Hemophilia: The Royal Disease

1
Hemophilia The Royal Disease

• Natalia A Palacio
• April 2006

2
Definition

• 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

3
History

• 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.

4
Incidence

• 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

5
Pathophysiology

• 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

6
Pathophysiology

• 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

7
Genetics

• 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)

8
Genetics

• Hemophilia in females
• If a carrier female mates with an affected male
  theres the possibility that half their daughters
  are homozygous for the disease
• Other possibility Turner syndrome (45,X0) with a
  defective X

9
Genetics

• 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

• In Hemophilia A there is no uniform abnormality.
  There are deletions, insertions, and mutations
• 200 genes studied-7 dif mutations
• 4-gttransposition of a single base-3 lead to stop
  codon, 1 changed an aa
• 3-gtdeletions
• Aprox 40 of severe hemophilia A is caused by a
  major inversion in the gene- the breakpoint is
  situated within intron 22

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Genetics

• 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

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Clinical manifestations

• Frequency and severity of bleeding are related to
  F VIII levels

Severity F VIII activity Clinical manifestations
Severe lt1 Spontaneous hemorrhage from early infancy Freq sp hemarthrosis
Moderate 2-5 Hemorrhage sec to trauma or surgery Occ sp hemarthrosis
Mild gt5 Hemorrhage sec to trauma or surgery Rare sp bleeding

• Coinheritance of prothrombotic mutations (i.e.
  Factor V Leiden) can decrease the risk of
  bleeding

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Clinical ManifestationsHemarthrosis

• 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

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Clinical ManifestationsHemarthrosis

• 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.

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Clinical ManifestationsHemarthrosis

• 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
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Clinical ManifestationsHemarthrosis-Images

• Stage III- early subchondral cyst

• Stage IV- narrowing of intraarticular space

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Clinical ManifestationsHematomas

• 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)fore
  arms
• 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

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Clinical manifestationsPseudotumors

• 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

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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Clinical manifestationsIntracranial hemorrhage

• 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

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Clinical manifestationsOthers

• 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.

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Laboratory diagnosis

• Nomenclature
• 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

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Differential Diagnosis

• 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.

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Carrier detection and Antenatal diagnosis

• Family history if we follow the inheritance
  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.

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Carrier detection and Antenatal diagnosis

• Coagulation based assays
• Generally heterozygous females have lt50 f VIII
  levels? but if normal it cant be excluded
• vWF is usually normal or elevated in female
  carriers, so F VIIIFvW 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

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TreatmentGeneral Considerations

• 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

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TreatmentFactor replacement

• 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

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TreatmentFactor 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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TreatmentFactor replacement

• Sources of F VIII
• 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

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TreatmentFactor replacement

• 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.

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TreatmentFactor replacement

• 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 Creutzfeld-Jakob

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TreatmentFactor replacement

• 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

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TreatmentFactor replacement

• 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
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TreatmentOthers

• Fibrin Glue
• Contains fibrinogen, thrombin and factor XIII
• Its placed in the site of injury and stabilizes
  clot
• Used in dental procedures and after circumcision
• Antifibrinolyitic Agents
• Epsilon aminocaproic acid
• Inhibit fibrinolysis by inhibiting plasminogen
  activator
• Adjuvant therapy for dental procedures
• Contraindicated in hematuria
• Desmopressin
• 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

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TreatmentGene Therapy

• 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.

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Course and prognosis

• 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

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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 prognosisDevelopment of Antibodies

• 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 gt5 Bethesda units, low responders lt5.

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Course and prognosisDevelopment 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

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Course and prognosisDevelopment of Antibodies

• 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
  inhibitorslt12 months with a peak of no more than
  200 BU/ml.
• The sooner initiated, the better

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Course and prognosisHepatitis and HIV

• 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.

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TreatmentProphylaxis

• 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.

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So WHY IS IT CALLEDTHE ROYAL DISEASE?!!?
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HistoryWhy the Royal disease?

• 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 Victorias first
  child Edward who was not affected. Hence this
  house is disease free.

44
HistoryWhy the Royal disease?

• Beatrice, Victorias 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 Victorias blood was
  recognized as defective and the king may have
  been warned about Eugenes carrier state.
  However, Royalty was more important than X
  chromosomes.

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HistoryWhy the Royal disease?

• 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.

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HistoryQueen Victorias pedigree
Russian House
Spanish House
British House
47
But wait..

• Which Hemophilia was it
• A or B????
• EITHER!

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References

• 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. 2017-2026.
• National Hemophilia Foundation www.hemophilia.org
• Benter E, Coller B et al. Williams Hematology,
  6th edition. 1639-1652. 2001
• Greer et al. Wintrobes Clinical Hematology, 11th
  edition.2003

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THANK YOU!