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The Effects of Continuous Venovenous Hemofiltration on Coagulation

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The Effects of Continuous Venovenous Hemofiltration on Coagulation Available online http://ccforum.com/content/10/5/R150 ResearchVol 10 No 5 Open Access The effects of continuous venovenous hemofiltration on coagulation activation Catherine SC Bouman1, Anne-Cornélie JM de Pont1, Joost CM Meijers2, Kamran Bakhtiari2, Dorina Roem3, Sacha Zeerleder3, Gertjan Wolbink3, Johanna C Korevaar4, Marcel Levi5 and Evert de Jonge1 1Department of Intensive Care, Academic Medical Center, University of Amsterdam, PO 22660, 1100 DD Amsterdam, The Netherlands 2Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands 3Laboratory for Experimental and Clinical Immunology, Sanquin Blood Supply Foundation, Amsterdam, The Netherlands 4Department of Clinical Epidemiology & Biostatistics, Academic Medical Center, University of Amsterdam, The Netherlands 5Department of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands Corresponding author: Catherine SC Bouman, [email protected] Received: 22 Jun 2006 Revisions requested: 25 Aug 2006 Revisions received: 29 Sep 2006 Accepted: 27 Oct 2006 Published: 27 Oct 2006 Critical Care 2006, 10:R150 (doi:10.1186/cc5080) This article is online at: http://ccforum.com/content/10/5/R150 © 2006 Bouman et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Introduction The mechanism of coagulation activation during the kallikrein–C1-inhibitor complex and activated factor XII–C1- continuous venovenous hemofiltration (CVVH) has not yet been inhibitor complex levels were significantly higher in group B, elucidated. Insight into the mechanism(s) of hemostatic whereas the platelet count was significantly lower in group B. activation within the extracorporeal circuit could result in a more For the other studied markers the differences between group A rational approach to anticoagulation. The aim of the present and group B at baseline were not statistically significant. During study was to investigate whether CVVH using cellulose CVVH the difference in the time course between group A and triacetate filters causes activation of the contact factor pathway group B was not statistically significant for the markers of the or of the tissue factor pathway of coagulation. In contrast to tissue factor system (soluble tissue factor, activated factor VII previous studies, CVVH was performed without anticoagulation. and tissue factor pathway inhibitor), for the markers of the contact system (kallikrein–C1-inhibitor and activated factor XII– Methods Ten critically ill patients were studied prior to the start C1-inhibitor complexes) and for the markers of the fibrinolytic of CVVH and at 5, 15 and 30 minutes and 1, 2, 3 and 6 hours system (plasmin–antiplasmin complexes, tissue-type thereafter, for measurement of prothrombin fragment F1+2, plasminogen activator and plasminogen activator inhibitor type soluble tissue factor, activated factor VII, tissue factor pathway I). inhibitor, kallikrein–C1-inhibitor and activated factor XII–C1- inhibitor complexes, tissue-type plasminogen activator, plasminogen activator inhibitor type I, plasmin–antiplasmin Conclusion Early thrombin generation was detected in a complexes, protein C and antithrombin. minority of intensive care patients receiving CVVH without anticoagulation. Systemic concentrations of markers of the Results During the study period the prothrombin fragment tissue factor system and of the contact system did not change F1+2 levels increased significantly in four patients (defined as during CVVH. To elucidate the mechanism of clot formation group A) and did not change in six patients (defined as group B). during CVVH we suggest that future studies are needed that Group A also showed a rapid increase in transmembrane investigate the activation of coagulation directly at the site of the pressure, indicating clotting within the filter. At baseline, the filter. Early coagulation during CVVH may be related to lower activated partial thromboplastin time, the prothrombin time and baseline levels of markers of contact activation. CRRT = continuous renal replacement therapy; CVVH = continuous venovenous hemofiltration; ELISA = enzyme-linked immunosorbent assay; F1+2 = prothrombin fragment F1+2; FVIIa = activated factor VII; FXIIa = activated factor XII; IL = interleukin; PAP = plasmin–antiplasmin; TFPI = tissue factor pathway inhibitor; t-PA = tissue type plasminogen activator. Page 1 of 8 (page number not for citation purposes) Critical Care Vol 10 No 5 Bouman et al. Introduction heparin within 12 hours prior to starting CVVH or low molecu- Acute renal failure requiring renal replacement therapy occurs lar weight heparin within 48 hours prior to starting CVVH; in approximately 4% of patients admitted to the intensive care treatment with extracorporeal techniques within 48 hours prior unit, and often these patients are treated with some form of to starting CVVH; or discontinuation of CVVH for any reason continuous renal replacement therapy (CRRT) [1]. CRRT other than clotting of the circuit (for example, transfer for a requires anticoagulation to allow the passage of blood through computed tomography scan). the extracorporeal circuit over a prolonged period. Mainte- nance of CRRT circuits for sufficient duration is important for Continuous venovenous hemofiltration efficacy, cost-effectiveness and minimization of blood compo- Vascular access was obtained by insertion of a 14 F double- nent loss. On the other hand, the systemic anticoagulation lumen catheter (Duo-Flow 400 XL; Medcomp, Harleysville, techniques used to prevent clotting of the circuit are important PA, USA) into a large vein (femoral, subclavian or internal jug- causes of morbidity in CRRT. Understanding the mechanisms ular vein). Hemofiltration was performed with computer-con- involved in premature clotting of the filtration circuit is manda- trolled, fully automated hemofiltration machines (Diapact; tory to optimize anticoagulation and to maintain filter patency. Braun AG, Melsungen, Germany). A 1.9 m2 cellulose triace- β tate hollow-fiber membrane with a sieving coefficient for 2- Several studies have addressed the pathophysiology of circuit microglobulin of approximately 0.82 was used (CT190G; Bax- thrombogenesis, but the exact mechanism by which it occurs ter, McGaw Park, IL, USA). The blood flow rate was 150 ml/ has not yet been elucidated. Multiple factors may play a role: minute and warmed substitution fluid was added in predilution the extracorporeal circuit itself, treatment modalities, platelet mode at a flow rate of 2 l/hour. The hemofiltration run contin- factors, coagulation factors, natural anticoagulants and fibri- ued until the extracorporeal circuit clotted. No anticoagulant nolysis [2,3]. Clotting of CRRT circuits could be caused by was used during CVVH, and neither was the extracorporeal increased activation of coagulation, initiated either by the circuit primed with any anticoagulant. (intrinsic) contact activation pathway or the (extrinsic) tissue factor/activated factor VII (FVIIa) pathway, or by low activity of Blood collection the endogenous anticoagulant pathways, such as the anti- Blood was drawn from the venous limb of the hemofiltration thrombin system, the protein C/protein S system and the tis- catheter before starting hemofiltration, and at 5, 15 and 30 sue factor pathway inhibitor system. In addition, decreased minutes and at 1, 2, 3 and 6 hours after commencement of fibrinolysis could also contribute to clotting of extracorporeal CVVH. For the determination of contact activation 4.8 ml circuits. blood was collected in siliconized vacutainer tubes, to which 0.2 ml of a mixture of ethylenediamine tetraacetic acid (0.25 Although much is known about the effect of a single hemodi- M), benzamidine (0.25 M) and soybean–trypsin inhibitor alysis treatment on the coagulation system, very few prospec- (0.25%) was added to prevent in vitro contact activation and tive studies have monitored the effects of repeated passage of clotting. All other blood samples were collected in citrated blood through a CRRT circuit, and these studies were always vacutainer tubes. Plasma was prepared by centrifugation of performed with concurrent administration of anticoagulants, blood twice at 2500 × g for 20 minutes at 16°C, followed by usually unfractionated heparin or low molecular weight heparin storage at -80°C until assays were performed. [4-7]. As heparin influences tissue-factor-mediated coagula- tion, contact-activated coagulation [7] and fibrinolysis [8], Assays however, studies on the activation of coagulation during CRRT The plasma concentrations of prothrombin fragment F1+2 should ideally be performed without anticoagulation. (F1+2) were measured by ELISA (Dade Behring, Marburg, Germany). Soluble tissue factor was also determined by In the present study in critically ill patients with acute renal fail- ELISA (American Diagnostica, Greenwich, CT, USA). The ure, we studied the effects of continuous venovenous hemofil- plasma concentration of FVIIa was determined on a Behring tration (CVVH) without the use of anticoagulation on the Coagulation System (Dade Behring) with the StaClot VIIa-rTF activation of coagulation and fibrinolysis. method from Diagnostica Stago (Asnières-sur-Seine, France). The tissue factor pathway inhibitor (TFPI) activity was
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