2. MSKCCMSKCC
Objectives
• Define hemophilia
• Treatment of bleeding in hemophilia
• Review main complications in hemophilia
• Factor replacement
• Adjunctive therapies
• Gene therapy
• Other bleeding disorders
3. MSKCCMSKCC
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
4. MSKCCMSKCC
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
6. MSKCCMSKCC
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
7. MSKCCMSKCC
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
8. MSKCCMSKCC
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
14. MSKCCMSKCC
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. MSKCCMSKCC
Treatment of Hemophilia
• Replacement of missing clotting protein
– On demand
– Prophylaxis
• DDAVP / Stimate
• Antifibrinolytic Agents
– Amicar
• Supportive measures
– Icing
– Immobilization
– Rest
16. MSKCCMSKCC
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
17. MSKCCMSKCC
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
18. MSKCCMSKCC
Factor Half-Life, hr. Increase After
1 U/kg
VIII 8-12 2 %
IX 24 1 %
Replacement Therapy Dose
Calculations
• 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. MSKCCMSKCC
On demand treatment for acute bleeds:
dosing guidelines for hemophilia
• 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. MSKCCMSKCC
North American Prospective Primary Prophylaxis Studies in
Boys with Severe Hemophilia A
Canadian Hemophilia
Primary Prophylaxis Study
(1)
( N=56 )*
USA Joint Outcome Study
(2)
( N=65 )**
Study design Single arm, dose-
escalation study
Randomized controlled
trial: full-dose prophylaxis
vs enhanced episodic
therapy
Age ( yr ) at study entry 1 – 2.5 < 2.5
First index joint
hemorrhage before
enrollment
45% ( 25/56 ) 48% ( 31/65 )
Status of study Ongoing Closed
* 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
21. MSKCCMSKCC
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
23. MSKCCMSKCC
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
24. MSKCCMSKCC
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
25. MSKCCMSKCC
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
26. MSKCCMSKCC
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
27. MSKCCMSKCC
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
28. MSKCCMSKCC
Immune Tolerance
• immune tolerance induction (ITI) program
to eradicate inhibitor
• Based on the long-term intravenous
infusion of large doses of FVIII
33. MSKCCMSKCC
Factor IX Padua
• gain-of-function mutation
• arginine 338 in the factor IX protein is
changed to leucine
• factor IX protein > 8 times normal activity,
• Finn et al: used sequence of abnormally
potent factor IX to construct improved gene
therapy vectors for hemophilia B
• Canine factor IX activity of 3.5% to 8% after 100
days, persisted for five years, bleed free dogs .
• Blood. 2012 Nov 29;120(23):4521-3. doi: 10.1182/blood-2012-06-440123. Epub 2012 Aug 23.
34. MSKCCMSKCC
Initial Evaluation of a Bleeding Patient -
1
Normal PT, Abnormal PTT
Normal thrombin time
Test for factor deficiency:
Isolated deficiency in intrinsic pathway (factors VIII,
IX, XI)
Repeat
with
50:50
mix
50:50 mix is
normal
50:50 mix is
abnormal
Test for inhibitor activity:
Specific factors: VIII,IX, XI
Non-specific (anti-phospholipid Ab)
35. MSKCCMSKCC
Initial Evaluation of a Bleeding Patient -
2
Abnormal PT, Normal PTT
Normal thrombin time
Test for factor deficiency:
Isolated deficiency of factor VII (rare)
Repeat
with
50:50
mix
50:50 mix is
normal
50:50 mix is
abnormal
Test for inhibitor activity:
Specific: Factor VII (rare)
Non-specific: Anti-phospholipid (rare)
36. MSKCCMSKCC
Initial Evaluation of a Bleeding Patient -
3
Abnormal PT, Abnormal PTT
Normal or abnormal thrombin time
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)
Repeat
with
50:50
mix
50:50 mix is
normal
50:50 mix is
abnormal
Test for inhibitor activity:
Specific : Factors V, X, Prothrombin,
fibrinogen (rare)
Non-specific: anti-phospholipid (common)
38. MSKCCMSKCC
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
39. MSKCCMSKCC
PAI-1 deficiency
• Autosomal recessive
• Glycoprotein serpin synthesized in liver
• Bleeding in homozygotes with wide
spectrum of clinical symptoms
• Measure PAI-1 activity
40. MSKCCMSKCC
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
