Maintaining blood flow in the extracorporeal circuit: haemostasis and anticoagulation

Abstract

Objectives

To review the methods and developments in maintaining extracorporeal circuits in critically ill patients.

Design

The review includes details of the pathophysiological processes of haemostasis and coagulation in critically ill patients, methods of maintaining blood flow in the extracorporeal circuit and methods of monitoring anticoagulation agents used.

Setting

Information is relevant to the management of critically ill patients requiring extracorporeal renal and respiratory support and cardiopulmonary bypass.

Conclusions

Heparin is the mainstay of anticoagulation for the extracorporeal circuit although the complex abnormalities of the coagulation system in critically ill patients are associated with a considerable risk of bleeding. Alternative therapeutic agents and physical strategies (prostacyclin, low molecular weight heparin, sodium citrate, regional anticoagulation, heparin bonding and attention to circuit design) may reduce the risk of bleeding but expense and difficulty in monitoring are disadvantages.

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References

  1. 1.

    Hellgren M, Egberg N, Eklund J (1984) Blood coagulation and fibrinolytic factors and their inhibitors in critically ill patients. Intensive Care Med 10:23–28

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Colman RW, Walsh PN (1987) Mechanisms of platelet aggregation. In: Colman RW, Hirsh, J, Marder VJ, Salzman EW (eds) Haemostasis and thrombosis. Lippincott, Philadelphia, pp 594–605

    Google Scholar 

  3. 3.

    Holmsen H (1987) Platelet secretion. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (eds) Haemostasis and thrombosis. Lippincott, Philadelphia, pp 606–617

    Google Scholar 

  4. 4.

    Sixma JJ (1987) Role of blood platelets, plasma proteins and the vessel wall haemostasis. In: Bloom AL, Thomas, DP (eds) Haemostasis and thrombosis. Churchill Livingstone, Edinburgh, pp 283–302

    Google Scholar 

  5. 5.

    Walsh PN (1982) The effects of collagen and kaolin on the intrinsic coagulant activities of platelets: evidence of an alternative pathway in intrinsic pathway in coagulation not requiring factor XII. Br J Haematol 22:393–405

    Google Scholar 

  6. 6.

    Zur M, Nemerson Y (1981) Tissue factor pathways of blood coagulation. In: Bloom AL, Thomas DP (eds) Haemostasis and thrombosis, Churchill Livingstone, Edinburgh, pp 124–139

    Google Scholar 

  7. 7.

    Schmaier AH, Silverberg M, Kaplan AP, Colman RW (1987) Contact activation and its abnormalities. In: Colman RW, Hirsh, J, Marder VJ, Salzman EW (eds) Hemostasis and thrombosis. Lippincott, Philadelphia, pp 18–38

    Google Scholar 

  8. 8.

    Kaplan AP, Meier HL, Mandle RJ (1976) The Hageman factor dependent pathways of coagulation, fibrinolysis, and kinin generation. Semin Thromb Hemost 3:1–26

    PubMed  CAS  Google Scholar 

  9. 9.

    de Agostini A, Lijnen HR, Pixley RA, Colman RW, Schapira M (1984) Inactivation of factor XII active fragment in normal plasma. Predominant role of C1-INH. J Clin Invest 73:1542–1549

    PubMed  Google Scholar 

  10. 10.

    Harpel PC (1987) Blood proteolytic enzyme inhibitors: their role in modulating blood coagulation and fibrinolytic enzyme pathways. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (eds) Haemostasis and thrombosis. Lippincott, Philadelphia, pp 219–234

    Google Scholar 

  11. 11.

    Owen WG, Esmon CT (1981) Functional properties of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 256:5532–5535

    PubMed  CAS  Google Scholar 

  12. 12.

    Rao LV, Rapaport SI, Bajaj SP (1986) Activation of human factor VII in the initiation of tissue factor-dependent coagulation. Blood 68:685–691

    PubMed  CAS  Google Scholar 

  13. 13.

    Oohira A, Wight TN, Bornstein P (1983) Sulfated proteoglycans synthesized by vascular endothelial cells in culture. J Biol Chem 258:2014–2021

    PubMed  CAS  Google Scholar 

  14. 14.

    Marcum JA, Rosenberg RD (1987) Anticoagulantly active heparin sulfate proteoglycan and the vascular endothelium. Semin Thromb Hemost 13:464–474

    PubMed  CAS  Google Scholar 

  15. 15.

    Bevilacqua MP, Pober JS, Majeau GR, Cotran RS, Gimbrone MA (1984) Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human endothelial cells. J Exp Med 160:618–623

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran S, Gimbrone MA (1986) Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with actions of interleukin 1. Proc Natl Acad Sci USA 83:4533–4537

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Hack CE, Nuijens JH, Strack van Schijndel RJM, Abbink JJ, Eerenberg AJM, Thijs LG (1990) A model for the interplay of inflammatory mediators in sepsis — a study in 48 patients. Intensive Care Med 16:S187-S191

    PubMed  Article  Google Scholar 

  18. 18.

    Hesselvik JF, Blombäck M, Brodin B, Maller R (1989) Coagulation, fibrinolysis and kallikrein systems in sepsis: relation to outcome. Crit Care Med 17:724–733

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Woodman RC, Harker LA (1990) Bleeding complications associated with cardiopulmonary bypass. Blood 76: 1680–1697

    PubMed  CAS  Google Scholar 

  20. 20.

    Thomson C, Forbes CD, Prentice CR (1973) The potentiation of platelet aggregation and adhesion by heparin in vitro and in vivo. Clin Sci Mol Med 45:485–494

    PubMed  CAS  Google Scholar 

  21. 21.

    Lazarowski ER, Santome JA, Behrens NH, Sanchez Avalos JC (1986) Aggregation of human neutrophils be heparin. Thromb Res 41:437–446

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Saba HI, Saba SR, Blackburn CA, Hartmann RC, Mason RG (1979) Heparin neutralization of PGI2: effects upon platelets. Science 205:499–501

    PubMed  CAS  Google Scholar 

  23. 23.

    Davies GC, Sobel M, Salzman EW (1980) Elevated plasma fibrinopeptide A and thromboxane A2 levels during cardiopulmonary bypass. Circulation 61:808–814

    PubMed  CAS  Google Scholar 

  24. 24.

    George JN, Pickett EB, Saucerman S, McEver RP, Kunicki TJ, Kieffer N, Newman PJ (1986) Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 78:340–348

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Dechavanne M, Ffrench M, Pages J, Ffrench P, Boukerche H, Bryon PA, McGregor JL (1987) Significant reduction in the binding of a monoclonal antibody (LYP 18) directed against the IIb/IIIa glycoprotein complex to platelets of patients having undergone extracorporeal circulation. Thromb Haemost 57:106–109

    PubMed  CAS  Google Scholar 

  26. 26.

    Wenger RK, Lukasiewicz H, Mikuta BS, Niewiarowski S, Edmunds LHJ (1989) Loss of platelet fibrinogen receptors during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 97:235–239

    PubMed  CAS  Google Scholar 

  27. 27.

    Abrams CS, Ellison N, Budzynski AZ, Shattil SJ (1990) Difect detection of activated platelets and platelet-derived microparticles in humans. Blood 75:128–138

    PubMed  CAS  Google Scholar 

  28. 28.

    Wachtfogel YT, Kucich U, Greenplate J, Gluszko P, Abrams W, Weinbaum G, Wenger RK, Rucinski B, Niewiarowski S, Edmunds LHJ (1987) Human neutrophil degranulation during extracorporeal circulation. Blood 69: 324–330

    PubMed  CAS  Google Scholar 

  29. 29.

    Wachtfogel YT, Harpel PC, Edmunds LHJ, Colman RW (1989) Formation of C1s-C1-inhibitor, kallikrein-C1-inhibitor, and plasmin-α2-plasmin inhibitor complexes during cardiopulmonary bypass. Blood 73:468–471

    PubMed  CAS  Google Scholar 

  30. 30.

    Gallimore MJ, Heller W, Fuhrer G, Wendel H, Klaffschenkel R, Hoffmeister HE (1992) Contact activation, heparins and cardiopulmonary bypass. Thromb Haemost 68:91–92

    PubMed  CAS  Google Scholar 

  31. 31.

    Furie B, Furie BC (1992) Molecular and cellular biology of blood coagulation. N Engl J Med 326:800–806

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    McLean J (1916) The thromboplastic action of cephalin. Am J Physiol 41:250

    Google Scholar 

  33. 33.

    Gregorius FK, Rand RW (1976) Scanning electron microscopy of the rat common carotid artery. III. Heparin effects on platelets. Surgery 79:583–589

    Google Scholar 

  34. 34.

    Chen J, Karlberg K-E, Sylven C (1991) Heparin and low molecular weight heparin but not hirudin stimulate platelet aggregation in whole blood from acetylsalicylic acid treated healthy volunteers. Thromb Res 63:319–329

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Zucker MB (1975) Effect of heparin on platelet function. Thromb Diath Haemorrh 33:63–65

    PubMed  CAS  Google Scholar 

  36. 36.

    Michalski R, Lane DA, Kakkar VJ (1977) Comparison of heparin and a semisynthetic heparin analogue. II. Some effects on platelet function. Br J Haematol 37:247–256

    PubMed  CAS  Google Scholar 

  37. 37.

    Bestermann EM, Gillet MP (1973) Heparin effects on plasma lysolecithin formation and platelet aggregation. Atherosclerosis 17:503–513

    Article  Google Scholar 

  38. 38.

    Koch KM, Bechstein PB, Fassbinder W, Kaltwasser P, Schoeppe W (1975) Occult blood loss and iron balance in chronic renal failure. Proc EDTA 112: 681–684

    Google Scholar 

  39. 39.

    Chong BH, Berndt MC (1989) Heparin induced thrombocytopenia. Blut 58: 53–57

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Gallimore MJ, Fuhrer G, Heller W, Hoffmeister HE (1991) The effects of fractionated and unfractionated heparins with and without aprotinin on plasma inhibition of alpha and beta FXII a. Agents&Actions 38:257–264

    Google Scholar 

  41. 41.

    Bjornsson TD, Wolfram KM, Kitchell BB (1982) Heparin kinetics determined by three assay methods. Clin Pharmacol Ther 31:104–113

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Schapira M, Christman BW (1990) Neutralization of heparin and protamine. Time for a change? Circulation 82:1877–1879

    PubMed  CAS  Google Scholar 

  43. 43.

    Kaplan AA, Petrillo R (1987) Regional heparinization for continuous arteriovenous hemofiltration (CAVH). Asaio Trans 33:312–315

    PubMed  CAS  Google Scholar 

  44. 44.

    Teng CL, Kim JS, Port FK, Wakefield TW, Till GO, Yang VC (1988) A protamine filter for extracorporeal blood heparin removal. Asaio Trans 34:743–746

    PubMed  CAS  Google Scholar 

  45. 45.

    Larm O, Larsson R, Olsson P (1983) A new non-thrombogenic surface prepared by selective covalent binding of heparin via a modified reducing terminal residue. Biomat Med Dev Artif Org 2:161–173

    Google Scholar 

  46. 46.

    Arnander C, Dryjski M, Larsson R, Olsson P, Swedenborg J (1986) Thrombin uptake and inhibition on endothelium and surfaces with a stable heparin coating. A comparative in vitro study. J Biomed Mater Res 20:235–246

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Bindslev L, Eklund J, Norlander O, Swedenborg J, Olsson P, Nilsson E, Larm O, Gouda I, Malmberg A, Scholander E (1987) Treatment of acute respiratory failure by extracorporeal carbon dioxide elimination performed with a surface heparinized artificial lung. Anesthesiology 67:117–120

    PubMed  CAS  Google Scholar 

  48. 48.

    Peters J, Radermacher P, Kuntz ME, Rosenbauer KA, Breulmann M, Bürrig KF, Hopf HB, Rossaint R, Schulte HD, Olsson P, Falke KJ (1988) Extracorporeal CO2 removal with a heparin coated artificial lung. Intensive Care Med 14:578–584

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Schrader J, Stibbe W, Armstrong VW, Kandt M, Muche R, Kostering H, Seidel D, Scheler F (1988) Comparison of low molecular weight heparin to standard heparin in hemodialysis/hemofiltration. Kidney Int 33:890–896

    PubMed  CAS  Google Scholar 

  50. 50.

    Schrader J, Stibbe W, Kandt M, Warneke G, Armstrong V, Muller HJ, Scheler F (1990) Low molecular weight heparin versus standard heparin. A long-term study in hemodialysis and hemofiltration patients. ASAIO Trans 36:28–32

    PubMed  CAS  Google Scholar 

  51. 51.

    Bertele V, Roncanglione MC, Donati MB, de Gaetano G (1983) Heparin counteracts the antiaggregating effect of prostacyclin by potentiating platelet aggregation. Thromb Haemost 49: 81–83

    PubMed  CAS  Google Scholar 

  52. 52.

    Turney JH, Williams LC, Fewell MR, Parsons V, Weston MJ (1980) Platelet protection and heparin sparing with prostacyclin during regular dialysis therapy. Lancet II:224–226

    Google Scholar 

  53. 53.

    Zusman RM, Rubin RH, Cato AE, Cocchetto DM, Crow JW, Tolkoff-Rubin N (1981) Haemodialysis using prostacyclin instead of heparin as the sole antithrombotic agent. N Engl J Med 304:934–939

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Keogh A, Rylance P, Weston M, Parsons V (1984) Prostacyclin haemodialysis in patients at risk of haemorrhage. Proc Eur Dial Trans Assoc 13:51–54

    Google Scholar 

  55. 55.

    Mehta RL, McDonald BR, Aguilar MM, Ward DM (1990) Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 38:976–981

    PubMed  CAS  Google Scholar 

  56. 56.

    Ahmad S, Yeo KT, Jensen WM, Landicho D, Geogory B, Moritz JL, Kenny M (1990) Citrate anticoagulation during in vivo simulation of slow hemofiltration. Blood Purif 8:177–182

    PubMed  CAS  Google Scholar 

  57. 57.

    Chien S, Jan KM (1973) Ultrastructural basis of the mechanism of rouleaux formation. Microvasc Res 5:155–166

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Webb AR, Nash GB, Dormandy JA, Bennett ED (1990) A comparison of the effects of artificial plasma substitutes, albumin and saline solutions on in vitro apparent blood viscosity. Clin Hemorheol 10:287–296

    Google Scholar 

  59. 59.

    Wendon J, Smithies M, Sheppard M, Bullen K, Tinker J, Bihari D (1989) Continuous high volume venous-venous haemofiltration in acute renal failure. Intensive Care Med 15:358–363

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    David S, Cambi V (1992) Hemofiltration: predilution versus postdilution. Contrib Nephrol 96:77–85

    PubMed  CAS  Google Scholar 

  61. 61.

    Oedekoven B, Bey R, Mottaghy K, Schmid-Schonbein H (1984) Gabexate mesilate (FOY) as an anticoagulant in extracorporeal circulation in dogs and sheep. Thromb Haemost 52:329–332

    PubMed  CAS  Google Scholar 

  62. 62.

    Royston D (1990) The serine antiprotease aprotinin (Trasylol): a novel approach to reducing postoperative bleeding. Blood Coag Fibrinolysis 1:55–59

    CAS  Google Scholar 

  63. 63.

    Fritz H, Wunderer G (1983) Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung 33:479–494

    PubMed  CAS  Google Scholar 

  64. 64.

    Philipp E (1978) Calculations and hypothetical considerations on the inhibition of plasmin and plasma kallikrein by Trasylol. In: Davidson JF, Rowan RM, Samama MM, Desnoyers PC (eds) Progress in chemical fibrinolysis and thrombolysis. Raven Press, New York, pp 291–295

    Google Scholar 

  65. 65.

    Fritz H (1978) Inhibition of plasmin and plasma kallikrein by the basic trypsin-kallikrein inhibitor from bovine organs (Trasylol) and similar protease inhibitors — theoretical considerations. In: Davidson JJ, Rowan RM, Samama MM, Desnoyers PC (eds) Progress in chemical fibrinolysis and thrombolysis. Raven Press, New York, pp 285–290

    Google Scholar 

  66. 66.

    Glenn TM, Herlich BL, Lefer AM (1973) Protective action of a protease inhibitor in hemorrhagic shock. Arch Int Pharmacodyn Ther 203:292–304

    PubMed  CAS  Google Scholar 

  67. 67.

    Nimmo GR, Cumming AD (1991) The effects of aprotinin in septic shock unresponsive to volume loading. Crit Care Med 19:S16

    Google Scholar 

  68. 68.

    van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur C (1990) Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Cardiovasc Surg 99:788–797

    Google Scholar 

  69. 69.

    Del Maschio A, Evangelista V, Rajtar G, Chen Z, Cerletti C, de Gaetano G (1990) Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents. Am J Physiol 258:H870-H879

    PubMed  Google Scholar 

  70. 70.

    Evangelista V, Rajtar G, de Gaetano G, White JG, Cerletti C (1991) Platelet activation by FMLP stimulated polymorphonuclear leukocytes: the activity of Cathepsin G is not prevented by antiproteinases. Blood 77:2379–2388

    PubMed  CAS  Google Scholar 

  71. 71.

    Faint RW, Mythen MG, Mackie IJ, Machin SJ (1993) Aprotinin inhibits platelet aggregation induced by purified neutrophils. Br J Haematol (in press)

  72. 72.

    Royston D, Bidstrup BP, Taylor KM, Sapsford RN (1987) Effect of aprotinin on need for blood transfusions after repeat open heart surgery. Lancet II:1289–1291

    Article  Google Scholar 

  73. 73.

    Dietrich W, Barankay A, Dilthey G, Henze R, Niekau E, Sebening F, Richter JA (1989) Reduction of homologous blood requirement in cardiac surgery by intraoperative aprotinin application. Thorac Cardiovasc Surg 37:92–98

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Brunet F, Mira JP, Belghith M, Lanore JJ, Schlumberger S, Toulon P, Dhainaut JF (1992) Effect of aprotinin on hemorhagic complications in ARDS patients during prolonged extracorporeal CO2 removal. Intensive Care Med 18:364–367

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Colvin BT, Barrowcliffe TW (1993) The British Society for Haematology Guidelines on the use and monitoring of heparin 1992: Second Revision. Clin Pathol 46:97–103

    CAS  Google Scholar 

  76. 76.

    Francis JL, Howard C (1993) The effect of aprotinin on the response of the activated partial thromboplastin time (APTT) to heparin. Blood Coag Fibrinolysis 4:35–40

    CAS  Article  Google Scholar 

  77. 77.

    Wendel HP, Heller W, Gallimore MJ, Bantel H, Muller-Beissenhirtz H, Hoffmeister HE (1993) The prolonged activated clotting time (ACT) with aprotinin depends on the type of activator used for measurement. Blood Coag Fibrinolysis 4:41–45

    CAS  Google Scholar 

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Correspondence to A. R. Webb.

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Webb, A.R., Mythen, M.G., Jacobson, D. et al. Maintaining blood flow in the extracorporeal circuit: haemostasis and anticoagulation. Intensive Care Med 21, 84–93 (1995). https://doi.org/10.1007/BF02425162

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Key words

  • Extracorporeal circuits
  • Anticoagulation
  • Haemostasis
  • Heparin
  • Prostacyclin
  • Citrate
  • Aprotinin