Periodontitis and circulating blood cell profiles: a systematic review and meta-analysis
2020; Elsevier BV; Volume: 93; Linguagem: Inglês
10.1016/j.exphem.2020.10.001
ISSN1873-2399
AutoresJoão Botelho, Vanessa Machado, Syed Basit Hussain, Syeda Ambreen Zehra, Luís Proença, Marco Orlandi, José João Mendes, Francesco D’Aiuto,
Tópico(s)Oral Health Pathology and Treatment
Resumo•Periodontitis is associated with hematologic changes (SORT A recommendation).•Higher leukocyte, neutrophil, and erythrocyte sedimentation rates are the most common findings.•Periodontitis treatment was associated with a decrease in leukocyte levels. Periodontitis is a chronic inflammatory disease with local and systemic implications. Evidence suggests consistent hematologic changes associated with periodontitis. Our aim was to critically appraise the available evidence on hemogram, leukogram, and thrombogram alterations in otherwise healthy patients suffering from periodontitis when compared with controls. For this systematic review (SR), we searched MEDLINE, Web of Science, EMBASE, and the Cochrane Library (CENTRAL) for studies published up to June 2020. Both observational and interventional studies with baseline standard hematologic levels were included. Outcomes of interest were baseline hemogram, leukogram, and thrombogram values and the impact of periodontitis treatment on these outcomes. Upon risk of bias assessment, data extraction and both qualitative and quantitative (standardized mean differences) analyses were performed. Random-effects meta-analyses were performed to provide pooled estimates. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed (PROSPERO Reg. No. CRD42020164531). A total of 45 studies, eight intervention and 37 case–control studies, were identified after the final search of 3,012 titles. Following quality assessment, 43 articles were deemed to have low risk of bias, and two articles moderate risk. Meta-analyses confirmed that periodontitis was associated with both white and red cell lineages. Severe chronic periodontitis was associated with greater white blood cell counts (mean difference [MD] = 0.53, 95% confidence interval [CI]: 0.26–0.79) when compared with controls. Periodontitis was associated with a larger number of neutrophils (MD = 7.16%, 95% CI: 5.96–8.37) and lower mean platelet volume (MD = 0.30 fL, 95% CI: 0.49 to −0.10) compared with healthy participants. Nonsurgical periodontal treatment was associated with a decrease in white blood cell (WBC) levels (MD = 0.28 109/L, 95% CI: −0.47 to −0.08) in patients with chronic periodontitis. Periodontitis is associated with hematologic changes (Strength of Recommendation Taxonomy [SORT] A recommendation). Higher WBC levels, higher neutrophil levels, higher erythrocyte sedimentation rate, and lower mean platelet volumes are the most common blood count findings. The association between periodontitis and WBC could be causal in nature. Further assessment to determine whether periodontitis causes changes in circulating blood cells and to identify the molecular mechanisms underlying these associations is warranted. Periodontitis is a chronic inflammatory disease with local and systemic implications. Evidence suggests consistent hematologic changes associated with periodontitis. Our aim was to critically appraise the available evidence on hemogram, leukogram, and thrombogram alterations in otherwise healthy patients suffering from periodontitis when compared with controls. For this systematic review (SR), we searched MEDLINE, Web of Science, EMBASE, and the Cochrane Library (CENTRAL) for studies published up to June 2020. Both observational and interventional studies with baseline standard hematologic levels were included. Outcomes of interest were baseline hemogram, leukogram, and thrombogram values and the impact of periodontitis treatment on these outcomes. Upon risk of bias assessment, data extraction and both qualitative and quantitative (standardized mean differences) analyses were performed. Random-effects meta-analyses were performed to provide pooled estimates. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed (PROSPERO Reg. No. CRD42020164531). A total of 45 studies, eight intervention and 37 case–control studies, were identified after the final search of 3,012 titles. Following quality assessment, 43 articles were deemed to have low risk of bias, and two articles moderate risk. Meta-analyses confirmed that periodontitis was associated with both white and red cell lineages. Severe chronic periodontitis was associated with greater white blood cell counts (mean difference [MD] = 0.53, 95% confidence interval [CI]: 0.26–0.79) when compared with controls. Periodontitis was associated with a larger number of neutrophils (MD = 7.16%, 95% CI: 5.96–8.37) and lower mean platelet volume (MD = 0.30 fL, 95% CI: 0.49 to −0.10) compared with healthy participants. Nonsurgical periodontal treatment was associated with a decrease in white blood cell (WBC) levels (MD = 0.28 109/L, 95% CI: −0.47 to −0.08) in patients with chronic periodontitis. Periodontitis is associated with hematologic changes (Strength of Recommendation Taxonomy [SORT] A recommendation). Higher WBC levels, higher neutrophil levels, higher erythrocyte sedimentation rate, and lower mean platelet volumes are the most common blood count findings. The association between periodontitis and WBC could be causal in nature. Further assessment to determine whether periodontitis causes changes in circulating blood cells and to identify the molecular mechanisms underlying these associations is warranted. Inflammation is a key host immune response triggered by a variety of factors including pathogens, damaged cells, and toxic substances [1Chen L Deng H Cui H et al.Responses and inflammation-associated diseases in organs.Oncotarget. 2018; 9: 7204-7218Crossref PubMed Scopus (1347) Google Scholar]. Cells and humoral changes are initiated by the host when a new inflammatory stimulus is identified. Monitoring body inflammation has over the years been possible thanks to a variety of cellular and circulating biomarkers [2Watson J De Salis I Salisbury C Hamilton W 'I'm fishing really'—Inflammatory marker testing in primary care: a qualitative study.Br J Gen Pract. 2016; 66: e200-e206Crossref PubMed Scopus (22) Google Scholar], among which white blood cell (WBC) count and erythrocyte sedimentation rate (ESR) are considered both reliable and affordable hematologic surrogates. When acute inflammation resolves and a chronic response ensues, important systemic implications can occur [3Furman D Campisi J Verdin E et al.Chronic inflammation in the etiology of disease across the life span.Nat Med. 2019; 25: 1822-1832Crossref PubMed Scopus (871) Google Scholar,4Franceschi C Garagnani P Parini P Giuliani C Santoro A Inflammaging: a new immune–metabolic viewpoint for age-related diseases.Nat Rev Endocrinol. 2018; 14: 576-590Crossref PubMed Scopus (838) Google Scholar]. It is recognized that all noncommunicable diseases, including diabetes and cardiovascular diseases, have a common chronic inflammatory basis. An understanding of all inflammatory triggering factors is urgently needed as it could affect both the onset and progression of common chronic diseases, as well their complications. Periodontitis is a major chronic multifactorial inflammatory disease caused by a dysbiotic dental biofilm [5Roberts FA Darveau RP Microbial protection and virulence in periodontal tissue as a function of polymicrobial communities: symbiosis and dysbiosis.Periodontol 2000. 2015; 69: 18-27Crossref PubMed Scopus (59) Google Scholar] and characterized by progressive destruction of the periodontium [6Papapanou PN Sanz M Buduneli N et al.Periodontitis: consensus report of Workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions.J Clin Periodontol. 2018; 45: S162-S170Crossref PubMed Scopus (404) Google Scholar]. Periodontitis is one of the leading causes of tooth loss worldwide [7Petersen PE Ogawa H The global burden of periodontal disease: towards integration with chronic disease prevention and control.Periodontol 2000. 2012; 60: 15-39Crossref PubMed Scopus (426) Google Scholar,8Kassebaum NJ Bernabé E Dahiya M Bhandari B Murray CJL Marcenes W Global burden of severe periodontitis in 1990–2010: a systematic review and meta-regression.J Dent Res. 2014; 93: 1045-1053Crossref PubMed Scopus (1003) Google Scholar]. It is characterized by an exaggerated gingival inflammation with a distinctive inflammatory cell infiltrate and plethora of pro-inflammatory mediators that is not only confined to the gingival tissues but also involved in systemic host changes [9Ebersole JL Dawson D Emecen-Huja P et al.The periodontal war: microbes and immunity.Periodontol 2000. 2017; 75: 52-115Crossref PubMed Scopus (84) Google Scholar,10Ebersole JL Graves CL Gonzalez OA et al.Aging, inflammation, immunity and periodontal disease.Periodontol 2000. 2016; 72: 54-75Crossref PubMed Scopus (94) Google Scholar]. Systemic repercussions as a result of periodontitis have been comprehensively explored and revised [11Jepsen S Caton JG Albandar JM et al.Periodontal manifestations of systemic diseases and developmental and acquired conditions: consensus report of Workgroup 3 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions.J Clin Periodontol. 2018; 45: S219-S229Crossref PubMed Scopus (126) Google Scholar,12Chan S Pasternak GM West MJ The place of periodontal examination and referral in general medicine.Periodontol 2000. 2017; 74: 194-199Crossref PubMed Scopus (10) Google Scholar]. Hence it is reasonable to hypothesize that such changes might be observed using hematologic surrogates. A recent systematic review linked periodontitis with lower levels of red lineage cell parameters [13França LF de C da Silva FRP di Lenardo D et al.Comparative analysis of blood parameters of the erythrocyte lineage between patients with chronic periodontitis and healthy patients: results obtained from a meta-analysis.Arch Oral Biol. 2019; 97: 144-149Crossref PubMed Scopus (10) Google Scholar], confirming the preliminary observational evidence that altered iron and ferritin levels are observed in patients with periodontitis when compared with controls [14Chakraborty S Tewari S Sharma RK Narula SC Effect of non-surgical periodontal therapy on serum ferritin levels: an interventional study.J Periodontol. 2014; 85: 688-696Crossref PubMed Scopus (18) Google Scholar, 15Latha S Thirugnanamsambandan S Arun R Masthan KMK Malathi L Rajesh E Serum ferritin level and red blood cell parameters in healthy controls and chronic periodontitis patients.J Pharm Bioallied Sci. 2015; 7: S184-S189PubMed Google Scholar, 16Guo LN Yang YZ Feng YZ Serum and salivary ferritin and hepcidin levels in patients with chronic periodontitis and type 2 diabetes mellitus.BMC Oral Health. 2018; 18: 1-9Crossref PubMed Scopus (18) Google Scholar, 17Leite FRM Nascimento GG Scheutz F López R Effect of smoking on periodontitis: a systematic review and meta-regression.Am J Prev Med. 2018; 54: 831-841Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 18Nibali L Darbar U Rakmanee T Donos N Anemia of inflammation associated with periodontitis: analysis of two clinical studies.J Periodontol. 2019; 90: 1252-1259Crossref PubMed Scopus (13) Google Scholar]. Similarly, patients with periodontitis appear to present with changes in WBC and platelet counts [18Nibali L Darbar U Rakmanee T Donos N Anemia of inflammation associated with periodontitis: analysis of two clinical studies.J Periodontol. 2019; 90: 1252-1259Crossref PubMed Scopus (13) Google Scholar, 19Temelli B Yetkin Ay Z Aksoy F et al.Platelet indices (mean platelet volume and platelet distribution width) have correlations with periodontal inflamed surface area in coronary artery disease patients: a pilot study.J Periodontol. 2018; 89: 1203-1212Crossref PubMed Scopus (13) Google Scholar, 20Zhan Y Lu R Meng H Wang X Sun X Hou J The role of platelets in inflammatory immune responses in generalized aggressive periodontitis.J Clin Periodontol. 2017; 44: 150-157Crossref PubMed Scopus (14) Google Scholar, 21Anand PS Sagar DK Mishra S Narang S Kamath KP Anil S Total and differential leukocyte counts in the peripheral blood of patients with generalised aggressive periodontitis.Oral Heal Prev Dent. 2016; 14: 443-450PubMed Google Scholar]. The aim of the present systematic review was to undertake a critical appraisal of the available evidence on hemogram, leukogram, and thrombogram alterations in otherwise healthy patients with periodontitis as compared with controls. A protocol was registered in PROSPERO (ID: CRD42020164531) according to the Cochrane Handbook of Systematic Reviews of Interventions [22Higgins JPT Green S Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011Google Scholar] and is hereby reported according to the PRISMA guidelines (Appendix S1, see Supplementary Data, online only, available at www.exphem.org) [23Liberati A Altman DG Tetzlaff J et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.PLoS Med. 2009; 6e1000100Crossref PubMed Scopus (9479) Google Scholar]. The following PI(E)CO questions were adopted:1."Do otherwise healthy patients suffering from periodontitis have altered hemogram, leukogram, and thrombogram levels when compared with controls?"2."Do hemogram, leukogram, and thrombogram levels decrease after nonsurgical periodontal treatment (NSPT)?" The review followed these respective PI(E)CO statements:1.Otherwise healthy patients (Patients, P); periodontitis (Intervention/Exposure, E); no periodontitis (Comparison, C); hemogram, leukogram, and thrombogram levels (Outcome, O) (detailed under Data Extraction Process and Data Items).2.Otherwise healthy patients with periodontitis (patients, P); nonsurgical periodontal treatment (intervention/exposure, E); baseline levels of hemogram, leukogram, and thrombogram levels (comparison, C); posttreatment hemogram, leukogram, and thrombogram levels (Outcome, O) (detailed under Data Extraction Process and Data Items). Studies were deemed eligible for inclusion based on the following criteria:1.Observational (cross-sectional case–control) studies reporting hemogram, leukogram, and thrombogram levels of individuals with and without periodontitis.2.Interventional studies (randomized controlled trials [RCTs] and controlled clinical trials [CCTs]) reporting on changes in hemogram, leukogram, or thrombogram levels after periodontal treatment in patients with periodontitis.3.Only studies including a clear periodontitis case definition.4.Only studies with clear reporting of hematologic levels (hemogram, leukogram, and thrombogram).5.Studies including only patients with periodontitis but no other comorbidities. Interventional studies may be included to address PI(E)CO 1 if they provide data comparing patients with and without periodontitis. Only interventional studies were included to address PI(E)CO 2. Detailed search strategies were conducted in the databases PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science until June 2020. The following search syntax was used: (periodontitis OR gingivitis OR periodontal health OR (periodontal diseases [MeSH])) AND (Hematologic Tests [MeSH] OR Blood Cell Count OR Erythrocyte Count OR Leukocyte Count OR Platelet Count OR Blood Coagulation Tests OR International Normalized Ratio OR Partial Thromboplastin Time OR Thrombelastography OR Prothrombin Time OR Thrombin Time OR Whole Blood Coagulation Time OR Blood Grouping and Crossmatching OR Blood Sedimentation OR Bone Marrow Examination OR Erythrocyte Aggregation OR Erythrocyte Indices OR Fibrin Clot Lysis Time OR FIGLU Test OR Hematocrit OR Hemoglobinometry OR Osmotic Fragility OR Platelet Function Tests OR Bleeding Time OR Clot Retraction OR Mean Platelet Volume OR Platelet Count OR Schilling Test OR ferritin). No restrictions on year of publication or language were applied. Gray literature was searched through appropriate databases and registers. Four periodontology journals were hand-searched (Journal of Clinical Periodontology, Journal of Periodontology, Periodontology 2000, and Journal of Periodontal Research) to identify any additional articles. Authors were contacted when necessary to provide additional data and/or clarification on their reports. Study selection was assessed independently by two investigators (JB and VM), who performed the assessment of titles and/or abstracts of retrieved studies. Interexaminer reliability after full-text assessment was computed (κ statistics), and any disagreements were resolved by discussion with a third author (SBH). Electronic data extraction included patients and study characteristics, first author's name, study design, publication year, country, inclusion and exclusion criteria, periodontitis case definition, mean age, number of participants, gender, smoking habits, and hematologic values. All data were independently extracted by two reviewers (VM and JB). With respect to consistency, the values are expressed in the following units: WBC, neutrophil, lymphocyte, monocyte, eosinophil, and platelet counts as 109/L; neutrophil, lymphocyte, hematocrit, and red cell distribution widths (RDWs) as percentages; red blood cell (RBC) count as 109/μL; mean corpuscular volume (MCV) and mean platelet volume (MPV) as fL; hemoglobin and mean corpuscular hemoglobin concentration (MCHC) as g/dL; mean corpuscular hemoglobin (MCH) as pg; ESR as mm/h; serum iron as μg/dL; ferritin as ng/mL. With respect to exposure, we found multiple case definitions for periodontitis. A lack of consistency in the case definitions hampered the assessment and interpretation of data. Studies were subgrouped according to a confident or nonconfident case definition of periodontitis based on previously reported criteria [24Muñoz Aguilera E Suvan J Buti J et al.Periodontitis is associated with hypertension: a systematic review and meta-analysis.Cardiovasc Res. 2020; 116: 28-39Crossref PubMed Scopus (98) Google Scholar], and established periodontitis case definitions (European Federation of Periodontology and/or American Academy of Periodontology) and other case definitions. Confident case definitions of periodontitis were as follows: generalized chronic periodontitis (at least 30% sites with clinical attachment loss [CAL] ≥4 mm) [25Armitage G Development of a classification system for periodontal diseases and conditions.Ann Periodontol. 1999; 4: 1-6Crossref PubMed Scopus (3439) Google Scholar]; at least two sites on different teeth with a CAL of 6 mm and at least one site with a probing pocket depth (PPD) of 4 mm (CDC/AAP periodontitis definition) [26Eke 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: 1449-1454Crossref PubMed Scopus (645) Google Scholar]; interdental CAL detectable at two or more nonadjacent teeth, or buccal or oral CAL ≥3 mm with pocketing >3 mm detectable at two or more teeth [27Tonetti MS Greenwell H Kornman KS Staging and grading of periodontitis: FRAMEWORK and proposal of a new classification and case definition.J Periodontol. 2018; 45: S149-S161Crossref Scopus (405) Google Scholar]; at least five sites with CAL ≥6 mm. For nonconfident case definitions, the following reported criteria were considered: community periodontal index of treatment need (CPITN) score 3/4 in at least one quadrant; "alveolar bone loss" without other measurements of PPD/CAL; unclear diagnostic criteria for periodontitis. The Newcastle–Ottawa (NOS) Scale for case–control and cohort studies was used by one calibrated reviewer appraising evidence from case–control and cross-sectional studies (SBH). For calibration purposes, a random sample of 10 studies were assessed and re-assessed 2 days later (agreement = 0.96). Studies with seven to nine stars were deemed to be of low risk of bias (RoB), studies with five or six stars were of moderate RoB, and studies with fewer than five stars were of high RoB. Any dispute was resolved by discussion with a second author (JB). For interventional studies, the ROBINS-I tool (Risk of Bias in Non-randomized studies—interventions) [28Sterne JA Hernán MA Reeves BC et al.ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.BMJ. 2016; 355: 4-10Google Scholar]. Continuous data were expressed as means and standard deviations (SD) and analyzed with standard mean difference (MD) and 95% confidence interval (CI). The units of measurements were standardized and converted appropriately as mentioned earlier. If median and interquartile range were reported in the selected studies, the mean and SD were calculated using a previously reported formula [29Hozo SP Djulbegovic B Hozo I Estimating the mean and variance from the median, range, and the size of a sample.BMC Med Res Methodol. 2005; 5: 1-10Crossref PubMed Scopus (14) Google Scholar]. In the present analysis, reported data were pooled irrespective of the individual case definition. Subgroup meta-analysis estimates were pooled using the DerSimonian–Laird random-effects strategy [30Schwarzer G Carpenter JR Rücker G Meta-analysis with R. Springer, 2015Crossref Google Scholar]. We used R Version 3.4.1 to calculate estimates through the DerSimonian–Laird random-effects model [30Schwarzer G Carpenter JR Rücker G Meta-analysis with R. Springer, 2015Crossref Google Scholar], as previously described [31Schwarzer G Meta: an R Package for meta-analysis.R News. 2007; 7: 40-45Google Scholar]. All random-effects meta-analyses and forest plots were performed using the meta package [31Schwarzer G Meta: an R Package for meta-analysis.R News. 2007; 7: 40-45Google Scholar]. We used the I2 index and Cochrane's Q statistic to inspect statistical heterogeneity (p < 0.1), and the χ2 test to calculate overall homogeneity [22Higgins JPT Green S Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011Google Scholar]. All tests were two-tailed, with α set at 0.05. Further, forest plots provided the weight percentage given to each study. For meta-analysis including ≥10 studies, we analyzed publication bias [22Higgins JPT Green S Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011Google Scholar]. Overall estimates were reported with 95% CIs. We have conducted the first sensitivity analysis to explore the influence of using an MD approach (which allows clinical interpretation of data) versus employing a ratio of means (RoM) approach (permits direct interpretation as a percentage difference between cases and controls and attenuates eventual heterogeneity within the estimates) [32Friedrich JO Adhikari NKJ Beyene J The ratio of means method as an alternative to mean differences for analyzing continuous outcome variables in meta-analysis: a simulation study.BMC Med Res Methodol. 2008; 8: 32Crossref PubMed Scopus (171) Google Scholar, 33Friedrich JO Adhikari NKJ Beyene J Ratio of geometric means to analyze continuous outcomes in meta-analysis: comparison to mean differences and ratio of arithmetic means using empiric data and simulation.Stat Med. 2012; 31: 1857-1886Crossref PubMed Scopus (26) Google Scholar, 34Higgins J White I Anzures-Cabrera J Meta-analysis of skewed data: combining results reported on log-transformed or rawscales.Stat Med. 2008; 28: 6072-6092Crossref Scopus (257) Google Scholar, 35Friedrich JO Adhikari NKJ Beyene J Ratio of means for analyzing continuous outcomes in meta-analysis performed as well as mean difference methods.J Clin Epidemiol. 2011; 64: 556-564Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar]. Then, a priori sensitivity analyses were defined when studies with moderate and high RoB were examined in the pooled estimates, and meta-regression was performed toward the influence of smokers present in the sample (through the ratio of smokers with periodontitis/without periodontitis) and the sex ratio (men-to-women ratio). Further, studies separating nonsevere from severe periodontitis cases were used to compare blood levels and, hence, to infer the influence of severity. We employed the Strength of Recommendation Taxonomy (SORT) to appraise the strength and quality of the evidence [36Newman MG Weyant R Hujoel P JEBDP improves grading system and adopts Strength of Recommendation Taxonomy grading (SORT) for Guidelines and systematic reviews.J Evid Based Dent Pract. 2007; 7: 147-150Crossref PubMed Scopus (33) Google Scholar]. The search strategy retrieved 6,107 possibly relevant publications. After removal of duplicates, 3,197 manuscripts were examined and 2,860 were excluded after review of titles and/or abstracts. Of the 158 remaining articles assessed for full text search/eligibility, another 114 articles were excluded (Appendix S2, see Supplementary Data). A total of 37 case–control studies and eight intervention trials were included for qualitative and quantitative synthesis (Figure 1). Good interexaminer reliability at the full-text screening was recorded (κ = 0.915, 95% CI: 0.929–0.943). The systematic review identified 37 case–control studies [14Chakraborty S Tewari S Sharma RK Narula SC Effect of non-surgical periodontal therapy on serum ferritin levels: an interventional study.J Periodontol. 2014; 85: 688-696Crossref PubMed Scopus (18) Google Scholar, 15Latha S Thirugnanamsambandan S Arun R Masthan KMK Malathi L Rajesh E Serum ferritin level and red blood cell parameters in healthy controls and chronic periodontitis patients.J Pharm Bioallied Sci. 2015; 7: S184-S189PubMed Google Scholar, 16Guo LN Yang YZ Feng YZ Serum and salivary ferritin and hepcidin levels in patients with chronic periodontitis and type 2 diabetes mellitus.BMC Oral Health. 2018; 18: 1-9Crossref PubMed Scopus (18) Google Scholar,18Nibali L Darbar U Rakmanee T Donos N Anemia of inflammation associated with periodontitis: analysis of two clinical studies.J Periodontol. 2019; 90: 1252-1259Crossref PubMed Scopus (13) Google Scholar, 19Temelli B Yetkin Ay Z Aksoy F et al.Platelet indices (mean platelet volume and platelet distribution width) have correlations with periodontal inflamed surface area in coronary artery disease patients: a pilot study.J Periodontol. 2018; 89: 1203-1212Crossref PubMed Scopus (13) Google Scholar, 20Zhan Y Lu R Meng H Wang X Sun X Hou J The role of platelets in inflammatory immune responses in generalized aggressive periodontitis.J Clin Periodontol. 2017; 44: 150-157Crossref PubMed Scopus (14) Google Scholar, 21Anand PS Sagar DK Mishra S Narang S Kamath KP Anil S Total and differential leukocyte counts in the peripheral blood of patients with generalised aggressive periodontitis.Oral Heal Prev Dent. 2016; 14: 443-450PubMed Google Scholar,37Zhan Y Lu R Meng H Wang X Hou J Platelet activation and platelet–leukocyte interaction in generalized aggressive periodontitis.J Leukoc Biol. 2016; 100: 1155-1166Crossref PubMed Scopus (14) Google Scholar, 38Zimmermann H Hagenfeld D Diercke K et al.Pocket depth and bleeding on probing and their associations with dental, lifestyle, socioeconomic and blood variables: a cross-sectional, multicenter feasibility study of the German National Cohort.BMC Oral Health. 2015; 15: 1-9Crossref PubMed Scopus (31) Google Scholar, 39Sharma A Astekar M Metgud R Soni A Verma M Patel S A study of C-reactive protein, lipid metabolism and peripheral blood to identify a link between periodontitis and cardiovascular disease.Biotech Histochem. 2014; 89: 577-582Crossref PubMed Scopus (9) Google Scholar, 40Kumar BP Khaitan T Ramaswamy P Sreenivasulu P Uday G Velugubantla RG Association of chronic periodontitis with white blood cell and platelet count—a case control study.J Clin Exp Dent. 2014; 6: 214-217Crossref Scopus (18) Google Scholar, 41Pereira LC Nascimento JCR Rêgo JMC et al.Apolipoprotein E, periodontal disease and the risk for atherosclerosis: a review.Arch Oral Biol. 2019; 98: 204-212Crossref PubMed Scopus (10) Google Scholar, 42Anumolu VSH Srikanth A Paidi K Evaluation of the relation between anemia and periodontitis by estimation of blood parameters: a cross-sectional study.J Indian Soc Periodontol. 2016; 20: 265-272PubMed Google Scholar, 43Gani DK Mallineni SK Ambalavanan Ramakrishnan Deepalakshmi Emmadi P Estimation of the levels of C-reactive protein, interleukin-6, total leukocyte count, and differential count in peripheral blood smear of patients with chronic periodontitis in a South Indian population.West Indian Med J. 2012; 61: 826-831PubMed Google Scholar, 44Gaddale R Mudda JA Karthikeyan I Desai SR Shinde H Deshpande P Changes in cellular and molecular components of peripheral blood in patients with generalized aggressive periodontitis.J Investig Clin Dent. 2016; 7: 59-64Crossref PubMed Scopus (10) Google Scholar, 45Anand PS Sagar DK Ashok S Kamath KP Association of aggressive periodontitis with reduced erythrocyte counts and reduced hemoglobin levels.J Periodontal Res. 2014; 49: 719-728Crossref PubMed Scopus (14) Google Scholar, 46Pejčić A Kesić L Pešić Z Mirković D Stojanović M White blood cell count in different stages of chronic periodontitis.Acta Clin Croat. 2011; 50: 159-167PubMed Google Scholar, 47Monteiro AM Jardini MAN Alves S et al.Cardiovascular disease parameters in periodontitis.J Periodontol. 2009; 80: 378-388Crossref PubMed Scopus (80) Google Scholar, 48Papapanagiotou D Nicu EA Bizzarro S et al.Periodontitis is associated with platelet activation.Atherosclerosis. 2009; 202: 605-611Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 49Shi D Meng H Xu L et al.Systemic inflammation markers in patients with aggressive periodontitis: a pilot study.J Periodontol. 2008; 79: 2340-2346Crossref PubMed Scopus (42) Google Scholar, 50Bizzarro S Van Der Veld
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