2. MSKCCMSKCC
Objectives
• Define hemophilia
• Treatment of bleeding in hemophilia
• Review main complications in hemophilia
• Factor replacement
• Adjunctive therapies
• Gene therapy
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
Robbins, R. J. (n.d.). Genetics and history: how a single mutation affected the entire world. Retrieved from
http://www.esp.org/misc/vignettes/alexis.html
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
R. K. Massie. 1967. Nicholas and Alexandra. New York: Atheneum. p. 506
Robbins, R. J. (n.d.). Genetics and history: how a single mutation affected the entire world. Retrieved from
http://www.esp.org/misc/vignettes/alexis.html
5. MSKCCMSKCC
One third of all cases of hemophilia are due to new
mutation in mother
Rogaev, E. I., Grigorenko, A. P., Faskhutdinova, G., Kittler, E. L. W. & Moliaka, Y. K. (2009, October 08).
Genotype analysis identifies the cause of the “royal disease”. Science Express , 326( 5954 817 ),
Retrieved from http://www.sciencemag.org/content/326/5954/817/F1.expansion.html
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
Rogaev, E. I., Grigorenko, A. P., Faskhutdinova, G., Kittler, E. L. W. & Moliaka, Y. K. (2009, October 08).
Genotype analysis identifies the cause of the “royal disease”. Science Express , 326( 5954 817),
Retrieved from http://www.sciencemag.org/content/326/5954/817/F1.expansion.html
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
R.M. Lawn The molecular genetics of hemophilia: blood clotting factors VIII and IX
Cell, 42 (1985), pp. 405–406
9. MSKCCMSKCC
Factor VIII deficiency:
Intron 22 inversion
Factor viii intron 22 inversion. (n.d.) Retrieved from
http://www.nibsc.ac.uk/science/diagnostics/genetic_reference_materials/factor_viii_intron_22_inversio.aspx
10. MSKCCMSKCC
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
12. MSKCCMSKCC
Pseudotumor/Pseudocyst
• Deep bleeds may evolve into a
pseudotumor.
– Increased pressure of hematoma plus proteases from
blood destroy surrounding tissues and gradually
expand.
(n.d.). Retrieved from http://img.medscape.com/pi/emed/ckb/hematology/197800-201319-3691tn.jpg
Stafford, J. M., James , T. T., Allen, A. M., & Dixon, L. R. (2003 ). Hemophilic pseudotumor: Radiologic-pathologic correlation.
RadioGraphics, 23(4), 852-856. Retrieved from http://radiographics.rsna.org/content/23/4/852.full.pdf html
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
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%
18. 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)
19. 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.
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
Warrier, I., Ewenstein, B., Koerper, M. A., Shapiro, A., Key, N., & DiMichele, D. (1997). Factor ix inhibitors and anaphylaxis in
hemophilia b. Journal of Pediatric Hematology/Oncology, 19(1), 23-27.
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
Warrier, I., Ewenstein, B., Koerper, M. A., Shapiro, A., Key, N., & DiMichele, D. (1997). Factor ix inhibitors and
anaphylaxis in hemophilia b. Journal of Pediatric Hematology/Oncology, 19(1), 23-27.
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
Abshire , T., & Kenet, G. (2004). Recombinant factor viia: review of efficacy, dosing regimens and safety in patients
with congenital and acquired factor viii or ix inhibitors. Journal of Thrombosis and
Haemostasis, 2(6), 899-909.
28. MSKCCMSKCC
Immune Tolerance
• immune tolerance induction (ITI) program
to eradicate inhibitor
• Based on the long-term intravenous
infusion of large doses of FVIII
Benson, G., Auerswald, G., Elezović, I., Lambert , T., Ljung, R., Morfini, M., Remor, E., & Šalek, S. Z. (2012). Immune
tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and
recommendations for clinical practice. European Journal of Haemotology, 88(5 ), 371-379. doi:
10.1111/j.1600-0609.2012.01754.x
29. MSKCCMSKCC
Future :2011 and beyond
• Longer acting factor concentrates
• Biogen has announced phase three
results of factor IX product with half life of
70 hours
• Gene therapy
Biogen reports a-long and b-long studies progress. (2013, February 8). Retrieved from
http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=286&contentid=2057
30. MSKCCMSKCC
Nathwani, A. C., Tuddenham, E. D. G., Rangarajan, S., Rosales, C., McIntosh, J., & Linch, D. C. ….Davidoff, A.M. (2011).
Adenovirus-associated virus vector–mediated gene transfer. The New England Journal of Medicine,
365(25), 2357- 2365. doi: 10.1056/NEJMoa1108046
