Methods of Hemodialysis Anticoagulation

Standard Heparin Anticoagulation

Unfractionated heparin (UFH) is the most commonly used anticoagulation agent during hemodialysis. UFH binds to the enzyme antithrombin III, inducing a conformational change that leads to an increased activity of this natural anticoagulant. This results in accelerated inactivation of coagulation factors, such as factor Xa and thrombin ( Fig. 10.1 ). UFH is affordable, reliable, easily reversible, and requires minimal staff intervention after a patient's heparin dose is determined. UFH can also be safely used during pregnancy since it does not cross the placenta. Although heparin is relatively well tolerated, there are certain known risks and complications associated with its use, including increased risk of bleeding, heparin- induced thrombocytopenia (HIT), hypertriglyceridemia, hypersensitivity reactions, pruritus, osteoporosis, and rarely hyperkalemia.

UFH has a rapid onset of action and relatively short half-life (approximately 1 hour in dialysis patients). However, it is important to keep in mind, however, that there is interpatient variability in heparin metabolism during hemodialysis. Heparin activity is highly determined by patient weight and other variables, such as dialyzer absorption, erythropoietin dose, thrombogenicity of the extracorporeal circuit, blood flow, and length of the hemodialysis treatment among others.

Anticoagulation with UFH during hemodialysis can be monitored by the determination of activated partial thromboplastin time (aPTT), which is targeted to 1.5–2 times above baseline value. However, this method requires frequent testing leading to increased cost and repeated blood draws. Another option is the determination of activated clotting times (ACTs), which can be obtained with point-of-care devices. ACT is typically targeted to 80% higher than baseline value. However, ACTs are used infrequently because of the need to be rigorously standardized, resulting in quality assurance and regulatory issues. In general, most outpatient dialysis units do not routinely measure anticoagulation parameters unless there is clinical evidence suggesting of dialyzer clotting (i.e., visual clots, increased extracorporeal circuit pressures, etc.) or signs of over-anticoagulation, such as prolonged bleeding at needle puncture sites following decannulation. Except on rare occasions, we do not regularly monitor anticoagulation levels in the inpatient and outpatient facilities of our institutions.

Currently, there are no standardized heparin dosages for anticoagulation during hemodialysis in the United States. A number of empirically-based protocols exist to address the competing issues of clotting and postdialysis bleeding from venipuncture sites. These methods require minimal staff intervention and are standard in most outpatient hemodialysis units; they are, however, unsuitable for patients with significant bleeding risks. Typically, the administration of heparin during hemodialysis requires an initial loading bolus, followed by a maintenance dose that can be given either as repeated separate boluses or as a continuous infusion. These strategies ensure systemic anticoagulation throughout the dialysis treatment. A routine repeated bolus regimen consists of an initial bolus of UFH (usually about 40–50 IU/kg body weight, or 2000–4000 IU) administered into the venous access needle, followed by a midtreatment dose of 1000–2000 IU to maintain suitable anticoagulation. Alternatively, heparin modeling can be performed using an initial bolus followed by a constant fixed infusion of heparin (usually 10–15 IU/kg body weight/h, or 500–2000 IU/h) to maintain an ACT of 200 to 250 seconds (normal ≈ 90 to 140 seconds). Heparin infusion should be terminated 30–60 minutes prior to the end of treatment to reduce postdialysis venipuncture bleeding. Some other protocols include the use of a single initial bolus dose with no maintenance doses, and the administration of a high bolus heparin dose (i.e., greater than 5000 IU) with decreasing infusion rates, as the treatment proceeds to minimize postdialysis bleeding. Furthermore, in facilities that practice dialyzer reuse, incorporation of a pharmacodynamic approach to heparin modeling has also been shown to increase dialyzer reuse rate.

The use of UFH with dialysis therapy ensures systemic anticoagulation throughout the dialysis treatment. It is reliable and requires minimal staff intervention after a patient's heparin dose has been determined. The three most commonly used standard anticoagulation regimens using UFH and different UFH protocols used in our institution are summarized in Tables 10.2 and 10.3 , respectively.

Low-Dose Heparin

The use of minimum-dose heparin is an alternative anticoagulation strategy for patients with high bleeding risk who are unable to complete heparin-free hemodialysis due to frequent clotting. Currently, there are no standardized dosages for this protocol. Initially, the extracorporeal circuit is rinsed with 2000 to 5000 IU of UFH followed by a saline rinse to remove the unbound anticoagulant. Generally, patients receive boluses of 500 IU of heparin every 30 minutes to keep the ACT no higher than 40% above the baseline (> 150 but < 200 seconds). Alternately, a continuous infusion of heparin with frequent ACT monitoring can be used to achieve the same degree of anticoagulation. Low-dose heparin protocols have been shown to reduce bleeding complications in high-risk patients when compared to regional anticoagulation with heparin and protamine neutralization. The major advantage of this technique is its simplicity. The main disadvantage is that some degree of systemic anticoagulation still occurs, necessitating careful monitoring. Also, because it involves the use of heparin, this method of anticoagulation is not suitable for patients with hehparin-induced thrombocytopenia.

Low-Molecular-Weight Heparins

Low-molecular-weight heparins (LMWHs) are derived from chemical or enzymatic depolymerization of commercial UFH and are about one-third of the molecular weight of UFH (4000 to 5000 daltons vs. mean 15,000 daltons for UFH). Like UFH, LMWHs inactivate factor Xa (see Fig. 10.1 ). Because LMWH molecules do not contain enough saccharide units to form the ternary complex required to simultaneously bind thrombin and antithrombin, their ability to inhibit thrombin activity is significantly less. Another important difference is that the anticoagulation effect of LMWHs is not reliably reversed by protamine sulfate. Anticoagulation monitoring also differs from UFH in that the aPTT is not accurate with LMWHs; heparinoid or anti–factor Xa activity must be measured to assess their anticoagulant activity. Currently, the recommendations are to aim for an anti-Xa activity of 0.4–0.6 IU/mL in the venous port of the extracorporeal circuit and < 0.2 IU/mL at the end of hemodialysis therapy. However, routine monitoring is typically not required and is recommended only in those patients at increased risk of bleeding.

LMWHs have been proposed to cause less bleeding and less thrombocytopenia than heparin. The LMWH dalteparin is used widely in European countries; however, the use of LMWHs for hemodialysis anticoagulation in the United States is very limited. While LMWHs have been demonstrated to be similarly safe and efficacious compared to UFH, it has generally not been found to be superior to heparin in terms of dialysis-related bleeding, and the increased cost may not justify the preferential use over UFH. It is also important to note that even though the incidence of HIT is lower than with UFH, LMWHs should not be used as a safe substitute in these patients because of the extensive cross-reactivity (> 90%) between LMWHs and standard UFH.

LMWHs can be used to decrease the thrombogenicity of the extracorporeal circuit itself by covalently coupling LMWH to all surfaces. Preliminary studies have shown that this strategy can be safely used without any additional agents, but the clinical and cost effectiveness of this approach to prevent thrombosis and bleeding compared to regional and no-heparin strategies has yet to be examined and is not readily available in outpatient dialysis units.