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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2002  |  Volume : 13  |  Issue : 1  |  Page : 40-44
Anticoagulation for Hemodialysis and Hemofiltration

81 Gloucester Avenue, Grimsby DN34 5BU, England

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How to cite this article:
Wardle E N. Anticoagulation for Hemodialysis and Hemofiltration. Saudi J Kidney Dis Transpl 2002;13:40-4

How to cite this URL:
Wardle E N. Anticoagulation for Hemodialysis and Hemofiltration. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2021 Apr 14];13:40-4. Available from: https://www.sjkdt.org/text.asp?2002/13/1/40/33200
Filter Thrombosis

Flow of blood through an extra-corporeal, non-endothelialized circuit activates the intrinsic and extrinsic coagulation pathways so that thrombin is formed, and converts fibrinogen to fibrin clot. In turn, thrombin stimulates release of factors that enhance platelet adhesion and aggregation. Circulating platelets adhere to the foreign surface. They release adenosine diphosphate (ADP), throm­boxane A 2 and other products from their granules. Aggregated platelets activate prothrombin (factor II) at their cell surface. In addition, platelets are activated by high shear stress, and by interaction with absorbed fibrinogen.

We normally think of activation of the extrinsic pathway when tissue injury causes release of thromboplastin. [1] Monocytes express tissue factor (TF) as a result of the action of cytokines or the effect of minute amounts of endotoxin that pass from dialysate fluid. When activated polymorpho-nuclear neutro­phils (PMNs) release reactive oxygen species (ROS), as happens in a foreign circuit, the ROS cause monocytes to express TF. As [Figure - 1] indicates, factor VIIa with tissue factor generate factor Xa, which can create sufficient thrombin [2] to cause aggregation of platelets and activation of critical factors V and VIII.

Heparinization (Unfractionated Heparin)

Under-anticoagulation carries a risk of clotting in the extra-corporeal circuit. Over­heparinization may provoke occult or overt bleeding, often from the gastrointestinal tract. Heparin is a set of glycosamino­glycans (GAGs) with molecular weights from 3,000 to 35,000 daltons, mean 15 kDa.

Heparin activates the serine protease inhibitor anti-thrombin III that inhibits conversion of prothrombin to thrombin and factors Xa and IXa. Since heparinization is an agent-blood interaction, and not an agent-dialyzer interaction, it really is not necessary to prime the extra-corporeal circuit with heparinized saline, albeit large doses of heparin do adsorbe to the artificial membranes after prolonged circulation. One starts with a bolus dose of heparin, and since it takes time to activate antithrombin, one must wait at least five minutes before connecting the patient. The bolus is 500 - 2000 units. Heavy patients need a larger dose. There is a formula [3] that can be used: Bolus (IU) = 1600 + (10 x wt in kilos - 76). This is followed by continuous infusion of 3-15 U/kg per hour. One aims to achieve a 1.5-2.0 times prolongation of the activated clotting time (ACT) or activated partial thromboplastin time (APTT). There is a computerized model [4] to take account of the patient sensitivity to heparin.

Adequate tests for bedside monitoring of anticoagulation are desirable. The whole blood clotting time (WBCT) is when whole blood is added to a test tube at 37°C and rotated every 30 seconds until it clots. Pre­dialysis results are 3-6 minutes and during hemodialysis (HD), 15-20 mins. For the whole blood activated clotting time (WBACT), an activator like kailin is added to speed the initial stage of coagulation. Pre-dialysis results are 90-140 seconds and during HD, 200-240 secs. The laboratory measured whole blood partial thromboplastin time (WBPTT) measures the activity of prothrombin, and is 60-85 secs pre-dialysis and during HD, 120-160 secs. [5] There is also the laboratory activated partial thrombo­plastin time (APTT) using plasma.

The required dose of heparin varies widely from patient to patient on HD. One can use tables [3] to allow for body weight, diabetic or non-diabetic status and to allow for smoking habit. Heparin dosage will also change with time on dialysis for individual patients.


Hemofiltration (HF) might result in more hemostatic activation because of concentration of coagulation factors along the filter. Yet, predilution infusions help by dilution of the prefilter hematocrit, clotting factors and platelet count. For critically ill patients requiring continuous arteriovenous hemo­dialysis (CAVHD)/HF the safe APTT is 1.5-2.0 times normal, giving a low incidence of hemorrhage, and yet good filter survival. [6],[7]

Low Molecular Weight Heparins (LMWH)

LMW heparins confer a lower risk of bleeding, since they interact less with platelets and with the vascular endothelium. Laboratory monitoring is not necessary. [8] LMWHs are obtained from porcine mucosal heparins by either chemical or enzymatic depolymerization to yield basic pentasaccharide subunits with a mean of 6 kDa, range 2-15. They have names like enoxaparin, dalteparin (Fragmin) and tinzaparin. By virtue of small chain length, LMWH do not bind thrombin so that they have reduced antithrombin effect, but there is a high anti-Xa/anti-IIa ratio. They have a more predictable pharmacokinetic and anticoagulant response, since they have a longer circulating half-life and greater bioavailability. As they differ in their molecular weights and in anti-Xa/IIa ratio, optimal doses should be determined for each of them. [9] There is less heparin resistance, decreased osteopenic potential and a lower risk of thrombocytopenia/ thrombosis.

Although the first studies of their use in HD were done in 1985, good studies on dosage are quite recent. [10] For assessment of anticoagulation efficacy one can use the APTT, chromogenic anti-Xa, [11] and markers of plasma coagulation like thrombin-anti­thrombin (TAT) and prothrombin fragment PF1+2. In fact, subclinical activation of coagulation may still occur. [12] More studies are required.

Heparin Induced Thrombocytopenia (HIT)

Heparin associated thrombocytopenia occurs in 10-20% patients who are put on heparin. There is mild transient thrombocytopenia 1­4 days after heparin with counts rarely falling below 100,000 x 10 9 /L. HIT is much more serious, [13] for there are IgG antibodies to the complex of heparin with PF4 leading to a hypercoagulable state and thrombosis. HIT manifests 5-10 days after heparin when platelets drop more than 50% to lower than 50,000 x 10 9 /L.

The action to be taken when there is HIT is not an easy decision. [14] All LMW heparins are contraindicated. Danaparoid (Orgaran) made of dermatan sulphate and chondroitin is a factor Xa inhibitor that is structurally distinct from heparin. Experience is limited and it is expensive and it causes prolonged anticoagulation. The direct thrombin inhibitor from the leech called hirudin [15] or lepuridin is costly too. Argotroban thrombin inhibitor is available commercially. The APTT is used for control, or the ecarin clotting time. [16]

Bleeding Risk Patients

The requirement for anticoagulation depends on the condition of the hemostatic system. Patients with acute or recent bleeding, those in post-surgery or post-trauma phase, and those who are coagulopathic as a result of sepsis or systemic inflammatory response syndrome (SIRs) may be given HD or HF without anti-coagulation. Giving pre-filter saline flushes 50-100 ml hourly can be useful. [17],[18] It is better to have a high blood flow rate.

Patients with acute renal failure often display reduced platelet function, decreased platelet counts, prolongation of their coagulation times and even activated coagulation due to disseminated intra­vascular coagulation. Additive problems include sepsis, liver dysfunction, fluid overload and heart failure.

Regional heparinization is achieved by infusion of protamine sulphate on the return line. The polycationic peptide neutralizes the anionic heparin, but there can be difficulty in titrating the dose. The stable complex will activate complement, and so patients may exhibit hypotension and pulmonary vasoconstriction. Generally the technique is reserved for problem patients. [6] The technique does not prolong filter life. ,[18]

What about the use of citrate to chelate calcium, so depleting a necessary cofactor [Figure - 1]? [19],[20] When used in HD/HF the systemic effect is reduced by rapid meta­bolism to bicarbonate. Again, regional infusion is required and there are many problems, like hypernatremia, metabolic alkalosis and citrate intoxication with ionized hypocalcemia. Liver dysfunction that limits citrate metabolism is a contra­indication.

Risk of bleeding is reduced by prosta­cyclin infusion into the extracorporeal circuit. The cost is a problem. Infusion of 4 nanograms/kg/min is started 10 mins before HD is started, and the dose adjusted downwards if hypotension and flushing are a problem, and upwards, if there are signs of clotting, [21] toward 8 ng/kg/min. Platelet function is inhibited but bleeding complications should not occur. In reality, use of prostacyclin is best in combination with heparin to prolong filter life in cases where there is frequent filter failure. [22]

   References Top

1.Osterud B, Bajaj MS, Bajaj SP. Sites of tissue factor pathway inhibitor (TFPI) and tissue factor expression under physiologic and pathologic conditions. Thromb Hemost 1995;73:873-5.  Back to cited text no. 1    
2.Broze GJ Jr. Tissue factor pathway inhibitor and the revised theory of coagulation. Ann Rev Med 1995;46:103-12.  Back to cited text no. 2    
3.Andrysiak P, Varughese PM, Orsini-Negroni J. Heparin therapy for hemodialysis patients. Dial Transplant 2001;223-4.  Back to cited text no. 3    
4.Nissenson AR, Fine RN. Dialysis therapy 2nd edition. Philadelphia. Hanley & Belfus Inc 1993;p 82.  Back to cited text no. 4    
5.Farrell PC, Ward RA, Schindhelm K, Gotch F. Precise anticoagulation for routine hemodialysis. J Lab Clin Med 1978;92:164-76.  Back to cited text no. 5  [PUBMED]  
6.Urwin S, Leary TS, Fletcher S. Hemo­filtration II-anticoagulation care of the critically ill 2001;17(3):99-103.  Back to cited text no. 6    
7.van de Wetering J, Westendorp RG, van der Hoeven JG, et al. Heparin use in continuous renal replacement procedures: the struggle between filter coagulation and patient hemorrhage. J Am Soc Nephrol 1996;7:145-50.  Back to cited text no. 7  [PUBMED]  
8.Kessler CM. Low molecular weight heparins: practical considerations. Semin Hematol 1997;34(Suppl 4):35-42.  Back to cited text no. 8    
9.Hirsh J, Warkentin TE, Raschke R, et al. Heparin and low molecular weight heparin. Mechanisms of action, pharmacokinetics dosing considerations, monitoring, effecacy and safety. Chest 1998;114(Suppl):489S­510S.  Back to cited text no. 9    
10.Sagedal S, Hartmann A, Sundstrom K, et al. A single dose of dalteparin effectively prevents clotting during haemodialysis. Nephrol Dial Transplant 1999;14:1943-7.  Back to cited text no. 10    
11.Ryan KE, Lane DA, Flynn A, et al. Dose finding study of a low molecular weight heparin, Innohep, in haemodialysis. Thromb Haemost 1991;66:277-82.  Back to cited text no. 11  [PUBMED]  
12.Sagedal S, Hartmann A, Sundstrom K, Bjornsen S, Brosstad F. Anticoagulation intensity sufficient for hemodialysis does not prevent activation of coagulation and platelets. Nephrol Dial Transpl 2001;16: 987-93.  Back to cited text no. 12    
13.Warkentin TE. Heparin induced thrombo­cytopenia: a ten year retrospective. Ann Rev Med 1999;50:129-47.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Chuang P, Parikh C, Reilly RF. A case review: anticoagulation in hemodialysis patients with heparin induced thrombo­cytopenia. Am J Nephrol 2001;21:226-31.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Vargas Hein O, von Heymann C, Lipps M, et al. Hirudin versus heparin for anti­coagulation in continuous renal replace­ment therapy. Intensive Care Med 2001; 27:673-9.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Kern H, Ziemer S, Kox WJ. Bleeding after intermittent or continuous r-hirudin during CVVH. Intensive Care Med 1999;25:1311-4.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Martin PY, Chevrolet JC, Suter P, Favre H. Anticoagulation in patients treated by continuous venovenous hemofiltration: a retrospective study. Am J Kidney Dis 1994;24:806-12.  Back to cited text no. 17  [PUBMED]  
18.Bellomo R, Teede H, Boyce N. Anti­coagulant regimens in acute continuous hemodiafiltration: a comparative study. Intensive Care Med 1993;19:329-32.  Back to cited text no. 18  [PUBMED]  
19.Mehta RL, McDonald BR, Aguilar MM, Ward DM. Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990; 38:976-81.  Back to cited text no. 19  [PUBMED]  
20.Meier-Kriesche HU, Gitomer J, Finkel K, DuBose T. Increased total to ionized calcium ratio during continuous venovenous hemo­dialysis with regional citrate anticoa­gulation. Crit Care med 2001;29:748-52.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Swartz RD, Flamenbaum W, Dubrow A, Hall JC, Crow JW, Cato A. Epoprostenol (PGI2, prostacyclin) during high risk hemo­dialysis: preventing further bleeding comp­lications. J Clin Pharmacol 1988;28:818-25.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Langenecker SA, Felfernig M, Werba A, et al. Anticoagulation with prostacyclin and heparin during continuous venovenous hemofiltration. Crit Care Med 1994;22:1774-81.  Back to cited text no. 22  [PUBMED]  

Correspondence Address:
E Nigel Wardle
81 Gloucester Avenue, Grimsby DN34 5BU, England

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