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  • Current guidelines for thromboprophylaxis recommend the use

    2021-09-15

    Current guidelines for thromboprophylaxis recommend the use of vitamin K antagonists (eg, warfarin), low-molecular-weight heparin (LMWH), or indirect inhibitor of factor Xa . Aspirin is also used for thromboprophylaxis in patients undergoing orthopedic procedures , . The efficacy and safety of LMWH (eg, enoxaparin) is well established , . LMWH has a long N-Methyl-D-aspartic acid synthesis and good bioavailability, is administered as a once daily subcutaneous dose without laboratory monitoring or dose adjustment, and is safe and effective for extended out-of-hospital prophylaxis after TKA or THA. Disadvantages associated with LMWH include the administration route, expense, potential thrombocytopenia, and patient adherence , . In a previous meta-analysis, patients who received enoxaparin prophylaxis had a lower incidence of DVT after knee arthroscopic surgery compared to patients who did not receive enoxaparin prophylaxis . New generations of oral anticoagulants, such as dabigatran etexilate, ximelagatran, rivaroxaban, and apixaban, are now available for prophylaxis against VTE in patients undergoing THA and TKA . Factor Xa inhibitors (ie, rivaroxaban, darexaban, and apixaban) and direct thrombin inhibitors (ie, ximelagatran and dabigatran etexilate) have more predictable anticoagulant effects compared with enoxaparin, removing the need to monitor patients receiving short-term thromboprophylaxis . However, disadvantages associated with these drugs include cost and lack of antidotes for timely reversal of bleeding .
    Introduction Thrombosis is the leading cause of death worldwide and plays a pivotal role in the pathogenesis of numerous cardiovascular diseases including acute coronary syndrome and deep vein thrombosis (Fares, 2013). Most thromboembolic processes require anticoagulant therapy, which explains the current efforts to develop specific and potent antithrombotic agents (Fares, 2013). Research targeting direct thrombin inhibitors was the focus of early antithrombotic drug development efforts and is indicative of the central role thrombin plays in thrombosis (Ostrem et al., 1998). However, clinical studies showed that the continuous production of thrombin from prothrombin is not blocked by direct inhibitors of thrombin (Antman, 1994, Philippides and Loscalzo, 1996). It is necessary to inhibit high concentrations of thrombin in vivo to produce efficient antithrombotic activity, which can lead to undesirable results in anticoagulation and an accompanying risk of increasing complications of hemorrhage. Therefore, the selective inhibition of coagulation factors located upstream of thrombin may be safer by reducing bleeding risk. In this context, FXa has emerged in recent years as a more attractive target for the development of new anticoagulants (Bauer, 2006, Loffredo et al., 2015). In addition, inhibition of FXa may prevent the continuous production of thrombin while maintaining its basal activity for primary hemostasis (Bauer, 2006). Upon exposure to activating agonists (e.g. thrombin, ADP, and collagen), platelets liberate arachidonic acid stored as phospholipid in the platelet plasma membrane that is converted into thromboxane A2 by sequential oxygenation of arachidonic acid by cycloxygenase and thromboxane A2 synthase (Malmsten, 1986, Samuelsson et al., 1978). The released thromboxane A2 acts as a positive feedback mediator in the activation and recruitment of more platelets to the primary hemostatic plug (Hourani and Cusack, 1991), which resulted in the formation of platelet plug. Thromboxane A2 exerts its actions via specific G protein-coupled receptors and has been described as either a potent platelet agonist (Hourani and Cusack, 1991, Shen and Tai, 1998). Herbal plant like Zingiber officinale is a natural dietary spice with potent anti-inflammatory, anti-oxidative and anti-cancer properties (Park et al., 1998). Zingerone [4-(4-hydroxy-3-methoxyphenyl) butan-2-one] is a stable active component of dry ginger rhizome (Sies and Masumoto, 1997) and has been reported to exhibit various pharmacological activities such as anti-inflammatory, anti-apoptotic, and protecting myocardial infarction and irritable bowel disorder (Banji et al., 2014, Hemalatha and Prince, 2015, Kim et al., 2010, Rao et al., 2011). However, the anti-FXa and anti-platelet effects of zingerone (ZGR) have not yet been studied. The goal of the present study was to analyze the effects of ZGR on blood clotting time, FXa activity, and platelet functions. Its antithrombotic activity was further characterized in animal models.