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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 l.jpg

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

Paula Bolton-Maggs

Consultant Haematologist

Manchester Royal Infirmary, UK





Slide8 l.jpg

North-America 1965-96:4 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


Rare coagulation disorders l.jpg
Rare coagulation disorders 1965-96

  • 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


Severe deficiency rare disorders l.jpg
Severe deficiency – rare disorders 1965-96

(data from Peyvandi, Rare coagulation disorders, thesis, 2000)


In vivo properties 1 rizza 1982 2 mannucci 2004 l.jpg
In vivo properties 1965-96(1:Rizza 1982, 2: Mannucci 2004)


What products are manufactured l.jpg

What products are manufactured? 1965-96

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


Fibrinogen treatment products l.jpg
Fibrinogen Treatment products 1965-96

  • Unlicensed virally inactivated concentrates

    • ZLB

    • SNBTS

    • LFB

  • Half life 3-5 days

  • Tranexamic acid

  • Cryo is a good source but not virally inactivated



Treatment for fii l.jpg
Treatment for FII 1965-96

  • 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


Treatment products fvii l.jpg
Treatment Products FVII 1965-96

  • 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)



Factor x treatment products l.jpg
Factor X Treatment Products 1965-96

  • 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



Therapeutic options in fxi deficiency l.jpg
Therapeutic options in FXI deficiency 1965-96

  • 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



Factor xiii deficiency l.jpg
Factor XIII deficiency 1965-96

  • 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.


Ssc working group on rare bleeding disorders rbds l.jpg
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


Slide24 l.jpg

North America:4 Disorders” (RBDs)

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


Slide25 l.jpg

Database development.3 Disorders” (RBDs)

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


Slide26 l.jpg

North-America Disorders” (RBDs): 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


Available treatments l.jpg

Database development.3 Disorders” (RBDs)

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


Problems with rbds treatments l.jpg

Database development.3 Disorders” (RBDs)

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


Slide29 l.jpg

Database development.3 Disorders” (RBDs)

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


Slide30 l.jpg

Genetic analysis Disorders” (RBDs)

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


Next steps l.jpg

Steering committee.4 Disorders” (RBDs)

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


Slide33 l.jpg

current databases.1 Disorders” (RBDs)

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


Slide34 l.jpg

Other registries Disorders” (RBDs)

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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