Danaparoid was first used to anticoagulate non-HIT patients requiring hemodia-lysis in one of several clinical settings: stable chronic renal failure (CRF) (ten Cate et al., 1985; Henny et al., 1990, von Bonsdorff et al., 1990) or intensive care unit (ICU) patients who developed postoperative acute renal failure (ARF) (Henny et al., 1983). Danaparoid was then used to treat very ill patients in intensive care settings who developed HIT during CRRT for ARF (Wester et al., 2000; LindhoffLast et al., 2001). Switching from UFH to danaparoid overcame the repeated deposition of fibrin on the hemodialysis/filtration membranes, thus restoring the lifespan of the filters and allowing continuation of extracorporeal circuit use without further incident (Burgess and Chong, 1997; van Eps et al., 2000; LindhoffLast et al., 2001). Such fibrin deposition may also be secondary to UFH-induced platelet aggregation and microthrombus formation and, because HIT antibodies are often absent, this may be a manifestation of non-immune heparin-associated thrombocytopenia (HAT) since significant thrombocytopenia usually does not occur (Burgess and Chong, 1997).
Danaparoid may accumulate in the blood of patients with moderate to severe renal dysfunction (creatinine clearance < 30mL/min) because it is cleared renally. During hemodialysis or hemofiltration, it is not cleared by the artificial kidney. Drug accumulation and the potential risk for bleeding can be minimized by suitable danaparoid dose reduction:
1. For intermittent hemodialysis, this is achieved by using a pre-dialysis iv bolus of 3750 U (2250 U if the body weight is < 55 kg) for the first two procedures and then reducing the pre-dialysis bolus (usually to 2250 or 3000 U) according to the previous pre-dialysis plasma anti-Xa levels. Thus, a plasma anti-Xa level should be performed before the second and subsequent dialyses and each level is used to adjust the danaparoid dose for the dialysis. The aim is to maintain the plasma anti-Xa level between 0.5 and 0.8 U/mL during dialysis. Usually by hemodialysis number 4 or 5, a "steady-state" pre-dialysis bolus dose has been found, which will allow effective anticoagulation during dialysis. Following this regimen, danaparoid has been used for up to 4 yr for intermittent hemodialysis (three times per week).
2. For CRRT, the dosing regimen is similar to the iv infusion regimen used for the treatment of venous thrombosis (Table 1). However, if severe hemofilter clotting had occurred with UFH or LMWH, then an initial higher maintenance infusion rate (up to 600 U/h if bleeding is not observed) may be needed until filter life has been restored to a reasonable duration. Danaparoid has been used for up to 39 days for continuous hemofiltration or hemodialysis in ICU patients.
A recent review (Magnani and Gallus, 2006) of 291 HIT and non-HIT ICU patients with or without renal failure showed that danaparoid can provide efficacious and safe anticoagulation for this patient population at high risk for thrombosis and bleeding. The incidence of major bleeding was 8.9% and thrombotic events (mainly circuit clotting) was 7.6%; the all-cause mortality rate was 24.4%. Many of the bleeding events and circuit clotting occurred during the danaparoid dose-adjustment phase and ceased after dose optimization (Lindhoff-Last et al., 2001). Most deaths appeared to be due to sepsis and/or multiple organ failure. A generally favorable experience in the use of danaparoid in 42 consecutive ICU patients with HIT was also reported by Tardy-Poncet and colleagues (1999).
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