MSKCCMSKCCMSKCCMSKCC100 years of Hemophilia: 1904-2012Rekha Parameswaran, M.D.10-11-2012
MSKCCMSKCCObjectives• Define hemophilia• Treatment of bleeding in hemophilia• Review main complications in hemophilia• Factor replacement• Adjunctive therapies• Gene therapy
MSKCCMSKCCCase 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 greatuncles• 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 sonRobbins, R. J. (n.d.). Genetics and history: how a single mutation affected the entire world. Retrieved fromhttp://www.esp.org/misc/vignettes/alexis.html
MSKCCMSKCCEuropean History• Kerensky, the head of the Provisional Government afterthe Tsar, claimed:• "Without Rasputin, there could have been no Lenin."Certainly, without Lenin, there would have been nocommunist Russia.• And, without Alexis hemophilia, there would have beenno Rasputin.• Could it be that the single mutation in the single cell thatbecame Victoria was responsible for the rise ofcommunism?• Entire family murderedR. K. Massie. 1967. Nicholas and Alexandra. New York: Atheneum. p. 506Robbins, R. J. (n.d.). Genetics and history: how a single mutation affected the entire world. Retrieved fromhttp://www.esp.org/misc/vignettes/alexis.html
MSKCCMSKCCOne third of all cases of hemophilia are due to newmutation in motherRogaev, 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
MSKCCMSKCCDegraded DNA from skeletal bone specimens from remainsof Romanov familyA to G intronic mutation located three base pairs upstream ofexon 4 in the factor IX geneRogaev, 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
MSKCCMSKCCHemophilia A and BHemophilia A Hemophilia BCoagulation factor deficiency Factor VIII Factor IXInheritance X-linked X-linkedrecessive recessiveIncidence 1/10,000 males 1/50,000 males50-60% severe 44% severe1:5000 male births 1: 30,000 male birthsSeverity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild injury5-25% - Mild - bleeding with surgery or trauma
MSKCCMSKCCGenetics• 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 resultof new spontaneousmutationR.M. Lawn The molecular genetics of hemophilia: blood clotting factors VIII and IXCell, 42 (1985), pp. 405–406
MSKCCMSKCCFactor VIII deficiency:Intron 22 inversionFactor viii intron 22 inversion. (n.d.) Retrieved fromhttp://www.nibsc.ac.uk/science/diagnostics/genetic_reference_materials/factor_viii_intron_22_inversio.aspx
MSKCCMSKCCClinical Bleeding• Immediate and delayed bleed with hemostaticchallenges• Spontaneous joint bleeds :Symptoms of jointbleed– Tingling or bubbling sensation– Stiffness– Warmth– Pain– Unusual limb position
MSKCCMSKCCPseudotumor/Pseudocyst• Deep bleeds may evolve into apseudotumor.– Increased pressure of hematoma plus proteases fromblood destroy surrounding tissues and graduallyexpand.(n.d.). Retrieved from http://img.medscape.com/pi/emed/ckb/hematology/197800-201319-3691tn.jpgStafford, 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
MSKCCMSKCCArrow head representscartilage thinningArrows representsjoint effusionArrows representhemosiderin depositionMRI study of an ankle joint
MSKCCMSKCCGoals of TreatmentLet’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 protein2) Prevent long term joint damage
MSKCCMSKCCTreatment of Hemophilia• Replacement of missing clotting protein– On demand– Prophylaxis• DDAVP / Stimate• Antifibrinolytic Agents– Amicar• Supportive measures– Icing– Immobilization– Rest
MSKCCMSKCCFactor 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 factorVIII level by 2 %• Cryoprecipitate NOT recommended
MSKCCMSKCCFactor 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 by1%
MSKCCMSKCCOn 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 diseaseonly)
MSKCCMSKCCFactor Half-Life, hr. Increase After1 U/kgVIII 8-12 2 %IX 24 1 %Replacement Therapy DoseCalculations• F VIII: 1 U/kg results in 2% rise in F VIII.– Dose twice daily.– “70 Kg” patient: 3500 units results in 100% plasmalevel.• 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% plasmalevel.
MSKCCMSKCCNorth American Prospective Primary Prophylaxis Studies inBoys with Severe Hemophilia ACanadian HemophiliaPrimary Prophylaxis Study(1)( N=56 )*USA Joint Outcome Study(2)( N=65 )**Study design Single arm, dose-escalation studyRandomized controlledtrial: full-dose prophylaxisvs enhanced episodictherapyAge ( yr ) at study entry 1 – 2.5 < 2.5First index jointhemorrhage beforeenrollment45% ( 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
MSKCCMSKCCProphylaxis• Scheduled infusions of factor concentratesto prevent most bleeding• Frequency: 2 to 3 times weekly to keeptrough factor VIII or IX levels at 2-3%• Types– primary prophylaxis– secondary prophylaxis• Use of IVAD necessary in some patients
MSKCCMSKCCComplications of therapy• Formation of inhibitors (antibodies)– 10-15% of severe hemophilia A patients– 1-2% of severe hemophilia B patients• Viral infections– Hepatitis B Humanparvovirus– Hepatitis C Hepatitis A– HIV OtherWarrier, I., Ewenstein, B., Koerper, M. A., Shapiro, A., Key, N., & DiMichele, D. (1997). Factor ix inhibitors and anaphylaxis inhemophilia b. Journal of Pediatric Hematology/Oncology, 19(1), 23-27.
MSKCCMSKCCOur patient’s course• At age 2, port-a-cath placed• He is started on prophylaxis withrecombinant factor VIII three times a weekwith 100% factor replacement dose• Eight months later, he develops repeatedbleeds despite above dosing
MSKCCMSKCCInhibitors• Definition– IgG antibody to infused factor VIII or IXconcentrates, which occurs after exposureto 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: rFVIIaWarrier, I., Ewenstein, B., Koerper, M. A., Shapiro, A., Key, N., & DiMichele, D. (1997). Factor ix inhibitors andanaphylaxis in hemophilia b. Journal of Pediatric Hematology/Oncology, 19(1), 23-27.
MSKCCMSKCCLabs• Factor VIII: <1%• Factor VIII inhibitor : 5 Bethesda units
MSKCCMSKCCrFVIIa• Pan hemostatic agent• Recombinant and does not carry risks ofplasma derived products• Dose is 90-120 microgram/kg given asbolus dose every 2 hours• Expense is a considerationAbshire , T., & Kenet, G. (2004). Recombinant factor viia: review of efficacy, dosing regimens and safety in patientswith congenital and acquired factor viii or ix inhibitors. Journal of Thrombosis andHaemostasis, 2(6), 899-909.
MSKCCMSKCCImmune Tolerance• immune tolerance induction (ITI) programto eradicate inhibitor• Based on the long-term intravenousinfusion of large doses of FVIIIBenson, G., Auerswald, G., Elezović, I., Lambert , T., Ljung, R., Morfini, M., Remor, E., & Šalek, S. Z. (2012). Immunetolerance induction in patients with severe hemophilia with inhibitors: expert panel views andrecommendations for clinical practice. European Journal of Haemotology, 88(5 ), 371-379. doi:10.1111/j.1600-0609.2012.01754.x
MSKCCMSKCCFuture :2011 and beyond• Longer acting factor concentrates• Biogen has announced phase threeresults of factor IX product with half life of70 hours• Gene therapyBiogen reports a-long and b-long studies progress. (2013, February 8). Retrieved fromhttp://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=286&contentid=2057
MSKCCMSKCCNathwani, 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