Alice Ma, MD

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Hemophilia Diagnosis and Management
Alice Ma, MD
University of North Carolina at Chapel Hill
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For it was taught if she circumcised her first
child and he died, and a second one also died,
she must not circumcise her third child
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History of Hemophilia

• 2nd century
• Rabbinical rulings exempt boys from circumcision
  if two brothers died from bleeding.
• 11th century
• Reference to bleeding condition in the writings
  of Arabic surgeon, Albucasis.
• 12th century
• The rabbinical ruling exempting boys from
  circumcision because of bleeding is extended to
  half-brothers with the same mother, in
  appreciation of the hereditary nature of the
  condition.
• 1828
• First use of the word hemophilia by Hopff at the
  University of Zurich to describe inherited
  bleeding disorders.
• 1840
• First use of a blood transfusion to control
  bleeding in hemophilia, described by Samuel Lane
  in The Lancet.

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History of Hemophilia

• 1853
• Leopold, son of Queen Victoria, first "Royal" to
  have hemophilia.
• 1904
• Alexis, heir to the Russian throne, is born with
  hemophilia.
• 1936
• First plasma transfusion to treat hemophilia
• 1939
• Kenneth Brinkhous identifies "antihemophilic
  factor", now called factor VIII, as the
  deficiency in people with hemophilia.
• 1944
• Edwin Cohn, an American biochemist, develops
  fractionation, the process of separating plasma
  into its different components.

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History of Hemophilia

• 1948
• First hemophilia dog colony established in Chapel
  Hill, North Carolina.
• 1952
• Researchers describe a new type of hemophilia,
  now known as factor IX deficiency. It is called
  Christmas Disease after the first patient,
  Stephen Christmas, of Toronto.
• 1952
• Thromboplastin test developed to determine if a
  patient had hemophilia--developed in Chapel Hill.
• 1952
• Coagulation cascade model described.

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• Hemophilia A - Factor VIII deficiency
• Hemophilia B - Factor IX deficiency.

• Both X-linked
• Both prolong the aPTT.

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Incidence and Prevalence

• 1 case of hemophilia (A or B) per 5,000 live male
  births
• Hemophilia A is 3 times more common than
  Hemophilia B
• 13.4 cases per 100,000 males
• Estimated 20,000 cases in US
• 1,000 cases in North Carolina
• All racial groups affected at similar rate.

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Clinical Classification of Hemophilia
Severity Factor VIII Clinical Features
(or IX ) level
Severe lt1 Spontaneous bleeding
Moderate 1-3 Severe bleeding after trauma or surgery
Mild 3-10 Moderate bleeding after trauma or surgery
Subclinical 10-25 May not have symptoms
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Bleeds in Hemophilia

• Minor Bleeds
• Oral mucosa
• Intra-articular
• GI/GU
• Intramuscular
• Major Bleeds
• Retroperitoneal
• Retropharyngeal
• Intracranial

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ACUTE JOINT BLEED
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RETROPERITONEAL BLEED
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CNS BLEED
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Acutely, bleeding in hemophilics can

• Compromise circulation.
• Close off airway
• Lead to compartment syndrome
• Cause neuropathy
• Cause pain
• Set up inflammatory synovitis, which can trigger
  more bleeding

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Chronically, bleeding in hemophilics can

• Compromise joint function and lead to accelerated
  DJD (hemophilic arthropathy)
• Lead to pseudotumor formation
• Weaken muscles
• Lead to permanent neurologic compromise.

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HEMOPHILIC ARTHROPATHY
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HEMOPHILIC ARTHROPATHY
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A Regal Pose?
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PSEUDOTUMOR
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Other complications of hemophilia

• Inhibitor formation
• Viral (and other) Infections
• Insurance bias
• Job bias

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Inhibitors in Hemophilia

• Are alloantibodies formed against Factor VIII
  (and less commonly FIX) in patients with
  congenital hemophilia
• Inactivate exogenously administered clotting
  factor
• Must be treated with bypassing agents which less
  efficacious in hemostasis
• Increase morbidity and mortality
• Are measured in Bethesda units, which increase
  logarithmically

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Mutation types and inhibitor incidence Hemophilia
A

Intron 22 inversions
Missense mutations
Stop mutations
Large deletions
TOTAL
Small deletions
Ann Hematol 76 1998
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Complications - Orthopedic

• Hemophilic arthropathy
• Surgeries
• synovectomy - arthroscopic or isotopic
• joint fusion - arthrodesis
• joint replacement - arthroplasty

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Complications - Viral infection

• HIV and hepatitis B and C
• Blood donation steps to improve viral safety of
  plasma-derived products
• 1. blood donors screened
• 2. donated blood tested for antibodies to
  hepatitis and HIV
• 3. all factor concentrate products are
  virally inactivated and purified
• HIV transmission by blood products since 1985 -
  very rare (4 cases)

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HEMOPHILIA TREATMENT CENTER
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Patients and families can use Home Therapy

• Typically used by patients with severe disease.
• Patients keep factor at home and treat at first
  sign of bleed (on-demand therapy), or sometimes
  treat on a regular schedule to maintain a FVIII
  level at trough of gt1 (prophylactic therapy)
• Benefits of home therapy
• more convenient
• earlier treatment after onset of bleeding
• enhanced control
• less pain and joint damage

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Factor VIII concentrates differ in purity and
manufacturing processes
Plasma-derived Plasma-derived Plasma-derived Recombinant Recombinant
Intermediate High Ultrapure Standard Human albumin-free
Humate-P Koate-HP Hemofil-M Recombinate Advate
Alphanate Monoclate Kogenate ReFacto-AF
Monarc-M Helixate
ReFacto
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Currently Available Factor IX Products
Recombinant
High Purity
Intermediate Purity (PCCs)
Mononine Alphanine
Konine 80 Proplex T Profilnine SD Bebulin VH
BeneFIX
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Agents for Bypassing Inhibitors

• FEIBA
• Plasma derived mixture of partially activated
  clotting factors, including VIIa, Xa, IIa
• Dosed at 50-75 units/kg IV q 8-12 hrs
• NovoSeven
• Recombinant VIIa
• Standard dosing 90-120 mcg/kg IV q2 hrs x 2-3
  doses
• High dose - 270 mcg/kg

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Principles of Factor Dosing

• Whats the desired clotting factor level?
• Whats the half life of the factor?
• FVIII - 12 hours
• FIX - 24 hours
• Clotting factor is dosed in Units
• 1 Unit is the amount of factor present in 1 ml of
  normal plasma
• Whats the volume of distribution and recovery?
• 1 unit of FVIII raises plasma level by 2
• 1 unit of FIX raises plasma level by 1

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Factor Replacement Therapy

• Bolus Dosing
• FVIII dose 0.5 (actual-desired ) x wt in kg
• FIX dose 1.0 (actual-desired ) x wt in kg
• For BeneFIX 1.2 (actual-desired ) x wt in kg
• Continuous infusion
• For FVIII - divide bolus dose by 12 hrs
• For FIX - divide bolus dose by 24 hrs

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Adjunctive Treatment for Hemophilia

• Amicar
• Epsilon amino caproic acid
• Inhibits fibrinolysis and increases clot
  stability
• Useful in mucosal bleeding
• Contra-indicated in upper pole urinary bleeding
• DDAVP
• Causes release of pre-formed stores of FVIII/VWF
  from Weibel-Palade bodies in endothelial cells
• May help in mild hemophilia A
• Can be given as a nasal spray
• Efficacy must be tested before-hand

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Hemophilia Management - In the ER

• History
• What kind of hemophilia?, how severe?
• Inhibitor in the past? What was last titer? Is
  it gone for good?
• What kind of factor does the patient normally
  take?
• Does the patient treat himself at home?
• Physical
• Wheres the bleed?
• Any organ, airway, neurovascular compromise?
• If there is a question of CNS bleed or airway
  compromise, TREAT FIRST BEFORE IMAGING!!!!!
• Labs
• Baseline factor level (unless pt has inhibitor)
• Bethesda titer

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Hemophilia Management - In the ER

• CALL THE HEMOPHILIA SERVICE
• 966-4736, coag fellow 216-5634
• Give clotting factor and pain meds
• At UNC, can only write for FVIII based on purity
  (recombinant or monoclonal) - monoclonal is found
  under antihemophilic factor in POE
• At UNC, BeneFIX is the only FIX replacement
  available
• Decide if admission is necessary
• If pt treats at home but is in ER, likely needs
  admission b/c home therapy wasnt successful
• If patient doesnt treat at home - determine
  effect of treatment before admission
• If patient has inhibitor - admission is highly
  probable

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Hemophilia Management - on the Floor

• If continuous infusion, follow daily Factor
  levels and adjust rate to target levels
• Do not send PT/PTT!!
• If treating with FEIBA or NovoSeven, dont send
  factor levels.
• Analgesia
• DVT prophylaxis if necessary
• Involve the hemophilia service
• 966-4736
• Nursing and social work!!

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A little about cost
Product Cost/dose
Recombinant FVIII 4400
Monoclonal FVIII 3300
BeneFIX 8800
Mononine 8300
FEIBA 5000
NovoSeven 6500 x 2
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Future of Hemophilia

• Primary prophylaxis
• Gene therapy
• Inhibitor prediction/treatment
• Prevention of
• hemophilic arthropathy
• viral contamination of factor products