Nairobi Kenya June 24 2013 Objectives Identify historical approaches used to treat hemophilia Describe treatment products currently available for use in hemophilia Distinguish classes of factor concentrates ID: 244734
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Slide1
Treatment Products in Hemophilia
Nairobi, Kenya
June 24, 2013Slide2
Objectives
Identify historical approaches used to treat hemophilia
Describe treatment products currently available for use in hemophilia
Distinguish classes of factor concentrates
Discuss donor screening and viral inactivationList adjuvant therapies for treatment of hemophiliaExplore future therapies
Additional text exampleSlide3
Historical treatment of hemophilia
Injections of adrenaline
Ingestion of such compounds
as
1:Strychnine − TurpentineLead − Female hormoneBromide extracts of egg
− Peanut
flour
2 whites Topical snake venom3First blood transfusion in 1840 by Dr. Samuel Lane4
1
Rosendaal
FR,
Smit
C,
Briët
E
.
Ann
Hematol
. 1991; 62:5-15.
2
Mainwaring
D,
Keldon
S.E.
Lancet
. 1964; 19:647.
3
MacFarlane
RG, Barnett, B.
Lancet
. 1934; ii: 985–987
.
4
Lane
, S.
Lancet
. 1840; i: 185-188.Slide4
Cryoprecipitate Discovered
1965:
Discovery of
cryoprecipitate
Judith Graham Pool, MD
File photo courtesy of HANDI, NHF
Pool JG, Shannon AE.
N
Engl
J Med
.
1965:273:1443-1447.Slide5
Factor Concentrates Soon Appear
1966:
Hyland announces commercial availability of FVIII concentrates
1969:
FIX concentrate licensed1 Allowed for greater independence1. Hoag MS, et al. N
Engl
J Med.1969;280(11):581-6Slide6
The Price of Independence
1983:
Suspicion that HIV threatened the worldwide blood supply
1983:
Hemofil-T, first heat-treated FVIII concentrate in the US1984: Montagnier1
and Gallo
2
discover HTLV-3 (HIV)1984: Efficacy of heat treatment for viral inactivation demonstrated1984: Recall of blood products initiated
1985:
ELISA test used to detect HIV antibodies among blood donors
1985:
Safety net:
1.
Barre-Sinoussi
F, et al.
Science
1983; 220(4599):868-71.
2. Gallo RC, et al.
Science
1984; 4;224(4648):500-3.
Donor deferral
Viral inactivation
methods
A
ntibody and NAT testingSlide7
CLOTTING FACTOR CONCENTRATES AND OTHER PLASMA PRODUCTS
Factor replacement therapy
Fresh
frozen plasma (FFP)
CryoprecipitatePlasma-derived concentrates Recombinant concentratesSlide8
WFH recommendation
The WFH strongly recommends the use of viral-inactivated plasma-derived or recombinant concentrates in preference to cryoprecipitate or fresh frozen plasma for the treatment of hemophilia
Guidelines for the Management of Hemophilia, 2
nd
edition, WFH 2012Slide9
Choice of treatment product
Choice
of
treatment product is an
important decisionInfusion products should be chosen with provider, NMO, and patient/family input
Important
issues regarding infusion
products:EfficacySafetyPurity
CostSlide10
Plasma-derived products: purity
Concentrates on the market vary widely in their purity
High purity
Just the clotting factor in the vial exclusive of added stabilizers
Activity/protein ratio is very highIntermediate
purity
More than just the clotting factor in the vial
Activity/protein ratio mid-range Concentrates of lower purity may give rise to allergic reactionsFVIII concentrates may contain variable amounts of VWF
For treatment of FIX deficiency, a product containing only FIX is more appropriate than PCCsSlide11
Plasma-derived products: safety
Viral inactivation is the biggest contributor to safety of treatment products
Heat treatment: effective against enveloped
and
non-enveloped viruses including (HIV, HAV, HBV and HBC)Solvent/detergent treatment: effective against non-enveloped viruses such as HIV, HBV, HCV but not HAV)Some viruses resistant to both types of process (e.g. parvovirus B19)
Products undergo one or two viral inactivation steps; if one, preferably one that is effective against viruses with and without lipid envelopesSlide12
Recombinant Products
All recombinant products are high purity
Not made from human plasma
1
st generation: Added albumin as stabilizer, human/animal protein exposure during production2nd generation: Albumin removed as stabilizer, human/animal protein exposure during production
3
rd
generation: No added human or animal protein during production or in final formulationSlide13
Fresh frozen plasma
Contains all the coagulation factors
Due to concerns about safety and quality of FFP, it is not recommended for treatment of hemophilia, if avoidable
Possible to apply some forms of viral inactivation to packs of FFP but may have impact on coagulation factors
Large volumes of plasma must be transfused, which can lead to a complication called circulatory overload Slide14
cryoprecipitate
Prepared by slow thawing of FFP
Contains significant quantities of FVIII, VWF, fibrinogen and FXIII but
no FIX
Less safe from viral contamination than factor concentrates; harder to store and administerVirally-inactivated cryo has been described (S/D
cryo
)
Preferable to FFP for the treatment of hemophilia ACryo cannot be used for treatment of hemophilia BSlide15
plasma-derived products
Additional text example
Blood Donation in South Africa
Plasma Products:
Fresh Frozen Plasma (FFP) and Hyperimmune FFP
Whole Blood Donation
from voluntary, non-paid blood donors
Blood Products:
Cellular Products
PLASMA FOR NBI
<24 hr FFP,
shock frozen to - 30°C
Hyperimmune Plasma donation
from voluntary, non-paid
Plasmapheresis
donors
Whole Blood
Red Cell Concentrate
Platelet Concentrate
Cryofibrinogen
Cryoprecipitate
FFP
– Therapeutic
NBI, WPBTS and SA Blood Transfusion Services work together to optimise the donor’s gift of lifeSlide16
Hemophilia A: Evolution of Therapy
Year
Therapy
1950
Plasma (1-FVIII U/ml)
1966
Cryoprecipitate (5-FVIII U/ml)
1975
Lyophilized concentrates (30-FVIII U/ml)
1983
Heat treatment of lyophilized concentrates for viral attenuation
1985
Introduction of a solvent detergent for viral inactivation
1988
Monoclonal antibody-purified FVIII concentrates with heat or solvent detergent treatment
1992
Recombinant DNA products: 1
st
generation
2000s
2
nd
& 3
rd
generation recombinant productsSlide17
Hemophilia B: Evolution of Therapy
Year
Therapy
1950
Plasma (1-FIX U/ml)
1975
Lyophilized
prothrombin
complex concentrates or PCC (30-FIX U/ml)
1985
Heat treatment of lyophilized concentrates for viral attenuation
Development of a solvent detergent for viral inactivation
1992
Chromatographic/monoclonal antibody-purified FIX concentrate with ultrafiltration and
thiocyanate
treatment
1997
Recombinant DNA productSlide18
Factor Replacement Products
FVIII products
Advate
[r-3rd gen]Xyntha [r-3rd gen]
Kogenate
FS
[r-2nd gen]Helixate FS
[r-2nd
gen]
Recombinate
[r-1st gen
]
Hemophil
-M
[
pd
-HP]
Monoclate-P [pd-HP] VWF productsHumate-P
[pd-HP]Alphanate [pd-HP]Wilate [pd-HP]
FIX products
BeneFIX
[
r-3rd gen
]
Mononine
[
pd
-HP]
Profilnine
[
pd
-PCC]
Bebulin
[
pd
-PCC]
Bypassing agents
Novo Seven
[
r-3rd gen
]
FEIBA
[
pd-APCC]
http://www.hemophilia.org/research/masac/masac151.htmMASAC document #151 & 106Slide19
Other treatment products
Desmopressin
Boosts plasma levels of FVIII and VWF
Does not affect FIX levels
May be treatment of choice for patients with mild or moderate hemophilia A and carriersLower cost than plasma products and no risk of viral transmissionTest patient response prior to useAdministration:
IV
SQ
IntranasalSlide20
OTHER treatment PRODUCTS
Antifibrinolytic
agents
Promote clot stabilityUseful as adjunctive therapy, particularly for skin and mucosal bleeding, e.g. oral bleeding, epistaxis, menorrhagiaTranexamic acid available orally, IV, mouthwashEpsilon aminocaproic acid (EACA) similar but less widely usedDo NOT use in patients with hemophilia
B treated with PCCsSlide21
Other treatment products
Hormone therapy (women)
OCPs
IUDs
Topical hemostatic agentsFibrin sealant (fibrin glue)ReplacementIronVitamin D Slide22
Future Treatment Therapies for Hemophilia
Longer
acting concentrates
Recombinant
therapy for VWDAlternate route therapies
Gene
transplantation
Elimination of transfusion-associated infectionsUnderstanding and
overcoming
inhibitor development
Quality
of life
issues
Elimination
of joint
morbidity
Optimizing
the individual’s social and academic performanceSlide23
Summary
Treatment in hemophilia continues to progress
FFP and cryoprecipitate are still used in many parts of the world
Replacement therapies are available in a variety of forms
Choosing a factor concentrate is important to all involved in careEfficacy, safety and cost remain important considerations when choosing a treatment productAdjuvant therapies are available to assist in hemophilia treatment
The future of hemophilia treatment appears promisingSlide24
WFH resources
Guide
for the Assessment of Clotting Factor Concentrates
Registry of Clotting Factor
ConcentratesFibrinolytic Inhibitors in the Management of Bleeding Disorders
Desmopressin (DDAVP) in the Treatment of Bleeding Disorders
Guidelines for the Management of Hemophilia, 2
nd ed