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Rarer Haemostatic Disorders Treatments (see UKHCDO guidelines 2004 Haemophilia 10, 593-628)

Rarer Haemostatic Disorders Treatments (see UKHCDO guidelines 2004 Haemophilia 10, 593-628). Paula Bolton-Maggs Consultant Haematologist Manchester Royal Infirmary, UK. Bleeding disorder patients registered at CMC Vellore, India, 1965-96. Total 1528 patients. 338.

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Rarer Haemostatic Disorders Treatments (see UKHCDO guidelines 2004 Haemophilia 10, 593-628)

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  1. Rarer Haemostatic DisordersTreatments(see UKHCDO guidelines 2004Haemophilia 10, 593-628) Paula Bolton-Maggs Consultant Haematologist Manchester Royal Infirmary, UK

  2. Bleeding disorder patients registered at CMC Vellore, India, 1965-96 Total 1528 patients 338

  3. Bleeding disorder patients registered at CMC Vellore, India, 1965-96 154 24 38

  4. Excluding FXI deficiency 1163

  5. North-America:4 centers, 33 pts Europe: 9 centers, 307 pts FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO FIX DDAVP rFVIII DDAVP FFP, cryo PCC rFVIIa Plasma concentrate Central & South America: 4 centers, 48 pts Asia/Middle East: 7 centers, 660 pts FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO recombinant other Blood FVIII Blood Preliminary data from the Rare Bleeding Disorders Registry

  6. Rare coagulation disorders • Autosomal recessive (?) inheritance • More common in racial groups where cousin marriage frequent • Factor XI common in Ashkenazy Jews • Generally, lack of clear correlation between bleeding and level of factor, so more difficult to manage

  7. Severe deficiency – rare disorders (data from Peyvandi, Rare coagulation disorders, thesis, 2000)

  8. In vivo properties (1:Rizza 1982, 2: Mannucci 2004)

  9. What products are manufactured? FV deficiency: no concentrate – use virally-treated FFP Octaplas – pooled from approx 1500 donations, SD treated, sourced from Austria, Germany and USA Methylene-blue treated single donor units Platelet disorders: DDAVP, fibrinolytic inhibitors, platelet transfusions and possibly rVIIa

  10. Fibrinogen Treatment products • Unlicensed virally inactivated concentrates • ZLB • SNBTS • LFB • Half life 3-5 days • Tranexamic acid • Cryo is a good source but not virally inactivated

  11. Fibrinogen products

  12. Treatment for FII • Beriplex PN (ZLB) contains II, VII, IX and X • DEFIX HT (SNBTS) contains II, IX and X • Prothromplex (Baxter) contains II, IX and X • Prothromplex T (Baxter) similar but also contains factor VII • Kaskadil (LFB) with VII

  13. Treatment Products FVII • rVIIa is the treatment of choice although little data • Factor IX concentrates containing FVII • Factor VII concentrates (LFB and Baxter) • (FFP) • A level of 10-15 u/dl is probably sufficient for surgery (level of 2 u/dl shown to normalise the thrombin generation test but not tested in clinical situation)

  14. Products for FVII deficiency

  15. Factor X Treatment Products • No factor X concentrate • Intermediate purity Factor IX concentrates • Increased risk of thrombosis • (FFP) • A level of 10-25 u/dl is probably sufficient for surgery • People with levels >10 u/dl probably require no replacement therapy

  16. Products for FX (and FII) deficiency

  17. Therapeutic options in FXI deficiency • Fresh frozen plasma (Virally treated) • Factor XI concentrates (BPL, LFB) but thrombogenic • Fibrinolytic inhibitors – very effective for dental extractions • Fibrin glue – main experience in Israel • DDAVP - unconvincing • rVIIa – risk of thrombosis

  18. Products for FXI deficiency

  19. Factor XIII deficiency • 6 patients managed from 19-35 years • Prophylaxis – long half life 11-14 days • Pasteurised plasma-derived concentrate available from ZLB (Fibrogammin-P) • Give 1000 units every 5-6 weeks which raises level to 30-35 u/dl (NB assay problems) • Platelets contain FXIII and in an emergency may be useful.

  20. SSC working group on “Rare Bleeding Disorders” (RBDs) In 2004, during the 50th SSC meeting organized by the ISTH and held in Venice, a SSC working group on "Rare Bleeding Disorders" (RBDs) was held within the framework of the FVIII/IX subcommittee Flora Peyvandi Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre University of Milan-Italy Slide provided by Flora Peyvandi

  21. North America:4 Europe:9 1 1 3 1 1 1 1 4 1 2 2 1 1 1 Asia/Middle East:7 3 South and central America:4 Database development.3 Hemophilia Treatment Centers already joined

  22. Database development.3 Preliminary result of initial participation In the period 30 June-30 July, 24completed “joining forms” came back out of 725 sent e-mails 416 Centres will be contact by ordinary mail due to the uncorrect or unavailable e-mail addresses

  23. North-America: 4 centers, 33 pts Europe: 9 centers, 307 pts FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO % % Asia/Middle East: 7 centers, 660 pts Central & South America: 4 centers, 48 pts FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO % % Database development.3 • Thelargest groups of patients were communicated from Iran and India (327 and 264 patients respectively) • Fibrinogen and FVII deficiencies were spread among all responding Centres • FVII and FXI deficiencies are the most prevalent worldwide

  24. Database development.3 North-America:4 centers, 33 pts Europe: 9 centers, 307 pts FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO FIX DDAVP rFVIII DDAVP FFP, cryo PCC rFVIIa Plasma concentrate Central & South America: 4 centers, 48 pts Asia/Middle East: 7 centers, 660 pts FXIII FXI FX FVII FV+FVIII FV FII AFIBRINO recombinant other Blood FVIII Blood Available treatments

  25. Database development.3 Problems with RBDs treatments • Inability to get product and costs: - Central and South America, Asia and Middle East, Russia - India: sometimes products are past expiration date • No availability of product: - Brazil and Vietnam: general lack of products - FXI reported by Arizona, Brazil, Belgium, London-UK, Switzerland centres - Denmark: sometimes stopped FIX-X product - Iran: Prothrombin complex • Adverse effects: mild urticaria, reaction to plasma, thrombosis with FXI in the past, fear of blood borne viral infections • Other: - Panama: products available only for insured patients

  26. Database development.3 Second step A specific tailored questionnaire will be sent to all Treatment Centers, after their joining to the RBDD, in order to collect more detailed information on all enrolled patients: • Phenotype and genotype analysis • Clinical manifestation • Type of treatment, on-demand/prophylaxis • Treatment-related complications To each clinician will be asked patients’ informed consent and IRB approval

  27. Genetic analysis Treatment Patient Treatment Duration Dose… Patient Gene Variation Genotype… Patient Pathology Tratment… Soggetto Phenotipic analysis Patient Coagulant activity Antigen level Method Data… Patient Type of bleeding Data Severity . . . Other pathologies Type of bleeding Clinical manifestations Complications Patient Type Incidence per year Type of deficiency Paziente Paziente Tipo di Tipo di sanguinam sanguinam . . Patient Treatment Complication Severity… Data Data Gravità… Gravità… Prenatal diagnosis Patient Deficiency Severity… Patient Diagnosis Abortion… Sicurezza Sicurezza Safety Family Soggetto Operatore Data… Soggetto Subject Operator Data… Soggetto Soggetto Soggetto Subject Paziente? Operatore Subject Family… indirizzo Famiglia… Data… Paese… Patient Address Country… Paziente? indirizzo Paese… Database development.3

  28. Steering committee.4 Next steps • Our work could represent the starting point for the establishment of an International Database under the supervision of an International Society such as WFH or ISTH • In order to create an International collaboration on RBDD and to decide eventual clinical trials, it will be necessary to build up a STEERING COMMITTEE composed by experts in clinic, treatment and genotype-phenotype characterization coming from all over the world

  29. current databases.1 ISTH Registries SSC Registries/Databases: Clotting Factor Concentrates www.wfh.org Factor IX Database www.kcl.ac.uk/ip/petergreen/haemBdatabase.html Allergic Reactions to Factor IX Concentrates International Registry in Acquired von Willebrand Syndrome www.intreavws.com Protein S Deficiency: A Database of mutations – First Update Registry on Thrombosis and Thrombotic Risk in Women Receiving Ovarian Stimulation for Pregnancy vWF Database www.sheffield.ac.uk/vwf/ Other Registries/Databases: Bernard-Soulier Syndrome Factor VII Mutation Database http://193.60.222.13/ Factor VIII Database http://europium.csc.mrc.ac.uk/WebPages/Main/main.html Fibrinogen Database www.geht.org/databaseang/fibrinogen/ Glanzmann’s Thrombasthenia Database http://sinaicentral.mssm.edu/intranet/research/glanzmann/menu Human Gene Mutation Database http://archive.uwcm.ac.uk Mutation causing rare bleeding Disorders Chapter 116 of William Hematology 7th Edition - 2005 Protein C Database www.xs4all.nl/%7Ereitsma/Prot_C_home.htm Slide provided by Flora Peyvandi

  30. Other registries current databases.1 • Seitz R et al. ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Study Group. Semin Thromb Hemost. 1996;22:415-8 • Mariani G et al. Clinical manifestations, management, and molecular genetics in congenital factor VII deficiency: the International Registry on Congenital Factor VII Deficiency (IRF7). Blood. 2000;96:374 • 6. Greifswalder Hämophilie-Tagung 2001: - Batorova A et al. Ntl registry of FVII deficiency in Slovakia-clinical survey of 230 patients - Astermark J et al. The Malmö registry of FVII deficiency - Herrmann F et al. Greifswald registry of FX congenital deficiency • Dossenbach-Glaninger A and Hopmeier P. Coagulation factor XI: a database of mutations and polymorphisms associated with factor XI deficiency. Blood Coagul Fibrinolysis. 2005;16:231-8 • FranceCoag. French database collecting epidemiologic, clinical, treatment, and genetic data on patients affected by bleeding disorders (www.francecoag.org) • Acharya S et al. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost 2004;2:248-56 (NHF-MASAC) • AHCDC –Canadian Hemophilia Registry (http://www.fhs.mcmaster.ca/chr/index.htm) • Abshire T, Sumner M. HTRS Registry - A collaborative effort between HTRS and NovoNordisk, Inc. providing a platform to collect a common set of data from Hemophilia Treatment Centers (HTCs) • CDC – Department of Health and Human Service, Centres for Disease Control and Prevention (http://www.cdc.gov/ncbddd/hbd/hemophilia.htm) Slide provided by Flora Peyvandi

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