title: Discrepant fibrinolytic response in plasma and whole blood during experimental endotoxemia in healthy volunteers.
abstract: BACKGROUND
  Sepsis induces early activation of coagulation and fibrinolysis followed by late fibrinolytic shutdown and progressive endothelial damage. The aim of the present study was to investigate and compare the functional hemostatic response in whole blood and plasma during experimental human endotoxemia by the platelet function analyzer, Multiplate and by standard and modified thrombelastography (TEG).
  
  
  METHODS
  Prospective physiologic study of nine healthy male volunteers undergoing endotoxemia by means of a 4-hour infusion of E. coli lipopolysaccharide (LPS, 0.5 ng/kg/hour), with blood sampled at baseline and at 4 h and 6 h. Physiological and standard biochemical data and coagulation tests, TEG (whole blood: TEG, heparinase-TEG, Functional Fibrinogen; plasma: TEG±tissue-type plasminogen activator (tPA)) and Multiplate (TRAPtest, ADPtest, ASPItest, COLtest) were recorded. Mixed models with Tukey post hoc tests and correlations were applied.
  
  
  RESULTS
  Endotoxemia induced acute SIRS with increased HR, temperature, WBC, CRP and procalcitonin and decreased blood pressure. It also induced a hemostatic response with platelet consumption and reduced APTT while INR increased (all p<0.05). Platelet aggregation decreased (all tests, p<0.05), whereas TEG whole blood clot firmness increased (G, p = 0.05). Furthermore, during endotoxemia (4 h), whole blood fibrinolysis increased (clot lysis time (CLT), p<0.001) and Functional Fibrinogen clot strength decreased (p = 0.049). After endotoxemia (6 h), whole blood fibrinolysis was reduced (CLT, p<0.05). In contrast to findings in whole blood, the plasma fibrin clot became progressively more resistant towards tPA-induced fibrinolysis at both 4 h and 6 h (p<0.001).
  
  
  CONCLUSIONS
  Endotoxemia induced a hemostatic response with reduced primary but enhanced secondary hemostasis, enhanced early fibrinolysis and fibrinogen consumption followed by downregulation of fibrinolysis, with a discrepant fibrinolytic response in plasma and whole blood. The finding that blood cells are critically involved in the vasculo-fibrinolytic response to acute inflammation is important given that disturbances in the vascular system contribute significantly to morbidity and mortality in critically ill patients.
authors.affiliation: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshospitalet, Copenhagen, Denmark. sisse.ostrowski@gmail.com
authors.forename: Sisse R
authors.initials: SR
authors.lastname: Ostrowski
authors.forename: Ronan M G
authors.initials: RM
authors.lastname: Berg
authors.forename: Nis A
authors.initials: NA
authors.lastname: Windeløv
authors.forename: Martin A S
authors.initials: MA
authors.lastname: Meyer
authors.forename: Ronni R
authors.initials: RR
authors.lastname: Plovsing
authors.forename: Kirsten
authors.initials: K
authors.lastname: Møller
authors.forename: Pär I
authors.initials: PI
authors.lastname: Johansson
mesh_terms: D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D001794:Blood Pressure; D002116:Calcitonin / Q000097:blood; D015740:Calcitonin Gene-Related Peptide; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood; D013916:Thrombelastography; D010959:Tissue Plasminogen Activator / Q000097:blood; D014914:Whole Blood Coagulation Time; D055815:Young Adult
chemical_list: C000606589:CALCA protein, human; D008070:Lipopolysaccharides; D011498:Protein Precursors; D005340:Fibrinogen; D002116:Calcitonin; D010959:Tissue Plasminogen Activator; D015740:Calcitonin Gene-Related Peptide
references.citation: Br J Haematol. 2008 Nov;143(4):559-69
references.pmid: 18950467
references.citation: J Surg Res. 2011 Jan;165(1):136-41
references.pmid: 19560161
references.citation: J Trauma. 2010 Dec;69(6):1403-8; discussion 1408-9
references.pmid: 21150521
references.citation: Crit Care Med. 2010 Feb;38(2 Suppl):S26-34
references.pmid: 20083910
references.citation: J Trauma. 2009 May;66(5):1349-54
references.pmid: 19430238
references.citation: N Engl J Med. 2001 Aug 9;345(6):408-16
references.pmid: 11496851
references.citation: Blood Coagul Fibrinolysis. 2007 Apr;18(3):227-36
references.pmid: 17413758
references.citation: Cor Vasa. 1985;27(6):456-63
references.pmid: 4092474
references.citation: Transl Res. 2009 Jul;154(1):34-9
references.pmid: 19524872
references.citation: J Intensive Care Med. 2009 Sep-Oct;24(5):293-316
references.pmid: 19703817
references.citation: Intensive Care Med. 1997 Apr;23(4):379-85
references.pmid: 9142575
references.citation: Resuscitation. 2013 Apr;84(4):454-9
references.pmid: 22922072
references.citation: Pflugers Arch. 2007 Jun;454(3):345-59
references.pmid: 17256154
references.citation: J Thorac Cardiovasc Surg. 2007 Jan;133(1):44-51
references.pmid: 17198779
references.citation: Blood Coagul Fibrinolysis. 2009 Sep;20(6):419-26
references.pmid: 19581801
references.citation: Crit Care Med. 2004 May;32(5 Suppl):S219-22
references.pmid: 15118521
references.citation: Crit Care Med. 2002 Oct;30(10):2242-8
references.pmid: 12394951
references.citation: J Leukoc Biol. 2007 Jan;81(1):137-43
references.pmid: 17020929
references.citation: Ann Vasc Surg. 2004 Sep;18(5):572-7
references.pmid: 15534737
references.citation: Nat Rev Immunol. 2013 Jan;13(1):34-45
references.pmid: 23222502
references.citation: Trends Cardiovasc Med. 2005 Nov;15(8):302-8
references.pmid: 16297768
references.citation: Acta Anaesthesiol Scand. 2005 Feb;49(2):222-31
references.pmid: 15715625
references.citation: Pediatr Surg Int. 1997 Apr;12(4):289-92
references.pmid: 9099648
references.citation: J Vasc Surg. 1995 Mar;21(3):484-91
references.pmid: 7877231
references.citation: Prog Clin Biol Res. 1987;236A:477-86
references.pmid: 3615447
references.citation: J Crit Care. 2013 Jun;28(3):317.e1-11
references.pmid: 23159146
references.citation: J Trauma. 2011 Feb;70(2):401-6; discussion 406-7
references.pmid: 21307741
references.citation: J Exp Med. 1997 Mar 17;185(6):1143-8
references.pmid: 9091588
references.citation: Am J Clin Pathol. 2010 Jul;134(1):97-102
references.pmid: 20551273
references.citation: Crit Care. 2006;10(6):R160
references.pmid: 17107615
references.citation: J Leukoc Biol. 2008 Mar;83(3):536-45
references.pmid: 18032692
references.citation: Thromb Res. 2011 Mar;127(3):184-8
references.pmid: 21075430
references.citation: Transfusion. 2008 Nov;48(11):2377-83
references.pmid: 18657078
references.citation: Blood Coagul Fibrinolysis. 2012 Mar;23(2):118-26
references.pmid: 22227956
references.citation: Blood. 2007 Apr 15;109(8):3161-72
references.pmid: 17110453
references.citation: Kaohsiung J Med Sci. 2010 Nov;26(11):584-92
references.pmid: 21126711
references.citation: N Engl J Med. 1980 Aug 21;303(8):436-44
references.pmid: 6248784
references.citation: JAMA. 1976 Mar 22;235(12):1230-4
references.pmid: 946230
references.citation: Shock. 2008 Dec;30(6):623-7
references.pmid: 18497712
references.citation: Blood. 2010 Mar 11;115(10):2048-56
references.pmid: 19996088
references.citation: J Trauma Acute Care Surg. 2012 Jul;73(1):60-6
references.pmid: 22743373
references.citation: Haematologica. 2012 Dec;97(12):1864-72
references.pmid: 22733025
references.citation: J Thromb Haemost. 2007 Feb;5(2):289-95
references.pmid: 17109736
references.citation: Scand J Gastroenterol. 2004 Sep;39(9):830-6
references.pmid: 15513380
references.citation: Br J Haematol. 1975 Mar;29(3):377-84
references.pmid: 1191556
references.citation: Med Hypotheses. 2010 Dec;75(6):564-7
references.pmid: 20708846
references.citation: J Thromb Thrombolysis. 2011 Jan;31(1):6-12
references.pmid: 20455008
references.citation: Life Sci. 1997;60(2):PL31-8
references.pmid: 9000123
references.citation: J Cell Biol. 2000 Feb 21;148(4):811-24
references.pmid: 10684261
references.citation: J Trauma. 2009 Jan;66(1):41-8; discussion 48-9
references.pmid: 19131804
references.citation: Circulation. 2007 Oct 23;116(17):1896-906
references.pmid: 17923576
references.citation: Crit Care. 2010;14(5):R178
references.pmid: 20929576
references.citation: Anesth Analg. 2012 Jun;114(6):1182-8
references.pmid: 22104068
references.citation: Ann Surg. 2010 Sep;252(3):434-42; discussion 443-4
references.pmid: 20739843
references.citation: Crit Care Med. 2000 Jul;28(7):2209-16
references.pmid: 10921542
references.citation: Curr Opin Crit Care. 2012 Dec;18(6):631-6
references.pmid: 23010636
references.citation: Liver Transpl. 2008 Jun;14(6):855-60
references.pmid: 18508379
references.citation: Ann Surg. 2011 Jul;254(1):10-9
references.pmid: 21368657
references.citation: Nat Rev Immunol. 2011 Apr;11(4):264-74
references.pmid: 21436837
references.citation: Eur J Haematol. 2000 Dec;65(6):357-69
references.pmid: 11168493
references.citation: Clin Sci (Lond). 2012 Nov;123(10):591-600
references.pmid: 22646240
references.citation: J Thromb Haemost. 2012 Feb;10(2):207-16
references.pmid: 22151659
references.citation: Thromb Res. 2007;120(1):87-93
references.pmid: 17023030
references.citation: Br J Anaesth. 2008 Jun;100(6):792-7
references.pmid: 18440953
references.citation: Br J Haematol. 2006 Oct;135(2):220-7
references.pmid: 17010048
references.citation: J Thromb Haemost. 2007 Jul;5 Suppl 1:116-24
references.pmid: 17635717
references.citation: J Vet Intern Med. 2011 May-Jun;25(3):524-31
references.pmid: 21418317
references.citation: Scand J Trauma Resusc Emerg Med. 2011 Oct 26;19:64
references.pmid: 22029598
references.citation: Haematologica. 2009 Mar;94(3):313-7
references.pmid: 19252173
references.citation: J Trauma. 2011 Aug;71(2 Suppl 3):S337-42
references.pmid: 21814101
references.citation: Cardiovasc Res. 2010 Jul 15;87(2):300-10
references.pmid: 20462866
references.citation: Shock. 2011 Apr;35(4):339-42
references.pmid: 21068699
references.citation: J Am Coll Cardiol. 2009 Nov 3;54(19):1747-62
references.pmid: 19874988
references.citation: Crit Care. 2012 Jan 16;16(1):R7
references.pmid: 22248019
references.citation: Blood Coagul Fibrinolysis. 2009 Jan;20(1):41-6
references.pmid: 19129727
references.citation: Thromb Haemost. 2006 May;95(5):822-8
references.pmid: 16676074
references.citation: J Thromb Haemost. 2006 Feb;4(2):411-6
references.pmid: 16420574
references.citation: Science. 2010 Apr 30;328(5978):562-4
references.pmid: 20430990
references.citation: Blood. 2012 Dec 20;120(26):5209-16
references.pmid: 23086755
references.citation: Clin Hemorheol Microcirc. 2004;30(2):107-15
references.pmid: 15004335
references.citation: J Am Coll Cardiol. 2005 Jul 5;46(1):21-8
references.pmid: 15992630
references.citation: Med Hypotheses. 2011 Nov;77(5):798-802
references.pmid: 21839585
references.citation: J Thromb Haemost. 2013 Feb;11(2):307-14
references.pmid: 23176206
references.citation: Crit Care. 2009;13(2):R42
references.pmid: 19331653
references.citation: J Trauma. 2008 May;64(5):1211-7; discussion 1217
references.pmid: 18469643
references.citation: Am J Physiol Regul Integr Comp Physiol. 2012 Dec;303(11):R1127-35
references.pmid: 23076874
references.citation: Scand J Trauma Resusc Emerg Med. 2009 Sep 23;17:45
references.pmid: 19775458
references.citation: J Thromb Haemost. 2004 Dec;2(12):2096-102
references.pmid: 15613012
references.citation: Blood Coagul Fibrinolysis. 2010 Mar;21(2):168-74
references.pmid: 20051844
references.citation: Acta Physiol Scand Suppl. 1960;49(173):1-123
references.pmid: 13841665
references.citation: J Lab Clin Med. 1997 Oct;130(4):401-11
references.pmid: 9358079
references.citation: Semin Thromb Hemost. 2008 Jul;34(5):417-24
references.pmid: 18956281
references.citation: Clin Vaccine Immunol. 2007 Mar;14(3):250-5
references.pmid: 17267590
references.citation: Acta Physiol Hung. 1993;81(4):363-70
references.pmid: 8067251
references.citation: J Trauma. 2009 Jul;67(1):125-31
references.pmid: 19590321
references.citation: Science. 1999 Apr 23;284(5414):647-50
references.pmid: 10213688
references.citation: Curr Med Chem. 2008;15(17):1697-705
references.pmid: 18673219
references.citation: Arterioscler Thromb Vasc Biol. 2011 Oct;31(10):2306-13
references.pmid: 21737785
references.citation: Thromb Haemost. 2009 Dec;102(6):1149-56
references.pmid: 19967145