Curr Infect Dis Rep (2014) 16:435 DOI 10.1007/s11908-014-0435-8

CARDIOVASCULAR INFECTIONS (D LEVINE, SECTION EDITOR)

The Role of Hemostasis in Infective Endocarditis Emanuele Durante-Mangoni & Rosa Molaro & Domenico Iossa

# Springer Science+Business Media New York 2014

Abstract Infective endocarditis (IE) is a thromboinflammatory disease of the endocardium, with pathophysiology mostly the result of the interplay between microorganisms and modifiers of the hemostasis system. In this setting, the evidence gathered so far warrants a more systematic appraisal. In this review article, experimental and clinical data on the role of hemostasis in IE are summarized. Starting from the current pathogenetic model of IE, we discuss the dual role of platelets in this condition, the microbial interaction with the hemostasis system, also describing nonspecific hemostasis changes during sepsis. We finally propose our hypothesis of thrombophilia as a possible trigger of IE, highlighting the challenges that the study of hemostasis in IE presents. The role of hemostasis in IE appears to be an exciting field of research. The activity of the hemostasis system is highly relevant in terms of susceptibility, progression, and treatment of IE. Pharmacologic modulation of hemostasis before and after IE onset is possible and represents still a largely unexplored area of study. Keywords Coagulation . Thrombosis . Endocarditis . Sepsis . Platelets . Thrombophilia

Introduction Historically viewed as a mere infection of heart valves due to a limited array of microorganisms, mostly gram-positive bacteria, infective endocarditis (IE) is currently emerging as a unique model of a thromboinflammatory disease of the endocardium. The interplay between host factors, This article is part of the Topical Collection on Cardiovascular Infections E. Durante-Mangoni (*) : R. Molaro : D. Iossa Internal Medicine, University of Naples S.U.N., Monaldi Hospital, Via L. Bianchi snc, 80131 Naples, Italy e-mail: [email protected]

particularly modifiers of the hemostasis system, and microorganisms invading the bloodstream translates into a complex pathophysiologic sequence whose consequences span from septic complications to embolic events and account for the never-changing mortality of IE. As the gathering of novel pathogenetic data proceeds slowly and is the product of few research groups, the evidence gathered so far warrants a more systematic appraisal. In this review article, we summarize experimental and clinical data ranging from fundamental microbiology to hemostasis biology, with the aim to stimulate a larger interest for this matter and to set the stage for further studies on this specific aspect of IE pathogenesis.

Current Pathogenetic Model of IE The hallmark of IE is the infected endocardial vegetation. It usually forms on a heart valve leaflet but may also develop on a prosthetic heart valve or a different implanted intracardiac device. Much less commonly, the IE vegetation can locate on other endocardial structures [1]. The vegetation is thought to originate from the initial deposition of platelets and fibrin on the heart endothelial lining [2–4]. In normal circumstances, the endocardium is non-thrombogenic [5]. However, when it gets damaged and/ or the subendothelium is exposed due to a valve abnormality with resultant blood flow disturbance or when a device is inserted, the endocardial lining may become a potent coagulation inducer [6]. Platelets are rapidly recruited and, once adhered to the subendothelium, release their granules, triggering the local deposition of fibrin [6, 7]. Thus, in the common instance of a focal endocardial lining damage, the hemostasis system activates locally and a platelet-rich microclot forms, being the potential root of small sterile endocardial vegetation [8]. This, in its turn, may behave as the docking site for

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bacteria circulating either in the free state or bound to resting platelets or antibodies. This second step gives rise to the initially infected vegetation that may subsequently grow and mature, causing clinically apparent disease [6, 9, 10]. The importance of mechanical microtrauma in the pathogenesis of IE is suggested by the fact that vegetations develop far more commonly on the left heart valves [1] where the faster blood flow due to greater contraction forces determines a higher rate of endothelial damage. Moreover, the turbulent flow that originates in the path of regurgitant blood acts as an efficient shear stress inducer that activates platelets and modulates endothelial function towards thrombogenesis [11, 12]. This underlies the common formation of IE vegetations on the valvular closure rim, usually on the atrial aspect of atrioventricular valves and the ventricular surface of semilunar valves. Different mechanisms are likely in place in prosthetic valve or device IE, especially when the host is also receiving antiplatelet or anticoagulant medications [13•]. Bacterial adherence is mediated by host-derived proteins and polysaccharide moieties that cover the device surface or may occur via direct binding to the prosthetic surface exposing polymeric macromolecules [14, 15]. The antithrombotic treatment may also variably influence the contribution of hemostasis to vegetation formation. As a matter of fact, vegetation size is typically smaller in mechanical prosthetic valve IE and, in a proportion of cases, vegetations are absent, with infection heralded by prosthetic dehiscence or paravalvular abscess formation [8]. Thus, in terms of coagulation system function, different pathways could be activated in native valve and prosthetic valve IE. Also, the hemostasis system could play a different role in IE involving bioprosthetic vs mechanical valves. In these cases, a differential effect of antithrombotic medications (antiplatelet and anticoagulant), variably taken by patients, may exist. There are indeed a few retrospective and a single prospective study that have assessed the effect of antithrombotic medications in IE, as extensively discussed in a recent review article [13•].

Dual Role of Platelets in IE Platelet microaggregates at the site of endothelial injury are likely the very initial substrate for IE [16, 17]. Our current understanding supports the notion that platelets have indeed a major role not only in the early phases of hemostasis but also as a natural antibacterial defense within the bloodstream [18]. Thus, as will be described elsewhere, on the one hand, direct binding of platelets to bacteria via membrane glycoprotein receptors may activate the coagulation cascade and favor bacterial seeding on valve lesions. On the other hand, however, platelets may exert an important innate antibacterial effect. They contribute to host defense mechanisms such as chemotaxis and phagocytosis and play a role in the immune response

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by binding immune globulins through the Fcγ receptor II and expressing the Toll-like receptor 4, a major lipopolysaccharide receptor. Most importantly, antibacterial effects are mediated by platelet microbicidal proteins (PMPs) [19]. PMPs are a diverse group of thrombin-induced cationic proteins released by platelets, including platelet basic proteins (CTAP-3, NAP2, and thrombocidin-1 and thrombocidin-2), gramicidin D, protamine, platelet factor 4, RANTES, fibrinopeptides A and B, and thymosin β4 [20–22]. The major actions of PMPs are microbicidal against a diverse range of pathogens; they are also chemotactic. The bactericidal effect appears to depend on the specific pathogen considered: for instance, PMP-1 shows a higher bactericidal effect against Staphylococcus aureus than Escherichia coli or Candida albicans [23]. Synergism among different PMPs has been observed [24]. It is interesting to note how the development of resistance to PMP-1 in S. aureus affects the efficiency of IE vegetation formation in an experimental model [25•], with vegetations significantly larger in cases due to PMP-1-resistant strains. PMP may also be an important host defense mechanism against viridans streptococci IE. Strains causing IE more frequently show resistance to PMPs compared to other streptococcal isolates. In addition, animals actively immunized against PMPs and showing seropositivity for antithrombocidin-1 and anti-thrombocidin-2 antibodies are more susceptible to streptococcal experimental IE [26].

Microbial Interaction with the Hemostasis System As we have illustrated in the prior sections, microbial infection of the human heart as well as intracardiac prosthetic devices encompasses a complex series of events. Microorganisms possess a number of virulence factors through which they can profoundly modulate this process. Adherence of bacteria to host or prosthetic surfaces is the first essential step in the initiation of IE. Together with causative pathogens, the hemostasis system is the other most important player. Bacterial adherence involves several microbial surface components, called adhesins, which are able to recognize and dock to both host cellular membrane molecules and extracellular matrix components. For this reason, bacterial adhesins that mediate binding to host molecules are commonly referred to as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) [14, 27]. Extracellular matrix components that allow bacterial adherence include factors of the hemostasis system, such as fibronectin, collagen, fibrinogen/fibrin, and other structural moieties, including elastin, vitronectin, laminin, as well as heparin sulfate-containing proteoglycans. Staphylococci and streptococci are clinically important gram-positive bacteria that cause most cases of IE

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worldwide. In particular, S. aureus is now the leading cause of IE. The association between these microbial genera and IE is not casual and has a defined molecular basis related to the production of peculiar MSCRAMMs. The specific binding of S. aureus to fibronectin was first reported by Kuusela [28]. Subsequently, two staphylococcal fibronectin-binding proteins, fibronectin-binding protein A (FnBPA) and FnBPB, and the corresponding genes were isolated and characterized [29–32]. Many staphylococci and streptococci have since been shown to bind fibronectin. At least a dozen of fibronectin-binding MSCRAMMs have been identified, and their corresponding genes have been sequenced. These MSCRAMMs exhibit structural features typical of other cell wallanchored proteins of gram-positive bacteria. Moreover, FnBPA and FnBPB trigger active internalization into eukaryotic cells in vitro and in vivo [33–35]. Other staphylococcal MSCRAMMs were shown to bind matrix proteins as diverse as fibrinogen [36, 37], elastin [38, 39], collagen [27], and keratin [40]. It has also been shown that binding of S. aureus to fibrinogen and fibronectin via FnBPA and also clumping factor A (ClfA) were essential steps in the development of experimental endocarditis in the rat model [34, 41]. Bacteria appear to interact with the hemostasis system differentially according to the actual stage of the pathogenetic sequence considered. In an early, crucial step of bacterial adherence, i.e., in the induction phase of IE, ClfA, and FnBPA, mediates fibrinogen binding. This, however, does not seem to be sufficient for disease progression. In contrast, although not sufficient to induce IE initiation, subsequent fibronectin binding is essential for cell invasion and, therefore, disease progression [34, 41]. Based on this two-step sequential model of disease initiation and progression, it was hypothesized that staphylococci may directly induce platelet activation via fibrinogen-mediated bridges between FnBPA and the platelet membrane fibrinogen receptor, the glycoprotein complex IIb/IIIa. Direct platelet activation may be a crucial event in the pathogenesis of IE. Indeed, FnBPA was shown in vitro to activate platelets even in the absence of fibrinogen [42, 43]. The direct effect of S. aureus and other IE causative pathogens on the hemostasis system is not limited to the induction of platelet activation. Secretion of microbial proteins functioning as proteases that activate proenzymes of blood coagulation and fibrinolysis systems may directly affect clot formation. One such bacterial exotoxin is staphylocoagulase, a well-known product of S. aureus that is able to activate prothrombin via a pathway different from the proteolytic cleavage mediated by the host p r o t h r o m b i n a s e c o m p l e x . I n t e r e s t i n g l y, t h i s nonproteolytic direct thrombin activation is not hampered by treatment with heparins, vitamin K antagonists, or

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hirudin but is inhibited by the direct thrombin inhibitor dabigatran in a concentration-dependent manner [44].

Nonspecific Hemostasis Changes During Sepsis Besides changes of coagulation and fibrinolysis directly exerted by IE pathogens, bacterial sepsis per se goes along with a significant modulation of the hemostasis system, affected by host inflammatory mediators [45]. The most important pathways of hemostasis system activation by inflammation and bacteremia are graphically recapped in Fig. 1. This modulation is biased towards a thrombophilic state characterized by coagulation factor activation coupled with inhibition of anticoagulant pathways and fibrinolysis. Activation of the coagulation cascade and clot formation has evolved in fact as host defense mechanism against infectious agents [46]. It is therefore conceivable that during IE—or even at the time of bacteremia progressing into IE—a thrombophilic state occurs, both systemically and locally, at the site of initial bacterial seeding to the endocardium. Bloodstream infections also activate endothelial cells [47, 48], triggering structural and functional changes that result in increased leukocyte recruitment and platelet adhesion. Thus, besides the direct local effects of turbulent blood flow, endothelial damage favoring IE vegetation formation may be fueled by mediators of inflammation and sepsis. An in-depth evaluation of the potential role of each procoagulant, anticoagulant, and fibrinolytic pathway and their cross talk with the endothelium function is an exciting challenge to foster our understanding of the IE pathogenesis. Among candidate factors, there are proteins and components having a pivotal role in the hemostasis system function, including tissue factor, thrombin, activated protein C, plasminogen activator inhibitor-1, as well as newer and less comprehensively studied players, such as protease-activated receptors, circulating microparticles and platelet membrane glycoprotein receptors. Platelets are naturally activated during sepsis [49–51] and not only promote coagulation but also propagate the proinflammatory cascade. They form white clots on damaged endothelial layers via interaction with von Willebrand Factor (vWF) bound to subendothelial collagen. vWF is released by endothelial cells [52–54], and this action is upregulated by proinflammatory cytokines. Other important cellular players of the inflammation- or sepsis-induced procoagulant state are monocytes and macrophages that may be induced to release tissue factor by the action of cytokines and C-reactive protein [55]. Of note, monocytes are present in the IE vegetation and contribute to its growth. In accordance with these data, we found that elevated levels of serum C-reactive protein correlated with vegetation size and embolic risk in IE

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Fig. 1 The major pathways of hemostasis system activation are shown, with specific reference to their networking with mediators of inflammation and sepsis and their interaction with bacterial pathogens invading the

bloodstream. Endothelial cells are in yellow, red blood cells in red, platelets in beige, leukocytes in blue, and bacteria in green

[56]. This is consistent with the clinical observation that the attenuation of the acute-phase reaction induced by effective antibiotic treatment progressively reduces the embolic rate in IE [57]. The role of C-reactive protein (CRP) is controversial, however, as it could also exert an inhibitory effect on platelet-to-platelet aggregation [58–60]. For this reason, we hypothesized that the decline of CRP concentration during treatment could reduce the rate of embolism by modifying platelet function within the vegetation, somehow stabilizing the clot and making it more compact [56]. Within the circulation of patients with bacterial sepsis, elevated amounts of cellular fragments derived from apoptotic or functionally activated cells can be found, which are referred to as microparticles. These cell debris particles are mostly made of membrane phospholipids, a key to the coagulation cascade activation, also expressing tissue factor [61]. The potential role of the microparticles in IE surely deserves attention. Bacterial infection may also affect anticoagulant systems, mostly endothelium-derived factors that act to prevent blood clotting at the endocardial surface, including tissue factor pathway inhibitor, antithrombin, and activated proteins C and S [62, 63]. Inherited or acquired deficiency of these factors is well-described, rather rare, clinical conditions, but their role in IE has never been assessed. In summary, the role of hemostasis in IE can be viewed as a double-faceted Janus [62, 64]. A state of coagulation

activation or thrombophilia may act as a predisposing substrate triggering the initial steps of nonbacterial vegetation formation. On the other hand, inciting bacterial infection can progress into a full-blown infectious process characterized by mature bacterial vegetation from which thromboembolic complications may ensue.

Thrombophilia as a Possible Trigger of IE The hypothesis that a prothrombotic condition may underlie IE is firstly based on epidemiologic considerations. Cardiac disorders and conditions that may predispose to IE are quite common in the general population, especially in the elderly. Similarly, bacteremia is a daily event. In the face of that, the incidence of IE is low, ranging from three to about ten cases per 100,000 patient-years [65–67]. The possibility that a prothrombotic condition is the discriminant between risk of and protection from IE in subjects with a predisposing cardiac condition surely warrants attention. In view of the key role played by the hemostasis system in this process, it appears reasonable to hypothesize that a prothrombotic state might favor the initiation of the IE vegetation development. However, whether an inherited thrombophilic state represents a predisposing condition for the initiation of an endocardial nonbacterial clot in patients at risk for IE is currently unknown.

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The study of hemostasis and thrombophilia in IE is challenging by itself. In fact, sepsis may induce changes in hemostasis that overlap with a thrombophilic state [45, 68]. This explains why very few studies have focused on this issue so far [69–72]. It also justifies the inherited thrombophilia hypothesis we pursued. Thrombotic disorders are multifactorial conditions underlied by inherited and acquired risk factors [73]. On pathophysiologic grounds, thrombotic events involving the arterial vessels are differentiated from those affecting the venous compartment. Arterial thrombosis is associated with hypertension, hyperlipidemia, smoking, diabetes mellitus, and blood hyperviscosity, as well as atherosclerosis, inflammation, and hypercoagulability [74, 75]. Venous thromboembolism is linked to blood flow reduction, lumen vessel damage, and hypercoagulability [73]. One factor appears to play a role in both instances, i.e., hypercoagulability. This may be defined as a tendency towards clot formation or thrombophilia with an inherited, acquired, or mixed etiology [76]. As IE may actually affect both sides of the heart and therefore develop in either an arterial or a venous blood flow compartment, it is conceivable that thrombophilia might play a differential role in its pathogenesis. Thrombophilia is by definition a tendency towards the development of venous or arterial thrombosis, based on defects of primary hemostasis, coagulation, or fibrinolysis [77–79]. An inherited thrombophilic state may be related to a quantitative deficiency or a qualitative defect of anticoagulant or fibrinolytic mechanisms as well as the presence of genetic polymorphisms related to the hemostasis cascade [80–83]. It is possible that both inherited and acquired factors contribute to the development of a prothrombotic state. Indeed, the existence of a thrombophilia does not necessarily imply a thrombotic event, unless an additional thrombogenic condition ensues [83–86]. The most important thrombophilias are inherited. Some of them, such as antithrombin or protein C or S deficiency, are quite uncommon with an estimated prevalence lower than 0.1 %. Other conditions, including activated protein C resistance, are much more frequent and include factor V Leiden and the G20210A mutation of the prothrombin (factor II) gene. Other common inherited conditions are represented by genetic polymorphisms of platelet membrane glycoprotein receptors that mediate all major steps of platelet function, including adhesion, aggregation, and granule secretion. The antiphospholipid syndrome is a commonly acquired condition of thrombophilia, wherein autoantibodies directed towards cardiolipin and beta2-glycoprotein I trigger platelet activation, causing both arterial and venous thromboses. Besides its potential role as a predisposing factor, a prothrombotic condition could influence a number of outcomes relevant to IE, including vegetation size, embolic events, and surgical complications. As of today, a very limited number of studies have investigated the hemostasis function in IE or have assessed the

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potential influence of thrombophilic states on IE incidence, vegetation growth, and embolic complications. A single study assessed the influence of antiphospholipid antibodies on different components of the hemostasis pathway as well as embolic events in IE [69]. Almost one in six IE patients showed elevated levels of antiphospholipid antibodies, and embolic events were significantly associated with this serologic condition. Presence of antiphospholipid antibodies was related to higher levels of procoagulant factors or markers of hemostasis activation, including prothrombin fragment F1+2, plasminogen activator inhibitor-1, and von Willebrand factor, and lower levels of activated protein C. Thrombin generation and endothelial cell activation were stronger in seropositive patients, who also more often had large endocardial vegetations [69]. In line with these data, a small study observed a high level of oxidized low-density lipoprotein/beta2-glycoprotein I complexes in IE patients compared to healthy controls [70]. Also, immunoglobulins M and G directed against the same complexes were found to be higher in IE, suggesting that oxidative stress and endothelial dysfunction may play a role in IE pathogenesis [70]. Endothelial cell activation markers, including P-selectin and E-selectin, were found to be upregulated in patients with IE and embolic complications by a Turkey-based group [87]. In the same patient cohort, these authors also observed that the occurrence of embolic events in IE was significantly associated with levels of prothrombin fragment 1 + 2, thrombin-antithrombin complexes, beta-thromboglobulin, and platelet factor 4. Moreover, embolic patients had higher levels of plasminogen activator inhibitor-1, a potent fibrinolysis antagonist. In accordance with these findings, limited to a small number of IE patients, the disease would be characterized by a sustained hypercoagulable state with systemic coagulation activation, enhanced platelet activity, and impaired fibrinolysis, which could contribute to the increased risk of thromboembolic events [71, 72]. It is conceivable that most of these procoagulant changes and alterations in platelet activity are directly or indirectly induced by inflammation [45, 68]. Consistent with this view is the observation that higher serum levels of CRP, a premier marker of inflammation, are observed in patients with IE complicated by major embolic events and that a reduction of the embolic risk occurs with declining CRP levels [56]. Two clinical observations led us to hypothesize a role for inherited thrombophilias in the pathogenesis of IE. A young subject with sterile vegetation on a bicuspid aortic valve [88] was found to have severe hyper-homocysteinemia associated with a homozygous mutation (C677T) within the methylenetetrahydrofolate reductase (MTHFR) gene, a common cause of an inherited prothrombotic state [89]. Another young patient who developed health careassociated C. albicans IE on a pacemaker lead with very

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large vegetation occupying the right heart chambers also had severe hyper-homocysteinemia and homozygous MTHFR C677T mutation [88]. None of these two patients had metabolic syndrome, suggesting a potential role of the inherited prothrombotic abnormality in inducing hyperhomocysteinemia. Whether elevated homocystein levels in these patients played any role in the induction of native valve endocarditis and lead-related endocarditis remains to be established.

Challenges of the Study of Hemostasis in IE In asking research questions about the role of hemostasis and thrombophilias in IE, one should firstly establish which methodological approach is better suited. As for any risk factor exploratory analysis, the ideal approach would be that of a prospective cohort study. Once the candidate risk factor relevant to hemostasis has been chosen, a cohort of unaffected subjects should be screened for this condition. After screening, the initial patient cohort will be comprised of positive and negative subjects. All of them should then be followed up over a sufficient time span to allow a proportion of them to develop IE. At the end of the study period, differences in IE incidence should be compared to assess the effect of the candidate risk factor on the disease onset. Taking into account an average IE population incidence of about 5 cases/100,000 person-years, millions of people would need to be screened for the study to be powered enough. Thus, this approach does not appear feasible. A surrogate approach could be to measure the prevalence of the candidate risk factor in a group of IE subjects and compare it with that observed in a matched control group without IE. Although less rigorous, this approach is surely more feasible but requires that the choice of the control group is appropriate and the sample size of the study well balanced with the expected difference between groups. Another major issue to consider is whether a genotypic approach would be preferable rather than a phenotypic approach. Indeed, the candidate risk factor may be a protein or other mediators implicated in platelet function (adhesion, activation, degranulation, aggregation) or coagulation cascade (clotting factors, activation markers). However, as previously discussed, each of these pathways become altered during inflammation, sepsis, and organ dysfunction, conditions that are all present in IE. Thus, when evaluating phenotypic changes in the hemostasis balance among IE patients, one cannot clearly distinguish whether these are the cause or a consequence of the disease. In contrast, inherited traits functionally affecting the hemostasis system are surely existent before IE onset and their investigation is not influenced by the disease activity. This is the major reason why our group has started to analyze the potential influence of several inherited thrombophilic conditions on IE onset and embolic

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complications. These studies are underway, and their results are going to be released in the near future.

Conclusions The role of hemostasis in IE remains a relatively neglected but exciting field of research. Slowly accumulating evidence suggests that the activity of the hemostasis system is highly relevant in terms of susceptibility to progression and treatment of IE. Pharmacologic modulation of hemostasis before and after IE onset is possible and represents a still largely unexplored area of study. The possibility that an inherent or developed state of thrombophilia could favor IE onset and progression surely warrants investigation.

Compliance with Ethics Guidelines Conflict of Interest Emanuele Durante-Mangoni was a board member for Pfizer, worked as a consultant for Pfizer and Novartis, and received payment for educational presentations for Novartis, Merck, and Gilead. Domenico Iossa and Rosa Molaro have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.

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