![]() ![]() It was also shown in a cohort study of more than 12,500 patients that LMWHs differ in the frequency of bleeding episodes ( van Rein et al., 2017). Differences in antifactor Xa/antifactor IIa activity ratio between LMWHs depend on their average molecular weight and molecular size distribution ( Gray et al., 2008). Because not all molecules of LMWHs contain 18 saccharide units that are necessary for factor IIa (thrombin) inhibition, LMWHs have antifactor Xa to antifactor IIa activity ratios between 1.6:1 and 8:1. All LMWHs catalyze antithrombin-mediated inactivation of coagulation factors. The principal mechanism of the anticoagulant action of LMWHs is similar and involves antithrombin. LMWHs are obtained from UFH by different methods of depolymerization. LMWHs are not a homogenous group of anticoagulants and may differ in their anticoagulant profiles, pharmacokinetic properties, and recommended dosing regimens ( Kearon et al., 2012). LMWHs offer numerous advantages over standard unfractionated heparin (UFH), including more predictable pharmacodynamics and pharmacokinetics, less restrictive monitoring, safer subcutaneous administration, and more favorable overall safety profile with reduced risk of nonhemorrhagic side effects ( Kearon et al., 2012). The global parenteral anticoagulant market is dominated by LMWHs and is still growing. Low-molecular-weight heparins (LMWHs) represent a group of parenteral anticoagulants for prevention and treatment of several thrombotic disorders, that is, unstable angina, myocardial infarction, and deep vein or cancer-associated thrombosis. Well-documented efficacy and safety of HBC both in vitro and in vivo make this polymer a promising candidate for LMWHs reversal. HBC completely reversed the effects of LMWHs on bleeding time and antifactor Xa activity in vivo after 20 minutes and retained ∼80% and ∼60% of reversal activity after 1 and 2 hours, respectively. Single doses up to 20 mg/kg of HBC were well tolerated by rats. We observed no effects on the viability of cardiovascular cells treated with HBC at concentrations up to 0.05 mg/ml. The complexes of HBC-LMWHs were below 5 µm. HBC completely reversed antifactor Xa activity prolonged in vitro by all LMWHs with an optimal weight ratio of 2.5:1. Rats were treated with LMWHs alone or followed by short-time intravenous infusion of HBC, and bleeding time and antifactor Xa activity were measured. ![]() Male Wistar rats were observed for up to 4 days after HBC administration for clinical evaluation, gross necropsy, and biochemistry and histopathological analysis. The rat cardiomyocytes and human endothelial cells were used for the assessment of in vitro toxicity. HBC-LMWH complexes were characterized using zeta potential, isothermal titration calorimetry, and dynamic light scattering. In the present study, we explored the safety profile of HBC and its potential to reverse enoxaparin, nadroparin, dalteparin, and tinzaparin in human plasma and at in vivo conditions. We developed diblock heparin-binding copolymer (HBC), which can neutralize the anticoagulant activity of parenteral anticoagulants. Moreover, protamine sulfate can cause life-threatening hypersensitivity reactions. Bleeding resulting from the application of low-molecular-weight heparins (LMWHs) may be treated with protamine sulfate, but this treatment lacks efficiency its action against antifactor Xa activity is limited to ∼60%.
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