Unfractionated heparin: focus on a high-alert drug.

Unfractionated heparin (UFH) is associated with a high rate of drug-related problems due to either its inherent pharmacologic properties or an extension of these properties often caused by medication errors. The drug-related problems associated with UFH can significantly hinder the success of therapy and negatively affect the overall cost of care. Unfractionated heparin has been classified as a high-alert drug by the Institute for Safe Medication Practices. Approximately 2.1% of the total records submitted to the MedMARx national error database were related to UFH; 4.5-5.5% of these errors reported were harmful. With this high potential for error, it is essential that all health care providers adopt a collaborative or systems approach to identify solutions to reduce the occurrence of these medication errors. The Joint Commission on Accreditation of Healthcare Organizations has published national patient safety goals for improving the safety of patient care, many of which are applicable to UFH therapy. Unfractionated heparin drug-related problems not necessarily related to medication errors include heparin-induced thrombocytopenia, bleeding events, and osteopenia. Heparin-induced thrombocytopenia is a serious complication of heparin therapy and remains seriously undiagnosed. Bleeding events often occur with therapeutic as well as prophylactic UFH administration even when monitoring indexes are within the therapeutic range. However, due to the variability associated with UFH monitoring methods, definitive guidelines are lacking to assist in avoiding such serious events. Osteopenia has been associated with long-term UFH therapy; one third of patients experience reductions in bone density, potentially leading to fractures. Today, safer alternative anticoagulation therapies are available, such as the low-molecular-weight heparins. When compared with UFH, these alternative therapies provide equivalent or superior efficacy for numerous indications.

Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454.

Platelets are known to play a role in blood borne metastasis. Previous experimental studies have suggested that platelet GpIIb/IIIa may be a therapeutic target. However, the need for intravenous administration limits the potential application of current GpIIb/IIIa inhibitors to cancer therapy. The aim of the present study was to assess the efficacy of a novel, non-peptide oral GpIIb/IIIa antagonist (XV454) on tumor cell-induced platelet aggregation in vivo and on experimental metastasis. A Lewis lung carcinoma (LL2) mouse model of experimental metastasis was used in this study. XV454 (100 micro g) was administered intravenously (via tail vein) or orally (gavages) to 20 g mice. To determine the effect of XV454 on platelet aggregation, blood samples were collected by cardiac puncture 10 minutes after intravenous and 1-24 hrs after oral XV454, and platelet function was assessed by aggregometry, thrombelastography and the Platelet Function Analyzer (PFA100). The effect of XV454 on tumor cell-induced thrombocytopenia was determined 10 minutes after intravenous and 3 hrs after oral XV454 administration. Tumor cells (2 x 10(6)) were injected intravenously and 15 minutes after cell injection, platelet count was measured and compared to baseline (pre-injection) counts. To assess the effect on metastasis, XV454 was administered intravenous or orally 10 minutes and 3 hrs before tumor cell injection, respectively. Eighteen days later, surface lung tumor nodules were counted and the total lung tumor burden assessed. In a fourth group, in addition to the initial oral dose (before tumor cell injection), oral XV454 was given daily for the first week and three times in the second week. Administration of XV454 (5 mg/kg) completely inhibited platelet aggregation and this effect persisted for at least 24 hrs after oral delivery. Both intravenous and oral XV454 significantly inhibited tumor cell-induced thrombocytopenia (P < 0.01), the number of surface lung tumor nodules (80-85%; P < 0.001) and total tumor burden (83% for intravenous group; 50% oral [single treatment] group; 91% oral [multiple treatment] group, P < 0.001). Overall, these data provide further evidence for the effect of oral and intravenous GpIIb/IIIa antagonism on tumor cell-platelet interaction and metastasis.