Bleeding Disorders, They`re Back
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Transcript 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
http://www.youtube.com/watch?v=_HgTRoesu8M
EARLY HISTORY
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
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
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.
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
1961-1970
Clotting factors therapies isolated from plasma
(cryoprecipitate)
Life expectancy rose to 53.8 years
Mid 1970s
Freeze dried concentrates
Federal legislation to establish and fund HTCs
HISTORY
1980’s
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
“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.
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
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.
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.
ASSESSING LIVER DISEASE
Liver transient elastography (fibroscanning)
Non invasive alternative to liver biopsy
APRI score
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
Hemophilia A
Hemophilia B (Christmas Disease)
between 6% and 49% of normal values
25% of hemophilia population
Moderate:
Factor IX deficiency
Normal Values are 50-150% of the laboratory control
Mild Hemophilia:
Factor VIII deficiency
1%-5% of normal values
Approximately 15% of the hemophilia population
Severe:
<1% of normal clotting factor
60% of hemophilia population
CLASSIFICATION
Mild Hemophilia
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
Severe Hemophilia
Most common
Diagnosed in infancy
Spontaneous bleeds into joints and muscles,
including TMJ.
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
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.
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
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
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
ORAL HEMORRHAGE
Most common causes
Dental extraction
Trauma
Gingival bleeding due to poor oral hygiene
Local Treatments
Direct pressure using damp gauze sponge
Sutures
Application of local hemostatic agents
Tranexamic acid mouthwash
Call HTC
AMINOCAPROIC ACID
It comes in tablet and liquid form
Tablets are either 500mg or 1000mg
Adult dose is 50/60mg/kg q4-6h
Max dose 24g/day
Syrup/solution: 1.25g/5mL
Can cause gastric upset
Liquid has a terrible taste
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
A 500mg tablet can be crushed and dispersed in
10mL of water immediately prior to administration
Also available as a syrup for pediatric use
Often prescribed for seven days post op following
dental extractions
Longer half life than AMICAR
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
JOINT BLEEDS (HEMARTHROSIS)
Characterized by rapid loss of range of motion
Associated with:
Pain
Unusual sensation
Swelling and warmth of skin over joint
A target joint: a joint in which 3 or more
spontaneous bleeds have occurred within a six
month period
TMJ
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:
Aching in the muscle
Tension and tenderness upon palpation and possible
swelling
COMPLICATIONS
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
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?)
COMPLICATIONS
Chronic hemophilic arthropathy
Caused by the effects of blood on articular cartilage
and reinforced by persistent chronic synovitis
A progressive arthritic condition develops
Pseudotumors
Unique to hemophilia
Occurs as a result of indquequately treated soft
tissue bleeds
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
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
Prevention of bleeding at the time of dental
procdures in patients with inhibitors to FVIII or
FIX requires careful planning
HEMOPHILIA AND AGING
Comorbidities
Osteoporosis
A dental evaluation is a necessity before starting a patient
with hemophilia on bisphosphonates
Obesity
Increased arthropathic pain
Diabetes
Hypertension
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
Cardiovascular Disease
Psychosocial impact
ANTIBIOTIC PROPHYLAXIS:
Not indicated for ports or shunts
Many people with bleeding disorders have them
History of intracranial bleeds
Ports for infusions
Joint replacement for people with hemophilia
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
Affects 1-2% of the population
Affects males and females equally
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
James, et al, 2011
VON WILLEBRAND DISEASE
Most
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
Secondary
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
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
Health history questionnaire should include the
following:
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:
Do your menstrual periods last longer than 7 days
with very heavy bleeding?
DIAGNOSTIC TESTS
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
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
VON WILLEBRAND FACTOR
Many factors are known to modify VWF levels
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
Planned invasive procedures
DDAVP
FVIII/vWF concentrate
Amicar
Tranexamic Acid
Chronic Gingival Bleeding
Tranexamic Acid Rinse
FVIII/vWF concentrate
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
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