Intern Emerg Med (2015) 10:539–541 DOI 10.1007/s11739-015-1258-9

IM - COMMENTARY

Coagulation and infective endocarditis: sooner or later Francesca Santilli1,2 • Paola Simeone1,2 • Giovanni Davı`1,2

Received: 29 April 2015 / Accepted: 18 May 2015 / Published online: 2 June 2015 Ó SIMI 2015

Infective endocarditis (IE) is one of the best-characterized clinical paradigms, where inflammation, infection and coagulation are deeply intertwined in a bidirectional crosstalk [1]. Since, in normal circumstances, bacteremia is a daily, harmless event, and the endocardium is non-thrombogenic, a focal endocardial lining damage is believed to occur, leading to activation in situ of the haemostasis system, resulting in a sterile clot, with subsequent bacterial seeding. Thus, the interactions between pathogens, platelets and the coagulation system are critical to vegetation initiation and growth [2]. The triggering prothrombotic abnormality is amplified by ongoing inflammation, sepsis, and organ dysfunction, all contributing to further shifting the haemostatic system towards a thrombophilic state. The extent of the ensuing procoagulant imbalance is likely to be a predictor of a number of diverse outcomes related to IE, including vegetation size, embolic events and surgical complications [2]. Subjects with IE form a heterogeneous group, ranging from those who are successfully treated with no adverse events, to those with severe complications and a high mortality. An early diagnosis, prompt empiric antibiotic treatment and a careful selection of patients at risk of embolic complications remain the cornerstones of IE management [3]. & Francesca Santilli [email protected] 1

Center of Excellence on Aging, ‘‘G. D’Annunzio’’ University Foundation, Via Colle dell’Ara, 66013 Chieti, Italy

2

Department of Medicine and Aging, University of Chieti ‘‘G. d’Annunzio’’ School of Medicine, Chieti, Italy

In critically ill patients admitted to general Intensive Care Unit, multiple factors related both to the underlying conditions and to the performed procedures facilitate the occurrence of both infective and non-infective endocarditis, whose incidence is largely underestimated [4, 5]. In the manuscript of Durante-Mangoni et al. [6], published in this issue of IEM, the original choice of inherited thrombophilia as the candidate risk factor evaluated in a large group of IE patients, takes the opportunity to test different hypotheses: first, the role of inherited thrombophilia, as an underlying substrate favouring IE occurrence; second, to exploit a model of prothrombotic condition uninfluenced by the disease activity and pre-existing to the onset of endocarditis, in order to dissect out the relative contribution of a prothrombotic state in the initiation of an endocardial bacterial clot, regardless of subsequent amplifying loops [6] (Fig. 1). It should be emphasized that the chosen polymorphisms, the factor V Leiden and prothrombin G20201A mutations, are not significantly correlated with myocardial infarction [7], and, although associated with a substantial increase in the relative risk of venous thromboembolism, the absolute risk remains low, in view of the low prevalence of any thrombophilia [8]. Therefore, larger studies are warranted before the hypothesis of an involvement of initial prothrombotic abnormalities on the initiation or progression of IE and related outcomes may be ruled out. Nevertheless, the issue raised by the present paper is relevant in terms of the feasibility of testing the efficacy of antithrombotic prophylaxis before IE onset. Although it has been demonstrated that antiplatelet and anticoagulant strategies have an impact on in vitro and animal models of IE [9–11], results from the available clinical studies are conflicting [12, 13]. A post hoc analysis of observational data comparing patients taking long-term aspirin prior to

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the onset of IE, who continued using aspirin after the diagnosis, versus ‘‘placebo-control’’ patients with IE who did not receive aspirin before or after the diagnosis of IE, shows a beneficial impact of aspirin therapy on the risk of an embolic event in IE [12]. Recently this assumption has been reinforced by observations performed on an experimental endocarditis rat model, showing that streptococci-platelet aggregates can induce neutrophil extracellular trap (NET) formation, thus providing the framework necessary for entrapping streptococci-platelet aggregates into biofilms, and for activating the coagulation system to expand the size of the vegetation [14] (Fig. 1). These findings provide sound rationale to support the prophylactic prescription of antiplatelet agents in addition to antibiotics to patients at high risk of endocarditis. Thus, while there is no indication for the initiation of antithrombotic drugs (thrombolytic drugs, anticoagulant or antiplatelet therapy) during the active phase of IE [15], in patients who have other indications for antiplatelet or anticoagulant treatment, the continuation of this treatment is deemed safe in the absence of hemorrhagic complications

[16]. In perspective, it is conceivable that continuous daily antithrombotic prophylaxis in primary prevention might prove to be beneficial, at least in selected patients with known underlying valvular abnormalities or prothrombotic conditions, who are at increased risk of developing IE. In this regard, the present study, although negative for the primary endpoint, since the prevalence of any mutation was not higher in the IE group as compared to the valvular heart disease (VHD) group, may be considered at least hypothesis-generating as to some secondary findings, for which the study is underpowered. Interestingly, the prothrombin G20210A mutation is significantly more prevalent in prosthetic valve endocarditis (PVE) cases (8.3 vs 2.2 % in native valve endocarditis). As all of these PVE patients were on anticoagulant or antiplatelet drugs, the Authors hypothesize that a higher prevalence of prothrombotic conditions may counteract the protective effect of a concomitant antithrombotic treatment, and justify the occurrence of the endocarditis despite ongoing prophylaxis. It is tempting to hypothesize that an inherited (or acquired) prothrombotic condition may synergize with a favouring anatomical perturbation, such as a prosthetic

Fig. 1 Coagulation plays a pivotal role both upstream and downstream infection, throughout the natural history of an infective endocarditis. Platelets also represent a link at the interface of haemostasis and antimicrobial host defence. Thrombin is one of the most potent platelet agonists and induces platelet shape change and the expression of sensors, like glycoprotein receptors for the connective tissue substrates collagen, laminin, fibronectin, von Willebrand factor (vWF), fibrinogen and vitronectin. Pathogens gain access to the bloodstream and can rapidly adhere via platelet fibrin deposition to an inflamed, or injured endothelium. Activated endothelial cells express integrins that promote the local deposition

of fibronectin, bacteria adhere to this protein, endothelial cells release tissue factor and cytokines causing blood clotting and promoting the extension of inflammation and vegetation formation. Bacteria are internalized, also by NET and p-selectin that activate platelets, entrap bacteria-platelet aggregates and induce coagulation. An underlying inherited thrombophilia, such as the mutations G20210A of the prothrombin (PTH) gene and G1691A of factor V (FV Leiden) gene, is likely to favour the initiation and progression of infective endocarditis. The described pathophysiology provides, at least theoretically, the rationale for antithrombotic prophylaxis in this setting

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valve, to accelerate the occurrence of the vegetation, despite ongoing antithrombotic prophylaxis prescribed for the underlying PV. These findings need to be verified in a larger, or more appropriately, in a more selected IE patient sample, such as PVE individuals. In addition, reasons for treatment failure of anticoagulant agents in this setting remain unanswered, and should be addressed from a mechanistic standpoint. In perspective, thrombin might be tested as a common downstream target blocking both the inflammatory and platelet activation components in addition to the procoagulant state [17] characterizing IE, especially in the presence of the factor V Leiden and prothrombin G20201A mutations [18]. Acknowledgments The authors’ studies were supported by a grant from the Italian Ministry of University and Research (PRIN n. 2010JS3PMZ to FS). Conflict of interest The authors have no conflict of interest to disclose. Statement of human and animal rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with human and animals performed by any of the authors. Informed consent

None.

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541 6. Durante-Mangoni E, Iossa D, Molaro R et al (2015) Prevalence and significance of two major inherited thrombophilias in infective endocarditis. Intern Emerg Med. doi:10.1007/s11739-0151214-8 7. Boekholdt SM, Bijsterveld NR, Moons AH, Levi M, Bu¨ller HR, Peters RJ (2001) Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review. Circulation 104:3063–3068 8. Soria JM, Morange PE, Vila J et al (2014) Multilocus genetic risk scores for venous thromboembolism risk assessment. J Am Heart Assoc 3:e001060. doi:10.1161/JAHA.114.001060 9. Kupferwasser LI, Yeaman MR, Shapiro SM et al (1999) Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial dissemination, and frequency of embolic events in experimental Staphylococcus aureus endocarditis through antiplatelet and antibacterial effect. Circulation 99:2791–2797 10. Kupferwasser LI, Yeaman MR, Nast CC et al (2003) Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus. J Clin Invest 112:222–233 11. Veloso TR, Que YA, Chaouch A et al (2015) Prophylaxis of experimental endocarditis with antiplatelet and antithrombin agents: a role for long-term prevention of infective endocarditis in humans? J Infect Dis 211:72–79 12. Anavekar NS, Tleyjeh IM, Anavekar NS et al (2007) Impact of prior antiplatelet therapy on risk of embolism in infective endocarditis. Clin Infect Dis 44:1180–1186 13. Chan KL, Tam J, Dumesnil JG et al (2008) Effect of long-term aspirin use on embolic events in infective endocarditis. Clin Infect Dis 46:37–41 14. Jung CJ, Yeh CY, Hsu RB, Lee CM, Shun CT, Chia JS (2015) Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets. Circulation 131:571–581 15. Habib G, Hoen B, Tornos P et al (2009) Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the prevention, diagnosis, and treatment of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J 19:2369–2413 16. Vanassche T, Peetermans WE, Herregods MC, Herijgers P, Verhamme P (2011) Anti-thrombotic therapy in infective endocarditis. Expert Rev Cardiovasc Ther 9:1203–1219 17. Santilli F, Davı` G (2009) Thrombin as a common downstream target blocking both platelet and monocyte activation. Thromb Haemost 101:220–221 18. Grandone E, Martinelli I, Margaglione M et al (2006) Platelet activation in subjects carrying factor V Leiden or factor II A20210 mutations. J Thromb Haemost 4:2496–2498

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Coagulation and infective endocarditis: sooner or later.

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