Abbreviations: aPTT, activated partial thromboplastin time; iv, intravenous.

Abbreviations: aPTT, activated partial thromboplastin time; iv, intravenous.

Patients in whom venous limb gangrene occurs typically have an elevated international normalized ratio (INR)—which represents a "surrogate marker" for greatly reduced protein C levels—and thrombocytopenia (surrogate marker for persistent thrombin generation in HIT). Prevention of limb gangrene can be accomplished through careful management of the DTI—warfarin transition, particularly the postponement of coumarin therapy pending substantial platelet count recovery. Patients with suspected coumarin-associated venous limb gangrene should immediately receive vitamin K (e.g., 10 mg iv over 30-60 min or 20 mg per os).

In patients who receive vitamin K antagonists before or concomitant with commencement of lepirudin, this can cause elevated aPTT values (due to coumarin-induced prothrombin level reduction) with the potential for inappropriate lepirudin dose reductions (Warkentin, 2006). Therefore, vitamin K should be given to HIT patients who have received vitamin K antagonists when lepirudin is started (Warkentin and Greinacher, 2004; Greinacher and Warkentin, 2006) (see Chapter 12).

In prospective trials, lepirudin caused minimal prolongation of the pro-thrombin time (PT) (or INR) once the therapeutic range had been reached. However, Stephens et al. (2005) reported that lepirudin elevates the INR in the absence of warfarin if a thromboplastin with a relatively high international sensitivity index (ISI) of >2 is used. A systematic laboratory study on the effects of different DTIs on the INR (Warkentin et al., 2005) revealed that the differing effects of the DTIs on PT prolongation are primarily driven by their respective molar plasma concentrations required for clinical effect. DTIs with a relatively low affinity for thrombin (e.g., argatroban) require high plasma concentrations to double the aPTT compared with those with a higher affinity for thrombin (e.g., lepirudin). These higher plasma concentrations, in turn, quench more of the thrombin generated in the PT, thereby prolonging the PT to a greater extent.

In general, the transition from lepirudin to warfarin therapy is usually less complicated than the transition from argatroban (Greinacher et al., 2000) (see Chapter 15). Notably, following start of vitamin K antagonist therapy in the prospective lepirudin studies, not a single case of venous limb gangrene occurred.

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