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3.5-4.5 mg/mL during CPBh

Note: Repeat aPTT determinations should be made 4-6 h after any dose adjustment. aA maximum body weight of 100 kg should be used for dose calculations. bAdjust for renal insufficiency.

cThe ratio is based on comparison with the normal laboratory mean aPTT. If Actin FS or Neothromtin reagents are used, the aPTT target range is usually 1.5-3.0.

dThis is the author's recommended starting dose in all HIT patients, unless life-or limb-threatening thrombosis is present eUsed in the HAT-1, -2, and -3 trials.

fTested in a prospective, randomized trial after orthopedic surgery with desirudin (Eriksson et al.,1996, 1997). gStop 15 min before and of CPB; put 5 mg into CPB after disconnection to avoid clotting of pump. hThe target lepirudin level pre-CPB (>2.5 mg/mL) is lower than the level sought during CPB (3.4-4.5 mg/mL) because of the addition of lepirudin to the pump priming fluid (0.2 mg/kg b.w.).

Abbreviations: aPTT, activated partial thromboplastin time; b.w., body weight; CPB, cardiopulmonary bypass; CVVH, continuous venovenous hemofiltration; ECT, ecarin clotting time; iv, intravenous; MI, myocardial infarction; PCI, percutaneous coronary intervention; UA, unstable angina.

Note: Repeat aPTT determinations should be made 4-6 h after any dose adjustment. aA maximum body weight of 100 kg should be used for dose calculations. bAdjust for renal insufficiency.

cThe ratio is based on comparison with the normal laboratory mean aPTT. If Actin FS or Neothromtin reagents are used, the aPTT target range is usually 1.5-3.0.

dThis is the author's recommended starting dose in all HIT patients, unless life-or limb-threatening thrombosis is present eUsed in the HAT-1, -2, and -3 trials.

fTested in a prospective, randomized trial after orthopedic surgery with desirudin (Eriksson et al.,1996, 1997). gStop 15 min before and of CPB; put 5 mg into CPB after disconnection to avoid clotting of pump. hThe target lepirudin level pre-CPB (>2.5 mg/mL) is lower than the level sought during CPB (3.4-4.5 mg/mL) because of the addition of lepirudin to the pump priming fluid (0.2 mg/kg b.w.).

Abbreviations: aPTT, activated partial thromboplastin time; b.w., body weight; CPB, cardiopulmonary bypass; CVVH, continuous venovenous hemofiltration; ECT, ecarin clotting time; iv, intravenous; MI, myocardial infarction; PCI, percutaneous coronary intervention; UA, unstable angina.

Lepirudin plasma levels in patients with renal impairment vs. no renal impairment

Lepirudin plasma levels in patients with renal impairment vs. no renal impairment

FIGURE 2 Time course of lepirudin plasma levels in patients with normal creatinine levels (lower line) and patients with increased creatinine levels (upper line). The dotted line indicates the upper therapeutic level. Both groups showed similar plasma concentrations after 4 h, which further increased in patients with renal impairment. Therefore aPTT should be also assessed in all patients 8 h after start of treatment to identify those with drug accumulation. Abbreviation: aPTT, activated partial thromboplastin time. Source: Lubenow et al., 2004.

Time after start of lepirudin treatment

FIGURE 2 Time course of lepirudin plasma levels in patients with normal creatinine levels (lower line) and patients with increased creatinine levels (upper line). The dotted line indicates the upper therapeutic level. Both groups showed similar plasma concentrations after 4 h, which further increased in patients with renal impairment. Therefore aPTT should be also assessed in all patients 8 h after start of treatment to identify those with drug accumulation. Abbreviation: aPTT, activated partial thromboplastin time. Source: Lubenow et al., 2004.

concentration (Hafner et al., 2002), and the ecarin chromogenic assay (ECA) (Lange et al., 2003, 2005).

The aPTT is a global coagulation assay and is the current method of choice for monitoring lepirudin therapy in most situations. In patients who require higher levels of plasma hirudin and aPTT values above ~70 s (depending on the reagent), the hirudin concentration-aPTT curve flattens, and even major changes in plasma levels cause only a minor change in the aPTT. Because the sensitivities of different aPTT reagents vary (Gosselin et al., 2004), it is strongly recommended that each laboratory involved in monitoring of DTIs should generate its own standard dose-response curve for their aPTT reagent using "spiked" normal pooled plasma samples, e.g., with 0.25, 0.50, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/mL lepirudin (Fig. 3). This will define the expected range over which the aPTT reliably reflects changes in the DTI plasma concentration. At concentrations above this range, the ECT is more reliable for DTI monitoring. This is especially true for very high doses, such as those used during cardiopulmonary bypass (CPB) surgery.

Unlike global coagulation tests, the ECT monitors prolongation of clotting time caused by thrombin inhibition alone (Callas et al., 1995; Nowak and Bucha, 1996; Potzsch et al., 1997a,b; Koster et al., 2000a; Fabrizio, 2001; de Denus and Spinier, 2002; Liu et al., 2002). Ecarin, which is obtained from snake venom, catalyzes the cleavage of prothrombin to meizothrombin (Kornalik and Blomback, 1975; Novoa and Seegers, 1980; Nishida et al., 1995). Meizothrombin is biologically similar to thrombin, except that it cleaves fibrinogen much more slowly than thrombin. The interaction of meizothrombin with hirudin, however, is similar to that of thrombin. Thus, when all the hirudin present in a blood sample has been neutralized by meizothrombin, thrombin will no longer be inhibited, and clotting will occur.

The ECT shows a linear correlation to lepirudin plasma levels over a wide range. At present, this assay is recommended for monitoring anticoagulation when higher concentrations of lepirudin are used. It is mandatory for monitoring of lepirudin during CPB.

FIGURE 3 Lepirudin standard curve. This curve was generated using seven normal plasmas spiked with various concentrations of lepirudin (mg/mL) using reagent Actin FS and the BCS analyzer (Dade-Behring, Germany). Note that incremental changes in aPTT are much smaller as the dose-response curve flattens at greater plasma lepirudin concentrations. Abbreviation: aPTT, activated partial thromboplastin time.

FIGURE 3 Lepirudin standard curve. This curve was generated using seven normal plasmas spiked with various concentrations of lepirudin (mg/mL) using reagent Actin FS and the BCS analyzer (Dade-Behring, Germany). Note that incremental changes in aPTT are much smaller as the dose-response curve flattens at greater plasma lepirudin concentrations. Abbreviation: aPTT, activated partial thromboplastin time.

Recently, an automated assay, the ECA, has been introduced that provides a linear dose-response curve for all DTIs independently of the patient's prothrombin and fibrinogen levels (Lange et al., 2003, 2005).

In 2005, a workshop compared several methods for monitoring DTIs: aPTT using local reagents and methods (Actin FS, Thrombosil I, Pathromtin SL, Synthasil aPTT, Automated aPTT, STA-PTT, STA—CK Prest 5); aPTT using a common reagent (C-aPTT; Actin FS; Aventis Pharma, Marburg, Germany); anti-IIa chromogenic assay with the S2238 chromogenic substrate from Instrumentation Laboratory/Haemochrom Diagnostica (Essen, Germany); ECT—wet chemistry (Wet ECT) reagents (University Jena, Germany); ECT—dry chemistry reagent (Cardiovascular Diagnostics Inc., Raleigh, NC, USA) with two ecarin concentrations (low ecarin reagent card: dry ECT; higher concentration ecarin card: TIM); EIA kit (Immuno Bind, Hirudin Elisa kit, American Diagnostica Inc., Greenwich, CT, USA). The interlaboratory variations for measurement of lepirudin were (from lowest to highest): TIM < C-aPTT < Dry ECT < L-aPTT < wet ECT < anti-IIa < EIA (Gray et al., 2005).

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