Point-of-Care-Diagnostik in der Traumatologie – Methoden und Evidenz

Zusammenfassung

Jeder 4. Schwerverletzte weist bereits bei Krankenhausaufnahme eine traumainduzierte Koagulopathie (TIK) auf, die mit einer 4-fach erhöhten Mortalität einhergeht. Rasche und zielgenaue Behandlung kann die TIK-assoziierte Sterblichkeit senken. Point-of-Care-Tests ermöglichen im Vergleich mit herkömmlichen Labormethoden eine zeitnahe und umfassende Bestimmung des Gerinnungsstatus sowie eine zielgerichtete Therapie.

Abstract

In severely injured patients, trauma-induced coagulopathy (TIC) present at hospital admission is associated with increased transfusion requirements, morbidity and mortality. Early and effective treatment contributes to improved survival rates. Laboratory coagulation assays have long turn-around times and evidence for their usefulness, especially in the context of TIC, is weak. Due to the lack of appropriate guidance, transfusion of allogeneic blood products frequently follows a ratio-based concept (e.g., transfusion of erythrocytes and plasma in a 1 : 1 ratio). Point-of-care (PoC) tests enable the assessment of prothrombin time (PT) and activated partial thromboplastin time in few minutes. However, although normal PT in these tests allows to rule out relevant effects of several anticoagulants, they are not able to detect patients with TIC and/or requiring subsequent massive transfusion. Viscoelastic tests (VETs) make it possible to assess defects in thrombin generation, hypofibrinogenaemia, thrombocytopenia, and hyperfibrinolysis, and thus enable targeted therapy. Impairment of platelet function is the common blind spot not detectable using both standard laboratory-based tests and VETs. However, PoC platelet function tests enable to detect platelet defects and patients taking anti-platelet. Furthermore, impaired platelet function has been identified as a strong predictor for coagulopathy and massive transfusion in trauma patients. In other clinical settings, coagulation management based on VETs is associated with decreased transfusion requirements, incidence of acute kidney failure, and mortality, respectively. Data of the first small prospective randomised trial indicate superiority of VET guided coagulation management solely using coagulation factor concentrates, when compared to plasma transfusions in severe trauma.

Kernaussagen

• Eine traumainduzierte Koagulopathie (TIK) ist bei 25 – 33% der Schwer- und Schwerstverletzten nachweisbar und mit vermehrten Fremdbluttransfusionen sowie erhöhter Morbidität und Mortalität vergesellschaftet.

• Eine frühe und effektive Behandlung kann dazu beitragen, die traumaassoziierte Sterblichkeit zu senken.

• Laborbasierte konventionelle Gerinnungstests weisen häufig Umlaufzeiten von mehr als 60 min auf, die Evidenz für ihren Nutzen zur Therapiesteuerung ist insgesamt äußerst gering.

• Aufgrund fehlender Messwerte ist eine zeitnahe zielgerichtete Therapie nicht möglich, weshalb oftmals die Transfusion von Blutprodukten z. B. in einem prädefinierten Erythrozyten-Blutplasma-Verhältnis (1 : 1) erfolgt.

• Mit Point-of-Care-Methoden können konventionelle Gerinnungstests wie die Prothrombinzeit und die aktivierte partielle Thromboplastinzeit innerhalb weniger Minuten gemessen werden.

• Eine normale Point-of-Care-PT lässt sicher die Einnahme von Vitamin-K-Antagonisten ausschließen und kann möglicherweise auch relevante Plasmakonzentrationen von Dabigatran und Rivaroxaban detektieren, sie ist aber nicht geeignet, Patienten mit einer TIK bzw. einem Massivtransfusionsrisiko zu identifizieren.

• Viskoelastische Tests (VET) der Blutgerinnung lassen innerhalb weniger Minuten Störungen der Thrombinbildung und Fibrinpolymerisation sowie eine Hypofibrinogenämie und Thrombopenie und eine Hyperfibrinolyse erkennen und ermöglichen eine zielgerichtete Therapie.

• Thrombozytenfunktionsstörungen und die Einnahme von Thrombozytenaggregationshemmern (TAH) bleiben sowohl bei konventionellen als auch viskoelastischen Tests unentdeckt.

• Mittels Point-of-Care-Thrombozytenfunktionstests können die Einnahme von TAH und eine traumainduzierte Thrombopathie nachgewiesen werden. Letztere ist ein hervorragender Prädiktor für eine Massivtransfusion.

• Eine anhand von VET gesteuerte Gerinnungstherapie ist im Vergleich mit konventionellen Tests oder keiner Gerinnungsdiagnostik mit einer geringeren Transfusionswahrscheinlichkeit, einer geringeren Inzidenz eines dialysepflichtigen Nierenversagens und einer geringeren Sterblichkeit vergesellschaftet.

• Erste Daten einer prospektiven randomisierten Studie geben Hinweise darauf, dass eine auf VET basierende zielgerichtete Therapie mit Gerinnungsfaktorkonzentraten der Therapie mit Blutplasma bei schwerem Trauma überlegen sein könnte.

Schlüsselwörter

Traumatologie - Gerinnungsstörung - Diagnostik - Koagulopathie - Thrombozytenfunktion

Key words

trauma - coagulation disorder - diagnostics - coagulopathy - platelet function

• Literatur

• 1 Debus F, Lefering R, Frink M. et al. Numbers of Severely Injured Patients in Germany. A Retrospective Analysis From the DGU (German Society for Trauma Surgery) Trauma Registry. Dtsch Arztebl Int 2015; 112: 823-829
• 2 MacLeod JB, Lynn M, McKenney MG. et al. Early Coagulopathy Predicts Mortality in Trauma. J Trauma 2003; 55: 39-44
• 3 Maegele M, Spinella PC, Schöchl H. The acute coagulopathy of trauma: mechanisms and tools for risk stratification. Shock 2012; 38: 450-458
• 4 Brohi K, Singh J, Heron M. et al. Acute traumatic coagulopathy. J Trauma 2003; 54: 1127-1130
• 5 Gonzalez EA, Moore FA, Holcomb JB. et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma 2007; 62: 112-119
• 6 Rossaint R, Bouillon B, Cerny V. et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Critical Care 2016; 20: 1-55
• 7 Wurmb T, Lier H, Fischer M. et al. Versorgung von Schwerverletzten. Anaesthesist 2017; 66: 1-12
• 8 Haas T, Fries D, Tanaka KA. et al. Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence?. Br J Anaesth 2015; 114: 217-224
• 9 Toulon P, Ozier Y, Ankri A. et al. Point-of-care versus central laboratory coagulation testing during haemorrhagic surgery. A Multicenter Study. Thromb Haemost 2009; 101: 394-401
• 10 Davenport R, Manson J, DeʼAth H. et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011; 39: 2652-2658
• 11 Brummel-Ziedins KE, Whelihan MF, Gissel M. et al. Thrombin generation and bleeding in haemophilia A. Blood 2009; 15: 1118-1125
• 12 Fenger-Eriksen C, Moore GW, Rangarajan S. et al. Fibrinogen estimates are influenced by methods of measurement and hemodilution with colloid plasma expanders. Transfusion 2010; 50: 2571-2576
• 13 Douxfils J, Ageno W, Samama CM. et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2017; 16: 209-219
• 14 Beynon C, Unterberg AW, Sakowitz OW. Point of care coagulation testing in neurosurgery. J Clin Neurosci 2015; 22: 252-257
• 15 Beynon C, Erk AG, Potzy A. et al. Point of care coagulometry in prehospital emergency care: an observational study. Scand J Trauma Resusc Emerg Med 2015; 23: 58
• 16 Herbstreit F, Winter EM, Peters J. et al. Monitoring of haemostasis in liver transplantation: comparison of laboratory based and point of care tests. Anaesthesia 2010; 65: 44-49
• 17 Cotte J, DʼAanda E, Chauvin V. et al. Point-of-Care Coagulation Testing for Trauma Patients in a Military Setting: A Prospective Study. J Spec Oper Med 2013; 13: 59-62
• 18 Niederdöckl J, Dempfle CE, Schönherr HR. et al. Point-of-care PT and aPTT in patients with suspected deficiencies of coagulation factors. Int Jnl Lab Hem 2016; 38: 426-434
• 19 Ebner M, Birschmann I, Peter A. et al. Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants. Critical Care 2017; 21: 32
• 20 Hartert H. Blutgerinnungsstudien mit dem Thrombelastographen, einem neuen Untersuchungsverfahren. Klinische Wochenschrift 1948; 26: 577-583
• 21 Görlinger K, Dirkmann D, Solomon C. et al. Fast interpretation of thromboelastometry in non-cardiac surgery: reliability in patients with hypo-, normo-, and hypercoagulability. Br J Anaesth 2013; 110: 222-230
• 22 Haas T, Spielmann N, Mauch J. et al. Reproducibility of thrombelastometry (ROTEM^®): point-of-care versus hospital laboratory performance. Scand J Clin ab Invest 2012; 72: 313-317
• 23 Dirkmann D, Görlinger K, Peters J. Assessment of early thromboelastometric variables from extrinsically activated assays with and without aprotinin for rapid detection of fibrinolysis. Anesth Analg 2014; 119: 533-542
• 24 Hagemo JS, Christiaans SC, Stanworth SJ. et al. Detection of acute traumatic coagulopathy and massive transfusion requirements by means of rotational thromboelastometry: an international prospective validation study. Crit Care 2015; 19: 97
• 25 Larsen OH, Fenger-Eriksen C, Christiansen K. et al. Diagnostic Performance and Therapeutic Consequence of Thromboelastometry Activated by Kaolin versus a Panel of Specific Reagents. Anesthesiology 2011; 115: 294-302
• 26 Hagemo JS, Naess PA, Johansson P. et al. Evaluation of TEG(^®) and RoTEM(^®) inter-changeability in trauma patients. Injury 2013; 44: 600-605
• 27 Rizoli S, Min A, Sanchez AP. et al. In Trauma, Conventional ROTEM and TEG Results Are Not Interchangeable But Are Similar in Clinical Applicability. Mil Med 2016; 181 (5 Suppl): 117-126
• 28 Sankarankutty A, Nascimento B, Teodoro da Luz L. et al. TEG^® and ROTEM^® in trauma: similar test but different results?. World J Emerg Surg 2012; 7 Suppl 1 (1): 3
• 29 Schöchl H, Frietsch T, Pavelka M. et al. Hyperfibrinolysis After Major Trauma: Differential Diagnosis of Lysis Patterns and Prognostic Value of Thrombelastometry. J Trauma 2009; 67: 125-131
• 30 Hagemo JS, Stanworth S, Juffermans NP. et al. Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study. Crit Care 2014; 18: R52
• 31 Kozek-Langenecker SA, Ahmed AB, Afshari A. et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016. Eur J Anaesthesiol 2017; 34: 332-395
• 32 Spahn DR, Bouillon B, Cerny V. et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 2013; 17: R76
• 33 Solomon C, Traintinger S, Ziegler B. et al. Platelet function following trauma. A multiple electrode aggregometry study. Thromb Haemost 2011; 106: 322-330
• 34 Short S, Kram B, Taylor S. et al. Effect of platelet inhibition on bleeding complications in trauma patients on preinjury clopidogrel. J Trauma Acute Care Surg 2013; 74: 1419-1424
• 35 Görlinger K, Jambor C, Dirkmann D. et al. Messung der Thrombozytenfunktion mit Point-of-Care-Methoden. Herz 2008; 33: 297-305
• 36 Olde Engberink RH, Kuiper GJ, Wetzels RJ. et al. Rapid and Correct Prediction of Thrombocytopenia and Hypofibrinogenemia With Rotational Thromboelastometry in Cardiac Surgery. J Cardiothorac Vasc Anesth 2014; 28: 210-216
• 37 Theusinger OM, Baulig W, Asmis LM. et al. In vitro factor XIII supplementation increases clot firmness in Rotation Thromboelastometry (ROTEM). Thromb Haemost 2010; 104: 385-391
• 38 Solomon C, Rahe-Meyer N, Schöchl H. et al. Effect of haematocrit on fibrin-based clot firmness in the FIBTEM test. Blood Transfus 2013; 11: 412-418
• 39 Schlimp CJ, Cadamuro J, Solomon C. et al. The effect of fibrinogen concentrate and factor XIII on thromboelastometry in 33% diluted blood with albumin, gelatine, hydroxyethyl starch or saline in vitro. Blood Transfus 2013; 11: 510-517
• 40 Dirkmann D, Görlinger K, Gisbertz C. et al. Factor XIII and tranexamic acid but not recombinant factor VIIa attenuate tissue plasminogen activator-induced hyperfibrinolysis in human whole blood. Anesth Analg 2012; 114: 1182-1188
• 41 Chowdhury P, Saayman AG, Paulus U. et al. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol 2004; 125: 69-73
• 42 Blasi A, Muñoz G, de Soto I. et al. Reliability of thromboelastometry for detecting the safe coagulation threshold in patients taking acenocoumarol after elective heart valve replacement. Thromb Res 2015; 136: 669-672
• 43 Dunham CM, Rabel C, Hileman BM. et al. TEG^® and RapidTEG^® are unreliable for detecting warfarin-coagulopathy: a prospective cohort study. Thromb J 2014; 12: 4
• 44 Seyve L, Richarme C, Polack B. et al. Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM). Int Jnl Lab Hem 2017; 5: 289
• 45 Kakouros N, Kickler TS, Laws KM. et al. Hematocrit alters VerifyNow P2Y12 assay results independently of intrinsic platelet reactivity and clopidogrel responsiveness. J Thromb Haemost 2013; 11: 1814-1822
• 46 Favaloro E. The Utility of the PFA-100 in the identification of von Willebrand disease: a concise review. Semin Thromb Hemost 2006; 32: 537-545
• 47 Hayward CPM, Harrison P, Cattaneo M. et al. Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 4: 312-319
• 48 Wohlauer MV, Moore EE, Thomas S. et al. Early platelet dysfunction: an unrecognized role in the acute coagulopathy of trauma. J Am Coll Surg 2012; 214: 739-746
• 49 Chapman MP, Moore EE, Moore HB. et al. Early TRAP pathway platelet inhibition predicts coagulopathic hemorrhage in trauma. Shock 2015; 43 (Suppl. 01) 33
• 50 Connelly CR, Yonge JD, McCully SP. et al. Assessment of three point-of-care platelet function assays in adult trauma patients. J Surg Res 2017; 212: 260-269
• 51 Holcomb JB. Optimal use of blood products in severely injured trauma patients. Hematology 2010; 2010: 465-469
• 52 Ho AM, Dion PW, Yeung JH. et al. Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology 2012; 116: 716-728
• 53 Holcomb JB, Tilley BC, Baraniuk S. et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma. JAMA 2015; 313: 471-482
• 54 Nascimento B, Callum J, Tien H. et al. Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients with severe trauma: a randomized feasibility trial. CMAJ 2013; 185: E583-E589
• 55 Tapia NM, Chang A, Norman M. et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg 2013; 74: 378-386
• 56 da Luz LT, Nascimento B, Shankarakutty AK. et al. Effect of thromboelastography (TEG^®) and rotational thromboelastometry (ROTEM^®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review. Crit Care 2014; 18 (05) 518
• 57 Whiting P, Al M, Westwood M. et al. Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis. Health Technol Assess 2015; 19: 1-228 v–vi
• 58 Innerhofer P, Westermann I, Tauber H. et al. The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma. Injury 2013; 44: 209-216
• 59 Nienaber U, Innerhofer P, Westermann I. et al. The impact of fresh frozen plasma vs. coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion. Injury 2011; 42: 697-701
• 60 Innerhofer P, Fries D, Mittermayr M. et al. Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial. Lancet Haematol 2017; 4 (06) e258-e271
• 61 https://static.healthcare.siemens.com/siemens_hwem-hwem_ssxa_websites-context-root/wcm/idc/groups/public/@de/@lab/documents/download/mdaz/nda2/~edisp/dx-de-befundungkonstellationen-pfa200-01435569.pdf Stand: 17.05.2018