Hyperfibrinolyse T. Pernerstorfer Abteilung für Anästhesie und Intensivmedizin Konventhospital der Barmherzigen Brüder Linz Alland,

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1 Alland Hyperfibrinolyse T. Pernerstorfer Abteilung für Anästhesie und Intensivmedizin Konventhospital der Barmherzigen Brüder Linz Alland,

2 PowerPoint.

3 wovon die Rede ist... 4 klinische Szenarien Sepsis Trauma Fruchtwasserembolie end of life 2 iagnostische Ansätze -imer ROTEM 1 Medikament Cyclokapron

4 das kommt nicht nur Ihnen chinesisch vor...

5 Fibrinolyse 2 (...schon wieder Thrombin) FVa (x150) FXa (x150) t-pa Plasminogen Thrombin Thrombomodulin PAI-2 (x0,1) PAI-1 TAFI Fibrin u-pa Plasmin a 2 -AP Fibrinspaltprodukte

6 Plasmin Fibrinolyse 4: Entstehung von Fibrinspaltprodukten E E E E E E E E E E E Plasmin spaltet die E- Bindungsstelle es entstehen -imere das Vorhandensein von -imeren ist Hinweis für abgelaufene Gerinnung

7 klinische Szenarien, bei denen Fibrinolyse eine Rolle spielt IC Sepsis Fruchtwasserembolie Schädel-Hirn-Trauma Polytrauma CPR Lebercirrhose

8 what IC stands for... I C

9 what IC stands for... eath Is Coming.

10 Verbrauchskoagulopathie (IC) Systemic Inflammatory Response Syndrome isseminated Intravascular Coagulation IC SIRS MOS Multiple Organ ysfunction Syndrome

11 er zeitliche Verlauf von Thrombinaktivierung und Fibrinolyse TAT w/o anti-il-6 PAP w/o anti-tnf-a Levi M, Eur J Clin Invest 1997; 27:3

12 ROTEM detektiert auch Fibrinolyse bei experimenteller Endotoxinämie Spiel AO, J Thromb Haemost 2006; 4: 411

13 niedrige Protein C Spiegel und hohe PAI-1 Spiegel sind assoziiert mit erhöhter Mortalität bei ARS (n=779) Ware LB, Crit Care Med 2007; 35: 1821

14 höhere Mortalität bei Patienten mit Hypoperfusion, vermehrter Thrombomodulinfreisetzung und Protein C Verbrauch Prospective cohort study 208 pts in ER 28min after trauma blood sampling 4 min after admission ISS 17 (9-26) HR>100/min 41% BP syst <100mm Hg 38% BE>6mEq/L 56% hypoperfusion = low Prot C & high TM = high mortality Brohi K, Ann Surg 2007; 245: 812

15 vermehrte Freisetzung von TM und Aktivierung von Protein C hemmt PAI-1, aktiviert Fibrinolyse higher mortality associated with hypoperfusion = high B low Prot C = low PAI-1 (activation of Protein exhausts PAI-1) net effect: hyperfibrinolysis leading to high -dimer Brohi K, Ann Surg 2007; 245: 812

16 vielfältige Interaktionen zwischen Gerinnungs- und Immunsystem Levi M, Crit Care Med 2010; 38: s26

17 PROWESS: 25% weniger Mortalität, aber einige Fragen zu esign und urchführung

18 PROWESS vs KYBERSEPT vs OPTIMIST PROWESS KYBERSEPT OPTIMIST Substanz rh TFPI Antithrombin rh TFPI No. Patienten APACHE 25 ± 7,8 25 ± 7,1 SAPS 49 ± 17 Mortalität % Blutungsrisiko % Placebo 30,8 38,7 33,9 Verum 24,7 38,9 34,2 p-wert <0,05 n.s. n.s. Placebo 17±2 12,8 24 / 22 Verum 30±3,5 22,0 30 / 33 p-wert 0,06 <0,001 n.s.

19 Xigris in septic shock 1697 patients RCT dotrecogin alfa (Xigris ) vs placebo infection, systemic inflammation plus vasopressors >4hrs Mortality 28d 26.4% vs 24.2%, n.s. Mortality 90d 34.1% vs 32.7%, n.s. rotaa did not significantly reduce mortality at 28 or 90 days compared with placebo in patients with septic shock Ranieri VM, NEJM 2012; 366: 2055

20 Xigris in septic shock Mortality at 28 days and 90 days 26.4% vs 24.2% (p=0.31), and 34.1% vs 32.7% (p=0.56%) subgroup analysis showed no effect in pts with Prot C deficiency Ranieri VM, NEJM 2012; 366: 2055

21 Interaktion von aktiviertem Protein C, Koagulation und Fibrinolyse Activated protein C in excess will consume PAI-1 and thus lead to a enhanced fibrinolytic activity and systemic hyperfibrinolysis inhibit activation of FV and FVIII leading to hypocoagulation Maegele M, Shock 2012; 38: 450

22 iagnostik 3 ISTH IC score efinition of the scoring system for disseminated intravascular coagulation (IC) as proposed by the ISTH Points Platelet count/nl > <50 -dimer, µg/ml < >5.0 Fibrinogen, g/l > Prothrombin Index, % > < 40 The score ranges from 0 to 8 points. A scoring for IC 5 is compatible with overt IC Angstwurm MWA; CCM 2006; 34: 314

23 10 Jahre nach PROWESS, KYBERSEPT etc... no magic bullets treat underlying cause adequate and timely antibiotic treatment

24 keep in mind: IC TIC... avenport R, Br J Haematol 2011; 155: 537

25 keep in mind: IC TIC... Methods: Observational study, n=80 pts. ISS 17 (10 to 28), mortality 18%. Results: No patients had overt IC whereas 15% had ACoTS (Acute Coagulopathy of Trauma & Shock). ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Conclusions: ACoTS and non-acots may represent a continuum of coagulopathy reflecting a progressive early evolutionary adapted hemostatic response to the trauma hit and both are parts of TIC whereas IC does not appear to be part of this early response. Johansson PI, Crit Care 2011; 15: R272

26 Hyperfibrinolyse lässt sich mit ROTEM gut diagnostizieren Schöchl H, J Trauma 2009; 67: 125

27 Hyperfibrinolyse lässt sich mit ROTEM gut diagnostizieren Schöchl H, J Trauma 2009; 67: 125

28 fulminante Hyperfibrinolyse assoziiert mit hoher und rascher Mortalität Schöchl H, J Trauma 2009; 67: 125

29 everything settled? The Incidence and magnitude of Fibrinolytic Activation in Trauma Patients Raza I, J Thromb Haemost 2013; 11: 307

30 everything settled? The Incidence and magnitude of Fibrinolytic Activation (FA) in Trauma Patients Title: Prospective cohort study, n=303pts. TEM, (ML>15%), PAP, -dimer, severity of injury, mortality Results: Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of moderate fibrinolysis with PAP levels elevated over twice normal (>1500μg/L) without lysis on TEM. TEM only detected clot lysis when PAP levels were increased 30 times normal (p<0.001) and antiplasmin levels were less than 75% of normal. Patients with FA had increased 28-day mortality compared with no FA (12% vs 1%, p<0.001), fewer ventilator-free days and longer hospital stay. Conclusions: FA occurs in the majority of trauma patients and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional thromboelastometry, an insensitive measure of endogenous fibrinolytic activity. Raza I, J Thromb Haemost 2013; 11: 307

31 Cyclokapron könnte Blutverlust minimieren Patients, RCT Placebo vs Tranexamic Acid All-cause mortality significantly lower under Tranexamic acid (1463 [14.5%] vs 1613 [16.0%] placebo group; relative risk 0.91, 95% CI ; p=0.0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs 574 [5.7%]; relative risk 0.85, 95% CI ; p=0.0077). Anonymous CRASH-2 Lancet 2010; 376: 23

32 Cyclokapron könnte Outcome verbessern Anonymous CRASH-2 Lancet 2010; 376: 23

33 Cyclokapron könnte Outcome verbessernn CRASH-2 subgroup of patients randomised for Placebo vs Tranexamic Acid within <3hrs 4 groups stratified by baseline risk, in each group mortality was lower w/txa <6% minus 17%, 6-20% minus 20%, 21-50% minus 30%, >50% minus 17% Roberts I, BMJ 2012; 345: e5839

34 Warum bed side Methoden besser sind...

35 Case Report: iagnose von Hyperfibrinolyse nach Fruchtwasserembolie mit ROTEM Collins NF, Int J Obstet Anesth 2012; Nov15: ahead of print

36 Case Report: after 8 units cyroprecipitate plus 1g TXA Collins NF, Int J Obstet Anesth 2012; Nov15: ahead of print

37 Fall GYN_OB_01. Postpartale Blutung (1) Klinisches Bild schwangere Patientin, 28 a, 178 cm, 89 kg Spontangeburt am Termin (Samstag, 06:00) 1h später atone Blutung RR 75/40 mmhg, HR 140/min Hk 18%; Hb 6.2 BE -3.4

38 Fall GYN_OB_01. Postpartale Blutung (2) Was wollen wir wissen? Wie viel Blut hat die Patientin verloren?. Einschätzung des Patienten - (Klinik, RR, Puls, Hb, HK) Handelt es sich um eine anhaltende Blutung? Fruchtwasserembolie?

39 Fall GYN_OB_01. Postpartale Blutung (3) atone Uterusblutung post partum Spontangeburt ohne Probleme geschätzter BV: >3L Hb: 6.2 g/dl Hkt: <20% ph: initial 7.27 BE: -3.4 mmol/l Uhrzeit

40 Fall GYN_OB_01. Postpartale Blutung (4) ifferentialdiagnose Hyperfibrinolyse, Verlustkoagulopathie Therapie: Curettage Bakriballon 5g Haemocomplettan 3g Cyclokapron 1800 I.E. Prothromblex 2 EK (O neg) Pabal Noradrenalin Uhrzeit

41 Fall GYN_OB_01. Postpartale Blutung (5) Verdachtsdiagnose: Hyperfibrinolyse aufgrund Fruchtwasserembolie Therapie insgesamt: 9 EK, 2 TK 11g Haemocomplettan 5400 I.E Prothromblex 5 FFP 3 g Cyclokapron 30µg Octostim Ca+ Uhrzeit Gerinnselfestigkeit normal, APTEM kürzere CT als INTEM

42 FXIII antagonisiert die Fibrinolyse in vitro EXTEM FIBTEM irkmann, Anesth Analg 2012; 114: 1182

43 Fall CPR_01 (1) Klinisches Bild männlicher Patient, 62 a, 178 cm, 89 kg Aufnahme im kardiogenen Schock Herzstillstand zuhause und CPR ph 6.82, BE-13.2, Laktat 17.7 Quick 34, INR 2.0, aptt 71.1s -dimer >35.00

44 Fall CPR_01 (2) ph 6.82, BE-13.2, Laktat 17.7 Quick 34, INR 2.0, aptt 71.1s -dimer >35.00

45 Hyperfibrinolysis in out of hospital cardiac arrest (OHCA) is associated with markers of hypoperfusion no fibrinolysis fibrinolysis p Median CPR 10 (7-18) 36 (15-55) ph 7.17 ± ± 0.11 <0.001 BE ± ± 3.53 <0.001 Lactate 8.0 ± ± dimers 2.3 ± ± pts with OHCA hyperfibrinolysis in 53% lysis onset time associated with CPR time, lactate, but not with BE Viersen VA, Resuscitation 2012; 83: 1451

46 Hyperfibrinolysis in out of hospital cardiac arrest (OHCA) is associated with markers of hypoperfusion lysis onset time associated with CPR time (r=0.76, p=0.003) lactate (r=0.68, p=0.01) not with BE (r=0.52, p=0.072) Viersen VA, Resuscitation 2012; 83: 1451

47 Is there a difference in coagulation and fibrinolysis parameters btw. brain dead and live donors? 30 brain dead organ donors vs 30 live donors for kidney transplant median time btw. declaration of brain death and organ donation 654min pt after trauma (n=15) on LMWH, hemorrhagic stroke or bleeding (n=15) without LMWH Lisman T, J Thromb Haemost 2012; 9: 1959

48 Is there a difference in coagulation and fibrinolysis parameters btw. brain dead and live donors? Lisman T, J Thromb Haemost 2012; 9: 1959

49 Is there a difference in coagulation and fibrinolysis parameters btw. brain dead and live donors? Our analyses demonstrate activation of blood platelets, evidence for fibrin generation, and a decreased capacity to clear fibrin clots in brain dead organ donors. This prothrombotic state may contribute to formation of microthrombi in transplantable organs,... Lisman T, J Thromb Haemost 2012; 9: 1959

50 I see a light...

51 Versuch einer schematischen arstellung Johansson PI, Crit Care 2011; 15: R272

52 er gegenwärtige Stand des Irrtums Prognostischer Wert eath is coming... iagnose ROTEM ML, -dimer PAP, PAI-1 Therapie Cyclokapron (1g Bolus, 1g über 4-8h) FXIII?

53 NOAC line, ein Service der ÖGARI, eine Bitte an Sie...

54 noch einbauen... shakur2010_40 (WOMEN and cyclokapron) levy2010_3 tauber br j anaesth theusinger 2012_1149 case reichl case CPR brohi2007_812 ware2007_1821 NEJM on xigris ranieri2012_2055 sepsis_badsassendorf_2006.ppt