REVIEW ARTICLE 외상성응고장애 을지대학교병원외과 김중석ㆍ설영훈 Traumatic Coagulopathy Joong Suck Kim, M.D., Young Hoon Sul, M.D., Ph.D. Department of Surgery, Eulji University Hospital, Daejeon, Korea Correspondence to: Young Hoon Sul, M.D., Ph.D. Department of Surgery, Eulji University Hospital, 95 Dunsanseo-ro, Seo-gu, Daejeon 35233, Korea Tel: +82-42-259-1351 Fax: +82-42-259-1111 E-mail: ssulyh@hanmail.net Trauma patients often suffer from a lethal triad comprised of three entwined interacting components: hypothermia, acidosis, and coagulopathy. When the patients blood vessels are injured, hemostatic mechanisms are activated to heal the injured vessels and reduce blood loss. Yet when the injury is substantial, hemostasis becomes insufficient, and coagulopathy develops. The patients coagulation factors are exhausted, and bleeding is uncontrollable, a condition similar to disseminated intravascular coagulopathy (DIC). However, traumatic coagulopathy may differ from DIC in term of mechanisms. Unlike DIC, traumatic coagulopathy results from increased protein C activity inhibiting thrombin. Moreover, overt blood loss results in shock, mandating urgent resuscitation. However imprudent resuscitation with massive fluid and transfusion may induce hypothermia and acidosis, aggravating the coagulopathy. Recent studies recommend thromboelastogram to diagnose the complex status of coagulopathy and indicate the best treatment. Physicians treating trauma patients should address these intertwined, complex complications thoroughly and thoughtfully. (J Acute Care Surg 2015;5:35-41) Key Words: Trauma, Coagulopathy, Thromboelstogram Received July 20, 2015, Revised August 18, 2015, Accepted August 24, 2015 Copyright 2015 by Korean Society of Acute Care Surgery cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ISSN 2288-5862(Print), ISSN 2288-9582(Online) http://dx.doi.org/10.17479/jacs.2015.5.2.35 서론 외상은전체사망원인중약 10% 를차지하며, 특히 40세이하의젊은연령대의사망원인중 1위를차지하고있다 [1,2]. 이처럼외상이사망원인의높은빈도를차지하는이유중하나로대량출혈이큰영향을미치는것으로알려져있는데, 실제외상환자의 25 35% 에서는응급실에도착했을때이미응고장애 (coagulopathy) 가발생한상태이며, 이로인해대량출혈이악화되고, 결과적으로다발성장기부전및높은사망률을나타내는결과를보이고있다 [3-5]. 응고장애는저체온증 (hypothermia), 산증 (acidocis) 과 함께상호인과관계를갖는연결고리로 죽음의 3 징후 (lethal triad of death) 를구성하고있다 (Fig. 1). 신속하고정확한치료를통해이러한연결고리를끊어주지않는다면, 환자의상태는악순환에빠지게되고, 그결과사망에이르게된다. 따라서이러한응고장애를동반한외상환자를진료하는의료진은응고장애의기전에대해이해를할필요가있으며 [6], 이에전세계적으로외상에의한응고장애에대한많은연구들이진행되고있고, acute traumatic coagulopathy, early coagulopathy of trauma, acute coagulopathy of trauma-shock, trauma-induced coagulopathy, trauma-associated coagulopathy 등과같이여러표현 J Acute Care Surg Vol. 5 No. 2, October 2015 35
J Acute Care Surg Vol. 5, No. 2, Oct. 2015 들로존재하며외과계열 ( 외과, 정형외과, 흉부외과, 신경외과 ) 뿐만아니라마취과학회, 혈액학회, 중환자의학회, 응급의학회등이포함되어다기관및다학제적인측면에서접근하고있다. 이에본저자들은외상성응고장애의기전에대한문헌고찰을통하여그특성을이해하고아울러외상환자진료에이바지하고자한다. 본론 혈액응고과정정상상태에서신체는응고 (coagulation), 항응고 (anticoagulation) 및섬유융해 (fibrinolysis) 가적절한균형을이루고있으며, 응고는여러응고인자 (factor) 들의다단계에의해형성된다 (Fig. 2). 응고인자 XII, XI, IX, VIII 등이관련되는내인성경로 (intrinsic pathway) 와응고인자 III인조직인자 (tissue factor), 응고인자 VII Fig. 1. The lethal triad. 등이관련되는외인성경로 (extrinsic pathway) 의동시적인작용에의해공통경로 (common pathway) 에서응고인자 X의활성화, 그리고응고인자 Va에의해응고인자 II인프로트롬빈 (prothrombin) 을응고인자 IIa, 트롬빈 (thrombin) 으로활성화시킨다. 이트롬빈은응고인자 I이라고도하는섬유소원 (fibrinogen) 을응고인자 Ia, 섬유소단량체 (fibrin monomer) 로활성화시키고이는응고인자 XIIIa, 섬유소안정인자 (fibrin stabilization factor) 에의해섬유소중합체 (fibrin polymer) 를형성하게된다. 칼슘 (Ca++) 은응고인자 IV로응고인자 XI, IX, X, VII 등의활성화에필요한이온이다. 출혈이발생하면위와같은응고단계가활성화를통해섬유소중합체와손상받은혈관의내피세포에혈소판응집이생겨혈전 (clot) 을생성하여손상된부위가임시적으로막힌다. 혈소판의겉면에는당단백질 (glycoprotein) 이있어폰빌레브란트인자 (von Willebrand factor) 에의해혈소판끼리, 그리고손상된내피세포에응집을유도한다. 또한폰빌레브란트인자는평소응고인자 VIII와결합되어있으며, 트롬빈의작용에의해응고인자 VIII을유리하고, 결합되어있지않은응고인자 VIII은분해가된다. 섬유융해는플라스미노겐활성화인자 (plasminogen activator) 에의해활성화된플라시민 (plasmin) 에의해이루어지며, 융해가된물질을섬유소원분해산물 (fibrinogen degradation products, FDP) 이라고부른다. 또한응고인자 XIV라고도불려지는단백질 C (protein C) 는당단백질이며단백질 S (protein S) 를보지인자 (cofactor) 로트롬보모듈린 (thrombomodulin) 과함께활성화되었 Fig. 2. The coagulation cascade. 36 www.jacs.or.kr
Joong Suck Kim ㆍ Young Hoon Sul: Traumatic Coagulopathy 을때는응고인자 Va와 VIIIa를비활성화시킨다. 이러한응고인자들이외에도응고및항응고에관련되는물질에는여러가지가있는데비타민 K는지용성비타민으로케일이나시금치같은녹색잎채소에많이함유되어있고혈액응고에중요한비타민이다. K는응고의독일어인 Koagulation 의앞글자에서나온것으로, 비타민 K은프로트롬빈전구체 (prothrombin precursor) 인응고인자 II 및응고인자 VII, IX, X을활성화시키는데필요한탈탄산효소 (carboxylase) 가포함된비타민 K epoxide 회로 (cycle) 의주요요소이다. 와파린은이회로중하나인비타민 K 환원효소 (expoxide reductase) 를방해하여비타민 K의응고기능을막는다 [7]. 항트롬빈 (antithrombin) III는세린단백분해억제효소 (serin protease inhibitor) 중하나로헤파린과결합하여응고인자 XIa, IXa, 트롬빈등의작용을방해한다. 파종성혈관내응고장애와소모성응고장애파종성혈관내응고장애 (disseminated intravascular coagulopathy, DIC) 와소모성응고장애 (consumptive coagulopathy) 는응고와섬유융해의균형이무너진상태이다. 전자는감염, 종양, 출혈에의해다양한크기의혈전이체내에서대량으로생성되고이러한혈전은불필요한곳에서색전을유발하는상태이며, 후자는응고인자들이급격히소모되어혈전생성이되지않아조절되지않는출혈이발생하는상태이다 [8]. DIC가경증인상태에선혈액검사에서혈소판감소, 프로트롬빈시간 (prothrombin time, PT) 연장, 활성화부분트롬보플라스틴시간 (activated partial thromboplastin time, aptt) 연장, 섬유소원감소, FDP 증가, D-이합체 (dimer) 증가등의이상소견이발견되며, 이학적검사에서손가락같은말단부위나콩팥에서색전에의한경색, 괴사가일어날수있고, 출혈성경향이높아진상태에선피부에출혈반이나타나고, 뇌, 호흡기, 위장관등에서심각한출혈이발생할수있다. DIC는섬유융해의정도에따라 3가지로나눌수있다. (1) 섬유융해기기억제된상태 (suppressed fibrinolysis) 는주로패혈증에의해발생하고색전에의한징후들이보이며, (2) 섬유융해가균등한상태 (balanced fibrinolysis) 는주로종양에의해발생하고, 색전에의한징후와출혈에의한징후가같이나타나게된다. (3) 섬유융해가심각한상태 (enhanced fibrinolysis) 는외상에의한출혈, 대동맥박리, 급성전골수성백혈병등에의해나타나고, 심각한출혈성징후들을보인다 [9]. 혈액검사에서섬유융해가낮으면플라스미노겐활성화인자억제효소 (plasminogen activator inhibitor) 가더욱증가되게되고섬유융해가높으면 D-이합체가더욱증가되게된다. DIC에서는조직인자와관련된응고단계가활성화되며, 응고인자가소모됨에따른징후들이발생한다. 외상의초기에는섬유융해가심각한생태를보여출혈성경향을나타내다가회복기에는섬유융해가억제된상태를보여혈전성경향으로변한다고할수있지만, 아직까지는초기에 DIC의소견을보인다는근거가명확하지는않다 [10,11]. DIC만으로는외상에서의응고장애를설명할수없기때문에 educational initiative on critical care bleeding in trauma에서외상성응고장애에대하여새로 coagulopathy of trauma, acute coagulopathy of trauma shock라는개념을제시하였다 [12,13]. 새롭게제시된외상성응고장애의기전은트롬보모듈린과단백질 C가활성화됨으로써응고인자 Va와 VIIIa의기능이억제되어발생하는전신적인항응고에대한반응으로트롬빈형성이감소하여출혈성경향이생기며, 활성화된단백질 C는플라스미노겐활성화인자억제효소의기능을중화하여섬유융해를악화시킬수있다. 그리고, 외상성응고장애에서는트롬보모듈린및단백질 C의기능이중요한반면 DIC처럼조직인자에의한트롬빈형성증가및응고인자의소모가없다는특징이있다 [14-16]. 외상성응고장애의기전에대한이론이하나더있는데신경호르몬이론이다 [16]. 외상이발생하면교감신경부신수질계에의해카테콜아민이분비되고이것이혈관내피세포에손상을가하게된다. 혈관내피세포의외벽에는있는당질피질 (glycocalyx) 이손상되게되며이는혈전발생을유도하게된다. 이러한혈전반응이전신적으로오면혈액순환에장애가올수있기때문에항상성을유지하기위해트롬보모듈린에의한항응고및플라스미노겐활성화인자에의한섬유융해가활성화된다. 심각한외상환자에서는이러한작용들의균형이조절이안되어응고장애로치우치게된다 [17]. 이렇게외상성응고장애는여러기전이있을수있고하나만으로는설명하기가힘들다. 외상성응고장애는 DIC와비슷하게여러혈액검사에서혈소판, 섬유소원, D-이합체, FDP 등이유사한결과를나타내고, 외상성응고장애만의명확한특징, 시간에따른경과, 예후가아직정립이안되었기때문에아직까지는섬유융해가심각한상태의 DIC와는별개의질병으로보기는어려운현실이다 [18]. 따라서외상환자의진료에있어서는이러한응고장애의개념을이해하면서저체온증및산증같은기타위험한요소를포함한포괄적인접근이필요하다. www.jacs.or.kr 37
J Acute Care Surg Vol. 5, No. 2, Oct. 2015 혈액응고장애원인 1) 저체온증과응고장애저체온증은응고인자 VIIa 및조직인자의기능감소를유발할수있으며특히손상된조직에혈소판에있는당단백질 Ib/IX가응집을유도하는폰빌레브란트인자의기능을저하시켜응고장애를발생시키는데, 환자의체온이 33 o C 이하이면이러한응고장애가더욱악화된다 [19-21]. 외상이발생하게되면환자는여러이유로체온이낮아지게되는데출혈자체에의해, 그리고상처부위에서증발되는열손실에의해저체온증이발생한다. 의식을잃어차가운바닥에오랜시간동안누워있게되면이또한추가적인체온손실이발생하며근육운동에의한열발생이감소하게된다. 또한초기소생술중하나인수액치료가저체온증을유발할수있다. 2) 수액치료외상환자의환자에서출혈이발생하면실혈량에따라여러활력징후들이달라지게되고실혈량이많을수록저혈량성쇼크가오게되며이는빨리치료하지않으면다발성장기부전및사망을야기할수있다. 이에실혈을대체할수있는물질을투입하게되는데가장이상적인물질은혈액제제일수있다. 하지만수혈은안전한투여를위하여사전에교차적합성 (crossmatch) 을확인해야하고준비된혈액이충분하지않기때문에신속성이나효율성이떨어지는측면이있다. 그래서저혈량성쇼크의위험이있는외상환자에서초기치료는먼저등장성정질액 (isotonic crystalloid solution) 을먼저투여하고그에대한반응을보며교차적합검사를시행하여수혈준비를하게된다 [22,23]. 이때투여하는등장성정질액은보통생리식염수 (0.9% saline) 나평형염류용액 (balanced salt saline) 을사용하게되고통상적으로실혈추정량의 3배정도의양을투여후그반응에따라추가투여를고려하게된다. 출혈환자의초기치료에서콜로이드용액은피하고있는데이는콜로이드제제에함유된전분 (starch) 이폰빌레브란트인자나응고인자 VIII 등을소모시켜응고장애를악화시킬수있기때문이다 [24,25]. 등장성정질액사용은신속성및비용효율성면에서우수하지만부작용이존재한다. 대부분수액제품들은상온인 20 25 o C에서보관되는데이를환자에게대량투여하게될경우저체온증을유발할수있다. 이는실혈에의해이미 죽음의 3 징후 에빠져있는환자의응고장애를악화시킬수있다. 또한대량의수액을투여하면희석효과에의해혈액의산소운반능력이낮아지게되고혈소판응집력약화, 응고인자희석, 혈전형성장애를유발하여응고장애를유발한다 [19,22]. 특히생리식염수같은경우인간혈장에비해나트륨및염소농도가높고 ph가낮아대량투여시대사성산증 (metablic acidosis) 을유발하게된다. 실혈량이많은사람에서는산소공급이부족해져무산소적대사가이루어지며이에의해유산 (lactic acid) 및케톤체 (ketone body) 가유리되어대사성산증이발생하는데생리식염수의투여는이를더욱악화시킬수있다. 산증은 죽음의 3 징후 중하나이며혈장단백분해효소 (plasma protease) 및응고인자 Xa/Va 기능을저하시켜응고장애를유발할수있다 [19-21]. 이러한생리식염수의부작용을완화하고자개발된수액이평형염류용액이다. 특히플라스마솔루션 (plasma solution) 이나플라스마라이트 (plasmalyte) 같은경우인간혈장구성과그구성이제일비슷하여산증위험성이적고나트륨및염소의과다투여를막을수있다. 한코호트연구에서생리식염수와평형염류용액을각각투여한군을비교한결과평형염류용액군에서수술후감염, 신장투석, 수혈그리고산증같은합병증이통계적으로유의하게낮게나왔다고발표하였다 [25]. 또한 Young 등 [26] 이시행한생리식염수와플라즈마라이트를외상환자에게투여하여비교한이중맹검, 무선할당통제연구 (double blind, randomized controlled trial) 결과플라즈마라이트를투여한군이식염수를투여한군보다산염기상태가좋았으며고염소혈증이낮았다고보고하여외상환자에서플라즈마라이트같은평형염류용액사용에대해더욱고려하고연구할필요가있다. 이러한수액투여의부작용을최소화하기위해온장고에보관한수액투여, 수액가열기사용, 평형염류용액사용등을고려하여응고장애를포함한 죽음의 3 징후 악화를최소화시킬필요가있으며수액제제가대량투여가필요할정도의환자에서는반드시수혈을고려하여한다. 3) 수혈외상을포함한모든출혈에의한허혈환자에서는가장이상적인수혈은전혈 (whole blood) 수혈이다 [27-29]. 하지만전혈은장기간보관이어렵고각각상황에맞게투여하기위해대부분헌혈된혈액은분리를하여성분에따라보관하게된다. 그중대표적인것으로적혈구 (red cell), 신선동결혈장 (fresh frozen plasma), 농축혈소판 (platelet concentrate) 등이있으며저온침강물 (cryoprecipitate) 같은응고인자제제도있다. 이중헤모글로빈이포함된적혈구는산소운반에있어중요한혈액제제이며, 보관시응고가될수있기때문에구연산 (citrate) 을첨가하여혈액 38 www.jacs.or.kr
Joong Suck Kim ㆍ Young Hoon Sul: Traumatic Coagulopathy 내칼슘과반응하여응고를방지하지만, 실혈량이많아대량수혈을하게되는환자에서는응고장애를유발하게된다. 또한적혈구가 2주이상보관될경우칼슘이킬레이트화 (chelation) 됨으로써저칼슘증상태로변하게되어이런적혈구는투여할경우에도응고장애를유발할수있다. 이러한부작용때문에대량수혈이필요한환자들의치료에있어서는대량수혈진료지침 (massive transfusion protocol) 과같은정량화된시스템을통해효율적이면서도환자에게적합한치료를해줄필요가있다 [30]. 대량수혈에의한부작용을최소화하려면수혈량을최소화하여야되는데이에가장중요한것은가급적빠른수술, 시술을통해추가적출혈을막는것이다. 또한적절한헤모글로빈수치를목표로하여수혈량을조절하고트라넥사민산 (tranexamic acid) 같은혈액응고제를사용을고려하여야한다 [31]. 뿐만아니라, 적혈구수집기 (cell salvage) 를이용하여자가수혈을하거나가족에게헌혈을받아전혈수혈을고려할수있고전혈수혈에가까운성분별동시수혈도고려할수있다. 미군연구에서는 prbc:ffp:platelet 비율을 1:1:1로권유하고있으며가정적절한비율을위해여러연구들이나오고있다. Pragmatic, randomized optimal platelet plasma ratios 연구에서는이비율을 1:1:1군과 2:1:1군으로나누어비교하였고두군간장기적사망률이나합병증발생률은통계적차이가없으나단기간사망률 (24시간내, 30일내 ) 은 1:1:1이낮다고보고하였다 [32]. 수혈을할때는적혈구외에도여러성분수혈을고려하여투여하여야하며환자의응고장애상태에따라조절할수있다. 응고장애를정도를판단하는데에는혈전탄성묘사도 (thromboelastograph, TEG) 를이용할수있다. 치료출혈이있는환자의상태를파악하기위해여러가지혈액검사를시행하는데일반혈액검사 (complete blood count) 를통한헤모글로빈, 혈소판수치로환자의실혈정도를판단하고, 혈액응고장애의유무및그정도를판단하기위해 PT, aptt, 활성혈액응고시간 (activated clotting time) 등을이용한다. 하지만, 환자가기저질환을가지고있거나아스피린이나와파린같은항응고약물을복용중이었다면그수치들의기준 (baseline) 을잡는데애매할수있다. 이러한기왕력이없는환자에서는일반적으로 PT는정상수치를 12 15초 (international normalized ratio, 0.8 1.2), aptt는 30 50초를기준으로하여그이상이면응고장애로진단하게된다. 하지만이러한기존검사들은민감도또는특이도가낮을뿐더러결과가나오는데 30분에서한시간이상이필요하기때문에정확하고즉각적인치료가어려울수있다. 이에최근 TEG의사용이고려되고있다. 이검사는 1948년 Hartert에의해고안된오래된방법이나결과가나오기까지 5 10분정도소요되기때문에환자에응고장애에신속하게대응할수있어최근에많은의료진들이이검사의활용을고려하고있다 [33-37]. 특히 1:1:1 수혈을하게되면혈액제제사용이증가할수있는데이검사를활용하여그수량을최소화할수있다. 이검사를통해혈전형성의시간과응고력, 융해등을알수있으며 (Fig. 3), 여러응고장애상황을한눈에알아볼수있다 (Fig. 4). 또한이검사는수혈중에수시로시행하여상황에맞게성분수혈등의대처를할수있다 (Table 1). Fig. 3. The thromboelastography. MA: maximum amplitude. Fig. 4. Thromboelastography patterns. www.jacs.or.kr 39
J Acute Care Surg Vol. 5, No. 2, Oct. 2015 Table 1. Thromboelastography-guided transfusion parameters Thromboelastograph value Normal range Trigger Transfusion R time 5 10 seconds >110 seconds Fresh frozen plasma K value 30 120 seconds >120 seconds Cryoprecipitate α Angle 66 82 <66 Cryoprecipitate Maximum amplitude 54 72 mm <54 mm Platelets Ly-30 (lysis at 30 minutes) 0 8% >8% Antifibrinolytics 결론 아직까지는외상성응고장애의기전에대하여명확한구분이이루어지지않은것이현실이지만, 외상성응고장애로인한출혈이외상에의한주된사망원인이라는점은변치않는사실이다. 따라서출혈에의한저혈량성쇼크가의심되는환자에서는외상성응고장애를악화시킬수있는저체온증을적극적으로예방하고, 가온된적절한수액을소생술에이용할뿐만아니라, 전혈수혈이가능한상황이아니라면효과적인성분수혈을위하여 TEG와같은최근에각광받는장비의사용을고려할수있다. References 1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3: e442. 2. Søreide K, Krüger AJ, Vårdal AL, Ellingsen CL, Søreide E, Lossius HM. Epidemiology and contemporary patterns of trauma deaths: changing place, similar pace, older face. World J Surg 2007;31:2092-103. 3. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003;55:39-44. 4. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003;54:1127-30. 5. Dewar DC, Tarrant SM, King KL, Balogh ZJ. Changes in the epidemiology and prediction of multiple-organ failure after injury. J Trauma Acute Care Surg 2013;74:774-9. 6. Kutcher ME, Howard BM, Sperry JL, Hubbard AE, Decker AL, Cuschieri J, et al. Evolving beyond the vicious triad: Differential mediation of traumatic coagulopathy by injury, shock, and resuscitation. J Trauma Acute Care Surg 2015;78: 516-23. 7. Eby C. Warfarin pharmacogenetics: does more accurate dosing benefit patients? Semin Thromb Hemost 2012;38:661-6. 8. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586-92. 9. Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care 2014;2:20. 10. Johansson PI, Sørensen AM, Perner A, Welling KL, Wanscher M, Larsen CF, et al. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study. Crit Care 2011;15:R272. 11. Rizoli S, Nascimento B Jr, Key N, Tien HC, Muraca S, Pinto R, et al. Disseminated intravascular coagulopathy in the first 24 hours after trauma: the association between ISTH score and anatomopathologic evidence. J Trauma 2011;71: S441-7. 12. Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011;254:10-9. 13. Bouillon B, Brohi K, Hess JR, Holcomb JB, Parr MJ, Hoyt DB. Educational initiative on critical bleeding in trauma: Chicago, July 11-13, 2008. J Trauma 2010;68:225-30. 14. Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma 2008;65:748-54. 15. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care 2007;13:680-5. 16. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 2007;245:812-8. 17. Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med Hypotheses 2010;75:564-7. 18. Gando S, Wada H, Thachil J; Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost 2013;11: 826-35. 19. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma 1997;42:857-61; discussion 861-2. 20. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma 2005;58:1002-9. 21. Wolberg AS, Meng ZH, Monroe DM 3rd, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma 2004; 40 www.jacs.or.kr
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