Download Bleeding Disorders, They`re Back

BLEEDING DISORDERS: THEY’RE
BACK
Recognition and Management of Patients with
Hemophilia/von Willebrand Disease and Platelet
Disorders
Rebecca Schaffer, DDS
Assistant Professor, Special Needs Care Unit
Associate Administrative Director, AEGD
Arizona School of Dentistry & Oral Health
Mesa, Arizona
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http://www.youtube.com/watch?v=_HgTRoesu8M
EARLY HISTORY
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References to excessive and unexplained
bleeding have been made since antiquity.
In the Talmud, a collection of Jewish
Rabbinical writings from the 2nd century AD, it
was written that male babies did not have to be
circumcised if two brothers had already died
from the procedure.
In the 12th century AD, an Arabian physician
from Cordoba named Albucasis wrote of males
in a particular village, who had died of
uncontrollable bleeding.
Occasional references to bleeding can be found
in the scientific literature of following
centuries
A ROYAL DISEASE
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Queen Victoria of England (18371901) was a carrier of the hemophilia
gene
She passed the disease on to the
Spanish, German and Russian royal
families…
And the disease changed the course
of world history….
THE FAMILY OF NICHOLAS AND ALEXANDRA
NICHOLAS AND ALEXANDRA
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Alexandra, Queen Victoria's granddaughter, married
Nicholas, the Tsar of Russia in the early 20th
century.
Alexandra was a carrier of the disease and her first
son Alexei, was born with hemophilia.
Nicholas and Alexandra were pre-occupied by the
health problems of their son at a time when Russia
was in turmoil.
The monk Rasputin gained great influence in the
Russian court, partly because he was the only one
able to help the young Tsarevich Alexei.
The illness of the heir to the Tsar's throne, the
strain it placed on the Royal family, and the power
wielded by the mad monk Rasputin were all factors
leading to the Russian Revolution of 1917.
GRIGORY YEFIMOVICH “RASPUTIN”
(1872-1916)
• Born in 1872 in Siberia to a peasant family
• At a young age he earned himself a reputation for
devoted debauchery
• His actual name of Grigory Yefimovich Novykh was
replaced with the surname 'Rasputin' - Russian for
'debauched one'
• Infamous 'holy man'
• ability to “heal” the Tsar and Tsarina's son Alexis led to
his being adopted as a supreme mystic at court.
• influence to the point where he effectively dictated policy
he was eventually assassinated by a group of court
conspirators in December 1916.
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The
WHAT IS HEMOPHILIA
X linked genetic defect causing a deficiency of
coagulation factor VIII in Hemophilia A and
factor IX in Hemophilia B
 Women are carriers, but can be symptomatic
 Males are usually affected, since they have only
one copy of the X chromosome
 The median age at diagnosis is 36 months for
people with mild hemophilia, 8 months for
moderate and 1 month for severe hemophilia.
 Pre-natal genetic testing is available

INCIDENCE AND PREVALENCE
It is evenly distributed among various races and
ethnicities
 Has an estimated frequency of approximately one
in 10,000 births
 The number of people in the US currently living
with hemophilia is approximately 20,000
 Worldwide, the number is 400,000
 That number is expected to rise, as current
treatments are extending life expectancy
 HIV and Hepatitis C are no longer a threat to
this population

FACTOR VIII AND HEMOPHILIA A
Acts as an essential cofactor for factor IX in the
intrinsic coagulation cascade
 Deficiency of factor VIII, or impaired function,
result in clinical disease Hemophilia A.
 Characterized by spontaneous bleeding into
joints and muscles
 Severe bleeding from trauma

GENE DEFECTS IN HEMOPHILIA A
 Hemophilia
A is more common, representing 8085% of total cases
 Cloned between 1982 and 1984
 Positioned the F8 gene in the most distal band
of the long arm of the X chromosome
 Single most clinically important defect is an
inversion
 Accounts for 50% of severe cases worldwide
 Insertions/deletions
 Single DNA base substitutions
 Novel mutations are added to the data base at
an undiminished pace
HISTORY

19th Century until 1960:
whole blood transfusions were standard of care
 Patients were disabled before they reached 20 years
of age
 Median life expectancy 39.7 years
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1961-1970
Clotting factors therapies isolated from plasma
(cryoprecipitate)
 Life expectancy rose to 53.8 years
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Mid 1970s
Freeze dried concentrates
 Federal legislation to establish and fund HTCs
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HISTORY
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1980’s
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gene for FVIII cloned
Led to production of recombinant factor VIII
Derived from the pooled blood products of up to
20,000 donors
Screening for Hepatitis and other diseases was in its
infancy
People with hemophilia had a 60% infectivity rate of
HBV and HCV
This was considered acceptable risk
HEMOPHILIA AND HIV/AIDS
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“The consistent improvement in
quality of life, quality of care, and
longevity for patients with
hemophilia seen in the years 1960 to
1980 halted unequivocally when
human immunodeficiency virus
(HIV) appeared in the blood supply
in the 1980s.”
Evatt, B: Infectious Disease in the Blood Supply and the Public Health
Response: Semin Hematol 43 (suppl3):S4-S9, 2006
HEMOPHILIA AND HIV/AIDS
By 1987, according to CDC analysis, 63% of the
15,500 patients with hemophilia in the U.S. had
been infected with HIV
 Many of these same people were co-infected with
HBV and HCV.
 As a result of these infections, the life expectancy
of patients with hemophilia plummeted from a
high of 60.5 to a low of 39.8 years
 From 1979-1998, 71% of the deaths of patients
with hemophilia A were attributed to HIV.
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HEMOPHILIA AND HCV
HCV infection a consequence of tainted factor
concentrates in the 1970s and 80s.
 80% of HCV infections are chronic
 Leads to liver failure and hepatocellular
carcinoma
 A significant number of patients with bleeding
disorders are co-infected with HIV and HCV
 All patients with bleeding disorders who received
blood products before 1992 should be tested for
HCV antibody
 Patients who are antibody positive should
undergo RNA PCR testing
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HEMOPHILIA AND HCV
HCV treatment guidelines are similar for people
with and without bleeding disorders
 Infusion with vWF, FVIII, FIX to control bleeding
caused by hemophilia will not control bleeding
caused by liver failure.
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THE PERFECT STORM
Hemophilia, HIV, HCV
 Patients coinfected w/ HIV and HCV are at
greater risk for, and progress more rapidly to
cirrhosis.
 These patients can be treated successfully, but
with teamwork and co-ordinated care.
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ASSESSING LIVER DISEASE
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Liver transient elastography (fibroscanning)
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Non invasive alternative to liver biopsy
APRI score
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Aspartate aminotransferase (AST) to platelet ratio
index
Can be done chairside if labs are available:
AST/ULN ( upper limit of normal/per lab)
Divide result by platelet count(109/L) x 100
Example: AST=63, ULN=42, PLTS=137,000
63/42=1.5
1.5/137 = 0.109x100=1.09
0.5-associated w/no significant fibrosis
1.5 or higher-significant fibrosis
HEMOPHILIA CLASSIFICATION
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Hemophilia A
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Hemophilia B (Christmas Disease)
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between 6% and 49% of normal values
25% of hemophilia population
Moderate:
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Factor IX deficiency
Normal Values are 50-150% of the laboratory control
Mild Hemophilia:
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Factor VIII deficiency
1%-5% of normal values
Approximately 15% of the hemophilia population
Severe:
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<1% of normal clotting factor
60% of hemophilia population
CLASSIFICATION
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Mild Hemophilia
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Bleeding problems may present only after serious
injury, trauma or surgery, especially dental surgery
Moderate Hemophilia
Bleeding episodes after injuries
 Spontaneous bleeds into joints and muscles
 Usually diagnosed in infancy
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Severe Hemophilia
Most common
 Diagnosed in infancy
 Spontaneous bleeds into joints and muscles,
including TMJ.
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CURRENT TREATMENT PROTOCOLS
Viral inactivated plasma derived or recombinant
concentrates
 There is a risk of prion mediated disease through
plasma derived products (Creutzfeldt-Jakob
disease)
 In the absence of an inhibitor, each unit of
FVIII/kg body weight will raise the plasma FVII
level approximately 2 IU dL-1
 Continuous infusion via pump
 Prophylactic infusions
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DENTAL CARE AND MANAGEMENT
Good oral hygiene is essential
 Regular dental exams, starting when baby teeth start
to erupt
 Oral hygiene regimen is no different from people
without bleeding disorders
 Orthodontic assessment between ages of 10-14.
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Especially indicated in people with bleeding disorders to
lower risk of periodontal disease
Communication with hematologist and hemophilia
team is essential
 Dentists are key members of a well organized
medical home for people with bleeding disorders
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DENTAL CARE AND MANAGEMENT
Treatment can be safely carried out under local
anesthesia as long as the patient is properly
infused
 Always communicate planned treatment to HTC
 Use local hemostatic measures: fibrin glue,
oxidized cellulose
 Have tranexamic acid on hand if treating people
with bleeding disorders
 Aspirin and NSAIDs must be avoided
 Use a rubber dam
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DENTAL MANAGEMENT
Following extraction, avoid hot food and drinks
 Same post op instructions as other patients
 Report bleeding problems to HTC immediately
 Oral antibiotics should only be prescribed if
clinically necessary
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ORAL HEMORRHAGE
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Most common causes
Dental extraction
 Trauma
 Gingival bleeding due to poor oral hygiene
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Local Treatments
Direct pressure using damp gauze sponge
 Sutures
 Application of local hemostatic agents
 Tranexamic acid mouthwash
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Call HTC
AMINOCAPROIC ACID
It comes in tablet and liquid form
 Tablets are either 500mg or 1000mg
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Adult dose is 50/60mg/kg q4-6h
 Max dose 24g/day
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Syrup/solution: 1.25g/5mL
 Can cause gastric upset
 Liquid has a terrible taste
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TRANEXAMIC ACID
TRANEXAMIC ACID
synthetic derivative of the amino acid lysine
 exerts its antifibrinolytic effect through the
competitive inhibition of the activation of
plasminogen to plasmin
 significantly reduces mean blood losses after oral
surgery in patients with hemophilia
 effective as a mouthwash in dental patients
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A 500mg tablet can be crushed and dispersed in
10mL of water immediately prior to administration
 Also available as a syrup for pediatric use
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Often prescribed for seven days post op following
dental extractions
 Longer half life than AMICAR
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TRANEXAMIC ACID
Oral tablet (15-25mg/kg tid x 3-5d)
 Intravenously: .5-1g/kg body weight bid
or tid, may be used pre-op and for 2 to 8
days following surgery
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JOINT BLEEDS (HEMARTHROSIS)
Characterized by rapid loss of range of motion
 Associated with:
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Pain
 Unusual sensation
 Swelling and warmth of skin over joint
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A target joint: a joint in which 3 or more
spontaneous bleeds have occurred within a six
month period
 TMJ
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MUSCLE BLEEDS
Can occur in any muscle of the body
 Usually from a direct blow or sudden stretch
 More commonly associated with large muscle
groups
 Symptoms:
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Aching in the muscle
 Tension and tenderness upon palpation and possible
swelling
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COMPLICATIONS
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Musculoskeletal
Most common sites of bleeding are the joints and
muscles of the extremities
 Without adequate treatment will lead to progressive
deterioration of the joints and muscles
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Synovitis
Following acute hemarthrosis, synovium becomes
inflamed, hyperemic and friable
 Results in repeated hemarthroses
 With repeated bleeding, synovium becomes
chronically inflamed and hypertrophied (chronic
synovitis) (TMJ?)
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COMPLICATIONS
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Chronic hemophilic arthropathy
Caused by the effects of blood on articular cartilage
and reinforced by persistent chronic synovitis
 A progressive arthritic condition develops
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Pseudotumors
Unique to hemophilia
 Occurs as a result of indquequately treated soft
tissue bleeds
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INHIBITORS
IgG antibodies that neutralize clotting factors
 Currently the most severe treatment-related
complication
 Should be suspected in any patient who fails to
respond clinically to clotting factors
 More common in severe hemophilia
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The lifetime risk of development is 20-30% in severe
hemophilia A
 5-10% in mild to moderate disease
 Much less common in Hemophilia B
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Prevention of bleeding at the time of dental
procdures in patients with inhibitors to FVIII or
FIX requires careful planning
HEMOPHILIA AND AGING
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Comorbidities
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Osteoporosis
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A dental evaluation is a necessity before starting a patient
with hemophilia on bisphosphonates
Obesity
 Increased arthropathic pain
 Diabetes
 Hypertension
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Hemophilia patients are twice as likely to have
hypertension
 Due to increased risk of bleeding, a blood pressure of less
than 140/90 should be maintained
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Cardiovascular Disease
 Psychosocial impact
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ANTIBIOTIC PROPHYLAXIS:
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Not indicated for ports or shunts
Many people with bleeding disorders have them
 History of intracranial bleeds
 Ports for infusions
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Joint replacement for people with hemophilia
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Newest guidelines site hemophilia as a risk factor for
joint infection
FACTOR VIII
VON WILLEBRAND FACTOR
WHAT IS VON WILLEBRAND DISEASE
First described by Erik Von Willebrand in 1926
 The most common hereditary bleeding disorder
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Affects 1-2% of the population
 Affects males and females equally
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Results from inherited defects in the structure,
function and/or concentration of von Willebrand
factor
 There are several different types of vWD,
responding to different treatment modalities
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James, et al, 2011
VON WILLEBRAND DISEASE
 Most
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common manifestations
Easy bruising
Prolonged, recurrent epistaxis
Menorrhagia
Excessive Mucocutaneous bleeding
without recognized trauma
 Spontaneous/excessive
oral cavity
bleeding
 Bleeding with oropharyngeal
surgery
ORAL MANIFESTATIONS
 Spontaneous,
unexplained bleeding
of gingiva, mucosal surfaces
 Prolonged
bleeding after invasive
procedures
May be the First Recognizable
Symptoms of vWD
WHAT IS VON WILLEBRAND
FACTOR?
 VWF
is a large adhesive glycoprotein
 Synthesized at two sites: endothelial
cells and megakaryocytes
 Stored in endothelium and platelet
alpha granules
 Composed of variable multimers
 vWF gene is located on the short
arm of chromosome 12
FACTOR VIII AND VWF
 vWF
stabilizes FVIII
 Inhibits factor vIII binding to
phospholipids
 Increases the half life of FVIII
 Ratio of vWF to FVIII is maintained at
50:1
 An increase or decrease in plama vWF
level results in a corresponding change in
the level of FVIII
THE FUNCTIONS OF VWF
 Primary
Hemostasis
Mediates platelet adhesion to injured blood vessel
sites.
 Promotes platelet aggregation at sites of vessel injury
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 Secondary
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Hemostasis
Stabilization of coagulation factor VIII in the
circulation
Protects circulating factor VIII from inactivation or
degradation
 Increases half-life of FVIII from <1hour to 8-12 hours
 When bound to VWF, factor VIII may localize to cells
and/or sites where it can participate in coagulation
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BINDING TO PLATELETS
 VWF
interacts with platelets to mediate
 platelet aggregation
 platelet localization to sites of
vascular injury
 Interacts with a receptor complex on the
surface of platelets (GPIb)
 Binding site uncovered after injury
Kroonen, et al, 2008
CLASSIFICATION OF VON WILLEBRAND DISEASE
Type
Molecular
Characteristics
Inheritance
Frequency
1
Partial Quantitative VWF
deficiency
Autosomal dominant, 1-30: 1,000 most
incomplete
common VWD
penetrance
variant(>70% of VWD
2A
Qualitative defect,
decreased VWF-dependent
platelet adhesion
Usually autosomal
dominant
10-15% of clincially
significant VWD
2B
Qualitative defect,
abnormal affinity for
platelet GPIb
Autosomal dominant
<5% of clinical VWD
2M
Qualitative defect,
decreased VWF-platelet
interaction
Autosomal dominant
Rare
2N
Qualitative defect;
decreased VWF-factor VIII
binding capacity
Autosomal recessive
Uncommon;
heterozygotes may be
prevalent in some
populations
3
Severe quantitative
reduction or absence of
VWF
Autosomal recessive
(or codominant)
1-5:1,000,000
RECOGNIZING VON WILLEBRAND
DISEASE-THE ROLE OF THE DENTIST
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Health history questionnaire should include the
following:
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Have you ever had prolonged bleeding after a tooth
extraction or dental work?
Do you bleed longer than five minutes from an
ordinary cut or bruise?
Do you have frequent nose bleeds?
Do you bruise easily?
Do your gums bleed a lot or for no reason?
Does anyone in your family bruise easily, or have a
bleeding disorder?
Women:
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Do your menstrual periods last longer than 7 days
with very heavy bleeding?
DIAGNOSTIC TESTS
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PTT/APTT
Factor VIII:C - this measures the factor VIII clotting
activity in the blood
VWF antigen - this measures the actual level of VWF in the
blood
VWF activity (ristocetin cofactor activity) - this tests how
well the VWF is working, and whether it functions normally
VWF multimers - this measures the structure of the VWF
molecules in the blood
Platelet function tests - to measure how well the platelets in
the blood are working
Bleeding time test - this test measures how long it takes for
a small cut to the skin to stop bleeding.
Some of these tests may need to be repeated, as levels of
clotting factor can fluctuate, especially in cases of mild
VWD when levels may be close to the normal range.
National Heart, Lung and Blood
DENTAL MANAGEMENT OF VWD
 Thorough
health history
 Communicate with patient’s hematologist
before procedures
 Be familiar with type, usual treatment
protocols for patients
 Minimize stress to patient
 Minimize invasive procedures per
appointment (unless patient needs FVIII)
DENTAL MANAGEMENT OF VWD
 DO
NOT prescribe aspirin, NSAIDS or
NSAID containing product
 Use sutures to obtain primary closure
 Degranulate areas of chronic
inflammation
 Use local, topical coagulants (gel foam,
tranexamic acid rinse, etc)
 Encourage good oral hygiene, including
brushing, flossing and use of daily
mouthwash
IDP
Individualized dental plan
 Think of it as a treatment plan “on steroids” that
considers the lifetime needs of your patient
 Develop it as a team with patient, family, other
healthcare providers
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DESMOPRESSIN (DDAVP)
1-desamino-8-D-arginine vasopressin
 Synthetic vasopressin analog
 Increases endogenous vWF and FVIII
 Useful in mild hemophilia A, certain types of
VWD
 Can be administered
 Intravenously
 Plasma vWF:FVIII levels are increased 2-4
times above baseline within 30 minutes and
last 6-8 hours
 Subcutaneously
 Intranasally-less predictable
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VON WILLEBRAND FACTOR
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Many factors are known to modify VWF levels
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ABO blood group
Secretor blood group
Estrogens
Thyroid hormone
Age
Stress
Pregnancy
Infection
Illness
High potential for false positive and negative
misdiagnoses, especially in mild cases
HEMOSTATIC MANAGEMENT
TYPE
1
DDAVP (desmopresin acetate)
Administered intravenously, subcutaneously, intranasal
spray
2A
DDAVP, Factor VIII replacement
2B
Factor VIII replacement
2M
DDAVP, Factor VIII replacement
2N
Factor VIII replacement
3
Factor VIII replacement
HEMOSTATIC MANAGEMENT OF
INTRAORAL BLEEDING
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Planned invasive procedures
DDAVP
 FVIII/vWF concentrate
 Amicar
 Tranexamic Acid
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Chronic Gingival Bleeding
Tranexamic Acid Rinse
 FVIII/vWF concentrate
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Trauma
Tranexamic Acid Rinse
 Compression using oxidized cellulose
 FVIII/vWF concentrate (higher doses)

ADJUVANT TREATMENTS
Similar to Hemophilia treatment
 Tranexamic acid

Oral rinse
 Oral tablet
 Intravenously:
 Ε-aminocaproic acid (Amicar)

Topical thrombin or Fibrin sealant
 Pre formed pressure splints
 Gelfoam (Pfizer)

ORAL HYGIENE AND VON WILLEBRAND
DISEASE
Regular brushing, flossing and dietary choices
correlate with decreased spontaneous gingival
bleeding
 Non surgical periodontal therapies (SRP) can be
administered to patients with vWD in consult
with hematologist
 Expect pocket depth reduction and stabilization
of disease similar to people without bleeding
disorder

SURVEY RESULTS
Conducted at National Conference for People and
Families with Von Willebrand Disease
 81% of respondents said their dentist was
unaware of von Willebrand Disease, and did not
contact hematologist prior to treatment
 20% reported that they were refused care
 43% had serious bleeding episode after a dental
visit
 70% had problems with chronic bleeding gums

Schaffer, R: unpublished data, 2011
TAKE HOME MESSAGE
Oral health care providers should recognize and
screen for VWD
 Refer to appropriate provider for further
evaluation
 Don’t be afraid to treat these patients.
 Modify treatment plans according to individual
genotype, phenotype
 Stress good oral hygiene, diet
 Communication with the patient’s hematologist
is essential when caring for these patients.

VON WILLEBRAND AND HEMOPHILIA
Von Willebrand
Hemophilia
Autosomal inheritance
X-linked
Affects both genders equally
Affects males only, women are
carriers
Can be diagnosed at any time
during life cycle
Usually diagnosed at birth
Mucocutaneous bleeds are
common, especially epistaxis,
oral bleeds
Joint bleeds are common
Menorrhagia, miscarriages
Women not affected
DENTAL MANAGEMENT
Oropharyngeal, soft tissue, or minor bleeding
should be treated with intravenous or nasal
DDAVP
 If elevation of VWF is necessary and response to
DDAVP is inadequate, VWF concentrate should be
used
 For persons with mild to moderate VWD,
antifibrinolytics combined with DDAVP are
generally effective for oral surgery. Topical agents,
such as fibrin sealant or bovine thrombin, are
useful adjuncts for oral surgery.
 Do Not prescribe Aspirin, NSAIDS, or NSAID
containing products to people with vWD

VWF
BLEEDING SITES AND FREQUENCY
Mucosal Bleeding
REFERENCES
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Federici, AB, James, P: Current Management of Patients with Severe von Willebrand Disease Type 3: A
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Gupta, A, Epstein, J, Cabay R: Bleeding Disorders of Importance in Dental Care and Related Patient
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