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Hemophilia fellow talk2014
- 1. 100 years ofHemophilia: 1904-2013 MMMMSSSSKKKKCCCCCCCC Rekha Parameswaran, M.D.
- 2. MMSSKKCCCC Objectives •Define hemophilia • Treatment of bleeding in hemophilia • Review main complications in hemophilia • Factor replacement • Adjunctive therapies • Gene therapy • Other bleeding disorders
- 3. MMSSKKCCCC 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. MMSSKKCCCC 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 ofall cases of hemophilia are due to new mutation in mother MMSSKKCCCC
- 6. Degraded DNA fromskeletal 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 MMSSKKCCCC
- 7. MMSSKKCCCC Hemophilia Aand 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. MMSSKKCCCC 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
- 9. MMSSKKCCCC Factor VIIIdeficiency: Intron 22 inversion
- 10. MMSSKKCCCC 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 MMSSKKCCCC
- 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 hemosiderindeposition Arrows represents joint effusion Arrow head represents cartilage thinning MMSSKKCCCC MMRRII ssttuuddyy ooff aann aannkkllee jjooiinntt
- 14. MMSSKKCCCC Goals ofTreatment 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 MMSSKKCCCC – 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 MMSSKKCCCC
- 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 MMSSKKCCCC
- 18. Replacement Therapy Dose MMSSKKCCCC 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 treatmentfor acute bleeds: dosing guidelines for hemophilia MMSSKKCCCC • 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 ProspectivePrimary Prophylaxis Studies in Boys MMSSKKCCCC 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
- 21. MMSSKKCCCC 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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- 23. MMSSKKCCCC Complications oftherapy • 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. MMSSKKCCCC Our patient’scourse • 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. MMSSKKCCCC 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. MMSSKKCCCC 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. MMSSKKCCCC 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. MMSSKKCCCC Immune Tolerance • immune tolerance induction (ITI) program to eradicate inhibitor • Based on the long-term intravenous infusion of large doses of FVIII
- 29. MMSSKKCCCC Future :2013and beyond • Longer acting factor concentrates • Gene therapy
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- 32. MMSSKKCCCC Coagulation andFibrinolysis Pathways Holly, MD, J. L. (2007). Cardiometabolic risk syndrome part v: Fibrinolytic dysfunction.
- 33. Initial Evaluation ofa Bleeding Patient - Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab) MMSSKKCCCC 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 ofa 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 ofa Bleeding Patient - Test for inhibitor activity: Specific : Factors V, X, Prothrombin, MMSSKKCCCC 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-Nowwhat? MMSSKKCCCC • Factor XIII deficiency • alpha-2-antiplasmin deficiency • PAI-1 deficiency • mild factor deficiency • vascular disorders: hereditary hemorrhagic telangiectasia
- 37. MMSSKKCCCC Factor XIIIdeficiency • 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
- 39. MMSSKKCCCC 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
Editor's Notes
- #40 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 Editor Information 1 Professor of Haemophilia, Director and Consultant Haematologist, Haemophilia Centre and Haemostasis Unit, The Royal Free Hospital, London, UK 2 Professor of Hemophilia, Lund University;, Director, Department of Coagulation Disorders, Malmö University Hospital, Malmö, Sweden 3 Professor of Pediatrics, University of Texas M.D. Anderson Cancer Center;, Professor of Pediatrics and Internal Medicine, University of Texas Medical School at Houston;, Medical Director, Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA 4 The Mary Weinfeld Professor of Clinical Research in Hemophilia, Mount Sinai School of Medicine, New York, NY, USA Publication History Published Online: 4 OCT 2007 Published Print: 12 JAN 2005 ISBN Information Print ISBN: 9781405127691 Online ISBN: 9780470987124