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Enhanced platelets aggregation and coagulation of methicillin-resistant Staphylococcus aureus compared to methicillin-sensitive Staphylococcus aureus

Thrombosis Journal volume 23, Article number: 98 (2025) Cite this article

Abstract

AbstractSection Introduction
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Staphylococcus aureus (S. aureus) is well known for its ability to activate platelets and to induce plasma coagulation through different pathways.

AbstractSection Gap statement

Enhanced human platelet aggregation and plasma coagulation by methicillin-resistant S. aureus (MRSA) have not been reported.

AbstractSection Aim

This study aims to investigate platelets and coagulation activities of MRSA strains compared to methicillin-sensitive strains of S. aureus (MSSA).

AbstractSection Methods

Well-characterized bacterial strains of Coagulase-negative Staphylococci (CoNS) (n = 25), and Coagulase-positive Staphylococci (CoPS) including MRSA (n = 25) and MSSA (n = 25) using phenotype and genotype analysis were compared for their coagulation and aggregation abilities. Isolates were tested for slide and tube coagulase test, mixed with human plasma and investigated for coagulation ability using manual and automated prothrombin time (PT), partial thromboplastin time (PTT), clotting time (CT), and thrombin time (TT) or mixed with human platelet rich plasma (PRP) and analyzed for reduced platelets count (aggregation) and for platelets aggregations using chrono-log aggregometer.

AbstractSection Results

MRSA isolates have faster, and stronger tube coagulase test compared to MSSA isolates. MRSA isolates compared to MSSA isolates have significantly reduced manual PT (7.2 ± 1.2 s vs. 10.5 ± 2 s, P < 0.0001), significantly reduced PTT (16.1 ± 1.5 s vs. 23.8 ± 2 s, P < 0.0001), and significantly reduced CT (84 ± 117.2 min vs. 148.3 ± 195 min, P < 0.0001). Similarly, MRSA isolates have significantly reduced PT, PTT, and TT compared to MSSA (P < 0.0001) using an automated coagulation analyzer. MRSA isolates induce a significant decrease in platelet count compared to MSSA (90.3 ± 35.9 vs. 121.1 ± 42.6, P < 0.001). MRSA isolates have significantly increased PRP aggregation compared to MSSA isolates indicated by increased aggregation maximum amplitude, aggregation slope, and area under the curve (P < 0.0001). PT test distinguishes CoPS from CoNS with 100% sensitivity and 98% specificity.

AbstractSection Conclusions

Enhanced plasma coagulation and platelet aggregation of MRSA compared to MSSA strains is another virulence factor that increases MRSA protection, decreases antibiotics diffusion, and leads to thrombotic/clotting complications. PT is a useful diagnostic test for distinguishing CoPS from CoNS.

Introduction

Staphylococcus aureus (S. aureus) is a common cause of multiple serious human infections including skin and burn infections, surgical site infections, respiratory infections, food poisoning and bacteremia [1]. Antibiotic-resistant strains of S. aureus are a worldwide concern as it is usually associated with high rates of morbidity and mortality [2]. Methicillin-resistant Staphylococcus aureus (MRSA) infections were reported since 1950 [3]. The rate of MRSA infections has increased dramatically over the past few decades, reaching up to 50%, with approximately 30% of infected patients dying within 30 days [2, 4]. MRSA exhibits resistance to β-lactam antibiotics due to the presence of the mecA gene, which encodes a modified penicillin-binding protein [5,6,7]. Recently, vancomycin-resistant S. aureus (VRSA) strains, commonly mediated by the vanA and vanB genes, which confer resistance to vancomycin, the last-resort antibiotic for S. aureus, have emerged as a new and critical challenge [6].

Platelets and the coagulation systems are well known to play a critical role in hemostasis, helping to prevent bleeding [8]. Abnormal function of platelets and/or the coagulation system can lead to life-threatening thrombosis and clotting disorders, including myocardial infarction and stroke [8]. There is increasing evidence supporting novel functions of platelets in immunity, antibacterial and antiparasitic defense, protein synthesis, inflammation, tumor metastasis, and liver regeneration [9]. Interactions between platelets and/or coagulation and infectious agents have been established for many pathogens [10, 11]. Staphylococci are well known for their ability to activate platelets and induce plasma coagulation through different pathways [12]. Classically, Staphylococci are classified based on their ability to coagulate plasma into coagulase-positive Staphylococci (CoPS), which include S. aureus, and coagulase-negative Staphylococci (CoNS), which include S. epidermidis and other species [6].

S. aureus secretes two coagulases: the classical coagulase (Coa) and von Willebrand factor-binding protein (vWbp), both of which can activate the coagulation cascade and promote fibrin formation [12]. It is speculated that fibrin protects bacterial cells during abscess formation [13]. Furthermore, S. aureus can form clumps of cells in the presence of plasma, independent of fibrin, through clumping factor A (ClfA)[12]. In addition, S. aureus induces platelet activation, secretion, and aggregation via multiple mechanisms. These include the secretion of bacterial α-toxin, the interaction of surface bacterial proteins—such as S. aureus protein A (SAP), ClfA, fibronectin-binding protein A (FnBPA)—with host molecules, and through specific immunoglobulin G (IgG). S. aureus can activate platelets either directly through GPIIb–IIIa binding or indirectly via thrombin generation through activation of the coagulation cascade [11, 14]. On the other hand, S. aureus produces staphylokinase, which dissolves fibrin clots, and extracellular fibrinogen-binding protein (Efb), which inhibits platelet aggregation [15]. Inhibition of coagulation using the thrombin inhibitor dabigatran, or inhibition of platelet aggregation through blockage of glycoprotein IIb/IIIa by abciximab, or through aspirin administration, has been shown to interfere with S. aureus-mediated coagulation and platelet aggregation [16, 17]. It is hypothesized that S. aureus-mediated platelet and coagulation activation leads to the formation of clots or aggregates that protect bacterial cells from immune responses by phagocytes and neutrophils, reduce the diffusion of antibiotics to the infection site, and facilitate bacterial dissemination via thromboembolic lesions [12]. Accordingly, the inhibition of S. aureus coagulase activity may represent a potential therapeutic target [15]. S. aureus is also among the most common organisms capable of forming biofilms, a process that depends in part on its clumping and coagulation abilities. Biofilm formation is known to enhance antimicrobial resistance and delay host immune defenses [18]. The exact role of platelet and coagulation interactions in enhancing bacterial virulence is not yet fully understood [11, 12, 14]. Of particular interest is the potential impact of this interaction on S. aureus antibiotic efficacy or resistance. Some studies have suggested indirect evidence supporting a possible role for this interaction in the development of antibiotic resistance. For example, the average plasma coagulation time of VRSA isolates was reported to be longer than that of vancomycin-susceptible isolates [19], Additionally, coagulase type II was most frequently observed in MRSA strains isolated from various skin infections [20]. Pretreatment of synovial fluid with plasmin, aimed at disrupting biofilm-like aggregates of S. aureus, was shown to improve antibiotic susceptibility [21]. Furthermore, MRSA-induced infection in diabetic mice was associated with increased inflammation and coagulation [22]. Notably, fast and slow coagulase variants of S. aureus have been identified, and the coagulase type is often associated with methicillin resistance [23]. To date, enhanced human platelet aggregation and plasma coagulation by MRSA strains has not been reported. Accordingly, this study aims to investigate and compare the platelet and coagulation activities of MRSA and methicillin-sensitive S. aureus (MSSA) strains.

Material and maethods

Bacterial strains

Bacterial isolates including CoNS (n = 25), MRSA (n = 25) and MSSA (n = 25) were previously isolated from the anterior nares of healthy individuals and hospitalized patients, or from infected patients. These isolates were characterized for antibiotic resistance using both phenotypic and molecular methods. American Type Culture Collection (ATCC) reference strains including MRSA (33591), MSSA (25923), and CoNS (S. epedermidise) (2228), were purchased and previously described [5,6,7]. All isolates had been previously characterized by Gram staining and microscopic examination, and were cultured on general and selective media, including mannitol salt agar. Biochemical and enzymatic profiling was conducted, including coagulase and catalase tests, using both manual methods and the automated Vitek 2 system [5,6,7, 24, 25]. Antibiotic susceptibility testing was performed using the Kirby-Bauer disc diffusion method, including cefoxitin diffusion for methicillin resistance, E-test for vancomycin resistance, and the Vitek 2 compact system, in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines [26]. In addition, molecular analysis was conducted to detect resistance genes including mecA (for methicillin resistance), vanA and vanB (for vancomycin resistance), as well as coa gene (for coagulase enzyme) and biofilm-forming genes, as described previously [5,6,7, 24]. Isolates were stored at − 80 °C and re-cultured from frozen stocks. Pure colonies were used for subsequent experimental procedures.

Human platelets rich plasma (PRP), and platelets poor plasma (PPP) Preparation

Human blood was obtained from multiple healthy donors (n = 10) after obtaining formal consent and ethical approval. Blood was collected using appropriate anticoagulant-containing tubes and withdrawn using a wide-pore syringe. Platelet-rich plasma (PRP) was prepared by centrifuging whole blood at 100 × g for 20 min at room temperature. Platelet-poor plasma (PPP) was then obtained by further centrifuging the PRP at 1000 × g for 10 min [25]. Commercially available rabbit plasma was purchased from Hardy Diagnostics (Santa Maria, CA 93455, USA) and used according to the manufacturer’s instructions [6].

Plasma coagulation studies

Slide coagulase test

Different bacterial strains, along with positive and negative controls, were mixed with undiluted plasma on a sterile slide. The appearance of coarse clumping of cocci visible to the naked eye within 10 s was considered a positive reaction [27].

Tube coagulase test

Bacterial strains, along with positive and negative controls, were added to diluted rabbit or human plasma in 0.85% NaCl and incubated for up to 24 h. The formation of a visible clot indicated a positive reaction. Clotting time (CT) was calculated as the time (in minutes) required to form a visible clot when human plasma was mixed with the bacterial strains or controls [26, 27].

Automatic and manual coagulation assessment

Manual measurements of prothrombin time (PT), partial thromboplastin time (PTT), and clotting time (CT) were performed as described previously [26, 28]. Briefly, citrated plasma was mixed with thromboplastin reagent for PT test or partial thromboplastin reagent and Calcium chloride for PTT test (International Medical Diagnostic, Diamond, Zarqa, Jordan) and then mixed with equal concentrations of different bacterial strains adjusted to 0.5 McFarland standard and incubated in a 37 °C water bath. Clot formation was monitored, and clotting time was recorded in seconds. Automated coagulation measurements were performed using a BIOBASE automated coagulometer (China), following the manufacturer’s instructions. Citrated plasma was mixed with PT, PTT, and thrombin time (TT) reagents and equal concentrations of bacterial strains (0.5 McFarland). Samples were placed in pre-warmed cuvettes at 37 °C. The instrument utilized optical colorimetry and density detection to automatically record clotting times in seconds [26, 28]. Reference ranges for PT and PTT tests were according standard [26, 28]. Diagnostic accuracy of PT and PTT tests to distinguish between isolates were assessed by sensitivity (the ability of a test to correctly identify true positives), specificity (the ability of a test to correctly identify true negatives), Positive Predictive Value (PPV) (the probability that a person with a positive test result actually has the disease), and Negative Predictive Value (NPV) (the probability that a person with a negative test result truly does not have the disease) as outlined by the World Health Organization [29].

Platelets aggregation studies

Platelets aggregation studies using CBC machine

An automatic complete blood count (CBC) machine, which measures the counts of all cellular blood elements, was used to assess the degree of platelet aggregation. When platelets aggregate, they are counted as a single particle. Therefore, a decrease in platelet count indicates an increase in aggregation. Bacterial strains suspension or control (50 µL) were mixed with (350 µL) of PRP after adjustment of platelets count to 3 × 108/mL, and the reduction in platelet count was measured as described previously using a Sysmex automated hematology CBC analyzer [30].

Aggregation studies using aggregometer

Platelet aggregation tests measure the ability of various agonists to induce in vitro platelet activation and platelet-to-platelet aggregation. Equal concentrations of different bacterial strains, adjusted to a 0.5 McFarland standard, were prepared and added to PRP. The ability of these strains to induce aggregation was assessed using an optical CHRONO-LOG® aggregometer (CHRONO-LOG corporation Havertown, PA, USA) [31]. Briefly, fresh blood obtained from healthy donors using 3.2% sodium citrate tubes. PRP and PPP were obtained as described above. Platelets count was adjusted to 3 × 108/mL. 50 µL of bacterial suspension, positive controls (collagen 1 µg/mL and epinephrine 5 µM), or negative controls (normal saline and Streptococcus thoraltensis) were added to 350 µL PRP in aggregometer cuvette pre-wormed to 37 °C. PPP was added into the reference cuvette. The samples were incubated for 2 min while stirring and the reaction was observed for 10 min [31]. The instrument calibration, manual, procedure, and standard setting followed manufacturer instruction. To eliminate donor to donor variability the procedure was performed with MRSA samples, MSSA samples, and controls on the same donor on the same day.

Statistical analysis

Statistical analysis was performed using SPSS version 24. A P-value less than or equal to 0.05 was considered statistically significant. Clotting and aggregation data were normally distribution as determined by Shapiro-Wilk test. Differences between the means of two groups were evaluated using the Student’s t-test, while differences among three or more groups were assessed using one-way ANOVA, followed by the LSD post-hoc test when significant differences were detected.

Results

Characterization of bacterial isolates

The bacterial isolates used in this study included ATCC strains (n = 4), S. aureus nasal isolates (n = 60), and S. aureus clinical isolates (n = 20) were characterized in depth [5,6,7, 24]. Species identity of all strains was confirmed using both manual and automated methods. Coagulase activity was tested by the coagulase tube test and detection of the coag gene. Methicillin resistance was confirmed by cefoxitin disc diffusion, Vitek 2 methicillin test, and detection of the mecA gene. All strains were susceptible to vancomycin as determined by E-test, and tested negative for the vanA and vanB genes associated with vancomycin resistance., details were summarized in (Table 1).

Table 1 Bacterial isolates characteristics
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Slide and tube coagulase test of bacterial strains

Different bacterial isolates were mixed with human or animal (rabbit) plasma and observed for visible clot formation using slide and tube coagulase tests. All CoPS (MRSA and MSSA) were able to induce visible clot formation in both human and animal plasma using the tube method. Whereas CoNS failed to induce any clot even after 24 h (Table 2). The slide coagulase test was positive for some CoPS strains but negative for all CoNS. MRSA strains induce visible plasma clotting faster and stronger than MSSA strains, an observation that was tested and quantified further in depth below.

Table 2 Human and animal plasma coagulation with bacterial isolates
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Coagulation of human plasma by bacterial isolates

Human plasma was treated with different bacterial isolates under similar conditions. CoPS isolates showed significantly reduced PT compared to control plasma (9 ± 2 s vs. 14 ± 2 s, P < 0.0001) and compared to CoNS isolates (9 ± 2 s vs. 16 ± 2 s, P < 0.0001) (Fig. 1A). Furthermore, both MRSA and MSSA isolates demonstrated significantly reduced PT compared to CoNS (7.2 ± 1.2 s and 10.5 ± 2 s vs. 16 ± 2 s, P < 0.0001) (Fig. 1B). Importantly, MRSA isolates had significantly reduced PT compared to MSSA isolates (7.2 ± 1.2 s vs. 10.5 ± 2 s, P < 0.0001) (Fig. 1B).

Fig. 1
figure 1

Manual human plasma prothrombin time (PT), partial thromboplastin time (PTT), and clotting time (CT) with bacterial isolates. A PT in seconds for control, CoNS (Coagulase Negative Staphylococci) and CoPS (Coagulase Positive Staphylococci). B PT for CoNS, CoPS, MRSA (Methicillin Resistant Staphylococci), and MSSA (Methicillin Sensitive Staphylococci). C PTT in seconds for control, CoNS and CoPS. D PTT for CoNS, CoPS, MRSA, and MSSA. E CT in minutes for CoNS, CoPS, MRSA, and MSSA. Numbers: normal plasma (n = 25), CoNS (n = 25), CoPS (n = 50), MRSA (n = 25), and MSSA (n = 25). **P < 0.001, *** P < 0.0001, ns: non-significant. One way ANOVA test with LSD post-hoc

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CoPS isolates showed significantly reduced PTT compared to control plasma (20.7 ± 4.7 s vs. 24 ± 2 s, P < 0.001) and compared to CoNS isolates (20.7 ± 4.7 s vs. 25.2 ± 1.8 s, P < 0.001) (Fig. 1C). MRSA isolates had significantly reduced PTT compared to MSSA isolates (16.1 ± 1.5 s vs. 23.8 ± 2 s, P < 0.0001) (Fig. 1D). CoPS isolates showed significantly reduced CT compared to CoNS (122.7 ± 168.3 min vs. 600 ± 0 min, P < 0.0001), in fact all CoNS did not induce clotting after 4, 10, 24 h, and for comparison and presentation CoNS CT was set to 10 h. MRSA isolates had significantly reduced CT compared to MSSA (84 ± 114.5 min vs. 148.3 ± 192.0 min, P < 0.0001) (Fig. 1E).

Similar results were obtained using automated coagulation analyzers where human plasma treated with different bacterial isolates indicated that MRSA isolates had significantly reduced PT (6.8 ± 1.3 s vs. 10.9 ± 1.9 s, P < 0.0001), PTT (17.2 ± 1.5 s vs. 22.9 ± 1.8 s, P < 0.0001), and TT (7.3 ± 1.1 s vs. 11.1 ± 2.0 s, P < 0.0001) compared to MSSA isolates (Fig. 2).

Fig. 2
figure 2

Automated human plasma PT (A), PTT (B), and thrombin time (TT) in seconds (C) with bacterial isolates. PT, PTT, and TT were recorded for CoNS (n = 25), MRSA (n = 25), and MSSA isolates (n = 25). **P < 0.001, *** P < 0.0001. One way ANOVA test with LSD post-hoc

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Aggregation of human platelets by bacterial isolates

Aggregated platelets can be measured indirectly by a reduced platelet count using automated counter. CoNS and CoPS isolates have significantly reduced platelets count compared to control respectively (123.9 ± 28.6, 105.7 ± 41.5, vs. 300.0 ± 0.0, P < 0.0001) (Fig. 3A). MRSA isolates have significantly reduced platelets count compared to MSSA and CoNS isolates (90.3 ± 35.9 vs. 121.1 ± 42.6 and 123.9 ± 28.6, P < 0.001) (Fig. 3B).

Fig. 3
figure 3

Platelets count using automated counter with bacterial isolates. A Human platelets treated with buffer (Negative control n = 10), CoNS (n = 25), and CoPS (n = 50). B Human platelets treated with CoNS (n = 25), MRSA (n = 25), and MSSA (n = 25) strains. **P < 0.001, ***P < 0.0001, ns: non-significant. One way ANOVA test with post-hoc

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Enhanced ability of MRSA isolates to induce platelets aggregation was confirmed using platelets aggregometer studies with human PRP (Fig. 4). PRP aggregation curve confirms the ability of MRSA and MSSA isolates to induce platelets aggregation compared to positive and negative controls (Fig. 4A). Notably, the enhanced ability of MRSA isolate to induce aggregation compared to MSSA, as aggregation slope (rate of aggregation per minute), platelets aggregation maximum amplitude (maxA), and area under curve (AUC) were increased with MRSA strain compared to MSSA strain, while the latency time (lag time) was less with MRSA isolate (Fig. 4A). Furthermore, it was noticed that different MRSA strains have different abilities to induce platelets aggregation when tested on the same donor PRP within the same experiment (Fig. 4B).

Fig. 4
figure 4

Platelets aggregation studies of platelets rich plasma (PRP) treated with different bacterial isolates or controls. A PRP treated with MRSA (channel 2) and MSSA (channel 3) compared to positive controls (collagen 1 µg/mL) and negative control (S. thoraltensis). B PRP treated with MRSA (channel 1, 2, and 3) and positive control (epinephrin 5 µM)

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To confirm the ability of MRSA isolates to induce stronger aggregation compared to MSSA isolates, aggregation parameters were compared for MRSA (n = 25) and MSSA isolates (n = 25). The aggregation maximum amplitude (maxA%) was significantly higher for MRSA isolates compared to MSSA isolates (43.00 ± 39.93 vs. 35.35 ± 27.06, P < 0.0001), the aggregation slope was significantly higher for MRSA isolates compared to MSSA isolates (24.95 ± 17.56 vs. 21.09 ± 16.44, P < 0.0001), and the AUC was significantly higher for MRSA isolates compared to MSSA isolates (396.86 ± 529.86 vs. 80.50 ± 74.58, P < 0.0001), while lag time (min.sec) was significantly lower for MRSA isolates compared to MSSA isolates (0.51 ± 0.99 vs. 2.45 ± 3.20, P = 0.003) (Table 3).

Table 3 Summary of platelets aggregation parameters with different bacterial strains
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Diagnostic ability of PT and PTT test to distinguish bacterial isolates

Considering the established reference range for PT (11–13 s) and PTT (25–35 s) [28], bacterial isolates were classified into high, normal, and low categories. All CoNS isolates (n = 25, 100%) had high manual and automated PT values, while only one CoPS (MSSA) isolate (n = 1, 2%) had high manual and automated PT values. Of CoPS (MSSA), 15 isolates (30%) were within the normal range (Table 4). This clearly indicates the ability of PT test to distinguish CoPS isolates from CoNS isolates for diagnostic purposes with a sensitivity rate of 100% (95% confidence intervale CI = 86.7 to 100%), specificity rate of 98% (95% CI = 89.5 to 99.6%), positive predictive value (PPV) of 96.2% (95% CI = 81.1 to 99.3%), and negative predictive value (NPV) of 100% (95% CI = 92.7 to 100%). Interestingly, since all CoNS isolates were within the high PT range, while all MRSA isolates were within the low PT range, manual and automated PT tests will be able to distinguish MRSA isolates from CoNS with 100% sensitivity, specificity, PPV and NPV.

Table 4 Manual and automated clotting characteristics of bacterial isolates
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For the PTT test, all CoNS isolates were within the normal range (n = 25, 100%), while 8 (16%) CoPS (MSSA) isolates were within the normal range and 41 (82%) isolates were within the low range (Table 4). Accordingly, the sensitivity rate of the PTT test to distinguish CoNS from CoPS isolates would be 100% (95% CI = 86.7 to 100%) but the specificity rate would be 84% (95% CI = 71.5 to 91.7%). Similar to the PT test, the manual PTT test can distinguish MRSA isolates from CoNS with 100% sensitivity, specificity, PPV and NPV. Both manual and automated PT, and PTT tests can distinguish MRSA isolates from MSSA isolates with high sensitivity rate (100%) but very low specificity rate (PT = 62.5%, and PTT = 33.3%).

Discussion

The interaction between bacterial pathogens and human coagulation and platelets is well established. Multiple mechanisms and a wide range of effects have been reported for different bacterial pathogens [10, 11, 32]. This interaction helps protect bacteria (anti-phagocytosis), increase bacterial virulence, enhance adhesion and penetration, and mediate or inhibit clotting and thrombosis within host [10, 11]. On the other hand, platelets play a role in defense against bacteria by innate function and internalization, trapping and localization, neutrophil attraction, antimicrobial activity, inflammatory response, immune modulation, and others [14, 32, 33]. Accordingly, the use of anti-platelets and anti-coagulant agents in the treatment of bacterial infections and their thrombotic/clotting-related complications has become an attractive option in recent years [34].

S. aureus is known to induce coagulation and to activate platelets [11, 12, 14] but also dislodge fibrin clots and inhibit coagulation through Staphylokinase activity [15]. The precise role of these two contradictory effects (coagulation/platelet activation versus fibrinolysis/platelet inhibition) and the exact role of coagulation/platelet as a defense line versus a helper to S. aureus infection is not fully understood due to the complexity of proposed mechanisms and interactions [11, 12, 14, 15]. Accordingly, the use of anti-platelets and anti-coagulation drugs in S. aureus infections is still controversial [16, 17]. Further research and better understanding of S. aureus interaction with coagulation and platelets are necessary to justify new treatment strategies and to improve patient outcomes.

Enhanced human coagulation and platelet aggregation of MRSA strains compared to MSSA strains have not been reported. This effect may help explain the increased thrombotic and clotting complication risk with MRSA [35,36,37], MRSA antimicrobial tolerance and poor efficacy [38] and support the clinical benefits of using anti-coagulant and anti-platelets therapy in MRSA infections [15, 34]. In this study, all CoPS showed reduced PT, PTT, CT, and TT compared to controls of CoNS reflecting their known coagulation ability [6]. MRSA isolates exhibited significant reductions in PT, PTT, CT, and TT compared to MSSA isolates indicating their enhanced ability to coagulate normal human plasma. Furthermore, human platelets aggregation was significantly enhanced by MRSA isolates compared to MSSA isolates.

This study utilizes a high number of well-characterized and diverse nasal and clinical isolates (n = 75), methicillin resistance was confirmed by multiple phenotypic tests and by the presence of mecA gene, and multiple coagulation and aggregation tests were used to confirm the results. Findings of the study will help to dissect the interactions between S. aureus and platelets/coagulation, indicate increased resistance, virulence, and thrombotic complications of MRSA infections, propose manual and automated coagulation markers (PT, PTT, CT, and TT) for differentiating CoPS from CoNS, and add further justification for using anti-platelets and anti-coagulants for MRSA infections.

MRSA infected diabetic mice have enhanced coagulation, inflammatory and endothelial activation compared to MSSA infected diabetic mice group. MRSA infection caused a significant increase in fibrinogen, fibronectin and vWF, especially in diabetic mice. Immunomodulatory and inflammatory mechanisms were proposed [22]. MRSA induced coagulation was linked to altered immune- inflammatory state in diabetes and cannot be generalized. Franks et al. reported increased platelet surface P-selectin expression, increased PF4 release, and accelerated thrombin generation when whole human blood or freshly isolated platelets were treated with MRSA strains compared to untreated control. A single α-toxin positive MRSA strain without inclusion of MSSA control strains were used in this study [39]. Zinzendorf et al. reported that fast coagulase strains are MRSA in 65% of cases compared to 48.5% of MSSA are low coagulase strains using clinical isolates tested with citrated rabbit plasma (P < 0.0001) [23].

The average plasma coagulation time for vancomycin-non-susceptible isolates was longer than susceptible isolates (12 vs. 2.6 h), nine vancomycin-intermediate S. aureus (VISA) isolates and four heterogeneous VISA isolates yielded a negative coagulase test after 24-hour incubation [19]. Similarly, vancomycin-resistant mutants have decreased coagulase activity [40]. Both studies used laboratory-induced/sub-passaged or mutant strains to induce vancomycin resistance. These findings suggest that methicillin resistance acts differently in terms of coagulation compared to vancomycin resistance indicating different mechanisms applied. All isolates in this study were vancomycin sensitive by phenotypic and molecular analysis which exclude its effects on study results.

Pretreatment of synovial fluid with plasmin to dislodge biofilm like aggregate of S. aureus infection improves antibiotics susceptibility [21]. Fibrinolytic agents like Streptokinase have been shown to reverse biofilm-associated antibiotic resistance in S. aureus [41]. Similarly, fibrinolytic agents were used as a novel treatment of S. aureus device-related infections [42]. Dabigatran, a potent staphylothrombin inhibitor, offers a new therapeutic agent to inhibit the virulence of staphylocoagulase in vitro and in vivo model and would improve outcome in S. aureus infections [17]. Accordingly, anti-platelets, anti-coagulant, and fibrinolytic agents would decrease coagulation and aggregation activities of MRSA, disrupt biofilm formation, restore antibiotic efficacy, and decrease thromboembolic complications.

Enhanced MRSA coagulation might be due to enhanced coagulase and vWbp activity while enhanced platelets aggregation could be related to increased clumping factors and surface proteins biding to GPIIb/IIIa [39]. Coagulase type II was most frequently observed in MRSA strains isolated from skin infections [20]. Increased α-toxin activity could also contribute to enhanced MRSA coagulation and aggregation [22, 39]. A subset of MRSA strains express a large surface protein called Pls that can interfere with clumping [12]. As PT, PTT, and TT in this study have all decreased it suggests that intrinsic, extrinsic and common pathways of coagulation are involved [25]. Furthermore, enhanced coagulation and platelets aggregation suggests an overlapping mechanism between the two connected systems [25]. Increased biofilm formation commonly associated with MRSA strains could also play an important role [18]. Isolates used in this study were characterized for biofilm formation and biofilm genes prevalence and MRSA isolates compared to MSSA isolates showed no significant difference [24].

In this study, tube coagulase test was able to distinguish all CoPS from CoNS accurately. It is considered the gold standard for detecting coagulase activity to differentiate CoPS from CoNS [26]. The test is labor intensive, time consuming, require animal plasma, with few false positive and false negative results occurred due to misinterpretation [26, 43]. The slide coagulase test is a rapid method used to detect bound coagulase on the surface of S. aureus (clumping factor). While useful for quick and simple identification, its accuracy has limitations as not all S. aureus strains express the clumping factor [43]. In this study slide coagulase test was positive in about 50% of CoPS isolates only. Commercially available latex agglutination tests are costly and not accurate [43, 44]. In this study, PT and PTT tests with established reference ranges distinguish CoPS from CoNS accurately with 100% sensitivity, yet PT test had higher specificity rate (98%), compared to PTT test (83%). PT and PTT tests are essential and widely used coagulation screening tests in clinical practice, being simple and fast, and can be performed manually or using automated coagulation analyzers available in most laboratories [26, 43]. The test requires special attention when preparing plasma samples, needs different reagents to conduct the test, and is temperature dependent and typically carried out at 37 °C [28].

Normal hemostasis, when triggered, will initiate coagulation and platelet activation, and once bleeding is stopped, fibrinolysis and platelet rest will evolve [11, 12]. Similarly, the activation of the immune system to combat infection needs to shut down once the targeted organism is eliminated [32, 33]. Loss of this feedback and control mechanisms will lead to thrombotic complication with hemostasis and autoimmunity and inflammation with the immune system [11, 32]. Perhaps S. aureus uses similar mechanisms by establishing coagulation and platelet activation for early protection to grow and enhance pathogenesis at the local level, and once infection is established, fibrinolysis and platelet inhibition commence to facilitate local and systemic spread. Cases of continuous S. aureus mediated coagulation and platelet activation will end by sepsis associated thrombotic complications. Early administration of proper antibiotics in MRSA infected animal model restored normal thrombin generation patterns [45].

The limitation of this study is that analysis was carried out in vitro which might not reflect in vivo situations. However, a pediatric swine model of MRSA sepsis-induced consumptive coagulopathy and disseminated microvascular thrombosis showed increased PT, d-dimer, and fibrinogen, and decreased platelet counts and coagulation factors that end by organ failure and death within 70 h [46]. Furthermore, many cases and cohort studies of S. aureus sepsis patients have reported severe thrombotic and coagulation disorders with MRSA strains including disseminated intravascular coagulation (DIC) [35,36,37].

Conclusions

Enhanced platelet aggregation and plasma coagulation of MRSA strains compared to MSSA strains were documented in this study. Faster, and stronger tube coagulase test were observed with MRSA isolates. Manual and automated PT, PTT, CT, and TT measurements of human plasma treated with bacterial isolates were significantly lower with MRSA isolates compared to MSSA isolates indicating enhanced coagulation. Furthermore, human PRP treated with bacterial isolates showed significant increase in platelets aggregation induced by MRSA isolates compared to MSSA isolates as measured by platelets aggregometer. PT and PTT tests reference ranges distinguish CoPS from CoNS with 100% sensitivity, and specificity rate of 98% and 83%, respectively. Additionally, PT and PTT tests distinguish MRSA isolates from CoNS with 100% sensitivity and specificity rates. Enhanced coagulation and aggregation of MRSA isolates facilitates their protection and escape form the immune system, decreases antibiotics efficacy, and increases the risk of thrombotic/clotting complications among infected patients. Clinical implications of the study findings include identification of another virulent factor for MRSA isolates, increased risk of coagulation disorders among MRSA infected patients that require follow up by coagulation and aggregation studies, and consideration of fibrinolytic, anti-coagulant, and anti-platelets therapy to improve antibiotics efficacy and to prevent thrombotic complications among MRSA patients. PT and PTT tests would be helpful for routine and rapid identification of coagulase activity among Staphylococci species.

Data availability

Data is available on request.

Abbreviations

MRSA:

Methicillin-resistant Staphylococcus aureus

MSSA:

Methicillin-sensitive Staphylococcus aureus

CoPS:

Coagulase-positive Staphylococci

CoNS:

Coagulase-negative Staphylococci

PT:

Prothrombin time

PTT:

Partial thromboplastin time

CT:

Clotting time

TT:

Thrombin time

Coa:

Coagulas

ClfA:

Clumping factor A

FnBPA:

Fibronectin-binding protein A

SAP:

Staphylococcus aureus protein A

Efb:

Fibrinogen-binding protein

VRSA:

Vancomycin-resistant Staphylococcus aureus

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Acknowledgements

This research was funded by a scientific grant provided by the scientific research deanship, The Hashemite University, Jordan. Principal investigator: Mohammad Al-Tamimi. We would like to thank the participants who agreed to be part of this study.

Funding

This research was funded by a scientific grant provided by the scientific research deanship, The Hashemite University, Jordan.

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Authors and Affiliations

  1. Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, Jordan

    Mohammad Al-Tamimi & Nisreen Himsawi

Authors
  1. Mohammad Al-Tamimi
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  2. Nisreen Himsawi
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Contributions

M. A. conceptualizes and designs research, provides funds and resources, analyzes results, and writes manuscript. N.H.performed and documented laboratory experiments and reviewed the manuscript.

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Correspondence to Mohammad Al-Tamimi.

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Al-Tamimi, M., Himsawi, N. Enhanced platelets aggregation and coagulation of methicillin-resistant Staphylococcus aureus compared to methicillin-sensitive Staphylococcus aureus. Thrombosis J 23, 98 (2025). https://doi.org/10.1186/s12959-025-00781-1

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Keywords

Thrombosis Journal

ISSN: 1477-9560

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