Many danaparoid-treated HIT patients also receive overlapping warfarin treatment, since oral anticoagulants are usually preferred when at least 3-6 mo of further anticoagulation is indicated because of venous or arterial thromboembolism. However, it generally takes at least 5 days for warfarin to achieve a therapeutic effect (Harrison et al., 1997). Although warfarin likely can be started safely at the beginning of danaparoid treatment in most patients with HIT-associated thrombosis, it is prudent to delay start of warfarin until the thrombotic process is controlled and substantial resolution of the thrombocytopenia has occurred (usually, to a platelet count >150 X 109/L). This caveat is based on the observation that warfarin can aggravate the thrombotic process during the first few days of its administration by reducing levels of the natural anticoagulant protein C, particularly when thrombin generation is high (Warkentin, 1996a; Warkentin et al., 1997; Potzsch et al., 1996) (see Chapters 2 and 12). Warfarin does not neutralize activated coagulation factors (which are increased in acute HIT), and even when sufficient time has passed for its antithrombotic effects to be achieved through reduction in the vitamin K-dependent procoagulant factors (particularly prothrombin), discontinuation of dana-paroid prior to resolution of HIT theoretically could result in warfarin-induced microthrombosis. Thus, during overlapping danaparoid-coumarin therapy, danaparoid usually is discontinued only when: the acute thrombosis appears controlled on clinical grounds, at least 5 days of overlapping danaparoid-coumarin therapy have been given, and at least two INR measurements (at least 24 h apart) are within the target therapeutic range (2.0-3.0). Unlike lepirudin and argatroban, danaparoid does not interfere with INR or activated partial thromboplastin time (aPTT) measurements during oral anticoagulant therapy; thus, the potential for underdosing of DTI therapy during concomitant coumarin therapy (Warkentin, 2006) does not apply to danaparoid.
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