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4.6. Anticoagulation

4.6. Anticoagulation

We recommend that patients without increased bleeding risk should be given unfractionated or low molecular weight heparin during dialysis to reduce clotting of the extracorporeal system. [1A]

We recommend that systemic anticoagulation should be omitted or minimised in patients with increased bleeding risk. [1C]

We recommend that patients with heparin allergies should be prescribed a non heparin form of anticoagulation. [1A]

Rationale

Platelet activation in the extracorporeal circuit accelerates thrombin generation via the intrinsic coagulation pathway, so that anticoagulation is usually required to prevent thrombosis. Unfractionated heparin is used as the standard anticoagulant worldwide in view of its proven efficacy, ease of use and long safety record unless the patient has recent or active bleeding, thrombocytopenia, heparin allergy or heparin induced thrombocytopenia.

With a mean half life of 1.5 hours, heparin is usually administered as a loading dose of 1000 2000 IU followed by a continuous infusion of 500 1500U/h that is discontinued approximately 30 minutes before the end of the dialysis session. Monitoring can be performed by measuring the activated partial thromboplastin time ratio (aPTTr) or the whole blood activated clotting time aiming for around 150% of pre dialysis or centre normal values [1,2]. However, in practice, the bolus dose, infusion rate, and stopping times are adjusted empirically, according to clot formation in the dialysis circuit, and the time for needle sites to stop bleeding. Heparin dose may need to be increased with higher haematocrit, or reduced/withdrawn in patients at risk of haemorrhage, those with thrombocytopenia or on long term anticoagulation [3].

Alternatively, a low molecular weight heparin may be used [4], having a longer half life, given as a single ‘arterial limb’ bolus at the start of dialysis [5]. Although monitoring can be performed using anti Xa activity, these are not always available and laboratory testing correlates less directly with clinical effect, so as with unfractionated heparin, dose adjustment is usually empirical, but larger or repeated doses may be needed depending on convective clearance and session length, and reduced doses for those at risk of haemorrhage [6]. Several systematic reviews comparing low molecular weight with unfractionated heparin have found no difference in the incidence of bleeding complications, post dialysis access bleeding, or thrombosis of the extracorporeal circuit [7 10]. With its convenience for nursing staff, the use of low molecular weight heparin is becoming more common in Europe.

For patients at increased risk of bleeding, several options are used in clinical practice. Firstly, several techniques require no anticoagulation to be administered during dialysis, including: combining a high blood flow rate and regular pre dialyzer circuit flushing every 15 30 minutes [11,12]; using a heparin coated dialyzer [13,14]; adding heparin to the rinsing solution [12]; or using a dialysate containing citrate [15 17].

Secondly, a regional anticoagulant can be used such as citrate, prostacyclin (epoprostenol), or nafamostat (not currently available in the UK). Regional anticoagulation with citrate [18] and epoprostenolol [19] have both been reported to reduce the risk of haemorrhage compared to heparin, though there are drawbacks: epoprostenol may induce hypotension and is costly, whereas citrate administration requires re infusion of calcium based on electrolyte monitoring, adding complexity and nursing staff time [20]. Finally, lower doses of unfractionated or low molecular weight heparin have been used with caution in patients at risk of bleeding [3,6].

Heparin induced thrombocytopenia, usually occurring shortly after regular exposure to heparin, and sometimes with thrombosis, may occur in heparin treated dialysis patients [21,22]. The risk of heparin induced thrombocytopenia can be estimated using the 4T scoring system [23], and is usually confirmed by laboratory testing and detailed guidelines on diagnosis and treatment are published by the British Society of Haematology, but in suspected or confirmed cases, all heparins should be withdrawn [24]. The risk of thrombosis increases with the severity of thrombocytopaenia, and anticoagulation is usually started with either the direct thrombin inhibitor argatroban [25], or a natural (danaparoid) or synthetic (fondaparinux) heparinoid [26,27]. Argatroban is reversible, given by continuous infusion, and requires careful laboratory monitoring with aPTTr. The heparinoids are renally excreted and have prolonged half lives in dialysis patients, such that monitoring of the bolus given with a dialysis session can be based on anti Xa activity prior to the following session. Once the platelet count returns to normal, patients are usually anticoagulated with warfarin, but in the majority of cases antibodies disappear with time, and patients have been successfully re challenged with unfractionated and low molecular weight heparins once laboratory testing becomes negative [28].

References

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  2. Brunelli SM, Cohen DE, Marlowe G, Liu D, Njord L, Van Wyck D, Aronoff G. Safety and efficacy of heparin during dialysis in the context of systemic anticoagulant and antiplatelet medications. J Nephrol. 2019 Jan doi: 10.1007/s40620 018 00576 w. PMID: 30604148
  3. Swartz RD. Hemorrhage during high risk haemodialysis using controlled heparinization. Nephron. 1981;28(2):65 9
  4. European Best Practice Guidelines for haemodialysis Part 1. Nephrol Dial Transplant 2002; 17: Supplement 7 S1 S111
  5. Dhondt A, Pauwels R, Devreese K, Eloot S, Glorieux G, Vanholder R. Where and When To Inject Low Molecular Weight Heparin in Hemodiafiltration? A Cross Over Randomised Trial. PLoS One. 2015;10(6):e0128634. doi: 10.1371
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  8. Palamaner Subash Shantha G, Kumar AA, Sethi M, Khanna RC, Pancholy SB. Efficacy and safety of low molecular weight heparin compared to unfractionated heparin for chronic outpatient haemodialysis in end stage renal disease: systematic review and meta analysis. PeerJ. 2015 Mar 10;3:e835. doi: 10.7717/peerj.835. eCollection 2015
  9. Shen JI, Winkelmayer WC. Use and safety of unfractionated heparin for anticoagulation during maintenance haemodialysis. Am J Kidney Dis. 2012;60(3):473 86
  10. Lazrak HH, René É, Elftouh N, Leblanc M, Lafrance JP. Safety of low molecular weight heparin compared to unfractionated heparin in haemodialysis: a systematic review and meta analysis. BMC Nephrol. 2017;18(1):187
  11. Sahota S, Rodby R. Inpatient haemodialysis without anticoagulation in adults. Clin Kidney J. 2014;7(6):552 6
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  13. Lavaud S, Paris B, Maheut H, Randoux C, Renaux JL, Rieu P, Chanard J. Assessment of the heparin binding AN69 ST haemodialysis membrane: II. Clinical studies without heparin administration. ASAIO J. 2005 Jul Aug;51(4):348 51
  14. Laville M, Dorval M, Fort Ros J, Fay R, Cridlig J, Nortier JL, Juillard L, Dębska Ślizień A, Fernández Lorente L, Thibaudin D, Franssen C, Schulz M, Moureau F, Loughraieb N, Rossignol P. Results of the HepZero study comparing heparin grafted membrane and standard care show that heparin grafted dialyzer is safe and easy to use for heparin free dialysis. Kidney Int. 2014;86(6):1260 7
  15. Kossmann RJ, Gonzales A, Callan R, Ahmad S. Increased efficiency of haemodialysis with citrate dialysate: a prospective controlled study. Clin J Am Soc Nephrol. 2009;4(9):1459 64
  16. Hanevold C, Lu S, Yonekawa K. Utility of citrate dialysate in management of acute kidney injury in children. Hemodial Int. 2010;14 Suppl 1:S2 6
  17. Sands JJ, Kotanko P, Segal JH, Ho CH, Usvat L, Young A, Carter M, Sergeyeva O, Korth L, Maunsell E, Zhu Y, Krishnan M, Diaz Buxo JA. Effects of citrate acid concentrate (citrasate®) on heparin N requirements and haemodialysis adequacy: a multicenter, prospective noninferiority trial. Blood Purif. 2012;33(1 3):199 204
  18. Kreuzer M, Bonzel KE, Büscher R, Offner G, Ehrich JH, Pape L. Regional citrate anticoagulation is safe in intermittent high flux haemodialysis treatment of children and adolescents with an increased risk of bleeding. Nephrol Dial Transplant. 2010;25(10):3337 42
  19. Swartz RD, Flamenbaum W, Dubrow A, Hall JC, Crow JW, Cato A. Epoprostenol (PGI2, prostacyclin) during high risk haemodialysis: preventing further bleeding complications. J Clin Pharmacol. 1988;28(9):818 25
  20. Wright S, Steinwandel U, Ferrari P. Citrate anticoagulation using ACD solution A during long term haemodialysis. Nephrology (Carlton). 2011;16(4):396 402
  21. Warkentin TE. Heparin induced thrombocytopenia in critically ill patients. Semin Thromb Hemost. 2015;41(1):49 60
  22. Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S. Heparin induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol. 1997;56(1):12 6
  23. Linkins LA, Bates SM, Lee AY, Heddle NM, Wang G, Warkentin TE. Combination of 4Ts score and PF4/H PaGIA for diagnosis and management of heparin induced thrombocytopenia: prospective cohort study. Blood. 2015 30;126(5) :597 603
  24. Scully M, Gates C, Neave L. How we manage patients with heparin induced thrombocytopenia. Br J Haematol. 2016. doi: 10.1111/bjh.14102 Renal Association Clinical Practice Guideline Haemodialysis– July 2019 50
  25. Murray PT, Hursting MJ. Heparin induced thrombocytopenia in patients administered heparin solely for haemodialysis. Ren Fail. 2006;28(7):537 9.
  26. Magnani HN. A review of 122 published outcomes of danaparoid anticoagulation for intermittent haemodialysis. Thromb Res. 2010;125(4):e171 6
  27. Mahieu E, Claes K, Jacquemin M, Evenepoel P, Op De Beek K, Bogaert AM, Kuypers D, Verhamme P, Meijers B. Anticoagulation with fondaparinux for hemodiafiltration in patients with heparin induced thrombocytopenia: dose finding study and safety evaluation. Artif Organs. 2013;37(5):482 7
  28. Dhakal P, Giri S, Pathak R, Bhatt VR. Heparin Reexposure in Patients With a History of Heparin Induced Thrombocytopenia. Clin Appl Thromb Hemost. 2015;21(7):626 31