Periodontitis Risk In Venous Acute Trombotic Events

Venous thrombosis is a disease with an incidence of about 0.1% in Europe and
carrying substantial morbidity and increased mortality (1). Venous thrombosis
is multi factorial etiology (2). However, in about 50% percent of the cases no
cause can be identified (3). Recently, focus has been shifted towards known
cardiovascular risk factors as potential risk factors for venous thrombosis,
including body mass index, diabetes mellitus and microalbumiuria (4, 5).
Periodontal disease is a common infectious disease of the oral cavity including
gingivitis and periodontitis. Pathogenic oral bacteria in the biofilm or dental
plaque play a major role in the development of periodontal disease. Gingivitis,
the mildest form of periodontal disease, is highly prevalent and readily
reversible by simple, effective oral hygiene promoting measures. Inflammation
that extends deep into the tissues and causes loss of supporting connective
tissue and alveolar bone is known as periodontitis. Periodontitis results in
the formation of soft tissue pockets or deepened crevices between the gum and
tooth root. Severe periodontitis can result in loosening of teeth, occasional
pain and discomfort, impaired mastication, and eventual tooth loss (6). A large
study estimated that about 22% of US adults had mild disease and 13% had
moderate or severe disease (7).
Both inflammation and infection have been associated with an increased risk of
cardiovascular disease and venous thrombosis (8-11). Furthermore, it is known
that inflammation and coagulation share common pathways (12). Recently,
periodontitis has been identified as a risk factor for cardiovascular disease
(13). The relative risk of cardiovascular disease associated with periodontitis
has been estimated between 1.6 and 2.2. The biologic model of the plausibility
of periodontitis as a risk factor for cardiovascular disease holds that
periodontitis poses an inflammatory burden through the production of local
inflammatory mediators entering the circulation. This inflammatory burden is
amongst others evidenced by increased serum C-reactive protein (CRP) levels
associated with periodontitis (14, 15). Periodontitis may also pose an
infectious burden, through bacteria and their products, which enter the
systemic circulation. Circulating oral bacteria and lipopolysacharides are also
able to stimulate hepatocytes to secrete CRP (16-18), adding again to an
increased inflammatory state. This increased inflammatory state caused by
periodontitis has been associated with increased risk of atherosclerosis and
cardiovascular diseases (19-22).
Thus, periodontitis appears to be a risk factor for cardiovascular disease.
Since many of the risk factors for cardiovascular disease have recently been
implicated as potential risk factors for venous thrombosis (4, 5),
periodontitis may also be a risk factor for venous thrombosis.
Currently, there are no data on the relationship between periodontitis and
venous thrombosis. Therefore, the aim of this study was to assess the
prevalence of periodontitis in both patients with and without deep vein
thrombosis, and calculate the relative risk of deep vein thrombosis associated
with periodontitis.

Primary Objective: To assess the relative risk of deep vein thrombosis
associated with periodontal disease.
Secondary Objective(s): To detect the prevalence of periodontal disease in
subjects with and without deep vein thrombosis thrombosis.

Out-patients presenting with complaints of the leg suspected of deep vein
thrombosis at the emergency department, will be evaluated by the primary
investigator, or another physician of the division of Haemostasis and
Thrombosis, according to routine clinical practice. This includes a peripheral
vena puncture for taking blood to determine standard laboratory measures,
including hemoglobine, thrombocytes, leucocytes, liver and kidney function
tests, D-dimers, fibrinogen and C-reactive protein.
After taking history and performing a physical examination, the physician will
inform patients about the study. Patients have 30 minutes to think about
participating in the study. Patients* periodontal status has to be evaluated
before diagnosis is made or laboratory tests become available, to decrease the
possibility of observer bias and the possibility of healthy-user bias (patients
with DVT could be getting more motivation to behave in a more healthy style
compared to controls, and therefore measurement of the periodontal status could
be influenced by this when measuring after more time). Furthermore,
anticoagulant medication prescribed to treat DVT likely increases the tendency
of bleeding on probing of the gingiva when measuring the depths of crevices
between the gum and tooth root. Since bleeding on probing is a parameter used
to indicate periodontitis presence and severity, this could obscure our
results. Thus, we want to perform the assessment when patients are present at
the emergency department, before laboratory tests become available, compression
ultra sound (CUS) will be made and before any therapy is initiated. An
additional advantage of this approach is that no additional visit to the
outpatient clinic is needed, reducing the burden of participating in this
study.
Next, after 30 minutes, patients who have agreed to participate are asked to
sign informed consent. They then will be asked a few questions, according to a
standardized questionnaire assessing their DVT symptoms, previous venous
thrombotic events, known cardiovascular and pro-thrombotic risk factors,
education level, length, weight, concomitant disease, and their dental status
(edentulous). This will take about 5 minutes of time. After that, they will get
the periodontal assessment while waiting for the results of the laboratory
tests and further work-up. One of two trained dental students will examine
patients, to assess the presence of periodontitis. This will also take place at
the emergency department, and will take about 30 minutes.
Consequently, laboratory tests will be available and D-dimer levels are used
together with the clinical decision rule according to Wells (23) by the
physician to calculate the probability of the presence of deep vein thrombosis
(DVT). When DVT can not safely be ruled out by this, CUS will be made,
according to normal clinical routine. Patients, in whom the presence of DVT
safely can be ruled out, are assigned to the control (no DVT) group. In
patients with a high probability of DVT, DVT will be proven or ruled out by
CUS. This allocates patients to the case (DVT) or control (no DVT) group, and
they will receive the appropriate treatment for their disease, according to
routine clinical practice. All can be viewed in the flowchart at the end of
this document (Figure 1.).
Patients will be informed about their periodontal status and are asked whether
they want their own dentist to get informed by means of a letter containing the
results of the periodontal examination. The latter requires patients to
explicitly indicate this on the informed consent letter. Hereafter, the study
participation will end for the patient.
Estimated duration of inclusion is about 6 months.

Participants are asked a few additional questions about their medical history,
periodontal disease and risk factors, venous thrombotic risk factors and
cardiovascular risk factors. Thereafter, they will undergo a oral cavity
examination to assess the presence and extent of periodontitis, which is an
extended version of a part of the normal clinical routine performed by dentists
at (half) yearly check-up. This will be performed by one of two trained dental
students, and will take about 30 minutes. The examination will be performed
before definite diagnosis of the complaints of the leg has been made, during
the time needed to wait for the results of laboratory tests. In this way, we
achieve a blinded condition for both patients and examiners and reduce the
burden of participation because no additional visits at the outpatient clinic
are needed. Patients will benefit of participation by receiving an update of
their periodontal status. Their treating dentist can receive this information
by letter if the patient explicitly approves of this. Finally, they will
receive a token for participating; there are no risks or adverse outcomes
expected by participating in this study.