Dabigatran Inhibits Staphylococcus aureus Coagulase Activity

Abstract

The ability of Staphylococcus aureus to clot plasma through conformational activation of prothrombin by staphylocoagulase is used to distinguish S. aureus from coagulase-negative staphylococci. We show that while the direct thrombin inhibitor dabigatran inhibits staphylocoagulase activity, the clinical use of dabigatran etexilate is not expected to interfere with direct tube coagulase testing.Since the early notion, developed more than a century ago, that the ability to clot plasma correlates with the pathogenic potential of staphylococci (3,14), this phenomenon has been used to distinguish Staphylococcus aureus from less virulent, coagulase-negative staphylococci. Although the use of new molecular methods for rapid identification of S. aureus from blood culture bottles is expanding (15, 17), detection of coagulase activity by direct tube coagulase (DTC) testing remains a costeffective, easy to perform, and reliable method for early detection of S. aureus in blood culture broth with a Gram stain result suggestive of staphylococci (10,13,16,23). Since false-negative results increase the therapeutic delay, the carryover of contaminants from either the culture broth or the patient's plasma that interfere with the tube test clotting reaction has to be avoided (23).Clotting occurs when fibrinogen is converted into fibrin by thrombin. Under physiological conditions, the proteolytic activation of the inactive precursor prothrombin into thrombin is the final step in the tightly regulated coagulation cascade. Staphylocoagulase secreted by S. aureus directly binds to prothrombin to form the staphylothrombin complex and thus bypasses the coagulation cascade and its physiological regulation (6). As a consequence of this unique nonproteolytic direct thrombin activation, treatment with heparins, vitamin K antagonists, or the thrombin inhibitor hirudin does not interfere with staphylothrombin function (9) and is of no concern for DTC testing.In view of the recent availability and increasing clinical use of the new direct thrombin inhibitor dabigatran etexilate, we studied whether dabigatran inhibits staphylocoagulase and whether clinical use of dabigatran etexilate is expected to interfere with DTC testing.To test these possibilities, we measured coagulation of citrated human plasma as the change in absorbance at 405 nm (A 405 ) after the addition of purified staphylocoagulase (3 nM) in the presence of increasing concentrations (0, 0.625, 1.25, 2.5, 5, and 10 nM) of dabigatran (Boehringer Ingelheim

Staphylococcal Protein A, Panton-Valentine Leukocidin and Coagulase Aggravate the Bone Loss and Bone Destruction in Osteomyelitis

“…Coa is an enzyme secreted by S. aureus. It directly binds to prothrombin and leads to plasma clot [39]. The effect of SpA, PVL and Coa on osteoblasts was studied through the following aspects including osteoblast proliferation, apoptosis, bone formation, bone mineralization and RANK-L expression.…”

Staphylococcus aureus Aggregation and Coagulation Mechanisms, and Their Function in Host–Pathogen Interactions

“…Most of the “traditional” anticoagulants cannot prevent S. aureus -induced coagulation, but this can be achieved with novel drugs of the univalent direct thrombin inhibitor family (Vanassche et al, 2010), such as dabigatran and argatroban. Their use in animal models confirmed their efficacy and potential to decrease disease severity, similar to the effect of coa and vWbp mutants (Peetermans et al, 2015).…”

Exploring Staphylococcus aureus pathways to disease for vaccine development

“…In this same manner, the staphylococcal coagulases are also able to circumvent the regulatory processes of the coagulation cascade [122]. Univalent direct thrombin inhibitors (DTIs) such as argatroban, melagatran, and dabigatran are exceptions and are effective in inhibiting the Coa Prothrombin complex as they only target and bind the active site [123, 124]. Differences in zymogen activation [109, 125] and possessing very distinct C-termini, suggests that the role of the two coagulases is not simply redundant and that each provides a unique contribution to establishment of disease.…”