
==== Front
Clin Oral Investig
Clin Oral Investig
Clinical Oral Investigations
1432-6981
1436-3771
Springer Berlin Heidelberg Berlin/Heidelberg

39212739
5893
10.1007/s00784-024-05893-y
Research
Association of periodontitis with cardiometabolic and haemostatic parameters
Groenewegen Hester h.groenewegen@umcg.nl

1
Borjas-Howard Jaime F. 2
Meijer Karina 2
Lisman Ton 3
Vissink Arjan 1
Spijkervet Fred K. L. 1
Nesse Willem 4
Tichelaar Vladimir Y. I. G. V. 2
1 grid.4494.d 0000 0000 9558 4598 Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, Groningen, 9700 RB The Netherlands
2 grid.4494.d 0000 0000 9558 4598 Department of Haematology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, Groningen, 9700 RB The Netherlands
3 grid.4494.d 0000 0000 9558 4598 Department of Surgical Research Laboratory, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, Groningen, 9700 RB The Netherlands
4 Department of Oral and Maxillofacial Surgery, Wilhelmina Hospital Assen, Postbus 30001, Assen, 9400 RA The Netherlands
30 8 2024
30 8 2024
2024
28 9 50623 1 2024
17 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Objective

To investigate the association between periodontitis and cardiometabolic and haemostatic parameters.

Materials and methods

Between 2014 and 2019, 54 individuals needing full mouth extraction, and 50 control individuals, were recruited for a combined cross-sectional (individuals versus controls) and longitudinal (individuals before and after extraction) study. Periodontitis severity was measured using the periodontal inflamed surface area (PISA). Blood was drawn to measure the haemostatic (Factor VIII, von Willebrand factor [VWF], endogenous thrombin potential, d-dimer, clot lysis time) and cardiovascular risk (C-reactive protein [CRP], lipid profile) parameters, prior to and 12 weeks post-extraction. The results were analysed group-wise.

Results

The mean VWF and CRP levels were higher and the high-density lipoprotein levels were lower in the individuals prior to extraction compared to the controls. The VWF was significantly correlated with the PISA (a 21% unit increase in VWF per 1000 mm2 increase in PISA, 95%CI: 6–36%, p = 0.01). The other analyses were comparable between the individuals and controls, and did not change in the individuals after the extraction.

Conclusion

VWF levels are associated with periodontitis severity; they do not improve after full-mouth extraction. Severe periodontitis in control individuals does not induce substantial changes in their haemostatic or inflammatory systems.

Clinical relevance

Treatment of periodontitis has been shown to improve the cardiometabolic blood profile of patients with established cardiometabolic disease. However, whether periodontitis treatment improves cardiometabolic and haemostatic profiles in people without cardiometabolic disease is uncertain.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00784-024-05893-y.

Keywords

Cardiovascular diseases
Periodontitis
Tooth extraction
Inflammation
Venous thromboembolism
Mandema stipendiumMan-26082014-14-01 issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Ongoing research has established that a wide range of inflammatory processes, such as acute/chronic infections or autoimmune diseases, are risk factors for both arterial and venous thrombotic events [1, 2]. Periodontitis is a chronic inflammatory process of the gums and deeper periodontal structures that results in destruction of the periodontal ligament and alveolar bone, with gingival recession and periodontal pocket formation [3].

Periodontitis has been shown to have systemic effects as well [4, 5], which likely caused by, haematogenous dissemination of bacterial translocation of oral microbiota or a spillover of inflammatory mediators from periodontal tissues to into the blood stream from the inflamed periodontium. A causal association between periodontitis and arterial as well as venous cardiovascular disease seems plausible and, indeed, observational studies established an association with arterial cardiovascular disease [6–8].

However, observational studies are prone to residual confounding. To assert causality more reliably, periodontal intervention studies are needed to assess whether they lead to a lower risk of cardiovascular disease. Due to the ethical problems in withholding periodontal treatment long enough to observe an effect on incident cardiovascular disease, studies have focused on the effect of an intervention on the underlying cardiometabolic blood parameters, using it as a surrogate for cardiovascular disease. Teeuw et al. (2014), published their results of a meta-analysis assessing an association between periodontitis treatment and changes in cardiometabolic biomarkers as a surrogate for cardiovascular disease [9]. Overall, the meta-analysis showed that an improvement in biomarker profile was observed in individual in the intervention arms, the primary result being a decline in C-reactive protein (CRP) levels. However, it became apparent from the subgroup analysis that these beneficial effects were limited to individuals who were already suffering from established cardiovascular disease or had diabetes. The effect was not seen in individuals without established disease. Hence, whilst periodontitis treatment might benefit individuals with established cardiometabolic disease or with hypertension and no established cardiovascular diseases, the potential benefit of periodontitis treatment in people without cardiometabolic disease remains unclear [10, 11].

Moreover, a paucity of data exists on the association between periodontitis and venous thromboembolism (VTE), for which there is also a well-established association with inflammatory disease processes [12]. Two trials and one one-armed intervention study assessed the effect of periodontal interventions on selected haemostatic parameters (von Willebrand factor [VWF], tissue plasminogen activator, plasminogen activator inhibitor 1 and fibrinogen) and found no association [13–15]. More recent research has established other haemostatic measures with stronger causal links to VTE, namely d-dimer, the endogenous thrombin potential and clot lysis time [16–18]. Therefore, it is valuable to reassess the association between periodontitis and VTE using a broader range of haemostatic parameters and a large intervention such as full mouth dental extraction in individuals with periodontal disease. The periodontal inflamed surface area (PISA) is used to reflect the surface area of bleeding pocket epithelium in square millimetres. It is assumed that PISA quantifies the inflammatory burden posed by periodontitis [19].

Hence, the aim of the current study was to investigate the association between periodontitis and both cardiometabolic and haemostatic parameters in individuals free of established cardiometabolic disease and VTE, in a full mouth dental extraction setting. Individuals for whom a full mouth dental extraction is indicated usually have higher levels of periodontitis than the average population [20, 21] We presumed that a full mouth dental extraction entails removing all the periodontitis tissue, and thus any systemic inflammatory burden resulting from the periodontitis will also be completely removed.

Methods

Design

This study entailed both a cross-sectional and longitudinal experimental design. In the former, we compared the individuals referred for full mouth dental extraction at baseline with control individuals from the community. Regarding the latter, we compared the before and after extraction outcomes. The indication for full mouth extraction was set by the treating dentist. The research question was developed following the PICO method:

P: Individuals needing a full mouth dental extraction due to periodontitis and extensive decayed dentition.

I: Full mouth dental extraction.

C: 1: Individuals matched for age and sex, but not having a desolate oral heath.

2: Initially included individuals after the full mouth dental extraction.

O: PISA, levels of cardiometabolic and haemostatic parameters.

Participants

Individuals aged 18 years or above referred by their dentist for removal of all their remaining teeth (full mouth dental extraction) due to periodontitis and extensive decay dentition to the outpatient department of oral and maxillofacial surgery in the University Medical Center Groningen and the Wilhelmina hospital Assen were screened for individual eligibility. Participants were excluded if they were unable to understand spoken/written Dutch and/or English, had documented liver dysfunction, were taking antithrombotic medication or non-steroidal anti-inflammatory drugs, suffered from chronic autoimmune disease and/or had a history of radiotherapy of the head/neck. The included patients had most cases severely decayed dentition and severe anxiety for oral examination/intervention.

Control individuals were recruited by poster advertisements in supermarkets and around the hospital for oral health status comparisons with the participating individuals. The control individuals had to be within the age range of the recruited individuals, but should not have a desolate dentition. Therefore, the recruitment of volunteers began after the 20 individuals who had been referred for a full mouth dental extraction were already included in the intervention arm. The exclusion criteria for the control individuals were the same as for the subject group.

Measurements

After signing the informed consent, all the participants were asked to complete a standardized questionnaire, and were subjected to a venepuncture and an assessment of their periodontal status.

Venepuncture

Blood was drawn from the antecubital fossa: 18 ml blood was drawn into citrate vials to measure haemostatic parameters; 9 ml of blood was drawn into lithium-heparin for routine biochemistry assessments, including serum insulin and lipid profile; 4.5 ml blood was drawn into EDTA vials for a full blood count; and 4.5 ml blood was drawn into fluoride vials to measure fasting blood glucose. For individuals undergoing tooth extraction we mandated citrate blood samples to be drawn maximal 6 weeks before the intervention during the pre-operative screening as we were concerned that pre-procedural stress/anxiety may influence haemostatic parameters- a citrate blood sample drawn day prior to the procedure was deemed acceptable. To investigate the effects of the extraction on haemostatic parameters, a second venepuncture was performed at least 12 weeks after the procedure. This minimum time frame was assumed to be sufficient for wound healing.

The citrate blood samples were centrifuged twice (2,000 g and subsequently 10,000 g) for 10 min. The samples were stored in a -80 °C freezer within 4 h of the venepuncture to be analysed batchwise.

For participants in the control group, blood was drawn the day of periodontal examination, prior to assessing the periodontal status because any pain due to this assessment could influence haemostatic parameters.

Laboratory outcomes

Haemostatic parameters consisted of prothrombin fragment 1 + 2, factor VIII, von Willebrand factor, endogenous thrombin potential (in the presence and absence of exogenously added soluble thrombomodulin) and its subcomponents (peak thrombin, velocity index, lag time), D-dimer and clot lysis time. The assay details can be found in the appendix.

The predefined laboratory measurements regarding cardiovascular risk biomarkers were high sensitivity CRP, total cholesterol, low-density lipoprotein, high-density lipoprotein (HDL-c ), and HOMA 1 insulin resistance model consisting of a calculation combining fasting plasma glucose and serum insuline levels, which was updated to the HOMA 2 model post-hoc [22].

Periodontal measurements

The periodontal examination of the individuals who were scheduled to have a full mouth dental extraction was done under general anaesthesia (most of them were anxious about routine dental care) just before the full mouth clearance. All the periodontal examinations were executed by the same experienced dental hygienist (HG). Probing pocket depth (PPD), gingival recession, bleeding on probing and clinical attachment level (CAL) were measured in millimetres (Williams probe 14 W, Hu-Friedy Mfg. Co., LLC, UK), rounded to the nearest whole millimetre. Bleeding on probing was recorded as either present or absent 30 s after probing. The number of missing teeth was recorded. All these measurements were entered into a spreadsheet to calculate the periodontal inflamed surface area (PISA); this quantifies the surface area of inflamed periodontal tissue in square millimetres and is a quantitative measure of the inflammatory burden posed by periodontitis [19]. The presence of periodontitis was also defined according to the CDC-AAP case definition of periodontitis surveillance for epidemiologic studies. Mild periodontitis was recorded for cases with ≥ 2 interproximal sites with a CAL ≥ 3 mm and ≥ 2 interproximal sites with a PPD ≥ 4 mm (not on the same tooth) or 1 site with a PPD ≥ 5 mm. The participants were classified as having moderate periodontitis in the presence of ≥ 2 interproximal sites with a CAL ≥ 4 mm (not on the same tooth) or ≥ 2 interproximal sites with a PPD ≥ 5 mm, also not on the same tooth. Severe periodontitis was recorded if the participants had ≥ 2 interproximal sites with clinical attachment loss, a CAL ≥ 6 mm, not on the same tooth, and ≥ 1 interproximal site with a PPD ≥ 5 mm [23–25].

Questionnaire

Data were collected about exposure to VTE risk factors (i.e., surgery, immobilization, long-haul travel, use of hormones) in the preceding 3 months, educational status, smoking status and whether there were any relevant comorbidities (including previous VTE) present. The data about the individuals’ heights and weights measured at the anaesthesiology outpatient clinic were extracted from the records. The control individuals’ heights and body weights were self-reported.

Statistical analysis

The study was powered to detect a 10% difference in endogenous thrombin potential 12 weeks after full mouth extraction, assuming a mean of 1050 nM IIa *min, SD 200 nM IIa *min with 80% power at alpha 0.05. To detect this difference, we needed 50 individuals. Individuals lost to follow-up after the extraction were supplemented with extra recruits until there were 50 individuals available for the longitudinal analyses. The controls were recruited to achieve a 1:1 ratio without a formal sample size calculation.

The normally distributed laboratory measurements were described as means with standard deviations and the not normally distributed ones were described as medians and interquartile ranges.

The between group (cross-sectional) analysis consisted of a comparison between the full mouth extraction individuals and the controls. Either the students t-test or the Wilcoxon rank sum test was used accordingly. A linear regression model was built for all the participants, with the laboratory measurement of interest as the dependent variable and PISA, modelled continuously in 1,000 mm2 increments, as the main independent variable of interest. The coefficients were adjusted for age, sex, educational status, smoking status (categorized as current, former and never) and BMI, modelled as a continuous variable.

In the intervention (longitudinal) analysis, paired differences were tested using a paired t-test or Wilcoxon signed-rank test. Regarding the regression analysis, the change in laboratory values was calculated by subtracting the value of the first value from the first from the second measurement (T2-T1) and defined this as the dependent variable, with PISA modelled as the independent variable. These coefficient values were not adjusted– nor was the baseline value– as suggested by Glymour et al. ( 2005) [26].

The assumptions of the linear models were checked by assessing residual normality. If the assumptions were violated, the models were rerun by first transforming the dependent variable, then by transforming the PISA, and subsequently by transforming both.

Sensitivity analyses were carried out by removing outlier values with specific characteristics, these were done post-hoc. First, the general outlier values were excluded, defined by examining the scatter plots and by examining the Cook’s distance in the linear regression models. Second, participants reporting antibiotic use at any time before their first measurement were excluded. Third, the participants with pathological outlying CRP values (defined as > 10 mg/L) were excluded. The underlying assumption here was that these values may have represented participants with an underlying (subclinical) infection, or recovering from such an infection. Moreover, we excluded the participants who had recently been exposed to a VTE risk factor, as this may have distorted haemostatic parameter results. Additionally, we explored the impact of potential measurement error in the control group’s self-reported BMI by a correction formula suggested by Dutton et al. (2014) [27] and refitted the cross-sectional regression models with these imputed BMI values. Additionally, because we found a linear relationship between HDL-C levels and PISA extracted, we tested whether this linear relationship was consistent for relatively low baseline levels of HDL-c, as a meta-analysis of HDL-C levels suggest a J/U shaped relationship between HDL-c levels and all-cause/cardiovascular mortality. In this meta-analysis, the lowest mortality was found for HDL-c levels around 1,5 − 1,7mmol/l. We thus reran models considering only participants with baseline values below this [28]. Finally, at peer review, a suggestion was made to model alternative metrics of smoking. We initially chose categorical smoking status (never/former/current smoking) as this had the lowest frequency of missing data. A brief literature search suggested that smoking intensity might be better predictor of cardiometabolic risk status [29]. Missing data with regards to smoking intensity was enriched by consulting referral letters and current smoking intensity was modelled as current amount of cigarettes smoked daily.

Results

One hundred and twenty-two individuals visited the outpatient clinic for full mouth dental extraction between December 2014 and December 2018. Eighty-three individuals were screened for eligibility and 54 were recruited. We recruited an additional 4 individuals because 4 were lost to follow-up after the teeth removal: we tried to contact these individuals with repeated phone calls and correspondence to their last known home addresses, but to no avail. The latter four individuals were thus included in the cross-sectional analysis. Fifty control individuals were recruited in the same way as described above. Therefore, for a total of 104 individuals, data were available for the cross-sectional analysis and 50 for the longitudinal analysis. A flowchart showing the individuals selection in the intervention group is depicted in Fig. 1.

Fig. 1 Flowchart depicting recruitment of individuals undergoing full mouth extraction

Table 1 shows the baseline characteristics within the two study arms. The arms were comparable regarding age and proportion of men participating. As expected, the PISA was higher in the intervention group compared to the control group. Also the individuals with severe periodontitis was much higher in the intervention group (98%), compared to 22% with severe periodontitis in the control group. In the intervention group there were no individuals with mild periodontitis and 2% with moderate periodontitis. In the controls 16% was having mild periodontitis and 62% moderate periodontitis. An overlap occurred mainly because 3 individuals in the intervention group only (< 10) teeth left for removal. The intervention individuals had a slightly higher BMI, had on average a lower educational status and were more frequently smokers than the control individuals.

Table 1 Baseline characteristics

	Full mouth dental extraction
(n = 54)	controls individuals
(n = 50)	
Mean age (SD)	45 (10,5)	48 (12,6)	
Male sex n (%)	29 (54%)	24 (48%)	
BMI (SD)	26,7 (6,4)	24,8 (3,1)	
 n missing	0	6	
Median PISA in mm (IQR)	2004 (1082–2613)	853 (463–1088)	
Periodontitis classification (%)			
 Mild periodontitis	-	8(16%)	
 Moderate Priodontitis	1(2%)	31(62%)	
 Severe Periodontitis	53(98%)	11(22%)	
Median number of elements (IQR)	22 (15–25)	27 (26–28)	
History of VTE (%)	3 (6%)	1 (2%)	
Other VTE risk factors (%)	9 (17%)	10 (20%)	
Education level (%)			
 secondary only	15 (28%)	4 (8%)	
 vocational education	35 (65%)	24 (48%)	
 college or higher	3 (6%)	21 (42%)	
 N Missing	1 (2%)	1 (2%)	
Smoking			
 never	6 (11%)	27 (54%)	
 former	5 (9%)	12 (24%)	
 current	43 (80%)	10 (20%)	
 Median number of cigarettes in current smokers group(IQR)	15(10–20)	10 (10–15)	
 N Missing		1	
Hypercholesterolemia (%)	6 (11%)	5 (8%)	
Hypertension (%)	4 (7%)	3 (5%)	
Diabetes (%)	2 (4%)	0 (0%)	
Use of antibiotics (%)	5 (9%)	2 (4%)	
BMI: body mass index; PISA: Periodontal inflamed surface area; VTE: venous thromboembolism

Table 2 shows the laboratory results of the cross-sectional analysis. The mean VWF and CRP levels were higher in the full mouth dental extraction individuals compared to the control group, while their HDL levels were lower.

Table 2 Cross-sectional laboratory parameter levels

Haemostatic parameters	Full mouth dental extraction (n = 54)	control individuals
(n = 50)	test p	
Mean Factor VIII % (SD)	119 (33)	110 (31)	0,21	
Mean VWF % (SD)	143 (62)	108 (42)	< 0.001	
Mean ETP in nM IIa*min (SD)	1131 (223)	1133 (168)	0,95	
Median ETP TM in nM IIa*min (IQR)	344 (174–500)	417 (332–592)	< 0.01**	
Median d-dimer in ng/mL (IQR)	252 (162–374)	205 (112–400)	0.19*	
Median CLT in minutes (IQR)	69 (61–76)	66 (60–72)	0.29**	
Inflammatory/metabolic parameters	
Median C-reactive protein (IQR)	2,2 (1,1–4,1)	1,0 (0.4–2.2)	0,01*	
n missing	3			
Mean TC in mmol/L (SD)	5,2 (1,1)	5,2 (1,1)	0,76	
n missing	2			
Mean LDL in mmol/L (SD)	3,6 (1,0)	3,5 (1,0.1)	0.62	
Mean HDL in mmol/L (SD)	1.3 (0.4)	1.6 (0.6)	0.01	
	1			
Median HOMA2 IR index (IQR)	0.92 (0.69–1.38)	0.9 (0.62–1.23)	0.82**	
* Wilcoxon signed rank test; ** t-test after log transformation; ETP: endogenous thrombin potential; TM: thrombomodulin; CLT: clot lysis time; CRP: c-reactive protein; TC: total cholesterol; LDL: low density lipoprotein; HDL: high density lipoprotein; IQR: interquartile range

Table 3 shows the multivariable regression results of the cross-sectional analysis. The scatter plots visually depicting the relationship between the PISA and dependent variables are shown in the appendix. After adjustment for covariates, there was strong evidence for an association between PISA and vWF, but the associations between periodontitis one the one hand with CRP and HDL-c levels seen in the groupwise analysis did not persist after adjusting for confounders.

Table 3 Cross-sectional regression analyses results

Laboratory marker	Coefficient*
1000 mm2 PISA increment (95% CI)	p	
Cross-sectional analysis	
Factor VIII	1 (-7 to 10)	0.73	
Von Willebrand factor	22 (7 to 37)	0.01	
ETP	36 (-13 to 84)	0.14	
ETP TM	21 (-23 to 76)	0.43	
Dimer (logarithm)	-0.0 (-0.3 to 0.3)	0.99	
CLT	-2 (-6 to 2)	0.36	
CRP (logarithm)	-0.18 (-0.47 to 0.12)	0.18	
Total cholesterol	-0.2 (-0.5 to 0.1)	0.18	
LDL	-0.2 (-0.5 to 0.1)	0.10	
HDL	0.01 (-0.11 to 0.14)	0.84	
HOMA2 IR (logarithm)	0.04 (-0.08 to 0.17)	0.52	
* adjusted for age, sex, BMI, smoking status and educational status; ETP: endogenous thrombin potential; TM: thrombomodulin; CLT: clot lysis time; CRP: c-reactive protein; TC: total cholesterol; LDL: low density lipoprotein; HDL: high density lipoprotein

Table 4 describes the intervention individuals’ laboratory values before and after full mouth dental extraction. None of the paired t-tests showed an improvement in the studied parameters before and after tooth extraction. The regression analyses incorporating PISA and changes in laboratory outcomes showed evidence for an elevation of HDL-C levels after full mouth extraction (p = 0,02).

Table 4 Longitudinal analysis of the full mouth dental extraction individuals (n = 50)

Haemostatic parameters	Before	After	Change	95% CI	p	Regression coefficient /1000 mm2
(95% CI)	
Mean Factor VIII,

% (SD)

	119 (34)	118 (37)	0 (26)	-8 to 8	0.92	1 (-8 to 10)	
Mean VWF,

% (SD)

	143 (58)	141 (54)	-2 (52)	-17 to 12	0.74	5 (-13 to 23)	
Mean ETP,

nM IIa*min (SD)

	1131 (223)	1081 (247)	-48 (240)	-116 to 20	0.16	-32 (-117 to 53)	
Median ETP TM,

nM IIa*min (IQR)

	343

(174 to 500)

	300

(211 to 527)

	-2

(-81 to 107)

	–	0.75*	-11 (-119 to 97)	
Median D-dimer, ng/ml (IQR)	252

(162 to 374)

	273

(154 to 452)

	2

(-79 to 76)

	-42 to 43	0.99	-27 (-80 to 26)	
Median CLT,

min (IQR)

	69 (61 to 76)	66

(59 to 77)

	-3

(-7 to 4)

	–	0.14*	0 (-4 to 4)	
Inflammatory/metabolic parameters	
median CRP (IQR)	2,1 (0,9 to 3,8)	2,0

(0,9 to 4,3)

	-0,1

(-0,7 to 1,0)

	–	0.91*	1.0 (-0.8 to 2.7)	
 n missing	3		3				
mean TC in mmol/L (SD)	5,1 (1,0)	5,2 (1,0)	0 (0,7)	-0,2 to 0,2	0,73	0.16

(-0.08 to 0.40)

	
 n missing	1	1	2				
Mean LDL

in mmol/L (SD)

	3,6 (1,0)	3,6 (1,0)	-0,1 (0,60)	-0,2 to 0,2	1	0.18

(-0.04 to 0.40)

	
Mean HDL

in mmol/L (SD)

	1,3 (0,4)	1,3 (0,3)	0 (0,20)	-0,1 to 0,1	0,83	0.08

(0.01 to 0.14)

	
HOMA2 IR (IQR)	0.92

(0.69 to 1.38)

	0.80

(0.59 to 1.36)

	-0.04

(-0.31 to 0.18)

	–	0.24	-0.04

(0.25 to 0.18)

	
 N missing***	6	5	7				
* Wilcoxon signed rank test; ** t-test after log transformation; *** includes missing for values that were incalculable vWF: von Willebrand factor; ETP: endogenous thrombin potential; TM: thrombomodulin; CLT: clot lysis time; CRP: c-reactive protein; TC: total cholesterol; LDL: low density lipoprotein; HDL: high density lipoprotein

Sensitivity analyses

The identification and removal of outliers, the removal of individuals exposed to antibiotics or VTE risk factors, and the correction of self-reported BMIs, did not change the overall results (see section on statistical analyses). Analyses for sex as an interaction variable and did not find any positive results. Limiting the longitudinal analysis to incrementally lower values of baseline HDL-c led to decreasing coefficients in relationship with PISA. Modelling of smoking intensity as opposed to smoking status did not change the results of the cross-sectional analysis. The results of the sensitivity analyses are shown in the appendix.

Discussion

In the current study we hypothesized that periodontitis severity would be associated with a disturbed state of haemostatic and cardiometabolic biomarkers and, thus, removing the inflammatory burden of periodontitis through a full mouth dental extraction would improve these parameters. Overall, we found limited evidence for this: although we found a solitary association between VWF levels and the amount of inflamed periodontal tissue in the cross-sectional analyses, the VWF levels did not improve after a full mouth dental extraction. This may suggest residual confounding. We found an association between removed inflammatory burden and increase in HDL-c levels. However, given the recently discovered non-linear relationship between HDL-c levels and all-cause/cardiovascular mortality, we amended this analysis, showing decreasing benefits in patients with low baseline HDL-c levels, which were also not significant.

Our study has several conceptual strengths. It complements the data available at the time we designed the study, which showed a limited association between periodontitis and biomarkers, by studying the effects of a more aggressive intervention: a total tooth extraction. We reasoned that, if an aggressive intervention does not produce a significant result, it can be questioned whether less aggressive routine periodontal interventions will be beneficial for hemostatic and cardiometabolic parameters of control individuals as several studies have indicated that initial periodontal treatment has a positive effect on hemostatic and cardiometabolic parameters [30–34].

Additionally, we measured periodontitis using PISA. PISA represents the amount of inflamed periodontal tissue better than any other continuous measurement (e.g., mean probing pocket depth). PISA has inherent statistical advantages (less misclassification and more power) over established periodontitis classifications that report discrete rather than continuous values [19, 35].

Before making conclusions, limitations should be considered. Although we consider the use of the PISA to quantify periodontal burden as a strength of our study, some issues remain. PISA estimates the inflammatory tissue area, but does not capture other quantitative (microbial load) and qualitative (microbe type) parameters which determine systemic inflammation and subsequent risk of another disease [19]. We expect these sources of measurement error would dilute effect sizes found, but the extent is difficult to ascertain [36]. This justifies also analysing the current data per group. The group-wise comparison results are consistent with those from the analysis incorporating PISA. Furthermore, there are some possible issues with potential confounding. The self-reported BMI measurements in the control group may have led to erroneous adjusted estimates. We explored this by imputing validated corrections of the self-reported BMIs, but our overall conclusions from the cross-sectional analysis did not change. A further possible residual confounder could have been the presence of inflammation due to another infection, obscuring the effect of periodontitis. A sensitivity analysis excluding individuals with outlier CRP values was done to explore this, and did not produce different results from the main analysis. Finally, and more specifically the cross-sectional association between von Willebrand factor and PISA could suffer from residual confounding due to imprecision in measurement of smoking- which is known to be correlated with vWF levels. We explored this further by analysing current smoking intensity, but this did not importantly change results. The potential for residual confounding due to measurement error in smoking as well as not finding any association in the longitudinal analysis between von Willebrand factor and PISA leads us to judge that we have not found convincing evidence of a causal relationship between periodontitis and von Willebrand factor.

It is important to stress the population studied. The control individuals were, on average, younger (mean 45 years) than the typical population at risk of cardiovascular disease and VTE (a median age of 66 years) in primary prevention statin trials [37], and a mean age of 57 years in VTE trials [38]. As shown by the aforementioned meta-analysis by Teeuw et al.(2014) [9] and reinforced by a recent analysis by Orlandi et al. (2022) [39], it so far appears that periodontitis interventions only appear to lead to improvements in cardiometabolic parameters in populations who already have established cardiovascular disease. Further evidence of the systemic benefits has accumulated since this meta-analysis including glycaemic control in people with diabetes as well as an improvement in the cardiovascular risk profile of people with metabolic syndrome [40, 41]. With regards to haemostatic biomarker findings, our study is also in agreement with previous analyses. This suggests that periodontitis does not elicit systemic effects on its own; it elicits a disturbed state in concert with other pathophysiological processes, and periodontal intervention in this setting partially restores the disturbed state. Although our study results imply that treating periodontitis may not be a sensible means of primary prevention, it is likely an effective means of secondary prevention in individuals with cardiovascular disease and individuals with diabetes- where questions remain about practical implementation.

With regards to secondary prevention of VTE, we should perhaps stress that our study does not exclude whether periodontitis treatment is an effective means of secondary prevention in individuals with (increased risk of) VTE. Therefore, efforts should be made to investigate whether periodontal interventions improve haemostatic parameters of participants who are at higher risk of VTE. The most obvious candidates would be individuals with VTE who have stopped their anticoagulant treatment, as done by Biederman et al.(2018) [42] by randomizing VTE individuals into statin and non-statin treatment groups. Another approach would be to investigate the effect of periodontal interventions in individuals with a generally higher risk of VTE. Participants with obesity problems would be an interesting field of study, given that the population’s risk of VTE is largely attributable to obesity [43].

In conclusion, this study shows hardly any evidence for a correlation between periodontitis and cardiometabolic and haemostatic parameters nor an effect of periodontal intervention on these parameters in control individuals with periodontitis.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Author contributions

HG was responsible for conducting the study, project administration and writing the manuscript. JFBH was responsible for conducting the study, analysis, and writing the manuscript (lead). KM was responsible for the study idea, supervision and reviewing the manuscript. TL was responsible for the study concept, laboratory analysis of the haemostatic parameters, and reviewing the manuscript. FKLS was responsible for the study idea, study supervision and reviewing the manuscript. AV supervised how the study was conducted and reviewed the manuscript. WN was responsible for the study idea, supervised how the study was conducted and reviewed the manuscript. VT was responsible for the study idea, supervised how the study was conducted and reviewed the manuscript. All authors have given final approval of the version to be published.

Funding

The current study was funded by the Mandema stipendium, grant code Man-26082014-14-01.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Dr. Meijer reports speaker fees from Bayer and Alexion, participating in a trial steering committee for Bayer, and consulting fees from Uniqure. The other authors have nothing to declare.

Ethical approval

This study was approved by the institutional review board of the University Medical Centre Groningen (dossier 2014/289) and was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2013. All the participants gave written informed consent.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Hester Groenewegen and Jaime F. Borjas-Howard shared first authorship.
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References

1. Jiménez D García-Sanchez A Rali P Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis Chest 2021 159 3 1182 1196 10.1016/j.chest.2020.11.005 33217420
Jiménez D, García-Sanchez A, Rali P et al (2021) Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Chest 159(3):1182–119633217420
2. Alves C Penedones A Mendes D Marques FB Risk of cardiovascular and venous thromboembolic events associated with janus kinase inhibitors in rheumatoid arthritis: a systematic review and network meta-analysis J Clin Rheumatol 2022 28 2 69 76 10.1097/RHU.0000000000001804 34741000
Alves C, Penedones A, Mendes D, Marques FB (2022) Risk of cardiovascular and venous thromboembolic events associated with janus kinase inhibitors in rheumatoid arthritis: a systematic review and network meta-analysis. J Clin Rheumatol 28(2):69–7634741000
3. Dommisch H, Kebschull M (2014) Chronic periodontitis. In: Newman MG, Carranza FA, Takei H, Klokkevold PR (eds) Carranza’s clinical periodontology, 12th edn. Elsevier health sciences, p 309
4. Paraskevas S Huizinga JD Loos BG A systematic review and meta-analyses on C-reactive protein in relation to periodontitis J Clin Periodontol 2008 35 4 277 290 10.1111/j.1600-051X.2007.01173.x 18294231
Paraskevas S, Huizinga JD, Loos BG (2008) A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clin Periodontol 35(4):277–29018294231
5. Ohki T Itabashi Y Kohno T Detection of periodontal bacteria in thrombi of patients with acute myocardial infarction by polymerase chain reaction Am Heart J 2012 163 2 164 167 10.1016/j.ahj.2011.10.012 22305832
Ohki T, Itabashi Y, Kohno T et al (2012) Detection of periodontal bacteria in thrombi of patients with acute myocardial infarction by polymerase chain reaction. Am Heart J 163(2):164–16722305832
6. Rydén L Buhlin K Ekstrand E Periodontitis increases the risk of a first myocardial infarction: a report from the PAROKRANK study Circulation 2016 133 6 576 583 10.1161/CIRCULATIONAHA.115.020324 26762521
Rydén L, Buhlin K, Ekstrand E et al (2016) Periodontitis increases the risk of a first myocardial infarction: a report from the PAROKRANK study. Circulation 133(6):576–58326762521
7. Lafon A Pereira B Dufour T Periodontal disease and stroke: a meta-analysis of cohort studies Eur J Neurol 2014 21 9 1155 1161 10.1111/ene.12415 24712659
Lafon A, Pereira B, Dufour T et al (2014) Periodontal disease and stroke: a meta-analysis of cohort studies. Eur J Neurol 21(9):1155–1161 e66-724712659
8. Tonetti MS Van Dyke TE Working group 1 of the joint EFP/AAP workshop. Periodontitis and atherosclerotic cardiovascular disease: Consensus report of the joint EFP/AAP workshop on periodontitis and systemic diseases J Periodontol 2013 84 4 Suppl S24 S29 23631582
Tonetti MS, Van Dyke TE (2013) Working group 1 of the joint EFP/AAP workshop. Periodontitis and atherosclerotic cardiovascular disease: Consensus report of the joint EFP/AAP workshop on periodontitis and systemic diseases. J Periodontol 84(4 Suppl):S24–S2923631582
9. Teeuw WJ Slot DE Susanto H Treatment of periodontitis improves the atherosclerotic profile: a systematic review and meta-analysis J Clin Periodontol 2014 41 1 70 79 10.1111/jcpe.12171 24111886
Teeuw WJ, Slot DE, Susanto H et al (2014) Treatment of periodontitis improves the atherosclerotic profile: a systematic review and meta-analysis. J Clin Periodontol 41(1):70–7924111886
10. Czesnikiewicz-Guzik M Osmenda G Siedlinski M Causal association between periodontitis and hypertension: evidence from mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy Eur Heart J 2019 40 42 3459 3470 10.1093/eurheartj/ehz646 31504461
Czesnikiewicz-Guzik M, Osmenda G, Siedlinski M et al (2019) Causal association between periodontitis and hypertension: evidence from mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy. Eur Heart J 40(42):3459–3470. 10.1093/eurheartj/ehz64631504461
11. Sharma S Sridhar S McIntosh A Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis Pharmacol Res 2021 166 105511 10.1016/j.phrs.2021.105511 33617973
Sharma S, Sridhar S, McIntosh A et al (2021) Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis. Pharmacol Res 166:105511. 10.1016/j.phrs.2021.10551133617973
12. Tichelaar YI Kluin-Nelemans HJ Meijer K Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review Thromb Haemost 2012 107 5 827 837 10.1160/TH11-09-0611 22437808
Tichelaar YI, Kluin-Nelemans HJ, Meijer K (2012) Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review. Thromb Haemost 107(5):827–83722437808
13. Taylor B Tofler G Morel-Kopp MC The effect of initial treatment of periodontitis on systemic markers of inflammation and cardiovascular risk: a randomized controlled trial Eur J Oral Sci 2010 118 4 350 356 10.1111/j.1600-0722.2010.00748.x 20662907
Taylor B, Tofler G, Morel-Kopp MC et al (2010) The effect of initial treatment of periodontitis on systemic markers of inflammation and cardiovascular risk: a randomized controlled trial. Eur J Oral Sci 118(4):350–35620662907
14. Tonetti MS D’Aiuto F Nibali L Treatment of periodontitis and endothelial function N Engl J Med 2007 356 9 911 920 10.1056/NEJMoa063186 17329698
Tonetti MS, D’Aiuto F, Nibali L et al (2007) Treatment of periodontitis and endothelial function. N Engl J Med 356(9):911–92017329698
15. Taylor BA Tofler GH Carey HM Full-mouth tooth extraction lowers systemic inflammatory and thrombotic markers of cardiovascular risk J Dent Res 2006 85 1 74 78 10.1177/154405910608500113 16373685
Taylor BA, Tofler GH, Carey HM et al (2006) Full-mouth tooth extraction lowers systemic inflammatory and thrombotic markers of cardiovascular risk. J Dent Res 85(1):74–7816373685
16. Folsom AR Alonso A George KM Roetker NS Tang W Cushman M Prospective study of plasma D-dimer and incident venous thromboembolism: the atherosclerosis risk in communities (ARIC) study Thromb Res 2015 136 4 781 785 10.1016/j.thromres.2015.08.013 26337932
Folsom AR, Alonso A, George KM, Roetker NS, Tang W, Cushman M (2015) Prospective study of plasma D-dimer and incident venous thromboembolism: the atherosclerosis risk in communities (ARIC) study. Thromb Res 136(4):781–78526337932
17. van Hylckama Vlieg A Christiansen SC Luddington R Cannegieter SC Rosendaal FR Baglin TP Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence Br J Haematol 2007 138 6 769 774 10.1111/j.1365-2141.2007.06738.x 17760809
van Hylckama Vlieg A, Christiansen SC, Luddington R, Cannegieter SC, Rosendaal FR, Baglin TP (2007) Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence. Br J Haematol 138(6):769–77417760809
18. Karasu A Baglin TP Luddington R Baglin CA van Hylckama Vlieg A Prolonged clot lysis time increases the risk of a first but not recurrent venous thrombosis Br J Haematol 2016 172 6 947 953 10.1111/bjh.13911 26773756
Karasu A, Baglin TP, Luddington R, Baglin CA, van Hylckama Vlieg A (2016) Prolonged clot lysis time increases the risk of a first but not recurrent venous thrombosis. Br J Haematol 172(6):947–95326773756
19. Nesse W Abbas F van der Ploeg I Spijkervet FK Dijkstra PU Vissink A Periodontal inflamed surface area: quantifying inflammatory burden J Clin Periodontol 2008 35 8 668 673 10.1111/j.1600-051X.2008.01249.x 18564145
Nesse W, Abbas F, van der Ploeg I, Spijkervet FK, Dijkstra PU, Vissink A (2008) Periodontal inflamed surface area: quantifying inflammatory burden. J Clin Periodontol 35(8):668–67318564145
20. Passarelli PC Pagnoni S Piccirillo GB Reasons for tooth extractions and related risk factors in adult patients: a cohort study Int J Environ Res Public Health 2020 17 7 2575 10.3390/ijerph17072575 32283707
Passarelli PC, Pagnoni S, Piccirillo GB et al (2020) Reasons for tooth extractions and related risk factors in adult patients: a cohort study. Int J Environ Res Public Health 17(7):2575. 10.3390/ijerph1707257532283707
21. McCaul LK Jenkins WM Kay EJ The reasons for the extraction of various tooth types in Scotland: a 15-year follow up J Dent 2001 29 6 401 407 10.1016/S0300-5712(01)00036-7 11520588
McCaul LK, Jenkins WM, Kay EJ (2001) The reasons for the extraction of various tooth types in Scotland: a 15-year follow up. J Dent 29(6):401–40711520588
22. Wallace TM Levy JC Matthews DR Use and abuse of HOMA modeling Diabetes Care 2004 27 6 1487 1495 10.2337/diacare.27.6.1487 15161807
Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27(6):1487–149515161807
23. Eke PI Page RC Wei L Thornton-Evans G Genco RJ Update of the case definitions for population-based surveillance of periodontitis J Periodontol 2012 83 12 1449 1454 10.1902/jop.2012.110664 22420873
Eke PI, Page RC, Wei L, Thornton-Evans G, Genco RJ (2012) Update of the case definitions for population-based surveillance of periodontitis. J Periodontol 83(12):1449–145422420873
24. Holtfreter B Albandar JM Dietrich T Standards for reporting chronic periodontitis prevalence and severity in epidemiologic studies: proposed standards from the Joint EU/USA Periodontal Epidemiology Working Group J Clin Periodontol 2015 42 5 407 412 10.1111/jcpe.12392 25808877
Holtfreter B, Albandar JM, Dietrich T et al (2015) Standards for reporting chronic periodontitis prevalence and severity in epidemiologic studies: proposed standards from the Joint EU/USA Periodontal Epidemiology Working Group. J Clin Periodontol 42(5):407–41225808877
25. Page RC Eke PI Case definitions for Use in Population-based surveillance of Periodontitis J Periodontol 2007 78 Suppl 7 1387 1399 10.1902/jop.2007.060264 17608611
Page RC, Eke PI (2007) Case definitions for Use in Population-based surveillance of Periodontitis. J Periodontol 78(Suppl 7):1387–139917608611
26. Glymour MM Weuve J Berkman LF Kawachi I Robins JM When is baseline adjustment useful in analyses of change? An example with education and cognitive change Am J Epidemiol 2005 162 3 267 278 10.1093/aje/kwi187 15987729
Glymour MM, Weuve J, Berkman LF, Kawachi I, Robins JM (2005) When is baseline adjustment useful in analyses of change? An example with education and cognitive change. Am J Epidemiol 162(3):267–27815987729
27. Dutton DJ McLaren L The usefulness of corrected body mass index vs. self-reported body mass index: comparing the population distributions, sensitivity, specificity, and predictive utility of three correction equations using Canadian population-based data BMC Public Health 2014 14 430 2458 10.1186/1471-2458-14-430 24885210
Dutton DJ, McLaren L (2014) The usefulness of corrected body mass index vs. self-reported body mass index: comparing the population distributions, sensitivity, specificity, and predictive utility of three correction equations using Canadian population-based data. BMC Public Health 14:430–2458 14-43024885210
28. Zhong G Huang S Peng Y HDL-C is associated with mortality from all causes, cardiovascular disease and cancer in a J-shaped dose-response fashion: a pooled analysis of 37 prospective cohort studies Eur J Prev Cardiol 2020 27 11 1187 1203 10.1177/2047487320914756 32283957
Zhong G, Huang S, Peng Y et al (2020) HDL-C is associated with mortality from all causes, cardiovascular disease and cancer in a J-shaped dose-response fashion: a pooled analysis of 37 prospective cohort studies. Eur J Prev Cardiol 27(11):1187–120332283957
29. Nance R Delaney J McEvoy JW Smoking intensity (pack/day) is a better measure than pack-years or smoking status for modeling cardiovascular disease outcomes J Clin Epidemiol 2017 81 111 119 10.1016/j.jclinepi.2016.09.010 27769836
Nance R, Delaney J, McEvoy JW et al (2017) Smoking intensity (pack/day) is a better measure than pack-years or smoking status for modeling cardiovascular disease outcomes. J Clin Epidemiol 81:111–119. 10.1016/j.jclinepi.2016.09.01027769836
30. Del Pinto R Landi L Grassi G Hypertension and periodontitis: a joint report by the Italian Society of Hypertension (SIIA) and the Italian Society of Periodontology and Implantology (SIdP) High Blood Press Cardiovasc Prev 2021 28 5 427 438 10.1007/s40292-021-00466-6 34562228
Del Pinto R, Landi L, Grassi G et al (2021) Hypertension and periodontitis: a joint report by the Italian Society of Hypertension (SIIA) and the Italian Society of Periodontology and Implantology (SIdP). High Blood Press Cardiovasc Prev 28(5):427–43834562228
31. Hajishengallis G Chavakis T Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities Nat Rev Immunol 2021 21 7 426 440 10.1038/s41577-020-00488-6 33510490
Hajishengallis G, Chavakis T (2021) Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 21(7):426–44033510490
32. Sanz M Del Marco A Jepsen S Periodontitis and cardiovascular diseases: Consensus report J Clin Periodontol 2020 47 3 268 288 10.1111/jcpe.13189 32011025
Sanz M, Del Marco A, Jepsen S et al (2020) Periodontitis and cardiovascular diseases: Consensus report. J Clin Periodontol 47(3):268–28832011025
33. Sanz M Ceriello A Buysschaert M Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology J Clin Periodontol 2018 45 2 138 149 10.1111/jcpe.12808 29280174
Sanz M, Ceriello A, Buysschaert M et al (2018) Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol 45(2):138–14929280174
34. Li X Wang H Yu X Saha G Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities Cell 2022 12 10 17091727e18
Li X, Wang H, Yu X, Saha G et al (2022) Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities. Cell 12(10):17091727e18
35. Eke PI Dye BA Wei L Thornton-Evans GO Genco RJ CDC Periodontal Disease Surveillance workgroup: James Beck (University of North Carolina, Chapel Hill, USA), Gordon Douglass (Past President, American Academy of Periodontology), Roy Page (University of Washin. Prevalence of periodontitis in adults in the United States: 2009 and 2010 J Dent Res 2012 91 10 914 920 10.1177/0022034512457373 22935673
Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ (2012) CDC Periodontal Disease Surveillance workgroup: James Beck (University of North Carolina, Chapel Hill, USA), Gordon Douglass (Past President, American Academy of Periodontology), Roy Page (University of Washin. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res 91(10):914–92022935673
36. Hutcheon JA Chiolero A Hanley JA Random measurement error and regression dilution bias BMJ 2010 340 c2289 10.1136/bmj.c2289 20573762
Hutcheon JA, Chiolero A, Hanley JA (2010) Random measurement error and regression dilution bias. BMJ 340:c228920573762
37. Ridker PM Danielson E Fonseca FA Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein N Engl J Med 2008 359 21 2195 2207 10.1056/NEJMoa0807646 18997196
Ridker PM, Danielson E, Fonseca FA et al (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359(21):2195–220718997196
38. Agnelli G Buller HR Cohen A Oral apixaban for the treatment of acute venous t7romboembolism N Engl J Med 2013 369 9 799 808 10.1056/NEJMoa1302507 23808982
Agnelli G, Buller HR, Cohen A et al (2013) Oral apixaban for the treatment of acute venous t7romboembolism. N Engl J Med 369(9):799–80823808982
39. Orlandi M Muñoz Aguilera E Marletta D Petrie A Suvan J D’Aiuto F Impact of the treatment of periodontitis on systemic health and quality of life: a systematic review J Clin Periodontol 2022 49 Suppl 24 314 327 10.1111/jcpe.13554 34791686
Orlandi M, Muñoz Aguilera E, Marletta D, Petrie A, Suvan J, D’Aiuto F (2022) Impact of the treatment of periodontitis on systemic health and quality of life: a systematic review. J Clin Periodontol 49(Suppl 24):314–32734791686
40. Bizzarro S van der Velden U Teeuw WJ Gerdes VEA Loos BG Effect of periodontal therapy with systemic antimicrobials on parameters of metabolic syndrome: a randomized clinical trial J Clin Periodontol 2017 44 8 833 841 10.1111/jcpe.12763 28621003
Bizzarro S, van der Velden U, Teeuw WJ, Gerdes VEA, Loos BG (2017) Effect of periodontal therapy with systemic antimicrobials on parameters of metabolic syndrome: a randomized clinical trial. J Clin Periodontol 44(8):833–84128621003
41. D’Aiuto F Gkranias N Bhowruth D Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial Lancet Diabetes Endocrinol 2018 6 12 954 965 10.1016/S2213-8587(18)30038-X 30472992
D’Aiuto F, Gkranias N, Bhowruth D et al (2018) Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol 6(12):954–96530472992
42. Biedermann JS Kruip MJHA van der Meer FJ Rosuvastatin use improves measures of coagulation in patients with venous thrombosis Eur Heart J 2018 39 19 1740 1747 10.1093/eurheartj/ehy014 29394348
Biedermann JS, Kruip MJHA, van der Meer FJ et al (2018) Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. Eur Heart J 39(19):1740–174729394348
43. Heit JA Ashrani A Crusan DJ McBane RD Petterson TM Bailey KR Reasons for the persistent incidence of venous thromboembolism Thromb Haemost 2017 117 2 390 400 10.1160/TH16-07-0509 27975103
Heit JA, Ashrani A, Crusan DJ, McBane RD, Petterson TM, Bailey KR (2017) Reasons for the persistent incidence of venous thromboembolism. Thromb Haemost 117(2):390–40027975103
