|DENTAL SCIENCE - ORIGINAL ARTICLE
|Year : 2012 | Volume
| Issue : 6 | Page : 221-225
Evaluative comparison of systemic aspirin therapy effects on gingival bleeding in post non-surgical periodontal therapy individuals
Elanchezhiyan Sundram1, Panishankar Kharaharilal2, Sugumari Ilavarasu3, Renukadevi4, Esther Nalini4, Venilla Karunamoorthy4
1 Department of Periodontia, KSR Inst of Dental Science and Research, Tiruchengode, India
2 Department of Periodontia, SRM Dental College, Kattankolatoor, India
3 Department of Periodontia, JKK Natarajah Dental College, Komarapalayam, Tamil Nadu, India
4 JKK Natarajah Dental College, Komarapalayam, Tamil Nadu, India
|Date of Submission||01-Dec-2011|
|Date of Decision||02-Jan-2012|
|Date of Acceptance||26-Jan-2012|
|Date of Web Publication||28-Aug-2012|
Department of Periodontia, KSR Inst of Dental Science and Research, Tiruchengode
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Gingival bleeding is considered as an important clinical sign for diagnosis of periodontal disease pathogenesis. Immune inflammatory reactions caused by local factors are considered as essential reasons for gingival bleeding, as also for the systemic bleeding disorders. In disease-free conditions of gingiva, the bleeding disorders are considered to be the main contender for bleeding. Other than these variables, many systemic drugs including systemic aspirin could also cause gingival bleeding. The main aim of the study was to evaluate the effect of buffered aspirin therapy on gingival bleeding. Materials and Methods: Totally, 36 systemically healthy individuals were included in the 15-day randomized, double-blinded, placebo-controlled clinical trial. The 15 days were divided as: control period for the first 7 days and study period for the following 7 days. On the 1 st day, all individuals were given oral prophylaxis after recording gingival parameters such as Plaque Index, probing depth, and Bleeding Index, and then blood samples were collected for hematological investigations. Then, all individuals were administered placebo capsules for 1 week as once daily dose. On the 8 th day, all procedures were repeated and the individuals were prescribed with 325 coated aspirin capsules for 1 week. On the 15 th day, all parameters were repeated and the results were statistically analyzed. Results: In the study period, the parameters such as Bleeding Index, bleeding time, and prothrombin time were increased significantly, compared to the control period. Conclusion: The variables such as systemic drug therapy should be considered for the examination of gingiva while the diagnosis is considered mainly based on gingival bleeding.
Keywords: Altered bleeding, altered platelet function, gingival sulcus bleeding, systemic aspirin
|How to cite this article:|
Sundram E, Kharaharilal P, Ilavarasu S, Renukadevi, Nalini E, Karunamoorthy V. Evaluative comparison of systemic aspirin therapy effects on gingival bleeding in post non-surgical periodontal therapy individuals. J Pharm Bioall Sci 2012;4, Suppl S2:221-5
|How to cite this URL:|
Sundram E, Kharaharilal P, Ilavarasu S, Renukadevi, Nalini E, Karunamoorthy V. Evaluative comparison of systemic aspirin therapy effects on gingival bleeding in post non-surgical periodontal therapy individuals. J Pharm Bioall Sci [serial online] 2012 [cited 2022 Aug 10];4, Suppl S2:221-5. Available from: https://www.jpbsonline.org/text.asp?2012/4/6/221/100210
Gingival sulcus bleeding is considered as an important clinical parameter in periodontal disease diagnosis. Despite numerous diagnostic advancements, gingival bleeding on probing is more sensitive and an early clinical indication of early gingival pathology. Several studies have shown that bleeding on probing is a positive predictor, but conversely lack of bleeding is a very strong negative predictor. Continued absence of bleeding on probing is considered as a strong predictor of continued periodontal health. 
Periodontal disease diagnosis and classification are almost entirely based on traditional clinical parameters like presence/absence of clinical inflammatory signs, probing depth, loss of attachment and bone.  Many studies revealed bleeding on probing as an earlier and more sensitive sign of gingival inflammation and also indicated that gingival bleeding may be associated with a lesion not dominated by inflammatory cells such as plasma cells. So, if active disease is characterized by a plasma cell dominated lesion, and then bleeding may not, in fact is a reliable indicator of disease activity.
It is also possible that bleeding tendency is unrelated to inflammatory cell type, but rather related to other pathologic changes associated with inflammation. Disorders like defective platelet function can also cause bleeding.  Acquired platelet dysfunction which is much more prevalent may induce gingival bleeding. Many drugs induce thrombocytopenia by eliciting an immune response in which the platelet is as innocent bystander. Platelets are damaged by complement activation following the formation of drug antibody complexes, which results in the acquired form of platelet dysfunction. 
Anti-platelet drug therapy is given in management of patients with arterial vascular disease, thromboembolism. Aspirin is the most widely used and studied drug, among the anti-platelet drugs. Aspirin induces inhibition of thromboxane A 2 (TXA 2 ) and prostacyclin and has opposing effects on hemostasis.  The antithrombotic effects of TXA2 inhibition predominate according to Patrono et al. As per Fitzgerald's study, the anti-platelet effects of aspirin are associated with prolonged bleeding time (BT) and inhibition of TXA2-dependent platelet aggregation. 
Since prescribing aspirin has increased many fold nowadays for systemic disorders such as cardiovascular diseases, the anti-thromboxane activity of systemic aspirin therapy should be considered in periodontal clinical examination since aspirin, acting as a non-disease factor, has the potential of altering the cause of bleeding.
| Aims and Objectives|| |
- To determine the causes of bleeding other than local immune inflammatory hyperemic events in healthy gingiva.
- To evaluate the effect of buffered aspirin on clinical parameter of bleeding.
- To evaluate the role of platelets in altering the bleeding mechanism.
| Materials and Methods|| |
Thirty-six male individuals were selected from Tamil Nadu Government Dental College and Hospital, fulfilling the following inclusion as well as exclusion criteria. Females were not considered because of physiological hormonal fluctuations. The inclusion criteria were: 1) individuals above 21 years age, 2) systematically healthy individuals, and 3) mean probing depth ≤3 mm. The exclusion criteria were: 1) contraindication to aspirin intake, 2) presence of compromising medical conditions, 3) use of tobacco in any form, 4) patients under antibiotic coverage, 5) intake of any nonsteroidal anti-inflammatory drugs (NSAIDs) 2 weeks prior to the start of study, 6) periodontitis with probing depth 4 mm and more, and 7) periodontally treated within 1 year other than routine oral prophylaxis. All individuals were informed about the details of the study and the board approved consents were obtained from them. Institutional ethical clearance was obtained before starting the study.
This study was designed as a randomized, double-blinded, placebo-controlled, 15-day clinical trial.
During the screening visit, subjects were assessed for suitability to be included in the study by an oral examination and complete medical and dental history. The selected subjects were taken into the baseline level.
At baseline, all the subjects were involved in complete oral examination and gingival health status along with local factors determination. The individuals were given complete oral hygiene instructions and oral prophylaxis. The samples were collected from them for hematological investigations. The subjects were given placebo capsules, 7 in number for 1 week as once daily. The subjects were recalled on the 8 th day.
The first 7 days were considered as control period. On the 8 th day, all the parameters were recorded again and blood samples were again taken. The individuals were given oral prophylaxis again and motivation in oral hygiene practice. The subjects were given 325 mg enteric coated aspirin capsules, 7 in number for a week as once daily. Both placebo and study capsules were identical in color and size. All the subjects were recalled on the 15 th day.
The second 7 days were considered as the study period. After the study period, on the 15 th day, all the parameters were repeated again and blood samples were again collected.
One calibrated examiner carried out the study and assessed all the outcome variables on all 3 days. The clinical parameters that were recorded in the entire mouth excluding third molars were: i) plaque on all four surfaces of all the teeth using Plaque Index by Sillness and Loe, ii) gingival bleeding using dichotomous yes/no evaluation by Gingival Bleeding Index as six sites per tooth on all teeth, given by Ainamo and Bay,  and iii) probing depth on all teeth as six sites per tooth using Vivacare Pressure sensitive probe.
Blood samples were also collected for the hematological parameters including i) BT with Dukes method where the normal range is 1-5 min, ii) clotting time (CT) with a normal range of 3-11 min, iii) prothrombin time (PT) as the time taken by the prothrombin activator to convert inactive prothrombin into active thrombin, with a normal of 14 (±2) seconds, iv) platelet counts to determine any abnormalities in the platelet amount, with a normal range of 15-40 million per mm 3 .
Both the clinical and hematological parameters were recorded on 1 st , 8 th , and 15 th days of the study. All data collected were analyzed statistically using analysis of variance (ANOVA) test.
The collected data of the study were analyzed statistically. ANOVA was the technique used in the study. ANOVA is used to test equality of means, when more than two populations are considered. The type used in this study was one-way classification. The one-way classification observations are classified according to one factor. This is exhibited column-wise.
Bonferroni test( Multiple range test) with a significance level 0.05 was used in this study.
| Results|| |
With 15 days as the total period of study, 36 male individuals were selected for the trial. The first 7 days were taken as the control period and the following 7 days as the study period. The data were analyzed using ANOVA statistical analysis.
The mean values for all subjected parameters were calculated. The clinical parameters including Bleeding Index, Plaque Index, probing depth mean values were calculated for baseline, control, and study periods. The hematological parameters including BT, CT, PT, and platelet count were analyzed and the mean for each parameter was calculated for baseline, control, and study periods. The mean ± SD for all parameters was calculated, and the P-value and F-value were derived.
The mean ± SD of gingival bleeding, BT, PT, and International Normal Range (INR) were statistically significant in the study period, compared with the control period.
Clinical parameter variables
The mean ± SD of plaque at baseline was 0.98 ± 0.32, while it was 0.41 ± 0.07 at the control period and 0.32 ± 0.05 at the study period. It shows that the mean ± SD of plaque was not significant statistically (P-NS).
The mean ± SD of probing depth at baseline was 2.94 ± 0.25, while it was 2.44 ± 0.15 at the control period and 2.38 ± 0.15 at the study period, which denotes that the probing depth was statistically not significant (P-NS).
The mean ± SD of gingival bleeding at baseline was 0.86 ± 0.16, while it was 0.42 ± 0.05 at the control period and 0.76 ± 0.0.07 at the study period. It denotes that the significantly high in study period while comparing control period (P = 000).
Hematological variables' outcome
The BT mean ± SD was 148.00 ± 13.86 at baseline, while it was 153.33 ± 15.08 at the control period and 241.33 ± 10.77 at the study period, denoting high statistical significance in the study period compared to the control period (P = 0.000).
The CT mean ± SD was 169.00 ± 6.60 at baseline, while it was 163.00 ± 7.02 at the control period and 173.33 ± 6.73 at the study period, denoting minimal statistical significance (P-NS).
The mean ± SD of platelet count at baseline was 2.12 ± 0.39, while it was 2.23 ± 0.36 at the control period and 2.29 ± 0.35 at the study period, which denotes the insignificant valueof platelet count (P-NS).
The mean ± SD of PT was 17.93 ± 2.19 at baseline, while it was 17.77 ± 2.06 at the control period and 33.05 ± 3.80 at the study period, denoting the highly statistically significant PT in the study compared to the control period (P = 0.000).
The INR mean ± SD at baseline was 1.24 ± 0.19, while it was 1.24 ± 0.19 at the control period and 2.70 ± 0.40 at the study period, denoting the higher significance of INR in the study compared to the control period (P = 0.000).
On comparing all the variables of baseline, control, and study periods, the gingival bleeding, BT, PT, and INR mean ± SD values were statistically higher in the study period, compared with the control period values, with significance at 5% level (P=0.000).
The other variables showed insignificant variations on comparing the study and control periods.
| Discussion|| |
Presence of gingival bleeding regardless of probing depth is globally accepted as an early objective sign of periodontal tissue disease. This rationale is supported by immune inflammatory changes in periodontal disease progression,  which states that bacterial plaque and calculus elicit an inflammatory immune response which ultimately liberates cytokines that in turn mediate hyperemic events.
Other than hyperemic events, variables such as defective platelet function can also result in bleeding as per Schrodi et al. Platelet dysfunction can either be congenital or acquired. Congenital platelet dysfunctions like Von Willebrand's disease are rare, while conditions like uremia and myeloproliferative disorders, drugs such as cytotoxic chemotherapeutic agents, NSAIDs, chloroquine, chlorothiazide, gold salts, excessive alcohol intake, and thiazide diuretics induce acquired platelet dysfunction which is more prevalent.  NSAIDs, the most commonly used anti-inflammatory drugs, could be the more important cause for defective platelet function. Most of the NSAIDs acting through inhibition of cyclooxygenase route result in altering the bleeding response.
Among the NSAIDs, aspirin is the most effective anti-inflammatory agent and the most commonly used too. It is widely used as an anti-platelet drug therapy for cerebrovascular disease, arteriovascular disease, and thromboembolism.  Increasing prevalence of lifestyle diseases and conditions such as coronary artery bypass graft operation, heart attack, stroke, arterial fibrillation, and acute coronary syndrome cause an increase in the number of anti-platelet therapy users and decrease in the mean age of these diseases definitely shifts the concern on aspirin since it is the widely used anti-platelet therapy drug.
The minimal anti-inflammatory dose of aspirin is 325 mg/day, while 86 mg/day is for given for anti-platelet action. Though use of aspirin in children is limited as it causes Reye's syndrome, cardiovascular diseases in children attract low dose of 75 mg aspirin daily. The minimal anti-inflammatory dose of aspirin is well enough to alter the platelet functions,  hence it was used in this trial. The irreversible inhibition of prostaglandins by aspirin was the prime consideration of the trial.
Many studies demonstrated that the usage of NSAIDs reduced the gingival inflammation.  Inhibition of platelet cyclooxygenase activity by NSAIDs is associated with variable effects on prostaglandin synthesis in the gastric mucosa and the kidney. Aspirin acetylates platelet cyclooxygenase and permanently inhibits TXA2 production in a dose-dependent manner, when a single dose of 0.1-0.2 mg/kg given for selective sparing of extra platelet cyclooxygenase activity by low-dose aspirin will result in increased antithrombotic efficacy. 
The action mechanism of aspirin is primarily by interfering with the biosynthesis of cyclic prostanoids, i.e. TXA2, PGI2, and other prostaglandins. Prostaglandins G and H are generated by the enzyme prostaglandin H (PGH) synthase, though its cyclooxygenase and peroxidase activities are derived respectively from the arachidonic acid.  Several studies revealed that aspirin exerts its primary anti-thrombotic effects through the inhibition of PGH synthase/COX by irreversible acetylation of a specific serine moiety.  Smith et al. predicted that COX 1 is completely inactivated by aspirin,  whereas COX 2 converts arachidonic acid into 15-R-HETE instead of PGH 2 . The COX 1 inhibition of aspirin is more potent than COX 2 inhibition  (N ~ 180).
The platelet production of TXA 2 in response for the amplification of platelet aggregation revealed by Wu et al.  Vascular endothelial cell production of PGs results in inhibition of platelet aggregation and induces vasodilatation. The vascular endothelial cells are able to regenerate new COX, and thus recover normal function, whereas COX inhibition in platelets is irreversible.  Aspirin induces inhibition of TXA2 and PGI2 and has opposing effects on hemostasis. A single dose of 100 mg aspirin effectively inhibits the production of TXA2 in normal individuals. As per Fitzgerald, the anti-platelet effect of aspirin is associated with prolonged BT and inhibition of TXA2-dependent platelet aggregation.
The aspirin intake affects hemostasis. It doubles the BT when taken for a week. Because its action is irreversible, its effects on platelets last for up to 8 days, i.e. until new platelets are formed. With optimal analgesic dose, aspirin inhibits the platelet aggregation second to the inhibition of thromboxane synthesis, which prolongs the BT. 
The results of the 15-day study trial with 36 patients showed a significant increase of bleeding-associated parameters. Thus, gingival bleeding was shown to be higher in the study period and all parameters associated with bleeding were higher. The mean gingival bleeding was statistically significant in the study period (0.76) compared with the control period (0.42). It denotes that the 1-week aspirin therapy increases the bleeding episode [Table 1].
|Table 1: Mean, standard deviation, and test of significance of mean values of baseline, control and study periods|
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A single dose of 80 mg aspirin causes slight prolongation in the BT. It almost doubles the normal BT on 1-week aspirin intake of 325 mg/day. In fact, the mean BT of 4′0″ for the study period supports that notion, while the control period mean was 2′33″ [Table 1] and [Table 2].
|Table 2: Correlation coefficients of baseline, control, and study periods|
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The CT not show much variation in this study [Table 1] and [Table 2] since aspirin is not an inhibitor of renal PGs, and at least 20% of platelets are functionally normal as the daily turnover rate is ~10% for platelets. Hence, aspirin intake does not affect the amount of the platelets, and the platelet count did not vary much in this study.
The aspirin intake affects prothrombin. The conversion of prothrombin into thrombin is affected by aspirin ingestion. Hence, aspirin intake for a week causes a twofold increase in PT. This was significantly increased in the study period (33.05 sec) compared with the control period (17.77 sec) [Table 1] and [Table 2].
The effect of aspirin on individuals depends on their tolerance to aspirin and other factors like their body weight and rate of metabolism. Long-term aspirin therapy may alter the platelet function. It exerts anti-platelet, anti-thrombotic effect by inhibiting prostaglandin synthesis. These effects cause alteration in bleeding. Long-term aspirin intake in healthy individuals, who are without any bleeding problems, may produce increased bleeding tendency without any specific cause. The significant increase of gingival bleeding in this study trial in healthy periodontium shows the effects of systemic short-term aspirin therapy.
This increase of bleeding on probing following aspirin ingestion would definitely challenge the notion that bleeding is essentially a sign of inflammation. This would also support the notion that gingival bleeding may be related to the proper functioning of platelets. Alteration in the sensitivity and specificity of bleeding on probing by aspirin is important to consider. The causes for altering the platelet function and other bleeding cascade mechanisms should be considered when the outcome of effects is measured by gingival bleeding tendency. The outcome of the present study supports the hypothesis that proper functioning of the platelets is an important factor to be considered in gingival bleeding specificity and sensitivity and its implication in diagnostic and treatment procedures.
| Conclusion|| |
The outcome of the study indicates a significant relationship between aspirin intake and bleeding on probing. This would support the notion that bleeding may be related to platelet functioning. Proper platelet function could be considered as an important factor for bleeding on probing. Bleeding is always critical to evaluate and the altered platelet function should be considered in systemically diseased individuals.
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[Table 1], [Table 2]
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