Download PDF
Semin Thromb Hemost 2015; 41(01): 091-098
DOI: 10.1055/s-0034-1398384
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hemostasis and Thrombosis in Continuous Renal Replacement Treatment

Heleen M. Oudemans-van Straaten
1   Department of Adult Intensive Care, VU University Medical Center, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Publication Date:
15 January 2015 (online)

    Permissions and Reprints

Abstract

During continuous renal replacement therapy, the delicate equilibrium of hemostasis is disturbed. Owing to a complex interaction of critical illness, uremia, use of an extracorporeal circuit and anticoagulation, patients exhibit both hypercoagulability and an increased risk of bleeding. Contact of blood with foreign material initiates coagulation by triggering the contact activation coagulation pathway, the tissue factor–factor VIIa pathway and activation of platelets and monocytes, which adhere to the membrane. The interaction with critical illness induced alterations further enhances coagulation and inflammation. Classical markers of coagulation, prothrombin and activated thromboplastin time, and platelet count do not detect the procoagulant state. Critically ill patients also have in increased risk of bleeding and anticoagulation used for circuit clotting enhances this risk. Heparin is most commonly used. Heparin increases the risk of bleeding. Its efficacy and safety are further compromised by antithrombin deficiency, heparin binding to acute phase proteins and apoptotic and necrotic cells, and by its unpredictable effects on inflammation. Its interference with anticoagulation is therefore unreliable during critical illness. Citrate provides regional anticoagulation and increases biocompatibility. It is better tolerated than heparin and confers less bleeding, less transfusion, and longer circuit life.

Keywords

coagulation - anticoagulation - sepsis - heparin - citrate - acute kidney injury
 

  • References

  • 1 Cohen JR, Sarfati I, Birnbaum E, Benacquista T, Wise L. The inactivation of antithrombin III by serum elastase in patients with surgical infections. Am Surg 1990; 56 (11) 665-667
    PubMedGoogle Scholar
  • 2 Hörl WH. Hemodialysis membranes: interleukins, biocompatibility, and middle molecules. J Am Soc Nephrol 2002; 13 (Suppl. 01) S62-S71
    PubMedGoogle Scholar
  • 3 Joannidis M, Oudemans-van Straaten HM. Clinical review: Patency of the circuit in continuous renal replacement therapy. Crit Care 2007; 11 (4) 218
    CrossrefPubMedGoogle Scholar
  • 4 Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013; 39 (5) 559-566
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Levi M, van der Poll T. Endothelial injury in sepsis. Intensive Care Med 2013; 39 (10) 1839-1842
    CrossrefPubMedGoogle Scholar
  • 6 Key NS. Analysis of tissue factor positive microparticles. Thromb Res 2010; 125 (Suppl. 01) S42-S45
    CrossrefPubMedGoogle Scholar
  • 7 Barteneva NS, Fasler-Kan E, Bernimoulin M , et al. Circulating microparticles: square the circle. BMC Cell Biol 2013; 14: 23
    CrossrefPubMedGoogle Scholar
  • 8 Levi M. Diagnosis and treatment of disseminated intravascular coagulation. Int J Lab Hematol 2014; 36 (3) 228-236
    CrossrefPubMedGoogle Scholar
  • 9 Delabranche X, Boisramé-Helms J, Asfar P , et al. Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensive Care Med 2013; 39 (10) 1695-1703
    CrossrefPubMedGoogle Scholar
  • 10 Holley AD, Reade MC. The 'procoagulopathy' of trauma: too much, too late?. Curr Opin Crit Care 2013; 19 (6) 578-586
    PubMedGoogle Scholar
  • 11 Oudemans-van Straaten HM, van Schilfgaarde M, Molenaar PJ, Wester JP, Leyte A. Hemostasis during low molecular weight heparin anticoagulation for continuous venovenous hemofiltration: a randomized cross-over trial comparing two hemofiltration rates. Crit Care 2009; 13 (6) R193
    CrossrefPubMedGoogle Scholar
  • 12 Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014; 89 (2) 228-232
    CrossrefPubMedGoogle Scholar
  • 13 Baldwin I, Tan HK, Bridge N, Bellomo R. A prospective study of thromboelastography (TEG) and filter life during continuous veno-venous hemofiltration. Ren Fail 2000; 22 (3) 297-306
    CrossrefPubMedGoogle Scholar
  • 14 van de Wetering J, Westendorp RG, van der Hoeven JG, Stolk B, Feuth JD, Chang PC. Heparin use in continuous renal replacement procedures: the struggle between filter coagulation and patient hemorrhage. J Am Soc Nephrol 1996; 7 (1) 145-150
    PubMedGoogle Scholar
  • 15 Oudemans-van Straaten HM, Wester JP, de Pont AC, Schetz MR. Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based?. Intensive Care Med 2006; 32 (2) 188-202
    CrossrefPubMedGoogle Scholar
  • 16 Cohen MJ, Call M, Nelson M , et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg 2012; 255 (2) 379-385
    CrossrefPubMedGoogle Scholar
  • 17 Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal failure. Semin Thromb Hemost 2004; 30 (5) 579-589
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Molino D, De Lucia D, Gaspare De Santo N. Coagulation disorders in uremia. Semin Nephrol 2006; 26 (1) 46-51
    CrossrefPubMedGoogle Scholar
  • 19 Lutz J, Menke J, Sollinger D, Schinzel H, Thürmel K. Haemostasis in chronic kidney disease. Nephrol Dial Transplant 2014; 29 (1) 29-40
    CrossrefPubMedGoogle Scholar
  • 20 Sirolli V, Ballone E, Di Stante S, Amoroso L, Bonomini M. Cell activation and cellular-cellular interactions during hemodialysis: effect of dialyzer membrane. Int J Artif Organs 2002; 25 (6) 529-537
    CrossrefPubMedGoogle Scholar
  • 21 Plé H, Maltais M, Corduan A, Rousseau G, Madore F, Provost P. Alteration of the platelet transcriptome in chronic kidney disease. Thromb Haemost 2012; 108 (4) 605-615
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Hirsh J, Warkentin TE, Shaughnessy SG , et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (1, Suppl): 64S-94S
    CrossrefPubMedGoogle Scholar
  • 23 Joannidis M, Kountchev J, Rauchenzauner M , et al. Enoxaparin vs. unfractionated heparin for anticoagulation during continuous veno-venous hemofiltration: a randomized controlled crossover study. Intensive Care Med 2007; 33 (9) 1571-1579
    CrossrefPubMedGoogle Scholar
  • 24 Manson L, Weitz JI, Podor TJ, Hirsh J, Young E. The variable anticoagulant response to unfractionated heparin in vivo reflects binding to plasma proteins rather than clearance. J Lab Clin Med 1997; 130 (6) 649-655
    CrossrefPubMedGoogle Scholar
  • 25 Selleng K, Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia in intensive care patients. Crit Care Med 2007; 35 (4) 1165-1176
    CrossrefPubMedGoogle Scholar
  • 26 du Cheyron D, Bouchet B, Bruel C, Daubin C, Ramakers M, Charbonneau P. Antithrombin supplementation for anticoagulation during continuous hemofiltration in critically ill patients with septic shock: a case-control study. Crit Care 2006; 10 (2) R45
    CrossrefPubMedGoogle Scholar
  • 27 Liu S, Hoke D, Julian J, Carson DD. Heparin/heparan sulfate (HP/HS) interacting protein (HIP) supports cell attachment and selective, high affinity binding of HP/HS. J Biol Chem 1997; 272 (41) 25856-25862
    CrossrefPubMedGoogle Scholar
  • 28 Young E, Podor TJ, Venner T, Hirsh J. Induction of the acute-phase reaction increases heparin-binding proteins in plasma. Arterioscler Thromb Vasc Biol 1997; 17 (8) 1568-1574
    CrossrefPubMedGoogle Scholar
  • 29 Linder A, Åkesson P, Inghammar M, Treutiger CJ, Linnér A, Sundén-Cullberg J. Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock. Crit Care 2012; 16 (3) R90
    CrossrefPubMedGoogle Scholar
  • 30 Gebska MA, Titley I, Paterson HF , et al. High-affinity binding sites for heparin generated on leukocytes during apoptosis arise from nuclear structures segregated during cell death. Blood 2002; 99 (6) 2221-2227
    CrossrefPubMedGoogle Scholar
  • 31 Warkentin TE. Heparin-induced thrombocytopenia: diagnosis and management. Circulation 2004; 110 (18) e454-e458
    CrossrefPubMedGoogle Scholar
  • 32 Leithäuser B, Schumacher J, Lendemans S, Tillmanns H, Matthias FR. Antithrombin attenuates microvascular leakage and leukocyte-endothelial interaction in response to endotoxin. Semin Thromb Hemost 2002; 28 (Suppl. 01) 87-94
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Hoffmann JN, Vollmar B, Laschke MW , et al. Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. Thromb Haemost 2002; 88 (2) 242-252
    PubMedGoogle Scholar
  • 34 Jordan RE, Nelson RM, Kilpatrick J, Newgren JO, Esmon PC, Fournel MA. Antithrombin inactivation by neutrophil elastase requires heparin. Am J Med 1989; 87 (3B): 19S-22S
    PubMedGoogle Scholar
  • 35 Heinzelmann M, Bosshart H. Heparin binds to lipopolysaccharide (LPS)-binding protein, facilitates the transfer of LPS to CD14, and enhances LPS-induced activation of peripheral blood monocytes. J Immunol 2005; 174 (4) 2280-2287
    CrossrefPubMedGoogle Scholar
  • 36 Gozdzikiewicz J, Borawski J, Koc-Zorawska E, Mysliwiec M. Effects of enoxaparin on myeloperoxidase release during hemodialysis (Epub ahead of print). Hemodial Int 2014;
    PubMedGoogle Scholar
  • 37 Gritters M, Borgdorff P, Grooteman MP , et al. Platelet activation in clinical haemodialysis: LMWH as a major contributor to bio-incompatibility?. Nephrol Dial Transplant 2008; 23 (9) 2911-2917
    CrossrefPubMedGoogle Scholar
  • 38 Borawski J, Naumnik B, Rydzewska-Rosołowska A, Myśliwiec M. Myeloperoxidase up-regulation during haemodialysis: is heparin the missing link?. Nephrol Dial Transplant 2006; 21 (4) 1128 , author reply 1128–1130
    PubMedGoogle Scholar
  • 39 Adam M, Gajdova S, Kolarova H , et al. Red blood cells serve as intravascular carriers of myeloperoxidase. J Mol Cell Cardiol 2014; 74: 353-363
    CrossrefPubMedGoogle Scholar
  • 40 Cornet AD, Smit EG, Beishuizen A, Groeneveld AB. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007; 98 (3) 579-586
    PubMedGoogle Scholar
  • 41 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2, Suppl): S26-S34
    CrossrefPubMedGoogle Scholar
  • 42 Tasaki H, Yamashita K, Tsutsui M , et al. Heparin-released extracellular superoxide dismutase is reduced in patients with coronary artery atherosclerosis. Atherosclerosis 2006; 187 (1) 131-138
    CrossrefPubMedGoogle Scholar
  • 43 Black SC, Gralinski MR, Friedrichs GS, Kilgore KS, Driscoll EM, Lucchesi BR. Cardioprotective effects of heparin or N-acetylheparin in an in vivo model of myocardial ischaemic and reperfusion injury. Cardiovasc Res 1995; 29 (5) 629-636
    CrossrefPubMedGoogle Scholar
  • 44 Luan ZG, Naranpurev M, Ma XC. Treatment of low molecular weight heparin inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats. Inflammation 2014; 37 (3) 924-932
    CrossrefPubMedGoogle Scholar
  • 45 Thourani VH, Brar SS, Kennedy TP , et al. Nonanticoagulant heparin inhibits NF-kappaB activation and attenuates myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 2000; 278 (6) H2084-H2093
    PubMedGoogle Scholar
  • 46 Hoffmann JN, Hartl WH, Faist E, Jochum M, Inthorn D. Tumor necrosis factor measurement and use of different anticoagulants: possible interference in plasma samples and supernatants from endotoxin-stimulated monocytes. Inflamm Res 1997; 46 (9) 342-347
    CrossrefPubMedGoogle Scholar
  • 47 Hochart H, Jenkins PV, Preston RJ, Smith OP, White B, O'Donnell J. Concentration-dependent roles for heparin in modifying lipopolysaccharide-induced activation of mononuclear cells in whole blood. Thromb Haemost 2008; 99 (3) 570-575
    PubMedGoogle Scholar
  • 48 Leitienne P, Fouque D, Rigal D, Adeleine P, Trzeciak MC, Laville M. Heparins and blood polymorphonuclear stimulation in haemodialysis: an expansion of the biocompatibility concept. Nephrol Dial Transplant 2000; 15 (10) 1631-1637
    CrossrefPubMedGoogle Scholar
  • 49 Kelton JG, Arnold DM, Bates SM. Nonheparin anticoagulants for heparin-induced thrombocytopenia. N Engl J Med 2013; 368 (8) 737-744
    CrossrefPubMedGoogle Scholar
  • 50 Ivandic B, Zorn M. Monitoring of the anticoagulants argatroban and lepirudin: a comparison of laboratory methods. Clin Appl Thromb Hemost 2011; 17 (5) 549-555
    CrossrefPubMedGoogle Scholar
  • 51 Curvers J, van de Kerkhof D, Stroobants AK, van den Dool EJ, Scharnhorst V. Measuring direct thrombin inhibitors with routine and dedicated coagulation assays: which assay is helpful?. Am J Clin Pathol 2012; 138 (4) 551-558
    CrossrefPubMedGoogle Scholar
  • 52 Warkentin TE, Cook RJ, Marder VJ , et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005; 106 (12) 3791-3796
    CrossrefPubMedGoogle Scholar
  • 53 James MF, Roche AM. Dose-response relationship between plasma ionized calcium concentration and thrombelastography. J Cardiothorac Vasc Anesth 2004; 18 (5) 581-586
    CrossrefPubMedGoogle Scholar
  • 54 Calatzis A, Toepfer M, Schramm W, Spannagl M, Schiffl H. Citrate anticoagulation for extracorporeal circuits: effects on whole blood coagulation activation and clot formation. Nephron 2001; 89 (2) 233-236
    CrossrefPubMedGoogle Scholar
  • 55 Oudemans-van Straaten HM, Bosman RJ, Koopmans M , et al. Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37 (2) 545-552
    CrossrefPubMedGoogle Scholar
  • 56 Faybik P, Hetz H, Mitterer G , et al. Regional citrate anticoagulation in patients with liver failure supported by a molecular adsorbent recirculating system. Crit Care Med 2011; 39 (2) 273-279
    CrossrefPubMedGoogle Scholar
  • 57 Nurmohamed SA, Jallah BP, Vervloet MG, Yldirim G, ter Wee PM, Groeneveld AB. Continuous venovenous haemofiltration with citrate-buffered replacement solution is safe and efficacious in patients with a bleeding tendency: a prospective observational study. BMC Nephrol 2013; 14: 89
    CrossrefPubMedGoogle Scholar
  • 58 Link A, Klingele M, Speer T , et al. Total-to-ionized calcium ratio predicts mortality in continuous renal replacement therapy with citrate anticoagulation in critically ill patients. Crit Care 2012; 16 (3) R97
    CrossrefPubMedGoogle Scholar
  • 59 Zhang Z, Hongying N. Efficacy and safety of regional citrate anticoagulation in critically ill patients undergoing continuous renal replacement therapy. Intensive Care Med 2012; 38 (1) 20-28
    CrossrefPubMedGoogle Scholar
  • 60 Dhondt A, Vanholder R, Tielemans C , et al. Effect of regional citrate anticoagulation on leukopenia, complement activation, and expression of leukocyte surface molecules during hemodialysis with unmodified cellulose membranes. Nephron 2000; 85 (4) 334-342
    CrossrefPubMedGoogle Scholar
  • 61 Böhler J, Schollmeyer P, Dressel B, Dobos G, Hörl WH. Reduction of granulocyte activation during hemodialysis with regional citrate anticoagulation: dissociation of complement activation and neutropenia from neutrophil degranulation. J Am Soc Nephrol 1996; 7 (2) 234-241
    PubMedGoogle Scholar
  • 62 Bos JC, Grooteman MP, van Houte AJ, Schoorl M, van Limbeek J, Nubé MJ. Low polymorphonuclear cell degranulation during citrate anticoagulation: a comparison between citrate and heparin dialysis. Nephrol Dial Transplant 1997; 12 (7) 1387-1393
    CrossrefPubMedGoogle Scholar
  • 63 Gritters M, Grooteman MP, Schoorl M , et al. Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis. Nephrol Dial Transplant 2006; 21 (1) 153-159
    CrossrefPubMedGoogle Scholar
  • 64 Andersson T, Dahlgren C, Pozzan T, Stendahl O, Lew PD. Characterization of fMet-Leu-Phe receptor-mediated Ca2+ influx across the plasma membrane of human neutrophils. Mol Pharmacol 1986; 30 (5) 437-443
    PubMedGoogle Scholar
  • 65 Ding F, Song JH, Jung JY , et al. A biomimetic membrane device that modulates the excessive inflammatory response to sepsis. PLoS ONE 2011; 6 (4) e18584
    CrossrefPubMedGoogle Scholar
  • 66 Bryland A, Wieslander A, Carlsson O, Hellmark T, Godaly G. Citrate treatment reduces endothelial death and inflammation under hyperglycaemic conditions. Diab Vasc Dis Res 2012; 9 (1) 42-51
    CrossrefPubMedGoogle Scholar