18 (8.7) 42 (20.2) 13 (6.2) 19 (9.2) 23 (11.1) 55 (26.5) Unprovoked PE (n = 142) 12 (8.5) 14 (9.9) 26 (18.3) 7 (4.9) 11 (7.7) 8 (5.6) 26 (18.3) Data are presented as number (percentage). Provoked PE (n = 65) 12 (18.5) 4 (6.2) 16 (24.6) 6 (9.2) 8 (12.3) 15 (23.1) 29 (44.6) Pvalue < 0.01 < 0.01 핍은 19% 로관찰된바있다. 13 만성폐색전증환자에서는 C 단백결핍환자는 20 명중 5 명 (25%) 이었고 S 단백결핍환자는 20 명중 1 명 (5%) 이었다. 14 본연구에서는 C 단백활성도가 50% 이상감소한군을기준으로할경우, 일시적인위험인자를가진폐색전증 16 명 (24%) 에서 C 단백활성도가감소되었고, 일시적인위험인자를가지지않은폐색전증의경우 26 예 (18%) 에서 C 단백활성도가감소되었다. 일시적인위험인자를가진폐색전증환자에서 C 단백활성도감소는 C 단백결핍과연관된것으로보인다 (Table 3). 일시적인위험인자를가진폐색전증환자의평균연령이 65 세인점과정맥혈전의과거력이 3% 인점을고려한다면후천적인요인으로인해 C 단백활성도와 C 단백결핍이발생한것으로보인다. S 단백은 FVa 와 VIIIa 의활성화를방해하면서체내에서항응고역할을담당하는중요한인자로서결핍시에는심부혹은표재정맥내에반복적인혈전형성뿐아니라다양한장기에서혈전증이유발될수있다. 15,16 S 단백결핍증의유병률은전체인구에서 %, 심부정맥혈전증환자에서는약 2% 로보고되어있으며, S 단백결핍증이있는경우는심부정맥혈전이발생할위험성이 배정도증가되는것으로알려져있다. 16 본연구에서는남자와여자모두 50% 이하를기준으로결핍증을정의한결과일시적인위험인자를가진폐색전증 29 명 (44.6%) 에서 S 단백활성도가감소되었고, 일시적인위험인자를가지지않은폐색전증의경우 26 예 (18.3%) 에서 S 단백활성도가감소되었는데, 이는 S 단백의유리형항원의감소와연관이있는것으로보인다 (Table 3). 비록감염의빈도는두군에서유의한차이를보이지않았으나환자군의나이와정맥혈전의과거력을고려할때감염등의후천적원인에의해혈액응고억제인자가감소된것으로추측된다. FVIII 이혈전을증가시키는기전은불명확하지만, 혈장 FVIII 의상승 은정맥혈전의발병의위험을증가시키는것으로알려져있다 본연구에서는일시적인위험인자를가진폐색전증의경우 FVIII 의평균이정상치보다는높았지만, 일시적인위험인자를가지지않은폐색전증보다는유의하게낮았다. 이러한점에볼때 FVIII 의경우일시적인위험인자를가지지않은폐색전증에서혈전형성에더관여할것으로추측된다. 그러나일시적인위험인자를가진폐색전증의경우에도 FVIII 이평균 140% 이상으로상승되어있어서, 20 발생에일부관여될가능성도있다. 항트롬빈 III 의경우본연구에서는일시적인위험인자를가진폐색전증군에서일시적인위험인자를가지지않은폐색전증에비해유의하게감소되어있다. 선천적요인에의한감소의정도는유전인자검사를하지않아서확인할수없지만, 감염등의후천적요인으로인해항트롬빈 III 의감소가일시적인위험인자를가진폐색전증에서이루어진것으로보인다. 예후인자를분석하면, 폐색전증환자에서사망의위험인자로대두되고있는백혈구는양군에서유의한차이를보이지않았고, 21 폐색전중증도지수 (pulmonary embolism severity index, PESI) 평균점수또한양군에서차이가없었다. 그러나혈류역학적인부분에서는우심실 / 좌심실직경비가일시적인위험인자를가진폐색전증에서유의하게높았고, 쇼크의빈도와 NT ProBNP 혈중농도또한일시적인위험인자를가진폐색전증에서일시적인위험인자를가지지않은폐색전증에비해높은경향을보였다. 본연구에서도위험인자를가진폐색전증군에서사망률이높은경향을보였으며, 이러한점들은기존의연구에서일시적인위험인자를가진폐색전증이사망률이높았던점을고려할때, 22 일시적인위험인자를가진폐색전증에서혈류역학적인문제를더심하게야기했을수있다. 23 이러한연구로 PESI 점수는여전히혈류역학적상황이충분히고려되지않은점을생각한다면, 일시적인위험인자를가진폐색전증환자에서는 PESI 점수로만중증도를평가하기에는문제가있을것으로보인다. 일시적인위험인자를가진폐색전증환자의경우더적극적으로심초음파및 NT ProBNP 등을측정하는것이필요하겠다. 24 결론적으로, 이연구에서는일시적인위험인자를가진폐색전증군과일시적인위험인자를가지지않은폐색전증군을비교했을때혈액응고억제와관련된 C단백, S단백, 항트롬빈 III 등이유의하게감소된것을알수있었다. 향후연구에서일시적위험인자를가진폐색전증환자에서혈액응고억제와관련된인자의결핍에대한임상적인의미에대해서추가연구가필요하다. 또한혈액응고억제와관련된인자결핍을전향적인연구를통해다시검증할필요가있겠다. Conflicts of Interest There are no conflicts of interest relevant to this article to report. References 1. Kim YK. Current management of pulmonary thromboembolism. Korean J Med 2013;84: Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest 2012;141(Suppl):eS Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Haematol 2008;143: Tugrul M, Camci E, Pembeci K, AlDarsani A, Telci L. Relationship between peripheral and central venous pressures in different patient positions, catheter sizes, and insertion sites. J Cardiothorac Vasc Anesth 2004; 18: Brody JS, Stemmler EJ, DuBois AB. Longitudinal distribution of vascular resistance in the pulmonary arteries, capillaries, and veins. J Clin Invest 1968;47: Morris TA, Marsh JJ, Chiles PG, Auger WR, Fedullo PF, Woods VL. Fibrin derived from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis. Am J Respir Crit Care Med 2006;173: Sakata T, Okamoto A, Mannami T, Tomoike H, Miyata T. Prevalence of protein S deficiency in the Japanese general population: the Suita Study. J Thromb Haemost 2004;2: Song KS, Park YS, Choi CR, Kim HK, Park Q, Kim HS. Hereditary protein C deficiency with recurrent thrombosis: identification of a missense mutation (C6218T). J Korean Med Sci 1998;13: Khan S, Dickerman JD. Hereditary thrombophilia. Thromb J 2006;4: Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344: Suehisa E, Nomura T, Kawasaki T, Kanakura Y. Frequency of natural coagulation inhibitor (antithrombin III, protein C and protein S) deficiencies in Japanese patients with spontaneous deep vein thrombosis. Blood Coagul Fibrinolysis 2001;12:

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012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar