Semin Thromb Hemost
DOI: 10.1055/s-0040-1714399
Letter to the Editor

Periodontal Disease and Venous Thromboembolism

Giuseppe Lippi
1  Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
Riccardo Nocini
2  Section of Ears, Nose and Throat (ENT), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Emmanuel J. Favaloro
3  Haematology, Sydney Centers for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
› Author Affiliations

Emerging evidence suggests that periodontal disease may be associated with some highly prevalent disorders, including cardiovascular disease, diabetes, and certain types of cancer.[1] The aim of this brief report is to summarize current evidence linking periodontal disease with venous thromboembolism (VTE), which encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE).

The first study to explore the potential association between periodontal disease and VTE was published by Sánchez-Siles et al in 2003.[2] This cross-sectional investigation was based on a total of 197 patients, comprising 97 with VTE (54 women and 43 men; mean age, 61 ± 15 years) and 100 healthy controls (46 women and 54 men; mean age, 55 ± 15 years). The entire population underwent comprehensive periodontal examination to establish the burden of periodontal disease. The prevalence of periodontal disease was found to be substantially higher in patients with VTE than in those without (73 vs. 45%; p < 0.001), so that the risk of VTE was nearly twofold higher in patients with periodontal disease than in those without ([Fig. 1]). Additional notable findings in VTE patients were the presence of a lower number of teeth (which is another surrogate measure of periodontal disease; 22 ± 8 vs. 27 ± 2; p < 0.001), as well as a larger prevalence of severe periodontal disease (16% vs. 7%; p < 0.001).

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Fig. 1 Summary of the risk of developing VTE in patients with periodontal disease. CI, confidence interval; RR, relative risk; VTE, venous thromboembolism.

A second epidemiologic investigation was recently published by Cowan et al in 2019.[3] This prospective study included as many as 7,856 participants (4,320 women and 3,536 men; mean age, 63 ± 6 years), derived from the Atherosclerosis Risk in Communities study, who were followed up for a mean period of 12.9 years. Periodontal disease, defined as self-reported tooth loss due to gum disease, was found to be more prevalent in patients who developed VTE on follow-up (n = 306; incidence rate, 4.53 per 1,000 person-years) than in those who did not (n = 7,550; incidence rate, 2.79 per 1,000 person-years), so that the risk of developing VTE was ∼1.5-fold higher in patients with periodontal disease than in those without ([Fig. 1]). Notably, the cure risk of VTE was increased by 1.9-fold [hazard ratio (HR), 1 to 91; 95% confidence interval (95% CI), 1.19–3.08), and 2.29-fold (HR, 2.29; 95% CI, 1.63–3.22) in patients with severe periodontal disease and edentulous compare to those with no clinical signs of periodontal disease, respectively.

Overall, the relative risk (RR) calculated from pooling data of these two studies (MetaXL software Version 5.3; EpiGear International Pty Ltd.) reveal that people with periodontal disease may have a nearly 60% higher risk of developing VTE (RR, 1.61; 95% CI, 1.25-2.08; heterogeneity, 38%) ([Fig. 1]).

Noteworthy evidence has also emerged from studies that have evaluated D-dimer values in patients undergoing periodontal treatment. Dikshit measured D-dimer in 40 subjects divided into four homogenous classes (no periodontitis, mild periodontitis, moderate periodontitis, and severe periodontitis),[4] reporting that biomarker values gradually and significantly increased across periodontitis severity classes, from 211 ± 20 ng/mL in those with no periodontitis, to 340 ± 37 ng/mL, 434 ± 20 ng/mL, and 536 ± 45 ng/mL in those with increasing disease severity, respectively. Notably, 4 weeks after periodontal therapy, D-dimer values decreased by 46, 58, and 62% in patients with mild, moderate, and severe periodontitis, respectively. Similar evidence was published by Sánchez-Siles et al.[5] D-dimer was assayed in 142 patients with unprovoked VTE (76 with DVT, 37 with PE and 29 with both DVT and PE; 71 with periodontal disease and 71 without). D-dimer values were found to be 56% higher (516 ± 498 vs. 324 ± 346 ng/mL; p = 0.010) in patients with periodontal disease than in those without. Patients with normal D-dimer values (< 250 ng/mL) also had a higher number of residual tooth than those with abnormal D-dimer levels (21.7 ± 7.3 vs. 17.7 ± 7.0; p = 0.023). Interestingly, Taylor et al also showed that treatment of advanced periodontitis by means of tooth extraction was effective to modestly but significantly lower fibrinogen values (from 3.9 to 3.7 g/L; -7.6%, p = 0.04) and platelet count (from 242 × 109/L to 230 × 109/L; -5.0%; p = 0.01).[6]

An interesting case has also been recently published by Ko et al,[7] who reported on a 42-year-old woman with acute and severe periodontitis who concomitantly developed septic cavernous sinus thrombosis and PE, probably as consequence of Peptostreptococcus disseminated infection. This case report demonstrates that untreated periodontitis can progress toward septicemia, accompanied by a sustained prothrombotic status, which may ultimately contribute to considerably increase the risk of developing VTE episodes. This evidence is in keeping with previous data showing that periodontitis is frequently associated with bacteremia,[8] and with various levels of systemic inflammation,[9] which can be both reversed by periodontal therapy along with a simultaneous reduction in the concomitant prothrombotic state.[6] Both bacteremia[10] and systemic inflammation[11] are well-known risk factors for VTE, and this would, therefore, provide a reasonable explanation for their association. Further evidence on the interplay between periodontitis and hemostasis comes from the work of Senini et al,[12] who showed that Gram-negative periodontal infections are associated with platelet hyperreactivity.

In conclusion, beyond several well-established VTE risk factors,[13] venous thrombosis may also be triggered by unusual and unsuspected conditions.[14] The current scientific evidence—although limited both in time and quantity—would support the existence of a causal relationship between periodontal disease (especially severe) and VTE. Further efforts should, therefore, be initiated to reinforce the promotion of oral health in the general population, especially in subjects with prothrombotic conditions or risk factors that confer higher risk of developing venous and arterial thromboembolic events.

Publication History

Publication Date:
23 September 2020 (online)

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