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FAQ

What anticoagulants can be given to a patient with heparin-induced thrombocytopenia during dialysis sessions?

Background
Patients receiving hemodialysis have a particularly high risk of forming a clot while being dialyzed. Patients who need dialysis will often experience vascular access thrombosis, which is further increased by the placement of arteriovenous fistulas and grafts to allow dialysis to occur. These patients are more hypercoaguable due to increased inflammation and endothelial damage as well as deficiencies in activated protein C and S. While dialysis is in progress, cells such as leukocytes and platelets will collect and granulocytes will express tissue factor, which is a potent activator of the coagulation cascade. The components needed for dialysis to occur such as the dialyzer, needles, catheters, tubing, and arterial and venous bubble traps further increase the risk of clot formation due to slowing of blood flow. Unfractionated heparin (UFH) is the gold standard anticoagulant used in patients receiving hemodialysis; however, heparin-induced thrombocytopenia (HIT) may occur.

There are 2 different types of HIT: HIT type 1 and HIT type 2. With type 1, there will be a modest reduction in platelet count 2 to 4 days following administration of heparin. It is deemed harmless and platelet counts increase with subsequent doses of heparin. HIT type 2, however, is a serious reaction that can occur 5 to 10 days following heparin therapy and can present with platelets of less than 100,000/microL. This is an immune-mediated response where antibodies form against the platelet and heparin complex. Heparin must be immediately discontinued. There are several options available, each with its own properties that may be beneficial. Argatroban has traditionally been used since it is hepatically metabolized; however, other options include the factor Xa inhibitor fondaparinux or the direct thrombin inhibitor lepirudin.

Overview of agents for HIT – literature review
Argatroban, approved by the Food and Drug Administration (FDA) for HIT, is a direct thrombin inhibitor that reversibly binds to the active thrombin site resulting in inhibition of fibrin formation, activation of clotting factors V, VIII, and XIII, activated protein C, and platelet aggregation. It does not need the co-factor antithrombin III for its action. It is metabolized in the liver and no dosage adjustment is needed for those with renal impairment making it an ideal agent for dialysis patients. Argatroban is dosed based on body weight with a usual starting dose of 2 mcg/kg/min, which must be lowered to 0.5 mcg/kg/min if hepatic impairment is present; the half-life is 39 to 51 minutes. Infusion rates should be titrated to achieve aPTT levels of 1.5 to 3 times the patient’s baseline aPTT and not to exceed 100 seconds. Several studies have evaluated argatroban use during dialysis patients with HIT. The studies showed that 2 mcg/kg/min was the starting dose in most patients; however, starting doses have ranged from 1.7 + 0.9 mcg/kg/min as well. All the studies demonstrated argatroban’s efficacy. Bleeding rates were minimal and similar to previous historical controls. The aPTT was within goal for all studies. Tang and colleagues were able to demonstrate that there was an insignificant amount of argatroban removed through dialysis compared to endogenous clearance although according to the product labeling, approximately 20% of the drug can be cleared through hemodialysis.

Lepirudin, another direct thrombin inhibitor, is also approved by the FDA for HIT. Approximately 48% of the dose is excreted in the kidney with 35% of it unchanged. The elimination half-life is about 1.3 hours. The dose should be adjusted to achieve an aPTT of 1.5 to 2.5 above a patient’s normal baseline. A case series showed lepirudin’s efficacy in 2 patients receiving intermittent hemodialysis. The first patient received an initial dose of 0.01 mg/kg/h, and the second patient received 0.005 mg/kg/h. Neither patient experienced major adverse thromboembolic or bleeding events. Both patients were successfully treated with lepirudin. The doses used are much lower than normal as they were adjusted for renal impairment. The authors caution that one should be observant of what type of dialyzer is used. Those that are low-flux tend to be impermeable to lepirudin, whereas high-flux are found to be permeable. Currently there are no clinical trials reviewing the administration of lepirudin hemodialysis; however, other case reports exist.

Unlike argatroban and lepirudin, fondaparinux is not FDA approved for use in HIT positive patients. Fondaparinux works by selectively binding to antithrombin III and inhibiting factor Xa, which interrupts the coagulation cascade. Approximately 77% of the dose is excreted unchanged through the kidneys, and 20% is removed through dialysis. Fondaparinux has an elimination half-life of 17 to 21 hours and is prolonged in renal impairment. It is contraindicated in patients with a creatinine clearance <30 mL/min; however, there are some case studies that have examined its use in hemodialysis. A prospective open-label study and a case report show it may be an acceptable alternative. The case report involved a patient who was initially treated with UFH and developed HIT. Fondaparinux was started at 2.5 mg being administered into the dialysis circuit on dialysis day. The patient did not develop a thrombus, bleeding, or clotting of the hemodialysis circuit.

Kalicki and colleagues compared fondaparinux with UFH in non-HIT patients (n=12) undergoing dialysis in an open-label, prospective study. The dose of UFH was reported as standard, whereas fondaparinux was given in an initial dose of 0.05 mg/kg, and the study design was sequential with heparin being administered during a run-in period followed by 2 phases of fondaparinux treatment. Anticoagulation efficacy was evaluated on an ordinal scale using a clotting score with 0 = no clotting/clean filter, 1 = traces of coagulation, and 3 = fully clotted system; 2 was arbitrarily assigned for those filters falling between 1 and 3.

During the heparin phase, only 1 patient developed clotting of the circuit. During the first phase of fondaparinux administration (one weekly UFH dose was changed to fondaparinux), the authors observed that fondaparinux was less efficient than UFH, even with increasing dosages to 0.06 or 0.08 mg/kg. The average clotting score was 0.65 for heparin compared to 1.6 for fondaparinux phase 1 (p<0.0005). In addition, more patients experienced bleeding at the puncture sites with fondaparinux therapy. For phase 2, fondaparinux given for 9 consecutive dialysis sessions increased anti-Xa activity, and the average clotting score decreased from 1.5 to 1 (p<0.05). Puncture site bleeding was also less frequent (p<0.05).

This study also included pharmacokinetic data and demonstrated that fondaparinux will accumulate despite having a percentage removed by dialysis. The authors concluded the fondaparinux was inferior to UFH, but more data are needed from larger trials.

When looking at these 3 alternatives, one must take into consideration individual patient characteristics; the characteristics of the agents are summarized in the table below. Argatroban appears to be the preferred alternative due to its hepatic metabolism and short half-life. Lepirudin also gives promise and has shown efficacy, but literature is limited. Fondaparinux has had demonstrated mixed results and needs more data to support its use. Argatroban should be the optimal agent when choosing an anticoagulant for a HIT positive patient on hemodialysis.

Table. Summary of anticoagulants used in hemodialysis for HIT

Conclusion
Argatroban is the optimal agent when choosing an anticoagulant for a HIT positive patient receiving hemodialysis.

References
Fischer KG. Essentials of anticoagulation in hemodialysis. Hemodial Int. 2007;11(2):178-189.

Argatroban [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.

Tang IY, Cox DS, Patel K, et al. Argatroban and renal replacement therapy in patients with heparin-induced thrombocytopenia. Ann Pharmacother. 2005;39(2):231-236.

Reddy BV, Grossman EJ, Trevino SA, Hursting MJ, Murray PT. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia requiring renal replacement therapy. Ann Pharmacother. 2005;39(10):1601-1605.

Refludan [package insert]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc.; 2007.

Dager WE, White RH. Use of lepirudin in patients with heparin-induced thrombocytopenia and renal failure requiring hemodialysis. Ann Pharmacother. 2001;35(7-8):885-890.

Artixtra [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.

Kalicki RM, Aregger F, Alerio L, Lammle B, Frey FJ, Uehlinger DE. Use of the pentasaccharide fondaparinux as an anticoagulant during haemodialysis. Thromb Haemost. 2007;98(6):1200-1207.

Haase M, Bellomo R, Rocktaeschel J, et al. Use of fondaparinux (ARIXTRA) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II. Nephrol Dial Transplant. 2005;20(2):444-446.