Transcript Hemophilia: The Royal Disease

Hemophilia:
The Royal Disease
Natalia A Palacio
April 2006
Definition
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Hemophilia- “love of bleeding”
2 types: A and B
Hemophilia A: X linked recessive
hereditary disorder that is due to
defective or deficient factor VIII
History
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First references are mentioned in Jewish texts in second century
AD by Rabbi Ben Gamaliel who correctly deduced that sons of
mother- that he did not know at that time- was an hemophilic
carrier bled to death after circumcision. Hence he made a ruling
that excepted newborn Jewish boys of this ritual if two previous
brothers had had bleeding problems with it.
Then Rabbi and physician Maimonides in the XII century noted
that the mothers were the carriers, hence the second ruling that
if she married twice the newborns from the second marriage
were also excepted.
In 1800 John Otto a physician in Philadelphia wrote a
description of the disease where he clearly appreciated the
cardinal features: an inherited tendency of males to bleed
In 1928 the word Hemophilia was defined.
Incidence
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It is the second most common inherited
clotting factor abnormality (after von
Willebrand disease)
1 in 5000-10000 live male births
No difference between racial groups
Pathophysiology
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Sequential activation of
a series of proenzymes
or inactive precursor
proteins (zymogens) to
active enzymes,
resulting in significant
stepwise response
amplification.
Two pathways: intrinsic
and extrinsic measured
by two lab tests
Pathophysiology
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F VIII is a cofactor for
intrinsic Xa
FvW is its carrier
Activated by Xa and
thrombin
Inactivated by activated
protein C in conjunction
with protein S
Genetics
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Transmitted by females, suffered by males
The female carrier transmits the disorder to half their
sons and the carrier state to half her dtrs
The affected male does not transmit the disease to his
sons (Y is nl) but all his dtrs are all carriers
(transmission of defected X)
Genetics
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Hemophilia in females
If a carrier female mates with an
affected male there’s the possibility that
half their daughters are homozygous for
the disease
 Other possibility: Turner syndrome
(45,X0) with a defective X
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Genetics
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Factor VIII gene
Xq28
 One of the largest genes known-186k
base pairs
 26 exons
 Its large size predisposes it to mutations
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Genetics
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In Hemophilia A there is no uniform
abnormality. There are deletions, insertions,
and mutations
200 genes studied-7 dif mutations
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4->transposition of a single base-3 lead to stop
codon, 1 changed an aa
3->deletions
Aprox 40% of severe hemophilia A is caused
by a major inversion in the gene- the
breakpoint is situated within intron 22
Genetics
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In 1/3 of hemophiliac patients, there is
no family history of bleeding. This is
consistent with the Haldane hypothesis
that predicted that maintenance of a
consistent frequency of a genetic
disorder in the population would require
that aprox 1/3 cases are spontaneous
mutations
Clinical manifestations
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Frequency and severity of bleeding are related to F VIII levels
Severity
F VIII activity
Clinical manifestations
Severe
<1%
Spontaneous hemorrhage from early
infancy
Freq sp hemarthrosis
Moderate
2-5%
Hemorrhage sec to trauma or surgery
Occ sp hemarthrosis
Mild
>5%
Hemorrhage sec to trauma or surgery
Rare sp bleeding
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Coinheritance of prothrombotic mutations (i.e. Factor V Leiden)
can decrease the risk of bleeding
Clinical Manifestations:
Hemarthrosis
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The most common, painful and most physically,
economically and psychologically debilitating
manifestation.
Clinically:
Aura: tingling warm sensation
Excruciating pain
Generally affects one joint at the time
Most commonly: knee; but there are others as
elbows, wrists and ankles.
Edema, erythema, warmth and LOM
If treated early it can subside in 6 to 8 hs and
disappear in 12 to 24 hs.
Ddx: DJD
Complications: Chronic involvement with joint
deformity complicated by muscle atrophy and
soft tissue contractures
Clinical Manifestations:
Hemarthrosis
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Pathophysiology:
Bleeding probably starts from synovial vessels into
the synovial space.
Reabsorption of this blood is often incomplete leading
to chronic proliferative synovitis, where the synovium
is more thickened and vascular, creating a “target
joint” with recurrence of bleeding.
There is destruction of surrounding structures as
well-bone necrosis and cyst formations, osteophytes
Terminal stage: Chronic Hemophiliac arthropathy:
fibrous or bony ankilosing of the joint.
Clinical Manifestations:
Hemarthrosis
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There is a radiological classification for the stages
Stage
Findings
0
Normal joint
I
No skeletal abnormalities, soft-tissue swelling present
II
Osteoporosis and overgrowth of epiphysis, no cysts, no narrowing of
cartilage space
III
Early subchondral bone cysts,preservation of cartilage space but with
irregularities
IV
Findings of stage III, but more advanced; cartilage space narrowed
V
Fibrous joint contracture, loss of joint cartilage space, extensive
enlargement of the epiphysis and substantial disorganization of
joint
Clinical Manifestations
Hemarthrosis-Images
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Stage III- early
subchondral cyst
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Stage IV- narrowing of
intraarticular space
Clinical Manifestations
Hematomas
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Subcutaneous and muscular
hematomas spread within fascial
spaces, dissecting deeper structures
Subcutaneous bleeding spreads in
characteristic manner- in the site of
origin the tissue is indurated
purplish black and when it extends
the origin starts to fade
May compress vital structures: such
as the airway if it is bleeding into
the tongue throat or neck; it can
compromise arteries causing
gangrene and ischemic contractures
are common sequelae, especially of
calves and forearms
Muscle hematomas:
1)calf,2)thigh,3)buttocks,4)forearms
Psoas hematoma- if right sided may
mimic acute appendicitis
Retroperitoneal hematoma: can
dissect through the diaphragm into
the chest compromising the airway.
It can also compromise the renal
function if it compresses the ureter
Clinical manifestations
Pseudotumors
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A pseudotumor is deforming
the cortex of the femur (arrow).
Other ossified masses in the
soft tissues (arrowheads) are
probably soft-tissue
pseudotumors.
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Dangerous and rare
complication
Blood filled cysts that are
gradually expanding
Occur in soft tissues or
bones.
Most commonly in the thigh
As they increase in size they
erode contiguous structures.
May require radical surgeries
or amputation, and surgery
is often complicated with
infection
Clinical manifestations
Intracranial hemorrhage
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Leading cause of death of
hemophiliacs
Spontaneous or following
trauma
May be subdural, epidural or
intracerebral
Suspect always in hemophilic
patient that presents with
unusual headache
If suspected- FIRST TREAT,
then pursue diagnostic
workup
LP only when fVIII has been
replaced to more than 50%
Clinical manifestations
Others
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Gastrointestinal Bleeding:
PUD is 5 times more common in hemophiliac
patients than regular males. Associated with
ingestions of NSAIDs for hemarthrosis. Frequent
cause of UGIB
Mucous Bleeding:
Epistaxis, gum bleeding.
Genitourinary Bleeding:
Frequently severe hemophiliac can experience
hematuria and a structural lesion should be ruled out.
Laboratory diagnosis
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Nomenclature:
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FVIII protein that is lacking or aberrant
FVIIIc functional FVIII measured by clotting assays
FVIIIag Antigenic protein that can be detected with
immunoassays
Deficit can be quantitative or qualitative
General Lab: prolonged aPTT, nl PT and BT
Mixing studies: aPTT corrects with normal plasma –if there are
no factor VIII antibodies present
Clotting assays: F VIII activity, expressed in % of normal
DecreasedQUANTITATIVE
Immunoassays: “Cross Reactive Material” Positive- there is an
antigen similar to the F VIII protein- QUALITATIVE
Differential Diagnosis
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Clinically impossible to differentiate from Hemophilia
B- FIX def- Christmas’ disease
Type 2N vWD, transmitted as an autosomal recessive
trait, is characterized by mutations in VWF within the
factor VIII binding domain. Affected patients present
with low levels of factor VIII (usually 5 to 15 percent
of normal), because of unimpeded proteolytic
cleavage of factor VIII, along with a clinical pattern
of bleeding similar to that seen in hemophilia A,
rather than that associated with classical vWD
Should be suspected in families in which an
autosomal recessive (rather than X-linked)
inheritance pattern is seen.
Carrier detection and
Antenatal diagnosis
 Family history: if we follow the inheritance
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pattern a female is a carrier if she:
Has an hemophilic father
Has two hemophilic sons
Has one hemophilic son and has a family
history
Has a son but no family history, there is a
67% chance that she is.
Carrier detection and
Antenatal diagnosis
 Coagulation based assays:
 Generally heterozygous females have <50% f VIII
levels but if normal it can’t be excluded
 vWF is usually normal or elevated in female carriers, so
F VIII:FvW ratio is low which adds sensitivity to these
tests
 DNA based assays:
 Southern blot can detect the inversion in intron 22
 If negative for that, there is the need for DNA
sequencing
 For prenatal diagnosis: DNA testing on choronic villi
samples obtained by biopsy at week 12
Treatment
General Considerations
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Hemophilia centers should be available for every
patient
Several medical specialists may be a part of the
patient's care team:
A hematologist
Hemophilia nurses and social workers
An orthopedic surgeon
A blood laboratory specialist
A family physician or internal medicine specialist
A dentist
A physical medicine and rehabilitation (PMR)
therapist
Avoidance of aspirin and NSAIDs if at all
possible sometimes it is difficult because of the
painful hemarthrosis
No IM injections
Counseling for patient and family, both genetic
and psychosocial, encouraging normal
socialization
Treatment
Factor replacement
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Replacement of F VIII is the cardinal step to prevent
or reverse acute bleeding episodes
Dosing: Replacement products can be given on the
basis of body weight or plasma volume ( aprox 5% of
body weight)
1 U/ml = 100% factor activity
Practically 1 unit of F VIII/kg increases F VIII
about 0.02 U/ml
In a severe hemophiliac, to raise F VIII to 100%
activity or 1 U/ml, we need 50 U/kg
Redosing is based on half life: 8-12 hs
Monitoring of Factor activity is crucial during therapy
Treatment
Factor replacement
Choice of treatment: is based on
 Purity of the factor (how concentrated
or “purified” the factor is)
 Safety
 Cost
 Nowadays most used therapies are
believed to be effective and relatively
safe
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Treatment
Factor replacement
Sources of F VIII
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Plasma
FFP was used as the only replacement therapy until
1960s.
Not really much effective since it could only raise f
VIII to 20%, by giving the patient many liters
Usually patients experienced severe volume overload
(luckily furosemide was introduced around this time)
Patients used to have to spend most of their time in
the hospital
Treatment
Factor replacement
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Cryoprecipitate
By mid 1960s Pool et al demonstrated that cold
insoluble material obtained from plasma contained
high levels of F VIII and fibrinogen, achieving a
major advance in hemophilia treatment
1 unit of FFP prepared by cryoprecipitate contains
50-120 U of VIII
Plasma Derived f VIII prepared by monoclonal
antibodies.
Treatment
Factor replacement
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Before 1985 all plasma derived products were
highly contaminated by blood borne virus
such as HIV, HBV and HCV which is now
incredibly reduced by the introduction of
donor screening and viral inactivation
techniques such as pasteurization, solvent
detergent treatment and ultrafiltration.
However, there is still some theoretical
concern about non lipid coated parvovirus,
HAV and prion disease such as CreutzfeldJakob
Treatment
Factor replacement
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Recombinant F VIII
First generation: derived from hamster cell culture.
Contains human albumin for stabilization (possible
source of viral contamination)
Second Generation: Mutated F VIII, lacking B domain
(no role in clotting) that can be stabilized by
sucrose “albumin free”
Porcine F VIII
Useful for hemophiliacs with F VIII inhibitors
It is antigenic, property that limits its use to one
treatment course
Treatment
Factor replacement
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Target level and duration of treatment: depend of
severity and site of bleeding
Site of hemorrhage
Desired F VIII
level
Duration of treatment
(days)
Hemarthrosis
30-50
1-2
Superficial intramuscular hematoma
30-50
1-2
GI tract
50
7-10
Epistaxis
30-50
Until resolved
Oral Mucosa
30-50
Until resolved
Hematuria
30-100
Until resolved
CNS
50-100
At least 7-10 days
Retropharyngeal
50-100
At least 7-10 days
Retroperitoneal
50-100
At least 7-10 days
Treatment
Others
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Fibrin Glue
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Antifibrinolyitic Agents
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Contains fibrinogen, thrombin and factor XIII
It’s placed in the site of injury and stabilizes clot
Used in dental procedures and after circumcision
Epsilon aminocaproic acid
Inhibit fibrinolysis by inhibiting plasminogen activator
Adjuvant therapy for dental procedures
Contraindicated in hematuria
Desmopressin
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Transient increase in F VIII levels in pts with mild hemophilia(2-4 times
above baseline)
Mechanism: release from endothelial storage sites
Has spared many hemophiliacs of blood borne products in the 1970s
Repeated administration results in a diminished response- tachyphylaxis
Side effects: hyponatremia, facial flushing and headache
Treatment
Gene Therapy
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Hemophilia is an ideal disease to target for gene
therapy since it is caused by mutations in a single
identified gene.
A slight increase in factor activity can make a severe
hemophilic in mild.
Tight regulation of gene expression is not essential.
Many animal models trials have been studied, being
the main problems encountered: immunogenicity and
short gene expression.
To date 3 hemophilia A trials in human (aprox 20
patients): transient increase of factor VIII activity and
good safety profile.
Main issue remains: finding of a gene delivery system
which is nonimmunogenic so as to allow for long
term expression.
Course and prognosis
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When FVIII concentrate emerged in 1960s,
the morbidity and mortality from bleeding in
hemophilia decreased
Unfortunately, between 1978-1985 the AIDS
crisis hit the hemophiliac community
AIDS still remain the leading cause of death
in older hemophiliacs
Patients treated after 1985 should expect to
have virtually normal life spans free of the
complications of HIV and hepatitis
Course and prognosis
Replacement therapy has its
complications and includes:
 Development of F VIII antibodies
 Liver disease resulting from hepatitis B
and C
 Infection with HIV
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Course and prognosis
Development of Antibodies
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Specific inhibitor antibodies that neutralize FVIII activity
Most frequently in severe affected patients- affecting 25%
Predisposing factors: severe disease, type of genetic mutation
(inversion, nonsense mutation, deletions), family history of
inhibitors development
Alloantibody-IgG4- against C2 domain of F VIII protein which
interacts with other cascade cofactors (phospholipids)
Seen aprox 9-11 days post factor VIII exposure
Diagnosis: mixing study does not correct aPTT.
Bethesda assay: which consists of serial dilutions of plasma is
pooled with normal plasma and incubated for 2 hs, then the
activity level is measured by coagulation assays. The higher
inhibitor titer, the greater the dilution required to demonstrate
residual FVIII activity. It is expressed on Bethesda Units: High
responders: >5 Bethesda units, low responders <5.
Course and prognosis
Development of Antibodies
 Treatment: of active bleeding and inhibitor ablation
via immune tolerance induction.
• High purity FVIII: treatment of life threatening hemorrhages
in pts that are low responders
• Porcine FVIII: high responders with high inhibitors levels
that have life threatening hemorrhages
• Prothrombin complex concentrates and activated
prothrombin complex concentrates: bypassing agents for
thrombosis (prothrombin, fVII, fIX, f X and Prot S and C).
Carries high risk of thrombosis and it is difficult to monitor.
• rFVIIa: Effective response in 90% of patients. Gets activated
by tissue factor, so thrombosis response is more modulated
than that of APCCs, however there are no studies comparing
them both
Course and prognosis
Development of Antibodies
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Immunotolerance Induction: process by
which a pt is made tolerant to FVIII by
repeated daily exposure
Aprox 70% success rate
Eligible pts: severe hemophiliacs with F
VIII inhibitors<12 months with a peak
of no more than 200 BU/ml.
The sooner initiated, the better
Course and prognosis
Hepatitis and HIV
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Almost all multitransfused patients before 1985 were
affected with one or more agents of chronic hepatitis
Around 50% can be expected to develop chronic
hepatitis that may lead to cirrhosis
Hepatic injury is worse with coinfection with HIV –
there is a five to sixfold increase in end stage liver
disease which is not uncommon.
Currently about 80% of older severe hemophiliacs
are HIV positive
As of 1985, rigid donor testing and availability of
recombinant products has greatly diminished viral
transmission.
Treatment
Prophylaxis
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Prophylactic treatment should be considered in all
patients with severe hemophilia
In 1997 was recommended by the Medical and
Scientific Advisory Council of the National Hemophilia
Foundation.
Candidate should be reliable to manage a central
venous catheter device
Administration is three times a week to make a
severe hemophiliac a moderate phenotype
There is significant improvement in the clinical
condition and quality of life.
So…
WHY IS IT CALLED
THE ROYAL DISEASE?!!?
History
Why the Royal disease?
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This is because Queen Victoria, Queen of England from 1837 to
1901, was a carrier.
Most likely a spontaneous mutation since the duke of Kent (her
father) was not affected and her mother did not have any
affected children from the previous marriage.
Her eighth child, Leopold, had hemophilia and suffered from
frequent hemorrhages. These were reported in the British
Medical Journal in 1868.
Leopold died of a brain hemorrhage at the age of 31, but not
before he had children. His daughter, Alice, was a carrier and
her son, Viscount Trematon, also died of a brain hemorrhage in
1928.
The British family descends from Victoria’s first child Edward
who was not affected. Hence this house is disease free.
History
Why the Royal disease?
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Beatrice, Victoria’s youngest child had two
hemophilic sons and a daughter- Victoria
Eugene that was a carrier
She introduced the hemophilia gene into the
Spanish royal family by marrying king Alfonso
XIII.
By this time, Queen Victoria’s blood was
recognized as “defective” and the king may
have been warned about Eugene’s carrier
state. However, Royalty was more important
than X chromosomes.
History
Why the Royal disease?
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Alexandra, Queen Victoria's granddaughter, married
Nicholas, the Tsar of Russia in the early 1900's.
Alexandra, the Tsarina, was a carrier of hemophilia
and her first son, the Tsarevich Alexei, was an
hemophiliac
The monk Rasputin gained great influence in the
Russian court, partly because he was the only one
able to help the young Tsarevich. He used hypnosis
to relieve Alexei's pain.
It is speculated that the illness of the heir to the
throne, the strain it placed on the Royal family, and
the influence of the corrupt and alcoholic monk
Rasputin were all factors leading to the Russian
Revolution of 1917.
History
Queen Victoria’s pedigree
Russian House
Spanish House
British House
But wait…..
Which Hemophilia was it
A or B????
EITHER!
References
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National heart lung blood institute www.nhlbi.nih.gov
www.uptodate.com
Goldman: Cecil textbook of medicine,22nd edition, 1070-1074.
Kessler. New Perspectives in Hemophilia Treatment. Hematology 2005;
429-435
Manucci et al. The hemophilias-from royal genes to gene therapy.
NEJM; 2001; 344(23)
Rick M, Walsh C. Congenital bleeding disorders. Hematology 2003;
559-574
Hoffman: Hematology basic principles and practice, 4th edition. 20172026.
National Hemophilia Foundation www.hemophilia.org
Benter E, Coller B et al. Williams Hematology, 6th edition. 1639-1652.
2001
Greer et al. Wintrobe’s Clinical Hematology, 11th edition.2003
THANK YOU!