Thrombocytopenia in Staphylococcus aureus Bacteremia: Risk Factors and Prognostic Importance

Anat Gafter-Gvili; Nariman Mansur; Assaf Bivas; Noa Zemer-Wassercug; Jihad Bishara; Leonard Leibovici; Mical Paul

doi:10.4065/mcp.2010.0705

. 2011 May;86(5):389–396. doi: 10.4065/mcp.2010.0705

Thrombocytopenia in Staphylococcus aureus Bacteremia: Risk Factors and Prognostic Importance

Anat Gafter-Gvili ^1,^✉, Nariman Mansur ¹, Assaf Bivas ¹, Noa Zemer-Wassercug ¹, Jihad Bishara ¹, Leonard Leibovici ¹, Mical Paul ¹

PMCID: PMC3084641 PMID: 21531882

Abstract

OBJECTIVE: To identify risk factors and outcomes associated with thrombocytopenia at sepsis onset in Staphylococcus aureus bacteremia.

PATIENTS AND METHODS: This single-center, retrospective, cohort study consists of all adult patients with a first episode of clinical S aureus bacteremia between April 1, 1988, and September 30, 1994, and between January 1, 1999, and December 31, 2007. Thrombocytopenia was defined as a platelet count less than 150 × 10⁹/L. The primary outcome was 30-day all-cause mortality. Risk factors for 30-day all-cause mortality were identified using univariate and multivariable analyses. Multivariable analysis was conducted using forward step logistic regression analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for risk of death.

RESULTS: A total of 1052 patients had clinical S aureus bacteremia. Thrombocytopenia at sepsis onset was present in 235 patients (22.3%). Thrombocytopenia was associated with community-acquired bacteremia, infections caused by methicillin-sensitive S aureus, high-magnitude bacteremia (defined as >4 positive blood cultures [≥3 separate positive blood culture sets]), and endocarditis. Patients with thrombocytopenia presented more commonly with severe sepsis reflected by septic shock and acute renal failure. Thirty-day mortality was significantly higher among patients with thrombocytopenia (132/235 [56.2%]) vs those without thrombocytopenia (281/817 [34.4%]; P<.001). Higher mortality was associated with the degree of thrombocytopenia. In multivariable analysis, thrombocytopenia at baseline remained an independent risk factor for 30-day mortality (OR, 2.82; 95% CI, 1.87-4.24). The adjusted association between thrombocytopenia and death remained similar among the 917 patients with monomicrobial bacteremia (OR, 2.88; 95% CI, 1.83-4.53) and the 945 patients who did not die within the first 48 hours (OR, 2.88; 95% CI, 1.87-4.45.).

CONCLUSION: We observed a strong association between thrombocytopenia at sepsis onset and all-cause mortality in S aureus bacteremia, possibly related to mechanisms other than sepsis alone.

The authors of this single-center, retrospective, cohort study observed a strong association between thrombocytopenia at onset of sepsis and all-cause mortality in patients with Staphylococcus aureus bacteremia, possibly related to mechanisms other than sepsis alone.

AUC = area under the curve; CI = confidence interval; Clf A = clumping factor A; DIC = disseminated intravascular coagulation; ICU = intensive care unit; INR = international normalized ratio; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-susceptible S aureus; OR = odds ratio

Staphylococcus aureus is a leading cause of both community-acquired and nosocomial bacteremia and is currently the most common cause of infective endocarditis.¹ S aureus has a unique interaction with platelets that has not been fully investigated in clinical studies.

Infection with S aureus can be accompanied by thrombocytopenia as a result of local activation of platelets and disseminated intravascular coagulation (DIC) if the activation of platelets becomes systemic.² S aureus can activate platelets, and this process is mediated by several surface-expressed proteins, such as clumping factor A (Clf A) and fibronectin-binding protein A³ or cell wall peptidoglycan.⁴ Moreover, S aureus is able to bind to adhered platelets, and this may be an important mechanism that contributes to colonization of endovascular epithelium or damaged heart valves, thus promoting infective endocarditis and endovascular infections.⁵ In turn, endocarditis may cause thrombocytopenia through shearing forces over the damaged valve.⁶ The adherence of S aureus to platelets leads to platelet activation and aggregation.⁷ When this occurs in a localized manner, it may result in formation of a thrombus; if the interaction occurs diffusely in the bloodstream, it may result in consumption of platelets, leading to thrombocytopenia. If the coagulation cascade is activated, DIC ensues.³

In clinical practice, we observed an association between thrombocytopenia and adverse outcomes more frequently in patients with S aureus bacteremia than in those with other bacteria. We sought to examine this formally.

PATIENTS AND METHODS

The study was conducted at Rabin Medical Center, Beilinson Hospital, a 900-bed primary and tertiary care university hospital. The hospital has 4 main intensive care units (ICUs) and small ICUs in which patients undergo mechanical ventilation within the 6 internal medicine and 2 surgical departments.

All consecutive adult patients who had been hospitalized with S aureus bacteremia were identified. Data were collected retrospectively between January 1, 1999, and December 31, 2007, by reviewing patients' medical records and were merged with data prospectively collected between April 1, 1988, and September 30, 1994. Results from these databases have been previously described.^8-10 Contaminants (S aureus isolated in a single set of blood cultures with no evidence of systemic inflammatory response syndrome within 48 hours of blood culture, in which the patient was not treated and did not die within 30 days) were excluded. Polymicrobial bacteremias were included, unless S aureus was considered contaminant. Patients were included only once, for the first episode of S aureus bacteremia. We excluded patients with hematologic and other actively treated malignancies, cirrhosis, and human immunodeficiency virus, in whom thrombocytopenia might result from the underlying condition rather than from infection and might be associated with mortality due to the underlying condition.

The study was approved by the Helsinki ethics committee at our institution.

Microbiology

Two separate sets of blood cultures were obtained routinely (up to 6 sets if endocarditis was suspected), with 10 mL of blood collected in one aerobic and one anaerobic bottle. The Bactec 460 was used between 1988 and 1992 and the Bactec 9240 microbial system (Becton Dickinson, Franklin Lakes, NJ) after 1992. Isolates were identified on the basis of morphologic features and API system (a plastic strip holding 20 miniaturized compartments, or cupules, each containing a dehydrated substrate for a different test; API system, BioMerieux, France). Susceptibility to antibiotics was tested by the disk diffusion method on Mueller-Hinton agar, according to Clinical and Laboratory Standards Institute (formerly National Committee for Clinical Laboratory Standards) procedures. Repeated blood cultures were obtained until results were negative.

Data Collection and Definitions

Data collected included demographics, background conditions and procedures with emphasis on risk factors for S aureus bacteremia and complications, sepsis onset and severity, source of infection, all antibiotic treatment, and outcomes. Bacteremia was retrospectively classified as community-acquired, health care–associated, or hospital-acquired, as previously defined.¹¹ All data on hospital and clinic admissions were electronically recorded throughout the study period. Appropriate empirical antibiotic treatment was defined as matching in vitro susceptibility of the S aureus isolate and given within 48 hours after obtaining blood culture, except for single use of aminoglycoside or rifampicin treatment. In our hospital, the standard treatment of methicillin-susceptible S aureus (MSSA) is cloxacillin or cefazolin and for methicillin-resistant S aureus (MRSA), vancomycin. Laboratory results were recorded on the date of the first positive blood cultures, including a complete blood cell count, creatinine, urea, albumin, glucose, and coagulation tests (partial thromboplastin time, prothrombin time-international normalized ratio [INR], and fibrinogen), when available. Thrombocytopenia was defined as a platelet count of less than 150 × 10⁹/L. Disseminated intravascular coagulation was defined on the basis of the International Society of Thrombosis and Haemostasis diagnostic scoring system (≥5 points compatible with overt DIC).¹² Because tests for fibrin markers (D-dimer or fibrinogen degradation product) were not performed routinely in our hospital, we modified the score so that any of the following combinations were compatible with DIC: platelet count <50 × 10⁹/L and fibrinogen <200 mg/dL; platelet count <50 × 10⁹/L, fibrinogen <400 mg/dL, and INR >1.5; or platelet count ≤100 × 10⁹/L, fibrinogen <400 mg/dL, and INR >3. Bacteremia relapse was defined when a phenotypically identical isolate was isolated in blood cultures obtained at least 30 days apart and within 1 year of first positive blood culture. Survival status was ascertained using the central registry of the Israeli Ministry of Internal Affairs.

Outcomes

The primary outcome was 30-day all-cause mortality. Secondary outcomes were the association of thrombocytopenia with mortality at 48 hours, 30 days, 90 days, and 1 year. We assessed persistence of bacteremia, bacteremia relapse, metastatic infection, and endocarditis as complications.

Statistical Analyses

We compared risk factors and outcomes of patients with and without thrombocytopenia. In sensitivity analyses, comparisons were restricted to patients with monomicrobial S aureus bacteremia and patients who did not die in the first 48 hours after infection.

Dichotomous variables were examined with the χ² test. Normally distributed continuous variables are described as the mean (standard deviation [SD]) and were compared using the t test. Skewed data are described as median (interquartile range), compared with the Mann-Whitney U test, and log transformed before inclusion in the multivariable analysis. We considered for inclusion in the multivariable model all variables associated with mortality with P<.10. We excluded from the model variables that were clinically associated and significantly correlated (Spearman rank correlation, ρ>0.45 for all). Missing laboratory values for the multivariable analysis were imputed with multiple imputation analysis using the Fully Conditional Specification method.¹³ With this model, regression models are used to impute missing variables. When a particular variable is imputed, all other variables are treated as factors and covariates in the imputation model. We imputed data for urea (4 of 1052 patients) and albumin (127 of 1052 patients) using these variables plus age, place of acquisition, functional status, presence of urinary catheter, malignancy, skin/wound source of infection, shock at onset, platelet counts, and oxacillin resistance. Five data sets were created, and imputed values in all were similar. Thus, a single data set was selected for further analysis.

Variables from the univariate analysis were all entered into a logistic regression analysis. Model fit was assessed using the Hosmer-Lemeshow test, and calibration was described by the area under the curve (AUC) plotted on a receiver operating characteristic curve. Odds ratios (ORs) with 95% confidence intervals (CIs) are reported. Time to death for patients with and without thrombocytopenia was compared using Kaplan-Meier survival analysis. Statistical analysis was performed using IBM SPSS Statistic 19 (IBM Corp, New York, NY).

RESULTS

A total of 1258 patients had a first episode of clinically important S aureus bacteremia; 65 were excluded because of missing platelet count at infection onset, and 141 were excluded because thrombocytopenia was due to a condition other than S aureus bacteremia; thus, 1052 patients were studied. Of these, 235 (22.3%) had thrombocytopenia at sepsis onset.

Risk Factors for Thrombocytopenia

Patient characteristics with and without thrombocytopenia at onset of infection are presented in Table 1. Confirmed community-acquired infections were rare but were more commonly associated with thrombocytopenia than were health care–associated or hospital-acquired infections. At onset of infection, patients with thrombocytopenia were less likely to have dementia or decubitus ulcers and had better functional status. Thrombocytopenia was significantly associated with corticosteroid treatment. Patients with diabetes were less likely to present with thrombocytopenia, as were those who had undergone an operation before occurrence of bacteremia. There were no significant differences with respect to other underlying conditions.

TABLE 1.

Characteristics of Patients With and Without Thrombocytopenia^a,b,c

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Differences were observed with regard to sepsis severity and infection characteristics. Thrombocytopenia was associated with septic shock at onset and later, renal failure at onset of infection, and the need for ICU admission. Disseminated intravascular coagulation, formally diagnosed in only 7 patients, was associated with thrombocytopenia (a full coagulation profile was available for only 69 [29.4%] of 235 patients with thrombocytopenia). Leukocyte counts at presentation were lower in patients who presented with thrombocytopenia. Patients with thrombocytopenia presented more commonly with MSSA (150/587 [25.6%]) than with MRSA (85/465 [18.3%]; P=.005). Thrombocytopenia was associated with endocarditis diagnosed at presentation more often (21/58 [36.2%]) compared with episodes without endocarditis (214/994 [21.5%]) and was significantly less frequent with skin/soft tissue or bone/joint infections. Isolation of S aureus in more than 2 sets of blood cultures (high-magnitude bacteremia) was more frequent in patients with thrombocytopenia.

Outcomes of Patients With Thrombocytopenia

Thirty-day all-cause mortality was significantly higher among patients with thrombocytopenia (unadjusted OR, 2.44; 95% CI, 1.82-3.28; P<.001) (Table 2). Higher mortality was associated with the degree of thrombocytopenia: death occurred in 23 (76.7%) of 30 patients with platelet counts of <50 × 10⁹/L; in 47 (62.7%) of 75 patients with platelet counts of 50-99 × 10⁹/L; in 62 (47.7%) of 130 patients with platelet counts of 100-149 × 10⁹/L; in 238 (35.1%) of 678 patients with platelet counts of 150-400 × 10⁹/L; and in 43 (30.9%) of 139 patients with an initial platelet count >400 × 10⁹/L. The difference in mortality according to platelet count was maintained at all time points assessed. Patients with thrombocytopenia died sooner than did those without thrombocytopenia (Figure).

TABLE 2.

Outcomes and Complications of Patients With and Without Thrombocytopenia^a

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FIGURE. — Cumulative survival of patients without and with thrombocytopenia.

All results were similar when the analysis was restricted to monomicrobial S aureus bacteremia. The 30-day mortality rate was 55.0% (111/202) for patients with thrombocytopenia vs 33.6% (240/715) for patients without (unadjusted OR, 2.41; 95% CI, 1.76-3.32; P<.001). Exclusion of patients who died in the first 48 hours did not change results; the 30-day mortality rate was 46.9% (91/194) vs 28.6% (215/751), respectively (unadjusted OR, 2.20; 95% CI, 1.59-3.04; P<.001).

Patients with thrombocytopenia were significantly more likely to develop acute renal failure after presentation (Table 2). There was no difference in the rates of persistence or relapse of the staphylococcal bacteremia. The percentage of patients diagnosed as having endocarditis as a complication, with a final diagnosis of endocarditis or with metastatic complications, was higher in those with thrombocytopenia, but the difference was not statistically significant. However, those outcomes could occur only in patients who did not die.

Risk Factors for Mortality

Univariate analysis for mortality is presented in the eTable (Supporting Online Material, a link to which is provided at the end of this article). All variables significantly associated with mortality were included in the multivariable model, except for clinically associated variables (eTable). Management modalities, such as device removal, could not be included because they apply only to the subpopulation with a device.

In the multivariable analysis, thrombocytopenia at baseline remained an independent risk factor for 30-day mortality (OR, 2.82; 95% CI, 1.87-4.24). Septic shock was also independently associated with death (OR, 3.02; 95% CI, 1.79-5.12). Appropriate empirical antibiotic treatment and infection management, including a surgical intervention, were associated with a significantly lower mortality rate. Other independent risk factors for mortality are depicted in Table 3. Methicillin-resistance S aureus was not significantly associated with mortality. The receiver operating characteristic generated using probabilities from the model showed good prediction (AUC, 0.86; 95% CI, 0.84-0.88; eFigure in Supporting Online Material, a link to which is provided at the end of this article).

TABLE 3.

Multivariable Analysis for 30-Day Mortality, N=1052^a

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Applying the same model to patients with monomicrobial bacteremia (n=917), thrombocytopenia remained significantly associated with mortality (OR, 2.88; 95% CI, 1.83-4.53). The same independent risk factors for death were retained in the model except for the inclusion of leukocyte count as an independent risk factor (OR, 1.46; 95% CI, 1.00-2.11). Also, MRSA was similarly excluded from the final model (P=.38), and the model was similarly predictive (AUC, 0.87; 95% CI, 0.84-0.89). Analysis of patients who did not die within the first 48 hours (n=945) did not affect the adjusted association between thrombocytopenia and 30-day mortality (OR, 2.88; 95% CI, 1.87-4.45). The effect of shock at onset was smaller in this analysis (OR, 2.21; 95% CI, 1.23-3.96).

DISCUSSION

Thrombocytopenia at sepsis onset was commonly observed in a cohort of adult patients with S aureus bacteremia. Less debilitated patients were more likely to have thrombocytopenia, but otherwise thrombocytopenia was not associated with other background conditions or predisposing risk factors. Thrombocytopenia was associated with community-acquired bacteremia, MSSA, high-magnitude bacteremia, and endocarditis, all of which are obviously linked. Patients with thrombocytopenia presented more commonly with severe sepsis—septic shock, acute renal failure, and need for ICU stay. Thrombocytopenia was significantly and independently associated with higher mortality, increasing the odds for death by 2.8 in the main analysis and sensitivity analyses. Mortality rates increased with increasing severity of thrombocytopenia. Patients with thrombocytopenia died sooner after bacteremia compared with patients without thrombocytopenia.

Thrombocytopenia is a known risk factor for death and complications in sepsis^14,15 and is included in several severity scores that have been validated in sepsis, such as the sequential organ failure assessment (SOFA)¹⁶ and the multiple organ dysfunction (MODS) score.¹⁷ Thrombocytopenia in sepsis occurs as part of DIC, as a result of impaired production due to infectious mediators, increased platelet consumption, or destruction due to ongoing generation of fibrin, hemophagocytosis, and most commonly as some combination of these.^18-20 Studies that assessed risk factors for death and predictive scoring systems in S aureus bacteremia most commonly did not address platelet counts or thrombocytopenia.^21-25 Only a few studies included thrombocytopenia as a variable, and in these studies thrombocytopenia was identified as a risk factor for death in patients with S aureus bacteremia or endocarditis.^26-28 The increased mortality observed with thrombocytopenia in our cohort might have been related to its association with severe sepsis. However, DIC was diagnosed in only a few of the patients with thrombocytopenia in our cohort. Thrombocytopenia was more common with MSSA. Thrombocytopenia remained significantly associated with mortality when adjusted to septic shock and also when adjusted to DIC. Although a difference in mortality between patients with thrombocytopenia and patients without thrombocytopenia was observed 48 hours after sepsis onset, the difference persisted for up to 1 year. The difference in mortality at long-term follow-up was not due solely to the mortality difference in the first 48 hours, pointing at other mechanisms relating thrombocytopenia to death in S aureus bacteremia.

The increased mortality might also be related to platelet activation and aggregation induced by S aureus. S aureus adheres to platelets, leading to platelet activation and aggregation,⁷ platelet consumption, and eventually thrombocytopenia. Initial studies focused on secreted mediators of platelet activation such as alpha-toxin,^29,30 which accelerates thrombin generation. Later studies focused on Clf A and fibronectin-binding protein A as the dominant surface proteins mediating platelet activation.³ Also, Clf A has been shown to be a virulence factor for endocarditis.³¹ This platelet activation process requires 2 mechanisms of S aureus binding to platelets: by a fibrinogen or fibronectin bridge to the platelet integrin GPIIb/IIIa and an immunoglobulin bridge to the Fc-γ-RIIa receptor.^32,33 Moreover, platelets may promote induction of endovascular infection and endocarditis by providing the pathogen an adherence surface on damaged endothelium.⁵ Indeed, an infective endocarditis model showed that diminished platelet binding in vitro by S aureus is associated with reduced virulence. Platelets are an integral component of the vegetation that is a hallmark of endocarditis in general, and specifically of S aureus endocarditis.^33-35 In our cohort, patients with thrombocytopenia were diagnosed as having endocarditis at presentation significantly more frequently than patients without thrombocytopenia (8.9% vs 4.5%, respectively). However, we could not assess the association between thrombocytopenia at baseline with thrombotic complications because the outcomes of bacteremia persistence, relapse, development of endocarditis, and metastatic complications are confounded by the fact that patients with thrombocytopenia died more frequently and sooner than did those without thrombocytopenia, and postmortem studies were not performed.

Limitations

Our adjusted analysis included factors commonly identified as risk factors for mortality in other studies.^23-25 However, other unmeasured variables may interact with thrombocytopenia. We assessed only baseline thrombocytopenia and did not conduct serial platelet counts. Previous studies of sepsis and infective endocarditis have shown that sequential platelet counts are better predictors of outcome than a single measurement.^26,36 A full coagulation profile was not obtained routinely in our study; thus, we probably underestimated the prevalence of DIC, and some of the effect of thrombocytopenia on mortality might have been mediated through DIC. We excluded patients in whom thrombocytopenia was probably due to underlying conditions rather than infection because these underlying conditions might have been associated with death. Results of an analysis including all patients were unchanged (data not shown). We had no data regarding typing of the S aureus isolates; thrombocytopenia might be related to certain clones. However, we observed no trends in the prevalence of thrombocytopenia over time. We did not perform molecular characterization of the isolates to examine other staphylococcal virulence factors, such as platelet microbicidal protein resistance and agr genotypes, which might interact with thrombocytopenia. Finally, an interesting question that could not be answered because of our study design and the data collected in our database is whether thrombocytopenia is more common with S aureus compared to other bacteria and whether the association of thrombocytopenia with mortality in S aureus bacteremia is indeed larger than that observed with other bacteria.

Implications for Practice

Thrombocytopenia may predict worst outcomes in S aureus bacteremia. The baseline platelet count might help clinicians assess the severity of the S aureus infection. Patients with thrombocytopenia at baseline may warrant enhanced evaluation for diagnosis of infective endocarditis in addition to intensive monitoring. Prediction scores for S aureus bacteremia should consider thrombocytopenia as a risk factor for mortality.

Implications for Research

Future clinical studies should compare the incidence and implications of thrombocytopenia in bacteremia caused by S aureus and other bacteria. Studies should evaluate whether the interactions between platelets and S aureus and the resulting thrombocytopenia are specific for certain strains, for example, strains of S aureus that are resistant to platelet microbicidal proteins. In a rabbit endocarditis model, aspirin was shown to reduce embolic complications³⁴; however, in a randomized controlled trial, aspirin was not shown to have a beneficial effect on outcomes of endocarditis.³⁷ Because we postulated that platelet aggregation has a major role in thrombocytopenia in S aureus bacteremia, it may be worthwhile to evaluate, first in large well-designed observational studies and then in clinical trials, whether antiplatelet drugs such as aspirin are useful in reducing mortality in patients with S aureus bacteremia and thrombocytopenia or specifically among those with community-acquired MSSA bacteremia.

CONCLUSION

In this retrospective analysis of 1052 patients with S aureus bacteremia, we observed a strong association between thrombocytopenia at sepsis onset and all-cause mortality. This association is possibly related to mechanisms other than sepsis alone.

Supplementary Material

Supporting Online Material

supp_86_5_389__index.html^{(561B, html)}

Footnotes

Online Supporting Material

www.mayoclinicproceedings.com/content/86/5/389/suppl/DC1

eTable

eFigure

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36. Vandijck DM, Blot SI, De Waele JJ, et al. Thrombocytopenia and outcome in critically ill patients with bloodstream infection. Heart Lung. 2010;39(1):21-26 [DOI] [PubMed] [Google Scholar]
37. Chan KL, Dumesnil JG, Cujec B, et al. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol. 2003;42(5):775-780 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Thrombocytopenia in Staphylococcus aureus Bacteremia: Risk Factors and Prognostic Importance

Anat Gafter-Gvili, MD

Nariman Mansur, MD

Assaf Bivas, MD

Noa Zemer-Wassercug, MD

Jihad Bishara, MD

Leonard Leibovici, MD

Mical Paul, MD

Abstract