INTRODUCTION — Hemodialysis (HD) and continuous kidney replacement therapies (CKRT) require blood access. Blood is exposed to surfaces of varying thrombogenicity as it travels through the HD and CKRT circuits. In the event of clotting in the blood circuit, approximately 180 to 200 mL of blood can be lost, due to an inability to return it back into the patient. In addition to loss of blood, clotting within the capillary fibers of the dialyzer results in reduced solute clearances and a shortened dialyzer lifespan. Thus, some form of anticoagulation (eg, unfractionated heparin [UFH]) is typically administered at the time of dialysis to prevent clotting in the blood circuit.
This topic discusses anticoagulation for intermittent HD delivered in the setting of acute kidney injury or end-stage kidney disease. Anticoagulation for continuous therapies is discussed elsewhere. (See "Anticoagulation for continuous kidney replacement therapy".)
ASSESSING BLEEDING RISK — The use of anticoagulation for intermittent hemodialysis (HD) is common due to the propensity for clotting within the circuit. However, the decision to administer anticoagulation begins with assessment of a patient's bleeding risk.
Patients who are on HD are generally prothrombotic, especially after a surgical procedure, and have an increased risk of clotting in the dialysis circuit. However, the risk of bleeding exceeds the risk of clotting in certain patient groups. These include patients with:
●Severe thrombocytopenia (platelet count of <20,000/microL)
●Evidence of active bleeding from the gastrointestinal tract, intra-abdominal bleeding, extensive bleeding from surgical wounds, or from arterial or venous catheters at the time of dialysis
●Major surgery (especially intra-ocular and spinal surgeries) in the prior 72 hours (table 1)
●Active intracranial or extradural hemorrhage
●Use of systemic anticoagulants
●Coagulation factor VII or VIII deficiency
Our approach to anticoagulation among these patients at high risk for bleeding is discussed below. (See 'Patients at high risk for bleeding' below.)
Patients who do not have the above conditions are deemed standard risk and are treated with anticoagulation as below. (See 'Standard-risk patients' below.)
Patients with deficiencies of clotting factors IX, XI, and XII are not considered high-risk for bleeding with anticoagulation during routine outpatient HD. This is because clotting of the hemodialysis circuit is primarily driven by factor VII, along with platelet and leukocyte activation. However, patients with hemophilia A (factor VIII deficiency) may have prolonged bleeding after needles are removed from the arteriovenous access site and may require administration of recombinant factor VIII prior to needle removal. Thus, deficiencies of clotting factors other than factor VII and VIII do not pose a higher risk for bleeding while the patients are on HD [1-3].
Use of antiplatelet agents alone is not considered a risk factor for bleeding among patients receiving HD. In addition, combinations of antiplatelet agents, such as aspirin and clopidogrel at standard doses, do not appear to increase the risk of bleeding at needle sites; however, one study reported that higher dose combinations may increase needle-site bleeding in patients using arteriovenous grafts .
Patients who have undergone major surgery are often prothrombotic shortly after the procedure. Their risk of bleeding falls exponentially with time, leaving them at no higher risk of bleeding beyond 72 hours of surgery as compared with standard-risk patients .
Our approach to identifying patients at high risk of bleeding is largely based upon our clinical experience. A majority of the literature in this area comes from an era when larger doses (than what we now recommend) of unfractionated heparin (UFH) were used to mitigate the thrombogenic potential of older HD equipment (which is no longer in use). Over time, there have been major improvements in the biocompatibility of materials used in the extracorporeal circuit and in the manufacturing processes, leading to greater surface smoothness. These changes have helped lower the thrombogenic potential of the dialysis circuit. As a result, the doses of UFH used in clinical practice have declined substantially over time. Thus, literature reflective of the prior era practices may not be entirely applicable to decision-making pertaining to the prevailing use of UFH [6-8].
Standard-risk patients — Patients with standard risk for anticoagulation constitute the majority of the dialysis population. The use of anticoagulation varies globally. Both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) protocols are effective, have similar safety profiles, and are equally acceptable strategies [9,10]. Thus, we use one of the following two approaches in standard-risk patients:
●Unfractionated heparin – Dialysis units in many regions, including North America, use UFH for anticoagulation during hemodialysis (HD). We administer a bolus of 2000 units at the beginning of dialysis, followed by a continuous infusion of 500 units per hour. This infusion is usually turned off 60 minutes before the end of the dialysis session but can be adjusted depending upon an individual patient's clotting tendencies in the last hour of dialysis. If clotting develops, then we stop 30 minutes before the termination of dialysis. Many centers in Europe use an initial UFH bolus dose of 1000 units rather than 2000 units.
An alternative approach is to customize the dose of the bolus to the patient's weight. With this approach, a bolus of 500 IU is administered for adult patients weighing <50 kg, 1000 IU for patients weighing between 50 and 100 kg, and 2000 IU for patients weighing >100 kg.
Various other permutations of UFH anticoagulation have been used by some units, although they may increase the burden on dialysis nursing staff, which may increase the chances of dosing errors, and therefore are less preferred. They include giving a bolus without a continuous infusion; a continuous infusion without a bolus; an initial bolus with a second mid-treatment bolus but without a continuous infusion; and an initial bolus followed by a declining infusion rate for the continuous infusion.
●Low-molecular-weight heparins – LMWH use for anticoagulation during HD predominates in Western Europe, parts of Asia, and Australia. Dosing of LMWHs depends upon the drug used, due to their varying half-lives, and upon the length of the dialysis session. As an example, tinzaparin (LMWH with the shortest half-life) is dosed as a bolus of 2500 anti-Xa units for a four-hour dialysis session, whereas enoxaparin (LMWH with the longest half-life) is dosed at 20 mg for a four-hour dialysis session. Patients treated with a short-acting LMWH like tinzaparin may also need a second bolus for sessions longer than four hours (either the same dose or smaller dose depending upon the time remaining on dialysis). We administer LMWH in the arterial limb of the dialyzer, which may lead to some loss of drug in the dialyzer . This loss can be minimized by administering the LMWH bolus after the patient has been on dialysis for approximately two to three minutes.
Alterations to this standard prescription may be needed if bleeding or clotting are encountered during an HD session:
●If there is clotting detected in the venous air chamber and dialyzer header in the first half of the dialysis session, then we increase the UFH bolus in 500 IU increments per treatment, for a maximum of 4000 units.
If clotting is detected in the second half of the session, then we increase the UFH infusion rate by 100 IU/hour every treatment to a maximum of 1000 IU/hour.
Patients who have clotting while being treated with LMWH have their bolus increased sequentially over the subsequent dialysis sessions.
Usually, the first of these changes to the dose of UFH or LMWH for clotting are made during the patient's next dialysis treatment.
If recurrent filter clotting continues to remain a problem despite appropriate titration of anticoagulants, then we evaluate the patient for a dialysis access inflow or outflow stenosis.
●If bleeding from needle sites at the end of the HD session takes longer than seven minutes to stop, then we lengthen the time between cessation of the UFH infusion and end of dialysis (typically 60 minutes) in 10-minute increments until the time required for the bleeding to stop is seven minutes or under. For patients on LMWH who have prolonged bleeding from their access, we lower the bolus dose for the following dialysis session. All patients with persistent prolonged access bleeding should also undergo evaluation of their HD access. (See "Overview of hemodialysis arteriovenous fistula maintenance and thrombosis prevention", section on 'Venous stenotic lesions' and "Overview of hemodialysis arteriovenous fistula maintenance and thrombosis prevention", section on 'Thrombosis without identified stenotic lesion'.)
Patients on HD are at greater risk of developing atrial fibrillation and stroke. As such, an increasing number of patients are treated with oral anticoagulants, including vitamin K antagonists (warfarin), anti-Xa antagonists (apixaban), and, more recently, anti-X1 monoclonals (osocimab/xisomab) . Patients prescribed warfarin anticoagulation for artificial metallic heart valves with an international normalized ratio target of 3.5 to 4.5 generally do not require additional anticoagulation for HD, whereas those anticoagulated for atrial fibrillation often require anticoagulation. However, the dose of systemic anticoagulant chosen should be minimized by reducing loading doses for UFH and LMWHs.
Our approach requires minimal staff intervention and is standard in most HD units [13,14]. In addition, our approach allows for individual modifications based upon issues encountered, and for variable heparin pharmacokinetics in a given patient.
Patients at high risk for bleeding — There is no standard practice to prevent clotting of the HD circuit among patients who are at high risk for bleeding. Protocols differ across institutions and countries. Two approaches used at our institutions are outlined below:
●No-heparin method – With this method, the circuit is primed with isotonic saline alone, prior to a patient's arrival. Then, while the patient is on HD, the arterial (predialyzer) limb of the circuit is flushed with 200 mL of isotonic saline every hour for the duration of the HD session (figure 1) [15-18]. This additional saline flushed is factored into the ultrafiltration goals for the treatment session in order to minimize hypervolemia. Nurses caring for such patients need to be vigilant for any arterial and venous pressure alarms, and for observing for any visible clots in the dialyzer and bubble traps. (See "Overview of the hemodialysis apparatus", section on 'Dialyzers' and "Overview of the hemodialysis apparatus", section on 'Dialysis tubing'.)
This approach of hourly saline flushes minimizes hemoconcentration and washes fibrin strands from the dialyzer into the bubble trap. A major disadvantage of this method is the need for closer staff supervision of the patient, and additional ultrafiltration is required to achieve adequate sodium removal.
●Heparinized solution rinse or heparin-bonded dialyzer – A heparinized saline solution, made by adding 10,000 to 20,000 units of UFH in 1000 to 2000 mL of isotonic saline, is flushed through the hemodialysis circuit prior to the patient's arrival. Then, this unfractionated heparinized solution is rinsed out with isotonic saline prior to connecting the patient to the HD circuit. Binding of heparin to the dialyzer depends upon surface composition and charge. Heparin-bonded dialyzers are also commercially available.
Whether or not using a heparinized solution rinse or heparin-bonded dialyzer is superior to the no-heparin method is unclear [19-21]. One trial found more shortened treatments, more membrane clotting, and greater thrombin generation with the use of heparin-bonded dialyzers with citrate-containing dialysate and no systemic anticoagulation compared with use of heparin-bonded dialyzers with systemic heparin .
●Predilution hemodiafiltration – Hemodiafiltration is an option in some countries, and predilution hemodiafiltration has similarities to the constant saline infusion technique. Studies have reported a greater than 90 percent treatment success when combining predilution hemodiafiltration with citrate-containing dialysate . However, this may be dependent on dialyzer hemocompatibility .
Most patients at high risk of bleeding are switched to a heparin-based protocol once their risk of bleeding is mitigated (eg, several days of stabilization after bleeding events or procedures). (See 'Standard-risk patients' above.)
Patients with recurrent filter thrombosis — Patients with standard risk for bleeding who have recurrent filter thrombosis should have the dose of UFH or LMWH adjusted as discussed above. (See 'Standard-risk patients' above.)
Patients with a high risk for bleeding who are treated with the no-heparin method and who have recurrent filter thrombosis can have the following interventions undertaken, depending upon local feasibility:
●Increase the blood flow rate and the needle gauge, if not already maximized. In countries where daily hemodiafiltration (HDF) is available, converting to short daily HDF with a high volume of predilutional (upstream) infusate (ie, >40 L) may be a reasonable option. Details of HDF are discussed at length elsewhere [25,26]. (See "Technical aspects of hemodiafiltration".)
●More frequent saline flushes (eg, every 30 minutes instead of every hour) as used in the "no-heparin method" among patients at high risk for bleeding. (See 'Patients at high risk for bleeding' above.)
Patients who fail these interventions and continue to have recurrent thrombosis can be transitioned to heparin-based anticoagulation (beginning at a lower dose), or be treated with either citrate dialysate or daily high-volume HDF combined with epoprostenol regional anticoagulation:
●Heparin-based anticoagulation – If the patient is transitioned to heparin-based anticoagulation, we treat with a 1000 unit bolus of UFH at the beginning of dialysis (sometimes referred to as "tight-heparin"). If clotting continues, we use a 1000 unit UFH bolus at the beginning of dialysis followed by an infusion at 500 units/hour, turned off in the last 60 minutes of dialysis (sometimes referred to as "mini-heparin"). If needed, the standard approach described above can be used (see 'Standard-risk patients' above). For patients treated with LMWH, we treat with lower doses.
●Citrate dialysate – Citric acid can be used as a partial or total replacement of acetate or bicarbonate in the dialysate [27,28]. Citrate dialysate results in reduced clotting compared with no-heparin dialysis (by binding to ionized calcium, thereby interfering with the clotting cascade). The major safety concern with citrate dialysate is the potential for a decrease in ionized calcium and magnesium. At a citric acid concentration of 2.4 mEq/L, a small change in serum calcium and magnesium does occur, although usually not enough to cause symptoms . Citrate dialysate is generally only used in a hospital-based dialysis unit where calcium and magnesium can be monitored.
●High-volume HDF with epoprostenol – The arachidonic metabolite epoprostenol is a vasodilator and inhibitor of platelet aggregation. The in-vitro half-life of epoprostenol is three to five minutes, due to rapid metabolism by endothelial smooth muscle. Epoprostenol regional anticoagulation involves the infusion of epoprostenol into the arterial limb of the dialyzer circuit at 4 to 8 ng/kg/minute [30,31]. Side effects include headache, lightheadedness, and facial flushing, largely resulting from vasodilation and hypotension. To avoid hypotension, the epoprostenol infusion is started at 0.5 ng/kg/min and then increased in a step-wise manner by doubling the infusion rate every two minutes up to a maximum rate of 8 ng/kg/min. Due to its short half-life, epoprostenol is metabolized by the time it enters the systemic circulation, thereby acting as a regional anticoagulant. The technique of short daily high-volume HDF is discussed elsewhere. (See "Technical aspects of hemodiafiltration".)
If a patient continues to have recurrent thrombosis despite dose modifications to their anticoagulation regimen and having their dialysis access evaluated, then we pursue a hematological evaluation to look for prothrombotic tendencies. This often involves consultation with a hematologist to interpret results of such testing and to formulate a management plan. Such evaluation for prothrombotic tendencies should include conditions such as thrombocythemia, increased factor VIII, prothrombin mutations, factor V Leiden, anticardiolipin antibodies, antibodies to platelet factor 4 (PF4), and reduced natural anticoagulants (antithrombin and proteins S and C).
Patients with heparin-induced thrombocytopenia — There are two forms of heparin-induced thrombocytopenia (HIT), only one of which is clinically significant (type 2):
●HIT type I is a mild, transient, and self-limited drop in platelet count that typically occurs within the first two days of UFH exposure. It appears to result from nonimmune platelet aggregation by a direct effect on platelets. No change in dialysis-related anticoagulation management is warranted for HIT type 1. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Terminology and HIT variants'.)
●HIT type II is a clinically significant condition resulting from antibodies to PF4 complexed to UFH, referred to as "HIT antibodies" or "PF4/heparin antibodies." These antibodies can cause thrombosis and thrombocytopenia. Suspected or confirmed HIT type 2 warrants anticoagulation using a nonheparin strategy. A diagnosis of HIT type II should be noted in patients' charts to prevent inadvertent instillation of a heparin lock at the end of a dialysis session. The treatment is often guided by a hematologist and is presented elsewhere. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Terminology and HIT variants' and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Pathophysiology' and "Management of heparin-induced thrombocytopenia".)
SPECIAL CONSIDERATIONS FOR INPATIENT HEMODIALYSIS
Inpatients with acute kidney injury requiring hemodialysis — We typically use the "no-heparin method" among inpatients who receive hemodialysis (HD) for acute kidney injury. If such patients have recurrent filter clotting, then we use the same unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) protocol as for standard-risk patients. (See 'Standard-risk patients' above.)
Inpatients who are on chronic hemodialysis — Among patients who are on chronic HD for end-stage kidney disease, we mimic the patient's outpatient anticoagulation regimen while they are admitted. The only exception to this is if a patient is admitted for evaluation and management of a bleeding event or about to undergo a major procedure. We assess their risk for bleeding during the admission as outlined above. (See 'Assessing bleeding risk' above.)
METHODS SELDOM USED
Methods seldom used for anticoagulation during dialysis include:
●Regional citrate anticoagulation – The regional citrate regimen involves the continuous infusion of isosmotic trisodium citrate solution (102 mmol/L) into the arterial limb of the dialyzer (figure 2) [32,33]. The anticoagulant activity of this regimen results from binding of citrate to calcium, which interrupts the coagulation cascade. Most centers use a calcium-free dialysate, and regional citrate anticoagulation can be used for low- and high-flux hemodialysis and hemodiafiltration . Centers differ in the citrate concentration entering the dialyzer (2.7 to 4 mmol/L), but higher concentrations have not been demonstrated to improve hemocompatibility , and others have reported successful dialysis sessions when using calcium-free dialysate alone without citrate and calcium reinfusion .
Citrate anticoagulation is reversed by the infusion of 5 percent calcium chloride into the venous return line at a rate of 0.5 mL/min. This rate is constantly adjusted according to frequent measurements of plasma calcium concentration to prevent hypocalcemia or hypercalcemia .
Comparative trials have shown a reduced incidence of bleeding with these regimens when compared with standard UFH protocols [38,39]. The major problem with regional citrate anticoagulation is hypocalcemia or hypercalcemia, hypernatremia (due to the hypertonic sodium citrate solution), and metabolic alkalosis (due to bicarbonate generated during the metabolism of citrate) that may require hydrochloric acid infusion. If closely monitored, however, the complication rate is relatively low [37,39,40]. Specifically designed dialysate may also lower the incidence of electrolyte abnormalities, including metabolic alkalosis .
●Regional anticoagulation with nafamostat – Nafamostat is a serine protease inhibitor that does not have the hypotensive side effects of prostacyclin . It is mainly used as an alternative to citrate or prostacyclin in Japan and South Korea. Nafamostat has a relatively short half-life of five to eight minutes and requires an initial bolus followed by an infusion, adjusted according to the activated partial thromboplastin time (aPTT). The main advantage of this drug is that no further titration is needed once goal aPTT is met, allowing for a tight control in patients at high risk of bleeding. It may, however, be associated with an unacceptably high incidence of clot formation. In one study using nafamostat, clot formation was observed in up to 36 percent of dialyzers despite adequate prolongation of the aPTT . In addition, nafamostat cannot be used with polyacrylonitrile dialysis membranes due to adsorption onto the membrane surface. Nafamostat is very expensive outside of Japan and is not yet available in the United States.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)
SUMMARY AND RECOMMENDATIONS
●General principles – Hemodialysis (HD) and continuous kidney replacement therapies (CKRT) are typically delivered with some form of anticoagulation (eg, unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) to prevent clotting in the blood circuit. (See 'Introduction' above.)
●Assessing bleeding risk – Patients on chronic HD are generally prothrombotic. However, the risk of bleeding exceeds the risk of clotting among patients who have severe thrombocytopenia, evidence of active bleeding, a history of major surgery within the prior 72 hours (table 1), active intracranial or extradural hemorrhage, uremic pericarditis, coagulation factor VII or VIII deficiency, or who are being treated with systemic anticoagulants. Patients who are on antiplatelet agents alone are not considered to be at a high risk for bleeding. (See 'Assessing bleeding risk' above.)
●Approach to anticoagulation – Our approach to anticoagulation depends upon an individualized assessment of a patient's risk of bleeding or thrombosis:
•Standard-risk patients – We treat standard-risk patients (who are not at higher risk for bleeding or thrombosis) with either UFH or LMWH. Details of dosing options, administration, and alterations in dosing in the setting of bleeding or thrombosis are discussed above. (See 'Standard-risk patients' above.)
•Patients at high risk for bleeding – Patients at high risk for bleeding are treated with the "no-heparin" method (figure 1), heparinized solution rinse, or heparin-bonded dialyzer. Most patients at high risk of bleeding are switched to a heparin-based protocol once their risk of bleeding is mitigated (eg, several days of stabilization after bleeding events or procedures). (See 'Patients at high risk for bleeding' above.)
•Patients with recurrent filter thrombosis – Patients at standard risk for bleeding who have recurrent filter thrombosis should have their UFH or LMWH increased. Patients at high risk for bleeding who have recurrent filter thrombosis should have their blood flow and needle gauge maximized and frequency of saline flushes increased. Those who continue to have recurrent filter thrombosis despite these interventions should either be transitioned to a UFH-based regimen, Citrasate (brand name) dialysate, or to hemodiafiltration with epoprostenol regional anticoagulation. Details of these methods are discussed above. (See 'Patients with recurrent filter thrombosis' above.)
•Patients with heparin-induced thrombocytopenia (HIT) – Patients who have HIT type I do not require any changes in their anticoagulation regimen. Patients who have HIT type II should not be treated with any UFH or LMWH products and need to be comanaged for HIT in concert with hematologists. (See 'Patients with heparin-induced thrombocytopenia' above and "Management of heparin-induced thrombocytopenia".)
●Inpatients with AKI – Patients who are admitted to a hospital with acute kidney injury (AKI) requiring HD are generally treated without anticoagulation, unless they have recurrent filter thrombosis, in which case they are treated with UFH or LMWH similar to standard-risk patients. (See 'Inpatients with acute kidney injury requiring hemodialysis' above.)
●Inpatients on chronic HD – Patients on chronic HD who are admitted to a hospital are continued on their outpatient anticoagulation regimen. The exception to this is made for patients who are admitted for evaluation of a bleeding event or for a major procedure, and such patients are treated without anticoagulation until their bleeding risk is mitigated. (See 'Inpatients who are on chronic hemodialysis' above.)
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