Direct oral anticoagulants and heparins: laboratory values and pitfalls in 'bridging therapy'.

Objectives: The three direct oral anticoagulants (DOACs) dabigatran, apixaban and rivaroxaban are now widely used in clinical practice. For patients requiring perioperative interruption of DOACs, heparin bridging is still under discussion. Here we show, for the first time, the influence of concomitantly used DOACs and heparins on laboratory assays. Methods: For spiking experiments, 10 healthy donors and nine patients treated with DOACs were investigated. The measurement of DOACs and heparins was performed with routine methods on the ACL TOP [HEMOCLOT ® direct thrombin inhibitor (CoaChrom Diagnostica, Austria), COAMATIC ® Heparin (Chromogenix, USA) calibrated with rivaroxaban, apixaban, unfractionated heparin (UFH) and low molecular weight heparin (LMWH), additionally PT reagent RecombiPlasTin 2G and aPTT reagent SynthASil (Instrumentation Laboratory, Germany)] and the DOACs were additionally quantified with liquid chromatography-mass spectrometry. A linear regression model has been used to estimate the effect of DOAC prestimulation. Results: No influence of dabigatran could be demonstrated in the anti-Xa testing methods for LMWH, UFH, rivaroxaban or apixaban. All FXa-inhibiting drugs affected all the anti-Xa testing methods in their own specific ways. Compared with heparin alone, measurement of heparins in samples with a basic concentration of DOACs (200 ng/ml) displays a more dramatic increase. Samples of patients with therapeutic intake of DOACs spiked with UFH and LMWH showed the expected pharmacokinetic profiles, but increased pharmacodynamic effects. Conclusions: Direct thrombin and FXa inhibitors exhibit distinct effects on assay results when used concomitantly with heparins. These interactions must be considered in the interpretation of assay results during bridging therapy.

Prevention effect of orally active heparin conjugate on cancer-associated thrombosis.

Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5 mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62±0.05 IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10 days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.