This document provides an overview of 100 years of hemophilia treatment from 1904 to 2013. It begins with a case study of Alexis Nicolaievich, the heir to the Russian throne who had hemophilia. It then discusses the history and genetics of hemophilia A and B, clinical presentations, complications, and advances in treatment including factor replacement therapies, inhibitors, immune tolerance induction, and future prospects like gene therapy. The goal of treatment is to treat acute bleeding and prevent long-term joint damage through replacement of the missing clotting factor.

1. 100 years of Hemophilia: 1904-2013
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Rekha Parameswaran, M.D.

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Objectives
• Define hemophilia
• Treatment of bleeding in hemophilia
• Review main complications in hemophilia
• Factor replacement
• Adjunctive therapies
• Gene therapy
• Other bleeding disorders

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Case history
• In 1904, Baby boy has persistent bleeding after birth
• One maternal uncle died of brain hemorrhage at age 31
• No history of bleeding in maternal grandfather or great
uncles
• Baby boy was His Imperial Highness Alexis Nicolaievich,
Sovereign Heir Tsarevich, Grand Duke of Russia
• No treatments available except rest for joint bleeds
• Distraught mother turns to Rasputin to “heal” her son

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European History
• Kerensky, the head of the Provisional Government after
the Tsar, claimed:
• "Without Rasputin, there could have been no Lenin."
Certainly, without Lenin, there would have been no
communist Russia.
• And, without Alexis' hemophilia, there would have been
no Rasputin.
• Could it be that the single mutation in the single cell that
became Victoria was responsible for the rise of
communism?
• Entire family murdered

5. One third of all cases of hemophilia are due to new
mutation in mother
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6. Degraded DNA from skeletal bone specimens from remains
of Romanov family
A to G intronic mutation located three base pairs upstream
of exon 4 in the factor IX gene
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Hemophilia A and B
Hemophilia A Hemophilia B
Coagulation factor deficiency Factor VIII Factor IX
Inheritance X-linked X-linked
recessive recessive
Incidence 1/10,000 males 1/50,000 males
50-60% severe 44% severe
1:5000 male births 1: 30,000 male births
Severity Related to factor level
<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-25% - Mild - bleeding with surgery or trauma

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Genetics
• Affected males
– All daughters are carriers
– No sons are affected
• Female carrier
– 50% risk for carrier daughter
– 50% risk for affected son
• 30% of cases are result
of new spontaneous
mutation

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Factor VIII deficiency:
Intron 22 inversion

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Clinical Bleeding
• Immediate and delayed bleed with hemostatic
challenges
• Spontaneous joint bleeds :Symptoms of joint
bleed
– Tingling or bubbling sensation
– Stiffness
– Warmth
– Pain
– Unusual limb position

11. Complications of Bleeding
• Flexion contractures
• Joint arthritis / arthropathy
• Chronic pain
• Muscle atrophy
• Compartment syndrome
• Neurologic impairment
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12. MMSSKKCCCC
Pseudotumor/Pseudocyst
• Deep bleeds may evolve into a
pseudotumor.
– Increased pressure of hematoma plus proteases from
blood destroy surrounding tissues and gradually
expand.

13. Arrows represent
hemosiderin deposition
Arrows represents
joint effusion
Arrow head represents
cartilage thinning
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MMRRII ssttuuddyy ooff aann aannkkllee jjooiinntt

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Goals of Treatment
Let’s take a case:
• Baby boy born in 2004
• Bleeds with circumcision
• PTT 85
• Factor VIII: <1%
• Our goals for this boy:
1) Treat acute bleeding episodes:
Replacement of missing clotting protein
2) Prevent long term joint damage

15. Treatment of Hemophilia
• Replacement of missing clotting protein
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– On demand
– Prophylaxis
• DDAVP / Stimate
• Antifibrinolytic Agents
– Amicar
• Supportive measures
– Icing
– Immobilization
– Rest

16. Factor VIII Concentrate
• Helixate®,Kogenate®,Recombinate®, Advate®,
Xyntha®
– IV push or continuous infusion
• Dose varies depending on type of bleeding
– Ranges from 20-50+ units/kg. body weight
• Half-life 8-12 hours
• Each unit/kg infused raises serum factor VIII
level by 2 %
• Cryoprecipitate NOT recommended
• Eloctate® –Fc fusion protein half life of 20 hours
or so
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17. Factor IX Concentrate
• BenefIX®
– IV push or continuous infusion
• Dose varies depending on type of bleeding
– Ranges from 20-100+ units/kg. body weight
• Half-life : 12-24 hours
• Each unit infused raises serum factor IX level by
1%
• Alprolix® - 86 hours half life allowing for once
weekly dosing
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18. Replacement Therapy Dose
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Calculations
FFaaccttoorr HHaallff--LLiiffee,, hhrr.. IInnccrreeaassee AAfftteerr
11 UU//kkgg
VVIIIIII 88--1122 22 %%
IIXX 2244 11 %%
• F VIII: 1 U/kg results in 2% rise in F VIII.
– Dose twice daily.
– “70 Kg” patient: 3500 units results in 100% plasma
level.
• F IX: 1 U/kg results in 1% (1-1.5%) rise in F IX.
– Dose once daily.
– “70 Kg” patient: 7000 units results in 100% plasma
level.

19. On demand treatment for acute bleeds:
dosing guidelines for hemophilia
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• Mild bleeding
– Target: 40% -50%dosing q8-12h; 2-4 days
– 20-25 U/kg f VIII or 40-50 U/kg FIX
– Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
• Major bleeding
– Target: 80-100% q8-12h; 7-14 days
– 40-50U/kg fVIII or 80-100units/kg fIX
– CNS trauma, hemorrhage, lumbar puncture
– Surgery
– Retroperitoneal hemorrhage
– GI bleeding
• Adjunctive therapy
– Epsilon amino caproic acid (Amicar) or DDAVP (for mild disease
only)

20. North American Prospective Primary Prophylaxis Studies in Boys
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with Severe Hemophilia A
CCaannaaddiiaann HHeemmoopphhiilliiaa
PPrriimmaarryy PPrroopphhyyllaaxxiiss SSttuuddyy
((11))
(( NN==5566 ))**
UUSSAA JJooiinntt OOuuttccoommee SSttuuddyy
((22))
(( NN==6655 ))****
SSttuuddyy ddeessiiggnn SSiinnggllee aarrmm,, ddoossee--
eessccaallaattiioonn ssttuuddyy
RRaannddoommiizzeedd ccoonnttrroolllleedd
ttrriiaall:: ffuullll--ddoossee pprroopphhyyllaaxxiiss
vvss eennhhaanncceedd eeppiissooddiicc
tthheerraappyy
AAggee (( yyrr )) aatt ssttuuddyy eennttrryy 11 –– 22..55 << 22..55
FFiirrsstt iinnddeexx jjooiinntt
hheemmoorrrrhhaaggee bbeeffoorree
eennrroollllmmeenntt
4455%% (( 2255//5566 )) 4488%% (( 3311//6655 ))
SSttaattuuss ooff ssttuuddyy OOnnggooiinngg CClloosseedd
* First case enrolled July 1997; ** first case enrolled August 1996
(1) Feldman BM et al J Thromb Haemost 2006; 4: 1228-1236
(2) Manco-Johnson MJ et al. N Engl J Med 2007; 357: 535-544

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Prophylaxis
• Scheduled infusions of factor concentrates
to prevent most bleeding
• Frequency: 2 to 3 times weekly to keep
trough factor VIII or IX levels at 2-3%
• Types
– primary prophylaxis
– secondary prophylaxis
• Use of IVAD necessary in some patients

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Complications of therapy
• Formation of inhibitors (antibodies)
– 10-15% of severe hemophilia A patients
– 1-2% of severe hemophilia B patients
• Viral infections
– Hepatitis B Human
parvovirus
– Hepatitis C Hepatitis A
– HIV Other

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Our patient’s course
• At age 2, port-a-cath placed
• He is started on prophylaxis with
recombinant factor VIII three times a week
with 100% factor replacement dose
• Eight months later, he develops repeated
bleeds despite above dosing

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Inhibitors
• Definition
– IgG antibody to infused factor VIII or IX
concentrates, which occurs after exposure
to the extraneous VIII or IX protein.
• Prevalence
– 20-30% of patients with severe hemophilia A
– 1-4% of patients with severe hemophilia B
• Treatment
– .Eradicate inhibitor: Immune tolerance
– Treat bleeding: rFVIIa

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Labs
• Factor VIII: <1%
• Factor VIII inhibitor : 5 Bethesda units
• Inhibitors develop in newly diagnosed children at
an average age of 2 to 3 years
• More frequently after 10 to 20 days of exposure
to FVIII
• Less frequently between 20 to 50 exposures
• seldom after 200 exposures

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rFVIIa
• Pan hemostatic agent
• Recombinant and does not carry risks of
plasma derived products
• Dose is 90-120 microgram/kg given as
bolus dose every 2 hours
• Expense is a consideration

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Immune Tolerance
• immune tolerance induction (ITI) program
to eradicate inhibitor
• Based on the long-term intravenous
infusion of large doses of FVIII

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Future :2013 and beyond
• Longer acting factor concentrates
• Gene therapy

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Coagulation and Fibrinolysis
Pathways
Holly, MD, J. L. (2007). Cardiometabolic risk syndrome part v: Fibrinolytic dysfunction.

33. Initial Evaluation of a Bleeding Patient -
Test for inhibitor activity:
Specific factors: VIII,IX, XI
Non-specific (anti-phospholipid Ab)
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1
Normal PT, Abnormal PTT
Normal thrombin time
Repeat
with
50:50
mix
50:50 mix is
normal
50:50 mix is
abnormal
Test for factor deficiency:
Isolated deficiency in intrinsic pathway (factors VIII,
IX, XI)

34. Initial Evaluation of a Bleeding Patient -
Test for inhibitor activity:
Specific: Factor VII (rare)
Non-specific: Anti-phospholipid (rare)
MMSSKKCCCC
2
Abnormal PT, Normal PTT
Normal thrombin time
Repeat
with
50:50
mix
50:50 mix is
normal
50:50 mix is
abnormal
Test for factor deficiency:
Isolated deficiency of factor VII (rare)

35. Initial Evaluation of a Bleeding Patient -
Test for inhibitor activity:
Specific : Factors V, X, Prothrombin,
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3
Abnormal PT, Abnormal PTT
Normal or abnormal thrombin time
Repeat
with
50:50
mix
50:50 mix is
normal
50:50 mix is
abnormal
Test for factor deficiency:
Isolated deficiency in common pathway: Factors V, X,
Prothrombin, Fibrinogen
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)
fibrinogen (rare)
Non-specific: anti-phospholipid (common)

36. Tests are normal-Now what?
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• Factor XIII deficiency
• alpha-2-antiplasmin deficiency
• PAI-1 deficiency
• mild factor deficiency
• vascular disorders: hereditary
hemorrhagic telangiectasia

37. MMSSKKCCCC
Factor XIII deficiency
• Composed of 2 subunits A and B: A synthesis is in
hematopoietic cells and B synthesis in the Liver
• Deficiency is 1 in million to 1 in 5 million
• FXIII-A def is know as Type 2 , FXIII-B def is Type-1(<%5
of reported cases).
• Associated with delayed bleeding
• Autosomal recessive
• Corifact® – plasma derived factor XIII
• Tretten® – recombinant factor XIII A-subunit
Hsieh , L., & Nugent , D. (2008). Factor xiii deficiency. Haemophilia,
14(6), 1190- 200. doi: 10.1111/j.1365-2516.2008.01857.x

38. MMSSKKCCCC
PAI-1 deficiency
• Autosomal recessive
• Glycoprotein serpin synthesized in liver
• Bleeding in homozygotes with wide
spectrum of clinical symptoms
• Measure PAI-1 activity

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Alpha-2 Antiplasmin
• Autosomal recessive
• Single chain glycoprotein synthesized in
the liver
• Bleeding in homozygotes
• Intracranial hemorrhage in full term
neonates
• Intramedullary hematomas of long bones
• Measure alpha 2 antiplasmin level
Shapiro, A. and Parameswaran, R. (2007) Miscellaneous Rare Bleeding Disorders, in Textbook of Hemophilia (eds C.
A. Lee, E. E. Berntorp, W. K. Hoots and L. M. Aledort), Blackwell Publishing Ltd, Oxford, UK.
doi: 10.1002/9780470987124.ch58