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Hemophilia fellow talk2015 dr parameswaran

Hemophilia fellow talk2015 dr parameswaran

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Hemophilia fellow talk2015 dr parameswaran

  1. 1. MSKCCMSKCCMSKCCMSKCC 100 years of Hemophilia: 1904-2015 Rekha Parameswaran, M.D.
  2. 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. 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. 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
  5. 5. MSKCCMSKCC One third of all cases of hemophilia are due to new mutation in mother
  6. 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. 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. 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
  9. 9. MSKCCMSKCC Factor VIII deficiency: Intron 22 inversion
  10. 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
  11. 11. MSKCCMSKCC Complications of Bleeding • Flexion contractures • Joint arthritis / arthropathy • Chronic pain • Muscle atrophy • Compartment syndrome • Neurologic impairment
  12. 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.
  13. 13. MSKCCMSKCC Arrow head represents cartilage thinning Arrows represents joint effusion Arrows represent hemosiderin deposition MRI study of an ankle joint
  14. 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. 15. MSKCCMSKCC Treatment of Hemophilia • Replacement of missing clotting protein – On demand – Prophylaxis • DDAVP / Stimate • Antifibrinolytic Agents – Amicar • Supportive measures – Icing – Immobilization – Rest
  16. 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. 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. 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. 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. 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. 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
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  23. 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. 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. 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. 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. 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. 28. MSKCCMSKCC Immune Tolerance • immune tolerance induction (ITI) program to eradicate inhibitor • Based on the long-term intravenous infusion of large doses of FVIII
  29. 29. MSKCCMSKCC Future :2015 and beyond • Longer acting factor concentrates • Gene therapy
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  32. 32. MSKCCMSKCC Coagulation and Fibrinolysis Pathways Holly, MD, J. L. (2007). Cardiometabolic risk syndrome part v: Fibrinolytic dysfunction.
  33. 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. 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. 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. 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)
  37. 37. MSKCCMSKCC Tests are normal-Now what? • Factor XIII deficiency • alpha-2-antiplasmin deficiency • PAI-1 deficiency • mild factor deficiency • vascular disorders: hereditary hemorrhagic telangiectasia
  38. 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. 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. 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

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