Coagulopathy in trauma patients

Coagulopathy in

Servicio  de  Medicina  Intensiva  Grupo  de  Inves3gación  49.IdiPAZ  

Hospital  Universitario  La  Paz-­‐Carlos  III.  Madrid.  

TRAUMA PATIENTS

Dr. M. Quintana

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Charlas, estudios investigación y ayudas a congresos •  XXXX •  XXXX •  XXXX

Pertenencia a Sociedades Científicas •  Miembro de la Comisión de Transfusiones del HULP •  Miembro del Documento de Sevilla “Alternativas a la Transfusión” •  Miembro del Documento “Hemomas” •  Miembro de GIEMSA/ AWGE/NATA •  Socio ESCIM/SEMICYUC/SETS/SEMES/SOMIUCAM

Hospital Universitario La Paz. Madrid

Facultad de Medicina. Universidad Autónoma de Madrid

| Declaración de conflicto de intereses .   2017  

Agradecimientos

• Dra MªJ Colomina/ BCN

• Dr F. Ariza/Cali

• Dr N. Suarez/ Madrid

• SEMICYUC Group of TyATSA

• CASTYM Group

“The  white  rabbit  wore  his  eyeglasses    —¿Where  do  I  start,  your  majesty?    —Start   from   the   biggining   —replied   the  king—.   Follow   un3l   you   get   to   the   end.  Then  stop.”  

Alice's Adventures in Wonderland. Lewis Carroll. 1865

What we know……

trauma = bleeding

•  In 2020 it will be the second cause of dead in all group of ages. •  Most of the patients do not get transfusions (91%) only a few

need massive transfusion (3%). •  These received more than 71% of the RBC (18% not crossed) •  Bleeding could be the in hospital cause of death even up to 1/3 of

the patients who died, specially in the first 24h of admission •  Mortality from 39% to 57%

–  Patients who recieve more than 10 RBC during their stay at the ICU ( 2.6% of all trauma patients) have a 39% mortality

–  Mortality of those who recieve more than 50 RBC whitin the first 24h (0.6% of all trauma patients) have a 57% mortality

•  Survival of the bleeding patients depends on the right tranfusion treatment

•  Just 1 patient can consume all the blood bank of a hospital

and what we learn about that……

Mortality  from  major  trauma  con2nues  to  be  a  worldwide  problem,  and  massive  haemorrhage  remains  a  major  cause  of  poten3ally  preventable  deaths.  Development  of  coagulopathy  further  increases  mortality  considerably,  and  coagulopathy  is  a  key  target  in  the  phase  of  bleeding.    The  concepts  of  ‘damage  control  surgery’  (DCS)  and  ‘damage  control  resuscita3on’  (DCR)  have  been  developed  during  the  past  10  years  to  ensure  early  control  of  bleeding  and  coagulopathy  in  order  to  reduce  morbidity  and  mortality  in  trauma  haemorrhage.  

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Norton  R,  Kobusingye  O.  Injuries.  N  Engl  J  Med  2013;  368:1723–1730.  Johansson  PI,  Stensballe  J,  Oliveri  R,  et  al.  How  I  treat  pa3ents  with  massive  hemorrhage.  Blood  2014;  124:3052–3058.  Holcomb  JB,  Jenkins  D,  Rhee  P,  et  al.  Damage  control  resuscita3on:  directly  addressing  the  early  coagulopathy  of  trauma.  J  Trauma  2007;  62:307–310.  Shapiro  MB,  Jenkins  DH,  Schwab  CW,  et  al.  Damage  control:  collec3ve  review.  J  Trauma  2000;  49:969–978.  

damage control hemostatic time!!!

Clinical issues

•  Bleeding is the first cause of death in severe trauma 1

•  Trauma associated coagulopathy at admission is related with trauma severity and its mortality 2

•  The right haemostatic treatment is fundamental in prognosis, just below a right ventilation3

1Sauaia A et al. J trauma 1995; 38:185-193 2Brohi K et al. J Trauma 2003; 54:1127-1130

3MacLeod JB et al. J Trauma 2003; 55:39-44

Clinical  issues  •  Primary  causes:  mechanic  injury  

•  Mechanic  organs  injury    •  Mechanic  vessels  injury  

•  Secondary  causes:  coagulopathy  

•  Bleeding  associated  coagulopathy  •  Trauma  associated  coagulopathy  

Lynn M Bloodline Reviews 2001

•  “baseline”  Coagulopathy  

•   “associated”  Coagulopathy  

•   “deriva1ve”  Coagulopathy  

•   “added”  Coagulopathy  

Coagulopathy  pathophysiology  

•  Defects  in  clot  strenght  due  to  fibrinogen  and  platelet  deficiency  

•  Defects  in  clot  stability  due  to  hyperfibrinolisis  and  FXIII  deficiency  

•  Delay  in  clot  forma3on  due  to  factors  deficiency  secondary  to  its  consume  

Bleeding  associated  coagulopathy  pathophysiology  

*Kozek-Langenecker S. Yearbook of Intensive care and Emergency Medicine 2007

What´s new……

•  Coagulopathy appears early after injury, before fluid infusion at the scene.

•  Coagulation factors and fibrinolysis are activated precociously •  Coagulopathy (more than bleeding) incidence is high •  Severity is related to injury and not to hypoperfusion

BLEEDING  CAUSES  IN  SEVERE  TRAUMA  

Severe  Trauma  

Coagulopathy  (Secondary)  

Coagulopathy  (Primary)  

• Consume  (IDC)  • Deple3on  

• Acidosis  and  hypoperfusion  • Hypothermia  • Cristaloid  infusion  • Insufficient  blood  products                  infusion  

Prom

oter

s

Arch  surg/vol  143  (no.  8),  Aug  2008  

Trauma associated coagulopathy is.. early, primary, acute and related to traumatic shock worsen by fluid therapy, acidosis, hypocalcemia, hypothermia...

•  no concept uniformity •  no animals model validity developed by now. •  retrospective, no controls • All of them include classical mortality trauma factors, but they dont study coagulation factors, fibrinolysis,..

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Classically,  coagulopathy  had  a  late  origin  due  to  factors  deficiency    lost  by  bleeding  added  to  dilu3on  of  the  exis3ng  ones  by  fluids  

infusion  

Current  studies  report  that  coagulopathy  appears  very  early  and  even  a  third  of  the  pa3ents  already  have  it  by  admission,  

even  before  fluid  infusion  

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Coagulopathy

•  This group vary according to laboratory criteria used to its diagnosis, showing to be less sensitive but more specific the APTT than PT

(4) McLeod JB, Lynn M, McKenedy MG, Cohn SM, Murtha. Early coagulopathy predicts mortality in trauma. J Trauma.2003;55: 39-44.

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Coagulation monitoring ¿how?

Experiences with quick thromboelastography could lead us to a more efficient therapy with blood products and

haemostatic related pharmacology Kashuk JL, Moore EE, Wohlauer M, Johnson JL, Pezold M, Lawrence J,et al. Initial experiences with point-of-care rapid thrombelastography for management of life-threatening postinjury coagulopathy. Transfusion. 2011. Jul 25. doi: 10.1111/j.1537-2995.2011.03264.x. [Epub ahead of print]

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MJ  Colomina.  Valencia  28  Abril  2007  

“Everybody  talks  about  it,  nobody  understands  it”            

     JH  Levy,  2000  

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 The  pathophysiology  of  coagulopathy  in  trauma  can  be  stra2fied  into  three  dis3nct  types  that  oRen  exist  in  varying  degrees,  as  single  en22es  in  the  less  sick  pa2ent  but  coexist  with  the  poten2al  to  amplify  in  the  bleeding  trauma  pa2ent:    •  acute  trauma3c  coagulopathy  (ATC),    •  coagulopathy  associated  with  the  lethal  (pentad?)  triad    •  consump3ve  coagulopathy  

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ACUTE  TRAUMATIC  COAGULOPATHY  

 –  ATC-­‐  

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Acute  coagulopathy  of  trauma  (ATC)  and  shock  (ACoTS),  is  observed  in  25–35%  of  trauma  pa3ents  at  hospital  arrival,  associated  with  significant  2ssue  injury,  shock  and  increased  mortality.    ATC  is  a  hypocoagulable  condi3on  evidenced  by  increased  prothrombin  2me    and  by  prolonged  cloVng  2me  as  evaluated  by  viscoelas2c  haemosta2c  assays  (VHA).  An  important  cause  of  this  coagulopathy  is  the  endogenous  an3coagula3on  that  develops  to  balance  the  increasingly  more  procoagulant  vasculature,  represented  by  the  systemically  injured  endothelium  .  

MacLeod  JB,  Lynn  M,  McKenney  MG,  et  al.  Early  coagulopathy  predicts  mortality  in  trauma.  J  Trauma  2003;  55:39–44.  Brohi  K,  Singh  J,  Heron  M,  et  al.  Acute  trauma2c  coagulopathy.  J  Trauma  2003;  54:1127–1130.  Co_on  BA,  Faz  G,  Hatch  QM,  et  al.  Rapid  thrombelastography  delivers  real2me  results  that  predict  transfusion  within  1  h  of  admission.  J  Trauma  2011;  71:407–417.  Davenport  R,  Manson  J,  De’ath  H,  et  al.  Func2onal  defini2on  and  characteriza2on  of  acute  trauma2c  coagulopathy.  Crit  Care  Med  2011;  39:2652–2658.  Ostrowski  SR,  Sorensen  AM,  Larsen  CF,  et  al.  Thrombelastography  and  biomarker  profiles  in  acute  coagulopathy  of  trauma:  a  prospec2ve  study.  Scand  J  Trauma  Resusc  Emerg  Med  2011;  19:64.  Johansson  PI,  Stensballe  J,  Rasmussen  LS,  et  al.  A  high  admission  syndecan-­‐  1  level,  a  marker  of  endothelial  glycocalyx  degrada2on,  is  associated  with  inflamma2on,  protein  C  deple2on,  fibrinolysis,  and  increased  mortality  in  trauma  pa2ents.  Ann  Surg  2011;  254:194–200.  Johansson  PI,  Henriksen  HH,  Stensballe  J,  et  al.  Trauma2c  endotheliopathy:  a  prospec2ve  observa2onal  study  of  424  severely  injured  pa2ents.  Ann  Surg  2016.  [Epub  ahead  of  print]  

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Causes  contribu3ng  to  endogenous  an3coagula3on    •  auto-­‐hepariniza2on  •  protein  C  ac2va2on  •  hyperfibrinolysis  

these  are  all  related  to  and  driven  by  the  state  of  the  endothelium  

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•  the  endothelial  glycocalyx,  consis2ng  of  a  thick  layer  of  proteoglycans  and  glycosaminoglycans,  becomes  shedded  secondary  to  the  endothelial  damage,  resul2ng  in  release  of  heparan  sulphate  and  similar  cons3tuents  with  heparin-­‐like  ac3vity  to  the  circula3ng  blood  (auto-­‐hepariniza3on)  

•  Reduced  levels  of  protein  C,  a_ributed  to  increased  produc2on  of  ac2vated  protein  C,  contribu3ng  to  the  hypocoagulablity  observed.  

•  Increased  fibrinolysis,  the  most  potent  endogenous  an2coagula2on,  is  observed  in  pa2ents  with  extensive  and  widespread  endothelial  ac2va2on  and  damage  secondary  to  trauma,  leading  to  enhanced  release  of  2ssue-­‐type  plasminogen  ac2vator  (tPA)  from  the  Weibel-­‐Palade  bodies  of  the  endothelial  cells,  inducing  premature  resolu2on  of  the  formed  clot.  

endogenous anticoagulation  

Kashuk  JL,  Moore  EE,  Sawyer  M,  et  al.  Primary  fibrinolysis  is  integral  in  the  pathogenesisoRheacutecoagulopathyoRrauma.AnnSurg2010;252:434–442.  Co_on  BA,  Harvin  JA,  Kostousouv  V.  Hyperfibrinolysis  at  admission  is  an  uncommon  but  highly  lethal  event  associated  with  shock  and  prehospital  fluid  administra2on.  J  Trauma  Acute  Care  Surg  2012;  73:365–370  

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Hyperfibrinolysis  is  an  important  cause  of  severe  haemorrhage  and  occurs  in  severely  injured  pa3ents  

correla3ng  with  poor  outcome  

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COAGULOPATHY  IN  THE  LETHAL  TRIAD  

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Hipotermia  

Hipocalcemia   Acidosis  

Hipotermia  

Hipoperfusión/Acidosis  Hipocalcemia  

Hiperglicemia  Hipoxia  

Coagulopatía

Cortesia Dr JN Carreño

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The  lethal  triad  is  frequently  observed  in  pa3ents  with  massive  haemorrhage  and  encompasses  

acidosis,  hypothermia  and  coagulopathy  associated  with  high  mortality.    

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•  Hypothermia-­‐induced  coagulopathy  is  atributed  to  platelet  dysfunc3on,  reduced  coagula3on  factor  ac3vity  and,  in  the  most  extreme,  induc3on  of  fibrinolysis.    

•  Acidosis  is  oRen  induced  by  hypoperfusion  and  to  some  extent  excess  administra3on  of  ionic  chloride,  that  is  NaCl,  during  resuscita2on.    

•  Acidosis  impairs  almost  all  essen2al  parts  of  the  haemosta2c  process  resul2ng  in,  for  example,  a  change  in  platelet  structure  and  shape  and  reduced  ac2vity  of  coagula2on  factor  complexes  on  the  cell  surface,  ul2mately  resul3ng  in  impaired  thrombin  genera3on.  

Duchesne  JC,  McSwain  NE  Jr,  Co_on  BA,  et  al.  Damage  control  resuscita2on:  the  new  face  of  damage  control.  J  Trauma  2010;  69:976–990.  DjaldeV  M,  Fishman  P,  Bessler  H,  et  al.  pH-­‐induced  platelet  ultrastructural  altera2ons.  A  possible  mechanism  for  impaired  platelet  aggrega2on.  Arch  Surg  1979;  114:707–710.  Mar2ni  WZ,  Dubick  MA,  Pusateri  AE,  et  al.  Does  bicarbonate  correct  coagula2on  func2on  impaired  by  acidosis  in  swine?  J  Trauma  2006;  61:99–106.  Mar2ni  WZ,  Holcomb  JB.  Acidosis  and  coagulopathy:  the  differen2al  effects  on  fibrinogen  synthesis  and  breakdown  in  pigs.  Ann  Surg  2007;  246:831–835.  

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Both  hypothermia  and  acidosis  impair  fibrinogen  availability  as  hypothermia  inhibits  fibrinogen  synthesis  and  acidosis  accelerates  fibrinogen  degrada3on,  leading  to  hypofibrinogenemia.    

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CONSUMPTIVE  COAGULOPATHY  

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Tissue   injury   induces   an   immediate   ac3va3on   of   the   coagula3on  system   through   exposure   of   2ssue   factor   and   other   2ssue   or  intracellular   components,   which   promotes   excessive   thrombin  genera3on.      To   protect   the   organism   against   intravascular   thrombin   by   excess  fibrin   forma2on,   the   ini3al   coagula3on   ac3va3on   is   followed   by  enhanced   plasminogen   ac3va3on   and   fibrinoly3c   ac3vity,   and   to  prevent   rebleeding   by   fibrinolysis,   the   plasminogen   ac2vator  inhibitor   (PAI)-­‐1   level   increases  progressively   in   the  hours   and  days  hereaRer.    

Drake  TA,  Cheng  J,  Chang  A,  et  al.  Expression  of  3ssue  factor,  thrombomodulin,  and  E-­‐selec3n  in  baboons  with  lethal  Escherichia  coli  sepsis.  Am  J  Pathol  1993;  142:1458–1470.  

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Importantly,   extensive   3ssue   injury   and   accompanying   shock  induces  widespread  endothelial  injury,  resul3ng  in  a  prothrombo3c  state   of   the   microvasculature   that   further   promotes   coagula2on  factor   and   platelet   consump2on,   ul3mately   leading   to  coagulopathy  and  further  risk  of  haemorrhage    Occasionally,   the   normal   an2coagulant   and   fibrinoly2c   control  mechanisms  fail  to  restrict  the  haemosta3c  ac3vity  to  the  area  of  3ssue  damage  resul3ng  in  disseminated  intravascular  coagula3on  (DIC).      Drake  TA,  Cheng  J,  Chang  A,  et  al.  Expression  of  3ssue  factor,  thrombomodulin,  and  E-­‐selec3n  in  baboons  with  lethal  Escherichia  coli  sepsis.  Am  J  Pathol  1993;  142:1458–1470.  

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•  Another   important  driver  of  consump3ve  coagulopathy   is   the  accompanying   inflammatory   response,   which   by   inducing  2ssue  factor  expression  on  various  cells  supports  a  viscous  cycle  of  reciprocal  ac3va3on  of  the  coagula3on  system.    

 A  cri3cal  driver  of  consump3ve  coagulopathy  is  sympathoadrenal  overac3va3on.  

Gando  S,  Sawamura  A,  Hayakawa  M.  Trauma,  shock,  and  disseminated  intravascular  coagula3on:  lessons  from  the  classical  literature.  Ann  Surg  2011;  254:10–19.  Levi  M,  van  der  PT.  Inflamma3on  and  coagula3on.  Crit  Care  Med  2010;  38:S26–S34.  

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This   occurs   in   response   to   excessive   3ssue   injury   and   shock/hypoxia,  leading  to  release  of  catecholamines  in  concentra2ons  that  are  directly  toxic  for  the  endothelium,  ul2mately  resul2ng  in  further  endothelial  damage  and  downstream  coagulopathy.    

 Catecholamines  are  potent  ac3vators  of  platelets  and  promote  coagula3on  factor  release  and  ac3va3on  

Makhmudov  RM,  Mamedov  Y,  Dolgov  VV,  et  al.  Catecholamine-­‐mediated  injury  to  endothelium  in  rabbit  perfused  aorta:  a  quan3ta3ve  analysis  by  scanning  electron  microscopy.  Cor  Vasa  1985;  27:456–463.  Cannon  WB.  A  considera3on  of  possible  toxic  and  nervous  factors  in  the  produc3on  of  trauma3c  shock.  Ann  Surg  1934;  100:704–713.  

and what´s about dilution……

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Coagulopathy  secondary  to  dilu3on  of  coagula3on  factors  and  platelets  is  also  an  important  part  of  the  lethal  triad  and  dilu2onal  coagulopathy  is  further  aggravated  when  synthe3c  colloids  are  administered.    Hydroxyethyl  starch  (HES)  causes  an  efflux  of  plasma  proteins  from  the  blood  to  the  inters22al  space,  reduces  the  plasma  concentra2on  of  coagula2on  factor  VIII  and  von  Willebrand  factor,  inhibits  platelet  func2on  and  interferes  with  the  interac2on  between  ac2vated  FXIII  and  fibrin  polymers  -­‐>This  may  contribute  to  the  increased  bleeding  and  mortality  of  HES  administra3on  in  bleeding  trauma      Be  careful  with  the  quan1ty  and  the  moment  of  administra3on!!!!  

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Administra3on  of  blood  products  also  contributes  significantly  to  coagulopathy  in  massive  bleeding  and  the  ‘best’  haemosta2c  capacity  possible  to  accomplish  with  administra2on  of  balanced  RBCs,  plasma  and  platelets  (1  :  1  :  1)  results  in  a  haematocrit  around  30%,  a  coagula2on  factor  concentra2on    60%  and  a  platelet  count  of  80  109  /l,  ……    

which  is  far  below  normal  concentra3ons  

We know the problm… but what´s about the solution?

Bleeding  Management  

First:  STOP  THE  BLEEDING  Second:  Transfusion  

Third:  Coagulophaty  Treatment  

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•  Defects  in  clot  strenght  due  to  fibrinogen  and  platelet  deficiency  

•  Defects  in  clot  stability  due  to  hyperfibrinolisis  and  FXIII  deficiency  

•  Delay  in  clot  forma3on  due  to  factors  deficiency  secondary  to  its  consume  

Bleeding  associated  coagulopathy  pathophysiology  

*Kozek-Langenecker S. Yearbook of Intensive care and Emergency Medicine 2007

Coagulophaty  Treatment  physiopathological  objec3ves  

•  Trombin  (genera2on)  •  (Func2onal)  fibrinogen  •  (Func2onal)  Platelets  •  (Modula2on  of  )  fibrinolysis  

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What do you need to take

home?

DCR:  main  components  

•  Haemosta3c  resuscita3on  –  early  use  of  blood  products  to  avoid  further  coagulopathy  in  respect  to  fluids  and  dilu2on.  

•  Permissive  hypotensive  resuscita3on  to  decrease  bleeding  and  support  bleeding  control.  

•  Regaining  homeostasis  and  avoid  further  coagulopathy  related  to  hypothermia,  acidosis  and  electrolyte  disturbances  (hypocalcemia,hyperkaliemia);  hypoxia  and  hyperglicemia   63  

Key  points  

•  Coagulopathy  is  a  key  target  for  diagnosis  and  aggressive  treatment  in  the  bleeding  phase.  

•  Haemosta3c  resuscita3on  aims  to  control  coagulopathy  early  and  consistently  in  bleeding  trauma  pa3ents.  

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•  trauma  pa3ents  present  with  an  inherent  risk  of  coagulopathy    

•  concurrent  with  the  rapidity  of  changes  in  the  haemosta3c  system  during  massive  bleeding  

•  the  importance  of  rapid  diagnosis  and  therapy  cannot  be  stressed  enough  

•  think  in  lethal  pentad  •  use  prohemosta3c  with  head  

Thank you for your attention

MQ

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