Gingival Bleeding and Von Willebrand Disease Typ 2 and 3

• Sponsor: Goethe University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03078595
• Collaborator: (none)
• Enrollment: 48
• Locations: 2
• Actual Duration (Months): 20.6
• Patients Per Site: 24
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

Von Willebrand disease (VWD) is the most common inherent bleeding disorder resulting in prolonged bleeding time. Gingival bleeding is a frequently reported symptom of VWD. However, gingival bleeding is also known as a leading symptom of plaque-induced gingivitis and untreated periodontal disease. Gingival bleeding in VWD patients may be triggered by gingival inflammation and not a genuine symptom. Thus, this study evaluates whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm.

Condition or Disease	Intervention/Treatment	Phase
Gingival Bleeding; Von Willebrand Diseases

Detailed Description

Patients

All patients with type 2 and 3 VWD consecutively consulting the Haemophilia Centre, Medical Clinic III/Institute for Transfusion medicine, Hospital of the Johann Wolfgang Goethe-University Frankfurt/Main are asked to participate in this study as cases. They are asked for bleeding and subjective symptoms indicating periodontal disease.

The study complies with the rules of the Declaration of Helsinki and was approved by the Institutional Review Board for Human Studies of the Medical Faculty of the Goethe-University Frankfurt/Main (Application# 143/15). All participating individuals are informed on risks and benefits as well as the procedures of the study and give written informed consent.

Controls

For each case (VWD) a respective hematologically healthy control is recruited from the gingivitis and periodontitis patients of the Department of Periodontology, Centre for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt/Main. Each control is matched to one of the respective cases for sex, age (±5 years), self-reported smoking status (current smoker/non-smoker), number of remaining teeth (±2 teeth), and periodontal diagnosis (gingivitis, chronic or aggressive periodontitis).

All participants are asked about current and past cigarette smoking habits. Patients who report smoking or have quit smoking for less than five years are classified as smokers. Additionally the amount of carbon monoxide (CO) in exhaled air is measured using a device (Bedfont Smokerlyzer; Bedfont Scientific Ltd, Rochester, Great Britain).

Hematologic examinations

20 ml of blood are sampled from an arm vein. The following data are assessed at the Haemophilia Centre for clinical routine during VWD patient care and due to study design in the controls:

• von Willebrand parameters (VWF antigen [VWF:Ag], Ristocetin cofactor [VWF:RCo], coagulation factor VIII [FVIII:C])

• Current medication if any VWF:Ag and VWF:RCo were measured turbidimetrically using a device (BCS, Siemens, Marburg, Germany). FVIII:C was assessed with specific agents on a coagulation analyser (ACL-300®, Instrumentation Laboratory, Kirchheim, Germany).

Periodontal examinations

The following clinical parameters are assessed at 6 sites per tooth (mesiobuccal, buccal, distobuccal, mesiolingual, lingual, distolingual):

• modified Gingival Bleeding Index (GBI)

• modified Plaque Control Record (PCR)

• PPD and recession to the nearest 0.2 mm using an electronic probe (Florida Probe, Version 3.2, Gainesville, USA). Recession is assessed from the cemento-enamel junction (CEJ) to the gingival margin. At sites where the CEJ was destroyed by restorations the restoration margin (RM) is used as reference. At sites where the CEJ or RM is located apically from the gingival margin the value for recession is negative

• Bleeding on probing (BOP) recorded as positive when bleeding occurs within 30 seconds from probing. For each patient a BOP index is calculated providing the amount of sites with positive BOP in % per patient.

Attachment loss (PAL-V) is calculated as sum of PPD and recession.

All individuals are classified into the following diagnoses:

• plaque-induced gingivitis (PPD < 3.6 mm; PAL-V ≤ 2 mm),

• generalized mild, localized moderate chronic periodontitis (PPD ≥ 3.6 mm; vertical probing attachment level [PAL-V] 3 to 4 mm ≤ 30% of sites; 1 to 2 mm > 30% of sites),

• generalized mild, localized severe chronic periodontitis (PPD ≥ 3.6 mm; PAL-V ≥ 5 mm ≤ 30% of sites; 1 to 2 mm > 30% of sites)

• generalised moderate chronic periodontitis (PPD ≥ 3.6 mm; PAL-V 3 to 4 mm > 30%)

• generalised moderate localised severe chronic periodontitis (PPD ≥ 3.6 mm; PAL-V 3 to 4 mm > 30%; ≥ 5 mm ≤ 30%)

In all individuals hematological and periodontal examinations are obtained within 24 hours. After dental and periodontal examination all patients receive oral hygiene instructions and professional tooth cleaning. In cases of untreated periodontal disease periodontal treatment is offered. VWD are asked to report any bleeding complications after periodontal probing and professional tooth cleaning.

Statistical analysis

The individual patient is used as statistical unit. All analyses are performed on patient level. GBI is defined as the main outcome variable and BOP as secondary outcome variable. All other parameters are control variables. Up to now there are no studies comparing GBI or BOP between VWD type 2 and 3 cases and hematologically healthy controls and there are no standard deviations of mean GBI and BOP for cases and controls. To detect a clinically relevant inter-group difference of 4% GBI or BOP with a type 1 error alpha < 0.05 and a test power of 80% with a standard deviation of group means of 5.5% a sample size of at least 31 individuals is required per group. Thus, it was decided to recruit 31 VWD cases and respectively matched 31 controls.

For all individuals, cigarette pack years are calculated. Group frequencies (VWD, control) are expressed for sex, current smoking. Group means and standard deviations are calculated for GBI, BOP, age, number of remaining teeth, pack years, CO, PCR, VWF:Ag, VWF:RCO, FVIII:C. Further, for each individual the following variables are calculated to describe the periodontal status:

• Mean±standard deviation of PPD and PAL-V

• Percentage of PPD < 4 mm, 4 to 6.8 mm, ≥ 7 mm

• Sum of all PPD, i.e. the sum of the PPD measured at all sites within a patient

• Sum of all PPD with BOP, ), i.e. the sum of the PPD measured at all sites exhibiting BOP within a patient

• Periodontal inflamed surface area (PISA). For each patient PPD were entered into an Excel sheet that can be downloaded freely (http://www.parsprototo.info/pisa.html).

From these group means and standard deviations are calculated. Comparisons between groups for dichotomous parameters are made by χ² or Fisher's exact test and for all other parameters by Mann-Whitney-U test. A post-hoc analysis is performed to estimate the test power that would be required to find a clinically relevant inter-group difference (δ) of 5% for GBI and BOP index with a type 1 error (α) of 0.05 for the actual sample size.

Using stepwise linear backward multiple regression analysis, factors shall be identified that influence GBI and BOP. The following independent variables are entered into the model for GBI: group (VWD/control), sex, age, number of remaining teeth, PCR, CO, pack years, PISA. The following independent variables are entered into the model for BOP: group (VWD/control), sex, age, number of remaining teeth, PCR, CO, pack years, PISA. Due to the fact that mean PPD is mathematically coupled to sum of PPD, sum of PPD with BOP, and PISA these 4 variables are not entered into the regression model at the same time. PISA provides the best representation of the subgingival inflamed area. Thus, PISA is chosen for the final model. The following parameters are described by dummy variables: group (control = 0, VWD = 1), sex (male = 0, female = 1), smoking status (never and former smoker = 0, current smoker = 1). All factors with p < 0.1 are kept in the models. For statistical analysis a PC program is used (SystatTM for Windows Version 12, Systat Inc., Evanston, USA).

Study Design

• Study Type: Observational
• Actual Enrollment: 48 participants
• Observational Model: Case-Control
• Time Perspective: Cross-Sectional
• Official Title: Is Gingival Bleeding a Symptom of Patients With Type 2 and 3 Von Willebrand Disease? A Case-Control Study
• Actual Study Start Date: Jul 16, 2015
• Actual Primary Completion Date: Apr 4, 2017
• Actual Study Completion Date: Apr 4, 2017

Arms and Interventions

Arm	Intervention/Treatment
von Willebrand disease type 2 and 3 Examinations (haematologically and periodontally) of von Willebrand disease patients with type 2 and 3 and healthy controls to evaluate whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm
controls For each case (VWD) a respective haematologically healthy control is recruited from the gingivitis and periodontitis patients of the Department of Periodontology, Centre for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt/Main. Each control is matched to one of the respective cases for sex, age (±5 years), self-reported smoking status (current smoker/non-smoker), number of remaining teeth (±2 teeth), and periodontal diagnosis (gingivitis, chronic or aggressive periodontitis).

Outcome Measures

Primary Outcome Measures

1. Bleeding on Probing (BOP) [cross-sectional: only one assessment at the time of examination]

   Using a periodontal probe probing pocket depths (PPD) are assessed with a force of 0.2 N at 6 sites per tooth (mesio-buccal, buccal, disto-buccal, disto-oral, oral, mesio-oral). After 30 seconds bleeding on probing is scored at each site. The frequency of bleeding sites of the total number of assessed sites is calculated as index.

Secondary Outcome Measures

1. Gingival Bleeding Index (GBI) [cross-sectional: only one assessment at the time of examination]

   A periodontal probe is gently moved through the gingival sulcus. Bleeding is assessed at 6 sites per tooth (mesio-buccal, buccal, disto-buccal, disto-oral, oral, mesio-oral). The frequency of bleeding sites of the total number of assessed sites is calculated as index.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria von Willebrand Patients:

• 18 - 80 years old

• no other bleeding disorder except 2 and 3 von Willebrand disease

Inclusion Criteria healthy controls:

• no bleeding disorder

• no anticoagulative medication

Exclusion Criteria von Willebrand Patients:

• requirement of systemic antibiotics for measures that may cause transitory bacteraemia

Exclusion Criteria healthy controls:

• bleeding disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University	Frankfurt am Main	Hessen	Germany	60596
2	Dept. of Periodontology, Center of Dentistry and Oral Medicine, Johann Wolfgang Goethe-University	Frankfurt am Main		Germany	60590

Sponsors and Collaborators

• Goethe University

Investigators

• Study Chair: Peter Eickholz, Prof., Dept. of Perio, Center for Dent. and Oral Med., JWG-University Frankfurt

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 27, 2015

More Information

Publications

None provided.

• Responsible Party: Peter Eickholz, Head of Periodontology, Goethe University
• ClinicalTrials.gov Identifier: NCT03078595
• Other Study ID Numbers: 143/15
• First Posted: Mar 13, 2017
• Last Update Posted: Feb 27, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Peter Eickholz, Head of Periodontology, Goethe University: periodontal disease; plaque-induced gingivitis; bleeding on probing; von willebrand disease; gingival bleeding
• Additional relevant MeSH terms: Gingival Hemorrhage; Von Willebrand Diseases; Hemorrhage

Study Results

Participant Flow

Recruitment Details	At the Haemophilia Centre, Medical Clinic III/Institute for Transfusion Medicine, Hospital of the Johann Wolfgang Goethe-University Frankfurt/Main approximately 1500 charts of VWD patients were screened rendering about 35 patients with VWD type 2 and 3.
Pre-assignment Detail	From July 16, 2015 to July 15, 2016 24 type 2 and 3 VWD cases were enrolled. Due to the difficulty to find more type 2 and 3 VWD patients willing to participate recruitment was stopped in March 2017 after enrolment of 24 individuals. From April 04, 2016 to March 24, 2017 24 patients that self-reported to be hematologically healthy were enrolled.

Arm/Group Title	Von Willebrand Disease Type 2 and 3	Controls
Arm/Group Description	Examinations (haematologically and periodontally) of von Willebrand disease patients with type 2 and 3 and healthy controls to evaluate whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm	For each case (VWD) a respective haematologically healthy control is recruited from the gingivitis and periodontitis patients of the Department of Periodontology, Centre for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt/Main. Each control is matched to one of the respective cases for sex, age (±5 years), self-reported smoking status (current smoker/non-smoker), number of remaining teeth (±2 teeth), and periodontal diagnosis (gingivitis, chronic or aggressive periodontitis).
Period Title: Overall Study
STARTED	24	24
COMPLETED	24	24
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Von Willebrand Disease Type 2 and 3	Controls	Total
Arm/Group Description	Examinations (haematologically and periodontally) of von Willebrand disease patients with type 2 and 3 and healthy controls to evaluate whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm	For each case (VWD) a respective haematologically healthy control is recruited from the gingivitis and periodontitis patients of the Department of Periodontology, Centre for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt/Main. Each control is matched to one of the respective cases for sex, age (±5 years), self-reported smoking status (current smoker/non-smoker), number of remaining teeth (±2 teeth), and periodontal diagnosis (gingivitis, chronic or aggressive periodontitis).	Total of all reporting groups
Overall Participants	24	24	48
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.9 (11.8)	46.6 (12.4)	46.3 (12.0)
Sex: Female, Male (Count of Participants)
Female	17 70.8%	17 70.8%	34 70.8%
Male	7 29.2%	7 29.2%	14 29.2%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Number of teeth (number of teeth) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [number of teeth]	26.7 (2.9)	26.8 (2.2)	26.7 (2.5)
current smokers (participants) [Number]
Number [participants]	7 29.2%	7 29.2%	14 29.2%
exhaled carbon monoxide (CO) (ppm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ppm]	3.9 (4.6)	2.8 (3.4)	3.4 (4.0)
Pack years (1 pack-year is equal to smoking 20 cigarettes (1 pack) per day for 1 year) (pack years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pack years]	3.3 (6.4)	1.6 (2.9)	2.4 (5.0)
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	71.6 (16.1)	68.5 (9.8)	70.0 (13.3)
HbA1C (percent of gycated hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent of gycated hemoglobin]	5.1 (0.6)	5 (0.4)	5.1 (0.5)
Gingivitis (participants) [Number]
Number [participants]	11 45.8%	11 45.8%	22 45.8%
generalized mild, localized moderate chronic periodontitis (participants) [Number]
Number [participants]	5 20.8%	5 20.8%	10 20.8%
generalized mild, localized severe chronic periodontitis (participants) [Number]
Number [participants]	3 12.5%	3 12.5%	6 12.5%
generalized moderate chronic periodontitis (participants) [Number]
Number [participants]	2 8.3%	2 8.3%	4 8.3%
generalized moderate localized severe chronic periodontitis (participants) [Number]
Number [participants]	3 12.5%	3 12.5%	6 12.5%
Von Willebrand antigen (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	44 (45.9)	122.1 (47.2)	83.0 (60.6)
Von Willebrand activity (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	24.7 (23.4)	122.1 (45.1)	73.4 (60.7)
Factor VIII (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	55.6 (46.3)	129.8 (27.5)	92.7 (53.2)
Plaque Control Record (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	53 (24.1)	49.5 (15.9)	51.3 (20.3)
activated matrix metalloproteinase 8 (aMMP8) (participants) [Number]
Number [participants]	8 33.3%	8 33.3%	16 33.3%
Probing Pocket Depth (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	1.8 (0.6)	1.9 (0.5)	1.9 (0.6)
vertical Probing Attachment Level (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	1.9 (0.7)	1.8 (1.9)	1.9 (0.6)
Sum of probing pocket depth (PPD) (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	295 (102.6)	306.7 (87.6)	300.8 (94.5)
Sum of PPD with BOP (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	54.4 (37.8)	49.7 (28.1)	52.1 (33.0)
Periodontal inflamed surface area (mm²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm²]	154.4 (124)	136.1 (95.3)	145.3 (109.8)
PPD < 4 mm (percent of sites) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent of sites]	98.5 (3.8)	98.7 (3.4)	98.6 (3.6)
PPD 4 to 6.8 mm (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	1.5 (3.8)	1.3 (3.4)	1.4 (3.6)

Outcome Measures

1. Primary Outcome

Title	Bleeding on Probing (BOP)
Description	Using a periodontal probe probing pocket depths (PPD) are assessed with a force of 0.2 N at 6 sites per tooth (mesio-buccal, buccal, disto-buccal, disto-oral, oral, mesio-oral). After 30 seconds bleeding on probing is scored at each site. The frequency of bleeding sites of the total number of assessed sites is calculated as index.
Time Frame	cross-sectional: only one assessment at the time of examination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Von Willebrand Disease Type 2 and 3	Controls
Arm/Group Description	Examinations (haematologically and periodontally) of von Willebrand disease patients with type 2 and 3 and healthy controls to evaluate whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm	For each case (VWD) a respective haematologically healthy control is recruited from the gingivitis and periodontitis patients of the Department of Periodontology, Centre for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt/Main. Each control is matched to one of the respective cases for sex, age (±5 years), self-reported smoking status (current smoker/non-smoker), number of remaining teeth (±2 teeth), and periodontal diagnosis (gingivitis, chronic or aggressive periodontitis).
Measure Participants	24	24
Mean (Standard Deviation) [percentage of sites]	14.5 (10.1)	12.3 (5.3)

2. Secondary Outcome

Title	Gingival Bleeding Index (GBI)
Description	A periodontal probe is gently moved through the gingival sulcus. Bleeding is assessed at 6 sites per tooth (mesio-buccal, buccal, disto-buccal, disto-oral, oral, mesio-oral). The frequency of bleeding sites of the total number of assessed sites is calculated as index.
Time Frame	cross-sectional: only one assessment at the time of examination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Von Willebrand Disease Type 2 and 3	Controls
Arm/Group Description	Examinations (haematologically and periodontally) of von Willebrand disease patients with type 2 and 3 and healthy controls to evaluate whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm	For each case (VWD) a respective haematologically healthy control is recruited from the gingivitis and periodontitis patients of the Department of Periodontology, Centre for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt/Main. Each control is matched to one of the respective cases for sex, age (±5 years), self-reported smoking status (current smoker/non-smoker), number of remaining teeth (±2 teeth), and periodontal diagnosis (gingivitis, chronic or aggressive periodontitis).
Measure Participants	24	24
Mean (Standard Deviation) [percentage of sites]	10.5 (9.9)	8.8 (4.8)

Adverse Events

Time Frame	1 week
Arm/Group Title	Von Willebrand Disease Type 2 and 3		Controls
Arm/Group Description	Examinations (haematologically and periodontally) of von Willebrand disease patients with type 2 and 3 and healthy controls to evaluate whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm		For each case (VWD) a respective haematologically healthy control is recruited from the gingivitis and periodontitis patients of the Department of Periodontology, Centre for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt/Main. Each control is matched to one of the respective cases for sex, age (±5 years), self-reported smoking status (current smoker/non-smoker), number of remaining teeth (±2 teeth), and periodontal diagnosis (gingivitis, chronic or aggressive periodontitis).
All Cause Mortality
	Von Willebrand Disease Type 2 and 3		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)
Serious Adverse Events
	Von Willebrand Disease Type 2 and 3		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Von Willebrand Disease Type 2 and 3		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)

Limitations/Caveats

Study is underpowered. A future study may investigate gingival bleeding in VWD and control individuals with more severe periodontal disease. Another interesting question is how hemophilia A and B affect gingival bleeding.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.