Download PDF
Thromb Haemost 2018; 118(09): 1545-1555
DOI: 10.1055/s-0038-1667198
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Plasma Proteolytic Cascade Activation during Neonatal Cardiopulmonary Bypass Surgery

Susan A. Maroney
1   Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States
,
Julie A. Peterson
1   Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States
,
Wes Zwifelhofer
1   Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States
,
Nicholas D. Martinez
1   Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States
,
Ke Yan
2   Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
,
Rachel S. Bercovitz
1   Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States
2   Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3   Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
,
Ronald K. Woods
4   Division of Pediatric Cardiothoracic Surgery, Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States
5   Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
,
Alan E. Mast
1   Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States
6   Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
› Author Affiliations Funding This work was supported by National Heart, Lung, and Blood Institute grant HL068835 (to A.E. Mast) and the Herma Heart Center at Children's Hospital of Wisconsin.
Further Information

Publication History

01 May 2018

08 June 2018

Publication Date:
07 August 2018 (online)

Also available at
   Permissions and Reprints

Correction to:

Erratum to: Plasma proteolytic cascade activation during neonatal cardiopulmonary bypass surgeryThromb Haemost 2018; 118(11): 2009-2009
DOI: 10.1055/s-0038-1675192

Abstract

Background Neonates undergoing cardiopulmonary bypass (CPB) surgery to correct congenital heart defects often experience excessive bleeding. Exposure of blood to artificial materials during CPB may activate coagulation, complement and inflammatory pathways. In addition, the surgical stress placed on the haemostatic system may result in cross-activation of other plasma proteolytic cascades, which could further complicate physiological responses to the surgical procedure and post-operative recovery. Plasma protease inhibitors undergo distinct conformational changes upon interaction with proteases, and, thereby, can serve as endogenous biosensors to identify activation of the different proteolytic cascades. We tested the hypothesis that changes in the concentration and conformation of protease inhibitors regulating plasma proteolytic cascades during neonatal CPB are associated with post-operative bleeding.

Patients and Methods Plasma samples from 44 neonates were obtained at four time points across the surgical procedure. Anti-thrombin, antitrypsin, anti-chymotrypsin, anti-plasmin, C1-inhibitor and tissue factor pathway inhibitor (TFPI) concentrations and conformations were evaluated by enzyme-linked immunosorbent assay, transverse urea gradient gel electrophoresis and sodium dodecyl sulphate-polyacrylamide gel electrophoresis.

Results/Conclusion The most striking changes were observed following heparin administration and were associated with the appearance of inactive forms of anti-thrombin and an increase in the plasma concentration of TFPI. Changes in anti-thrombin and TFPI remained evident throughout surgery and into the post-operative period but were not different between patients with or without post-operative bleeding. The concentration of antitrypsin decreased across surgery, but there was no significant accumulation of inactive conformations of any inhibitor besides anti-thrombin, indicating that widespread cross-activation of other plasma proteolytic cascades by coagulation proteases did not occur.

Keywords

cardiopulmonary - coagulation - neonate - serpin - TFPI

Authors' Contributions

S.A. Maroney: designed research, performed experiments, interpreted data and wrote the manuscript. J.A. Peterson: designed research, interpreted data and wrote the manuscript. W. Zwifelhofer: performed experiments. N.D. Martinez: performed experiments. K. Yan: interpreted data and performed statistical analysis. R.S. Bercovitz: designed research and interpreted data. R.K. Woods: performed surgery, designed research and interpreted data. A.E Mast: designed research, interpreted data and wrote the manuscript.


 

  • References

  • 1 Arnold PD. Coagulation and the surgical neonate. Paediatr Anaesth 2014; 24 (01) 89-97
    CrossrefPubMedSearch in Google Scholar
  • 2 Whiting D, Yuki K, DiNardo JA. Cardiopulmonary bypass in the pediatric population. Best Pract Res Clin Anaesthesiol 2015; 29 (02) 241-256
    CrossrefPubMedSearch in Google Scholar
  • 3 Ferrer-Marin F, Stanworth S, Josephson C, Sola-Visner M. Distinct differences in platelet production and function between neonates and adults: implications for platelet transfusion practice. Transfusion 2013; 53 (11) 2814-2821
    CrossrefPubMedSearch in Google Scholar
  • 4 Hézard N, Potron G, Schlegel N, Amory C, Leroux B, Nguyen P. Unexpected persistence of platelet hyporeactivity beyond the neonatal period: a flow cytometric study in neonates, infants and older children. Thromb Haemost 2003; 90 (01) 116-123
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Rajasekhar D, Kestin AS, Bednarek FJ, Ellis PA, Barnard MR, Michelson AD. Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 1994; 72 (06) 957-963
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Cade JF, Hirsh J, Martin M. Placental barrier to coagulation factors: its relevance to the coagulation defect at birth and to haemorrhage in the newborn. BMJ 1969; 2 (5652): 281-283
    CrossrefPubMedSearch in Google Scholar
  • 7 Andrew M, Paes B, Milner R. , et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70 (01) 165-172
    CrossrefPubMedSearch in Google Scholar
  • 8 Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J, Gruel Y. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood 1996; 88 (03) 900-906
    PubMedSearch in Google Scholar
  • 9 Strauss T, Sidlik-Muskatel R, Kenet G. Developmental hemostasis: primary hemostasis and evaluation of platelet function in neonates. Semin Fetal Neonatal Med 2011; 16 (06) 301-304
    CrossrefPubMedSearch in Google Scholar
  • 10 Journois D, Pouard P, Greeley WJ, Mauriat P, Vouhé P, Safran D. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines, and complement components. Anesthesiology 1994; 81 (05) 1181-1189
    CrossrefPubMedSearch in Google Scholar
  • 11 Sonntag J, Dähnert I, Stiller B, Hetzer R, Lange PE. Complement and contact activation during cardiovascular operations in infants. Ann Thorac Surg 1998; 65 (02) 525-531
    CrossrefPubMedSearch in Google Scholar
  • 12 Sato H, Yamamoto K, Kakinuma A, Nakata Y, Sawamura S. Accelerated activation of the coagulation pathway during cardiopulmonary bypass in aortic replacement surgery: a prospective observational study. J Cardiothorac Surg 2015; 10: 84
    CrossrefPubMedSearch in Google Scholar
  • 13 Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113 (06) 1319-1333
    CrossrefPubMedSearch in Google Scholar
  • 14 Morizumi S, Hiramatsu Y, Matsuzaki K. , et al. Early heparin administration attenuates tissue factor-mediated thrombin generation during simulated cardiopulmonary bypass. J Card Surg 2014; 29 (01) 35-40
    CrossrefPubMedSearch in Google Scholar
  • 15 Ignjatovic V, Than J, Summerhayes R. , et al. Hemostatic response in paediatric patients undergoing cardiopulmonary bypass surgery. Pediatr Cardiol 2011; 32 (05) 621-627
    CrossrefPubMedSearch in Google Scholar
  • 16 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
    CrossrefPubMedSearch in Google Scholar
  • 17 Ge X, Yamaguchi Y, Zhao L. , et al. Prochemerin cleavage by factor XIa links coagulation and inflammation. Blood 2018; 131 (03) 353-364
    CrossrefPubMedSearch in Google Scholar
  • 18 Loebermann H, Tokuoka R, Deisenhofer J, Huber R. Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function. J Mol Biol 1984; 177 (03) 531-557
    CrossrefPubMedSearch in Google Scholar
  • 19 Mast AE, Enghild JJ, Pizzo SV, Salvesen G. Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-antiplasmin, angiotensinogen, and ovalbumin. Biochemistry 1991; 30 (06) 1723-1730
    CrossrefPubMedSearch in Google Scholar
  • 20 Mast AE, Enghild JJ, Salvesen G. Conformation of the reactive site loop of alpha 1-proteinase inhibitor probed by limited proteolysis. Biochemistry 1992; 31 (10) 2720-2728
    CrossrefPubMedSearch in Google Scholar
  • 21 Pizzo SV, Mast AE, Feldman SR, Salvesen G. In vivo catabolism of alpha 1-antichymotrypsin is mediated by the Serpin receptor which binds alpha 1-proteinase inhibitor, antithrombin III and heparin cofactor II. Biochim Biophys Acta 1988; 967 (02) 158-162
    CrossrefPubMedSearch in Google Scholar
  • 22 Bercovitz RS, Shewmake AC, Newman DK. , et al. Validation of a definition of excessive postoperative bleeding in infants undergoing cardiac surgery with cardiopulmonary bypass. J Thorac Cardiovasc Surg 2018; 155 (05) 2112-2124
    CrossrefPubMedSearch in Google Scholar
  • 23 Dietzen DJ, Jack GG, Page KL, Tetzloff TA, Hall CL, Mast AE. Localization of tissue factor pathway inhibitor to lipid rafts is not required for inhibition of factor VIIa/tissue factor activity. Thromb Haemost 2003; 89 (01) 65-73
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Ellery PER, Hilden I, Sejling K. , et al. Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and protein S. Res Pract Thromb Haemost 2018; 2 (01) 93-104
    CrossrefPubMedSearch in Google Scholar
  • 25 Maroney SA, Haberichter SL, Friese P. , et al. Active tissue factor pathway inhibitor is expressed on the surface of coated platelets. Blood 2007; 109 (05) 1931-1937
    CrossrefPubMedSearch in Google Scholar
  • 26 Faraoni D, Willems A, Savan V, Demanet H, De Ville A, Van der Linden P. Plasma fibrinogen concentration is correlated with postoperative blood loss in children undergoing cardiac surgery. A retrospective review. Eur J Anaesthesiol 2014; 31 (06) 317-326
    CrossrefPubMedSearch in Google Scholar
  • 27 Hakacova N, Laluhova-Striezencova Z, Zahorec M. Disturbances of coagulation in neonates with functionally univentricular physiology prior to the first stage of surgical reconstruction. Cardiol Young 2008; 18 (04) 397-401
    CrossrefPubMedSearch in Google Scholar
  • 28 Damus PS, Hicks M, Rosenberg RD. Anticoagulant action of heparin. Nature 1973; 246 (5432): 355-357
    CrossrefPubMedSearch in Google Scholar
  • 29 Travis J, Salvesen GS. Human plasma proteinase inhibitors. Annu Rev Biochem 1983; 52: 655-709
    CrossrefPubMedSearch in Google Scholar
  • 30 Collen D. Identification and some properties of a new fast-reacting plasmin inhibitor in human plasma. Eur J Biochem 1976; 69 (01) 209-216
    CrossrefPubMedSearch in Google Scholar
  • 31 Bangert K, Johnsen AH, Christensen U, Thorsen S. Different N-terminal forms of alpha 2-plasmin inhibitor in human plasma. Biochem J 1993; 291 (Pt 2): 623-625
    CrossrefPubMedSearch in Google Scholar
  • 32 Koyama T, Koike Y, Toyota S, Miyagi F, Suzuki N, Aoki N. Different NH2-terminal form with 12 additional residues of alpha 2-plasmin inhibitor from human plasma and culture media of Hep G2 cells. Biochem Biophys Res Commun 1994; 200 (01) 417-422
    CrossrefPubMedSearch in Google Scholar
  • 33 Kluft C, Los N. Demonstration of two forms of alpha 2-antiplasmin in plasma by modified crossed immunoelectrophoresis. Thromb Res 1981; 21 (1-2): 65-71
    CrossrefPubMedSearch in Google Scholar
  • 34 Davis III AE, Whitehead AS, Harrison RA. , et al. Human inhibitor of the first component of complement, C1: characterization of cDNA clones and localization of the gene to chromosome 11. Proc Natl Acad Sci U S A 1986; 83 (10) 3161-3165
    CrossrefPubMedSearch in Google Scholar
  • 35 Schoenberger OL, Sprows JL, Schechter NM, Cooperman BS, Rubin H. Limited proteolysis of C1-inhibitor by chymotrypsin-like proteinases. FEBS Lett 1989; 259 (01) 165-167
    CrossrefPubMedSearch in Google Scholar
  • 36 Rao LV, Rapaport SI. Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 1987; 69 (02) 645-651
    CrossrefPubMedSearch in Google Scholar
  • 37 Wood JP, Bunce MW, Maroney SA, Tracy PB, Camire RM, Mast AE. Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation. Proc Natl Acad Sci U S A 2013; 110 (44) 17838-17843
    CrossrefPubMedSearch in Google Scholar
  • 38 Broze Jr GJ, Lange GW, Duffin KL, MacPhail L. Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1994; 5 (04) 551-559
    PubMedSearch in Google Scholar
  • 39 Novotny WF, Palmier M, Wun TC, Broze Jr GJ, Miletich JP. Purification and properties of heparin-releasable lipoprotein-associated coagulation inhibitor. Blood 1991; 78 (02) 394-400
    CrossrefPubMedSearch in Google Scholar
  • 40 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50 (06) 803-813
    CrossrefPubMedSearch in Google Scholar
  • 41 Donahue BS, Gailani D, Mast AE. Disposition of tissue factor pathway inhibitor during cardiopulmonary bypass. J Thromb Haemost 2006; 4 (05) 1011-1016
    CrossrefPubMedSearch in Google Scholar
  • 42 Stiller B, Sonntag J, Dähnert I. , et al. Capillary leak syndrome in children who undergo cardiopulmonary bypass: clinical outcome in comparison with complement activation and C1 inhibitor. Intensive Care Med 2001; 27 (01) 193-200
    CrossrefPubMedSearch in Google Scholar
  • 43 Mast AE, Stadanlick JE, Lockett JM, Dietzen DJ. Solvent/detergent-treated plasma has decreased antitrypsin activity and absent antiplasmin activity. Blood 1999; 94 (11) 3922-3927
    CrossrefPubMedSearch in Google Scholar