RECOMMENDATION

Principles of treatment and update of recommendations for the

management of haemophilia and congenital bleeding disorders in Italy
Angiola Rocino1, Antonio Coppola2, Massimo Franchini3, Giancarlo Castaman4,5, Cristina Santoro6,
Ezio Zanon7, Elena Santagostino8, Massimo Morfini9 on behalf of the Italian Association of Haemophilia
Centres (AICE) Working Party (see appendix 1)

1
Haemophilia and Thrombosis Centre, San Giovanni Bosco Hospital, Naples; 2Regional Reference Centre for
Coagulation Disorders, Federico II University Hospital, Naples; 3Department of Transfusion Medicine and
Haematology, Carlo Poma Hospital, Mantua; 4Haemophilia and Thrombosis Centre, Department of Haematology,
San Bortolo Hospital, Vicenza; 5Centre for Bleeding Disorders, Careggi University Hospital, Florence;
6
Haematology, Department of Cellular Biotechnology and Haematology, Sapienza University of Rome, Rome;
7
Haemophilia Centre, Department of Cardiologic, Thoracic and Vascular Sciences, University of Padua Medical
School, Padua; 8Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, IRCCS Ca' Granda Foundation,
Maggiore Hospital Policlinico, Milan; 9Italian Association of Haemophilia Centres (AICE), Italy

1. Introduction
Patients with congenital bleeding disorders
(CBD) in Italy are regularly followed by 52
l
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to recognise any side effects, and to keep accurate
records of each infusion made. To this purpose, the
HTCs periodically organise courses and training
educational activities to grant qualification for home

i
Haemophilia Treatment Centres (HTCs) distributed
throughout the country1. The expertise gained from
these HTCs is coordinated within the framework
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treatment to the patients or their family members.
The HTCs are also responsible for a periodic review
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of the Italian Association of Haemophilia Centres and assessment of skills for self-management of
(AICE, Associazione Italiana Centri Emofilia). home treatment for each individual patient. All
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This medical organisation promotes an uniform
approach to the treatment of haemophilic syndromes,
developing shared therapeutic strategies, conducting
collaborative clinical research activities and handling
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these procedures are governed by specific regional
regulations4.
In the last decade there have been significant
advances in the therapy of haemophilia and related

the organisational aspects of the facilities providing inherited bleeding disorders. The technological
care of CBD patients in Italy. AICE collaborates with evolution of the processes of purification and viral
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the National Institute of Health (Istituto Superiore di inactivation has allowed the marketing of new
Sanità, ISS) in the management and updating of the plasma-derived concentrates5, while progress with the
National Registry of Congenital Coagulopathies1. It production of factor VIII (FVIII) and factor IX (FIX)
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also holds a database for the census and monitoring in animal cells by recombinant DNA technology
of patients with CBD, registries collecting data on has enabled the progressive elimination of human
specific aspects of treatment (e.g., AICE Registry and animal proteins from various stages of the
©

of Immune Tolerance Induction [ITI] in severe
haemophilia A patients with inhibitors; RENAWI,
National Registry of von Willebrand disease) and
databases of gene mutations in haemophilia A and B
patients. Some HTCs members of AICE participate
in the European Haemophilia Safety Surveillance
(EUHASS).
The management of patients with CBD is
essentially based on home treatment2 which allows
replacement therapy to be carried out as soon as
possible and is associated with a higher therapeutic
efficacy and a better quality of life3. Self-treatment at
home does, however, imply that the patient (and/or
his caregiver) is specifically trained to take decisions
on the proper timing of administration of replacement
therapy, to adhere strictly to the prescribed dosage,
manufacturing process. Some recombinant products
have, therefore, been replaced by newer generation
products and other innovative molecules are currently
in an advanced experimental or registration stage6.
Considering these important developments, the AICE
working group has updated the Italian treatment
guidelines7, taking into account the recommendations
by the World Federation of Haemophilia (WFH)8, by
the European Association of Haemophilia and Allied
Disorders (EAHAD)9, and the recent approval of an
agreement of the national State-Regions Conference,
which defined care pathways to meet the specific needs
of CBD patients and to ensure uniform levels of care
throughout the country4. The AICE working group also
carried out systematic reviews of the literature aimed
to assess the quality of the available evidence on issues

Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14

© SIMTI Servizi Srl
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still controversial, in particular the risk of development
of inhibitor in previously untreated patients (PUPs) with
severe haemophilia A10. In addition, a survey among
Directors of HTCs that are members of AICE, which
was attended by 77% (40/52) of them, was carried
out11. An ad hoc questionnaire (19 questions), was
specifically designed to determine the opinion of
clinicians about the most important aspects of the
treatment of haemophilia, including the choice of
products for replacement therapy in patients with
different clinical characteristics, indications for
prophylaxis and ITI treatments and the modality of
implementation of these regimens. The reviews of the
literature and the results of the survey were used to
define cornerstone "principles" for the management
and treatment of patients with CBD, which have
been shared with the Italian Federation of Haemophilia
Associations (FedEmo, Federazione delle Associazioni
Emofilici) and were approved by AICE members on
October 8, 2013.
2. Factor concentrates for replacement
treatment in Italy
Coagulation factor concentrates in Italy are used in
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hospital and in the home setting according to national
and regional rules. Licensed plasma-derived and
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recombinant products are provided by the National
Health Service and distributed mainly by health service
pharmacies, free of cost for patients. Only HTCs
recognised at a regional level can prescribe replacement
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products, on the basis of individual therapeutic plans.
These prescriptions are updated at the patients' regular
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follow-up visits, usually every 3-6 months but at
intervals not exceeding 12 months.
The characteristics of FVIII, FIX, bypassing agent
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and prothrombin complex concentrates available in Italy
are summarised in Tables I, II, III and IV, respectively,
and can be found in the international registries12,13.
©
Table V shows other factor concentrates used for the
treatment of von Willebrand's disease (VWD) and rare
CBD. Most of the latter are not licensed in Italy, but can
be provided by direct import after specific authorisation
from the Italian Agency for Drugs (AIFA, Agenzia
Italiana del Farmaco) to be used under the prescribers'
responsibility.
3. Safety of factor concentrates for replacement
therapy of congenital bleeding disorders
3.1 Pathogen safety
Until the mid-1980s, the infusion of large amounts of
non-virally inactivated plasma products from single donor
and/or plasma-derived concentrates obtained from pools
of thousands of donors transmitted hepatitis viruses B and
C (HBV, HCV) to more than 90% of patients undergoing
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Rocino A et al
replacement therapy14,15. The epidemic spread of human
immunodeficiency virus (HIV) infection affected about
30 and 70% of Italian hemophilia A and B patients,
respectively16. However, more than a quarter of a century
has elapsed since FVIII and FIX concentrates produced
with recombinant DNA technology and virally inactivated
plasma-derived concentrates became available and no
cases of transmission of blood-borne viruses through
plasma-derived products have been recorded over the
last 25 years17-19. Furthermore, the high safety profile of
all the products for replacement therapy of haemophilia
and CBD was recently confirmed as part of a monitoring
programme underway in Europe since 2008 (EUHASS,
www.EUHASS.org)20.
Several factors have contributed to the significant
improvement of the viral safety of plasma-derived
factor concentrates, including the adoption of quarantine
of plasma units used for industrial fractionation and
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the introduction of nucleic acid amplification testing
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for five viruses (HIV 1-2, HBV, HCV, hepatitis A
virus and parvovirus B19) for all factor concentrates
currently commercialised. In addition, in Italy, Kedrion
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is producing and distributing coagulation factor
concentrates using plasma collected from the network
of Italian transfusion centres, which have undergone
nucleic acid amplification testing for three viruses
(HIV 1-2, HBV, HCV). Furthermore, the so-called Plasma
Master File is being implemented throughout the country
and the full extension to all Italian transfusion centres
is expected by December 31, 201421. Viral inactivation
techniques (dry heating, pasteurisation, vapour and
solvent/detergent [S/D] procedures), which have become
integral part of their manufacturing process, are attributed
an essential role in the viral safety of factor concentrates.
It is known that HIV is particularly sensitive to heat
treatment, while hepatitis viruses necessitate higher
temperatures for longer periods of time to be inactivated and
non-enveloped viruses (e.g., hepatitis A virus and
parvovirus B19) are not inactivated by S/D treatment22.
Thus, to minimise the viral infectious risk, the great majority
of producers have adopted two inactivation methods in the
preparation of coagulation factor concentrates, combining
S/D methods with heating, and introducing ultrafiltration
and nanofiltration techniques, which remove smaller and
non-enveloped viruses22. The safety profile of recombinant
products has also been improved. Together with the
implementation of viral inactivation techniques, similar
to those used for plasma-derived products, manufacturers
have pursued the progressive removal of human and
animal proteins from the production process and the
final formulation. The first generation of recombinant
FVIII (rFVIII) products used animal-derived proteins in
the cell culture medium, and had human serum albumin
added to stabilise the protein in the final formulation23.
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
 Table I - Plasma-derived and recombinant factor VIII concentrates available in Italy.

Plasma-derived FVIII concentrates

Brand Specific activity

Fractionation Viral inactivation Comments
(Company) (IU/mg of total proteins)
Alphanate* Precipitation/heparin ligand Solvent/detergent (TNBP/Tween 80) + ~100 Albumin +
(Grifols, Sant Cugat chromatography dry heat 80 °C, 72 h VWF +
del Vallès, Spain) VWF:RCo/FVIII:C=1.03
250 IU and 500 IU in 5 mL solvent
1,000 IU and 1,500 IU in 10 mL solvent
Beriate P Ion exchange chromatography Pasteurization at 60 °C, 10 h 170 Albumin –
(CSL Behring, King VWF –
of Prussia, PA,
© 250 IU in 2.5 mL solvent
USA) 500 IU in 5 mL solvent
1,000 IU and 2,000 IU in 10 mL solvent
Italian principles for haemophilia treatment

EMOCLOT Ion exchange chromatography Solvent/detergent (TNBP/Tween 80) + >80 Albumin –

(Kedrion, dry heat 100 °C, 30 min VWF +
SI
Castelvecchio 500 IU and 1,000 IU in 10 mL solvent
Pascoli (LU), Italy)
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Fanhdi* Precipitation/heparin ligand Solvent/detergent (TNBP/Tween 80) + ~100 Albumin +
(Grifols) chromatography dry heat 80 °C, 72 h VWF +
VWF:Rco/ FVIII:C=1.48

Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14

250 IU, 500 IU and 1,000 IU in 10 mL solvent; 1,500 IU in 15 mL solvent
TI
Octanate Adsorption on aluminium hydroxide gel, Solvent/detergent (TNBP/Polysorbate 80) ≥100 Albumin –
(Octapharma ion exchange chromatography, filtration + dry heat 100 °C, 30 min VWF+
AG, Lachen, 250 IU in 5 mL solvent
Switzerland) 500 IU and 1,000 IU in 10 mL solvent
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Haemate P* Multiple precipitation Pasteurisation at 60 °C, 10 h ~38 Albumin +
(CSL Behring) VWF +

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VWF:Rco/FVIII:C=2.4
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500 IU in 10 mL solvent
1,000 IU in 15 mL solvent
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Haemoctin Precipitation on aluminium hydroxide gel, Solvent/detergent (TNBP/Tween 80) + 103.5 Albumin –
(Biotest AG, anion exchange chromatography dry heat 100 °C, 30 min VWF +
Dreieich, Germany)
i 250 IU in 5 mL solvent
500 IU and 1,000 IU in 10 mL solvent
Talate* Ion exchange chromatography Detergent (Polysorbate 80) + 70 Albumin +
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(Baxter Healthcare, vapour heat 60 °C, 10 h VWF +
Deerfield, IL, USA)
l VWF:Rco/FVIII:C=1.1
1,000 IU in 10 mL solvent
Wilate* Precipitation on aluminium hydroxide, ion Solvent/detergent (TNBP/Octoxynol) + >100 Albumin –
(Octapharma) exchange chromatography, size exclusion dry heat 100 °C, 2 h VWF +
chromatography VWF:Rco/FVIII:C=1.0
450 IU and 500 IU in 5 mL solvent
900 IU and 1,000 IU in 10 mL solvent
continues on next page

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Table I - Plasma-derived and recombinant Factor VIII Concentrates available in Italy (continued from previous page).
Recombinant FVIII concentrates
Brand Fractionation Viral Inactivation Specific activity Comments
(Company) (IU/mg of total proteins)
Recombinate MoAb affinity cromatography, ion None >4,000 Octocog alfa; full-length rFVIII derived from CHO cells;
(Baxter) exchange chromatography Albumin +
VWF −
© 250 IU, 500 IU and 1,000 IU in 10 mL solvent

Kogenate Bayer^ Ion exchange chromatography, MoAb Solvent/detergent 2,600-6,800 Octocog alfa; full-length rFVIII derived from BHK cells;
(Bayer Healthcare, affinity chromatography, metal chelate (TNBP/Polysorbate 80) Albumin –
Berkeley, CA, affinity chromatography, cationic exchange VWF –
SI
USA) chromatography 250 IU, 500 IU and 1,000 IU in 2.5 mL solvent; 2,000 IU and
M 3,000 IU in 5 mL solvent

Helixate NexGen Ion exchange chromatography, MoAb Solvent/detergent 2,600-6,800 Octocog alfa;full-length rFVIII derived from BHK cells;
(CSL Behring)# affinity chromatography, metal chelate (TNBP/Polysorbate 80) Albumin –
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affinity chromatography, cationic exchange VWF –
chromatography 250 IU, 500 IU and 1,000 IU in 2.5 mL solvent; 2,000 IU and
3,000 IU in 5 mL solvent
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No other uses without permission

Advate MoAb affinity chromatography, ion Solvent/detergent 4,000-10,000 Octocog alfa; full-length rFVIII derived from CHO cells;
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(Baxter) exchange chromatography (TNBP/Triton X-100/ Polysorbate 80) Albumin –
VWF –
250 IU, 500 IU, 1,000 IU, 2,000 IU and 3000 IU in 5 mL solvent
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ReFacto AF Ion exchange chromatography, Solvent/detergent (TNBP/Triton 7,600-13,800 Moroctocog alfa; B-domain-deleted rFVIII derived from CHO cells;
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ReFactoAF hydrophobic interaction chromatography, X-100), nanofiltration (35 nm pore size Albumin –
fuseNGO° size exclusion chromatography, affinity filter) VWF –
(Pfizer Inc., New chromatography with a synthetic peptide
l 250 IU, 500 IU, 1,000 IU, 2,000 IU and 3,000 IU in 4 mL solvent
York, NY, USA) (27 amino acids)

* Licensed for use in patients affected by haemophilia A and VWD; ^ The package contains a pre-filled diluent syringe; # Dealer distribution company (the product is the same as that manufactured by Bayer);
° The package contains a dual chamber pre-filled syringe; MoAb: monoclonal antibody (murine); BHK: baby hamster kidney; CHO: Chinese hamster ovary.

Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14

Rocino A et al
Italian principles for haemophilia treatment

Table II - Plasma-derived and recombinant factor IX foncentrates available in Italy.

Plasma-derived FIX concentrates

Brand Specific activity

Fractionation Viral inactivation Comments
(Company) (IU/mg of total proteins)

AIMAFIX Ion exchange Solvent/detergent (TNBP/Tween 80) 100 Antithrombin +

(Kedrion) chromatography, heparin + dry heat 100 °C, 30 min Heparin +
affinity chromatography, Albumin –
filtration 200 IU in 5 mL solvent.; 500 IU
and 1,000 IU in 10 mL solvent

AlphaNine Ion exchange Solvent/detergent + nanofiltration >210 Heparin +

(Grifols) chromatography, dual (15 nm pore size filter) Antithrombin –
polysaccharide ligand Albumin –
chromatography 500 IU, 1,000 IU, 1,500 IU in 10
mL solvent

FIXNOVE Ion exchange Detergent (Polysorbate 80) ~100 Antithrombin –

(Baxter) chromatography, + vapour heat, 60 °C 10 h, 190 mbar Heparin –
hydrophobic interaction + 80 °C, 1 h, 375 mbar 1,200 IU in 10 mL solvent
chromatography

l
Sr
Haemobionine Anion exchange Solvent/detergent (TNBP/ >100 Heparin +
(Biotest) chromatography, MoAb Polysorbate 80) + nanofiltration Albumin –
affinity chromatography, (15 nm pore size filter) 250 IU and 500 IU in 5 mL

i
hydrophobic interaction solvent

Octanine
chromatography

Ion exchange Solvent/detergent

iz >100
1,000 IU in 10 ml solvent

Heparin +
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(Octapharma) chromatography, heparin (TNBP/Polysorbate 80) + Albumin –
affinity chromatography, nanofiltration 500 IU in 5 mL solvent
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ultrafiltration/diafiltration 1,000 IU in 10 mL solvent

Mononine MoAb affinity Sodium thiocyanate + ultrafiltration >190 Albumin –

(CSL Behring) chromatography (35 nm pore size filter) 500 IU in 5 mL solvent
1,000 IU in 10 mL solvent
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Recombinant FIX concentrate

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Brand Specific activity

Fractionation Viral Inactivation Comments
(Company) (IU/mg of total proteins)
SI

BeneFIX Ion exchange Nanofiltration >200 Nonacog alfa; no human or

(Pfizer) chromatography; (20 nm pore size filter) animal proteins used in the
metal chelate affinity manufacturing process;
chromatography 250 IU, 500 IU, 1,000 IU, 2,000
©

IU and 3,000 IU in 5 mL solvent

MoAb: monoclonal antibody (murine).

Table III - Characteristics of bypassing agent products for treatment of haemophilia patients with inhibitors available in Italy.

Brand (Company) Fractionation Viral inactivation Comments

FEIBA TIM 3 (Baxter)
Adsorption, filtration, ion exchange
chromatography
Vapour heat 60 °C, 10 h + 80 °C
1 h, nanofiltration (75 and 35 nm
pore size filters)
Activated prothrombin complex
concentrate (activated and zymogen factors
II, VII, IX and X).
Contains traces of FVIII.
1,000 FEIBA units in 20 mL solvent

NovoSeven (Novo Nordisk
A/S, Bagsvaerd, Denmark)
Ion exchange chromatography,
MoAb affinity chromatography
Triton X-100, nanofiltration
(20 nm pore size filter)
Eptacog alfa (recombinant activated
FVII). Contains sucrose as stabiliser and
methionine as antioxidant.
1 mg in 1.1 mL solvent; 2 mg in 2.1 mL
solvent; 5 mg in 5.2 mL solvent

MoAb: monoclonal antibody (murine).

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 Rocino A et al

Table IV - Characteristics of prothrombin complex concentrates available in Italy.

Brand* Fractionation Viral inactivation Clotting factor content Anticoagulant proteins Heparin
(Company) (IU/mL) (IU/mL) (IU/mL)
FII FVII FIX FX PC PS AT
UMAN COMPLEX Ion exchange Solvent/detergent 25 - 25 20 - - 0.125 12.5
(Kedrion) chromatography (TNBP/Tween 80)
+ dry heat 100 °C,
30 min

Protromplex TIM 3 Ion exchange Detergent 30 - 30 30 - - - 1.5

(Baxter) chromatography (Polysorbate 80) +
vapour heat 60 °C,
10 h at 190 mbar
+ 80 °C, 1h at 375
mbar

Confidex Ion exchange Pasteurisation 20-48 10-25 20-31 22-60 15-45 12-38 0.2-1.5 0.4-2.0
(CSL Behring) chromatography 60 °C, 10 h;
nanofiltration
(75 nm and 35 nm
pore size filters)

l
Sr
Pronativ Ion exchange Solvent/ 14-38 9-24 25 18-30 13-31 12-32 NQ 5.0-12.5
(Octapharma) chromatography detergent (TNBP/
Polysorbate 80)
+ nanofiltration

i
(20 nm pore size
filter)
PC: protein C; PS: protein S; AT: antithrombin; NQ: not quantified.
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*All the products are available in formulations of 500 IU with the exception of Protromplex® (600 IU). The total reconstitution volume is 20 mL for all products.
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However, some studies demonstrated the presence of recombinant products used for the replacement
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viral particles related to Transfusion Transmitted Virus treatment of Gaucher's and Fabry's diseases, which
(TTV) in such first generation recombinant products24. resulted in a significant slowdown of production and
Thus, second-generation products use human or a temporary shrinkage of the two products on the
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animal-derived proteins in the culture medium but have market28.

no albumin added to the final formulation. Finally, The report of the autopsy detection of variant
third-generation rFVIII products, manufactured without Creutzfeldt-Jacob disease in the spleen of an
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human- or animal-derived proteins in either the culture asymptomatic UK patient infused with FVIII concentrates
medium or the final formulation, have been developed23. from plasma pools known to include donations from a
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However, as for any biological product, it is not donor with variant Creutzfeldt-Jacob disease9 has raised
possible to guarantee the complete absence of risk. some concerns on the possibility of prion transmission
For plasma-derived products, the risk is represented through plasma-derived concentrates. Although the
©

mainly by non-enveloped viruses such as Parvovirus,
Picornavirus and Circovirus25,26. Cases of Parvovirus
B19 seroconversion following transfusion of plasma-
derived concentrates have been documented 27 .
Furthermore, although most of the manufacturers
currently use nucleic acid amplification testing to
exclude the presence of this virus, the seroprevalence
of Parvovirus B19 continues to be two times higher
in haemophilia patients who receive plasma-derived
concentrates than in the general population of the
same age27. Even for recombinant products, despite
the sophisticated technologies used in the production
process, it is not possible to rule out a risk, albeit
theoretical, of cross-species infection. Such a risk
was highlighted by the occurrence of contamination
with viruses belonging to the Vesivirus family of
cell cultures employed in the manufacturing of two
route of transmission of prion in this patient was not
definitively ascertained, plasma-derived concentrates
were considered the most likely source of infection29.
However, it should be noted that none of the 604 British
patients exposed, between 1987 and 1999, to lots of
plasma-derived concentrates from donors who
subsequently developed variant Creutzfeldt-Jacob
disease, showed clinical signs of the disease after a
median of 15 years30. In addition, the risk that plasma-
derived products could be contaminated by prions has
now been considerably reduced by the application of
strict rules of selection of blood donors. Furthermore,
experimental studies have demonstrated that the plasma
fractionation process and subsequent purification
procedures are highly effective at eliminating infectious
agents, including human prions. In this respect, the
reduction of the contamination risk achievable with

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Italian principles for haemophilia treatment

Table V - Other factor concentrates for the treatment of von Willebrand's disease and rare congenital bleeding disorders.
Brand Indication for use in Fractionation Viral inactivation Specific activity (IU/ Comments
(Company) patients affected by mg of total proteins)
CLOTTA-FACT* Fibrinogen defects Ion exchange Solvent/detergent >0.8^ -
(LFB, Les Ulis, chromatography (TNBP/Polysorbate 80)
France) + dry heat 80 °C, 72 h +
nanofiltration (35 nm pore
size filter)
Confidex FII deficiency, FX Multiple Pasteurisation at 60 °C, FII ~ 3.5 Protein C 300-900 IU/vial;
(CSL Behring) deficiency; precipitation; 10 h; nanofiltration FVII ~ 1.7 Protein S 240-760 IU/vial
Combined vitamin adsorption FIX ~ 2.5 Antithrombin +,
K-dependent factors FX ~ 4.1 Heparin +,
deficiency Albumin +
Factor X P* Factor X deficiency Multiple Pasteurisation at 60 °C, 10 h 4-60 Contains some amount
(CSL Behring) precipitation and of FIX; antithrombin and
adsorption steps heparin added, no albumin
Fibrogammin P* FXIII deficiency Multiple Pasteurisation at 60 °C, 10 h 3.9-10.4 Albumin +
(CSL Behring) precipitation;
ion exchange
chromatography

l
Haemocomplettan* Fibrinogen defects Adsorption Pasteurisation at 60 °C, 20 h 1.7^ Albumin +

Sr
(CSL Behring) on aluminum
hydroxide gel;
filtration

i
HEMOLEVEN* FXI deficiency Ion exchange Solvent/detergent (TNBP/ 50-150 Heparin 30-60 IU/vial+
(LFB) chromatography;
depth filtration
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Tween 80)+Nanofiltration
(15 nm pore size filter)
Antithrombin 25-55 IU/
vial +C1 esterase inhibitor
17-40 IU added
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NovoSeven FVII deficiency Ion exchange Triton X-100+nanofiltration 50 KU Eptacog alfa (recombiant
(Novo Nordisk) chromatography; (20 nm pore size filter) activated FVII). Contains
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MoAb affinity sucrose as stabiliser and

chromatography methionine as antioxidant.
NovoThirteen FXIII A-subunit Anion exchange None° ~165 Catridecagog; produced
(Novo Nordisk) deficiency (DEAE) in yeast cells (Saccharo-
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chromatography; myces cerevisiae); no

double filtration human or animal derived
(0.2 μM) materials.
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Provertin-UM FVII deficiency Ion exchange Vapour heat 60 °C, 10 h at >2 Heparin added
(Baxter) chromatography 190 mbar and 80 °C, 1 h at
375 mbar+nanofiltration
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(35 nm pore size filter)

UMAN COMPLEX FII deficiency, FX Ion exchange Solvent/detergent FII ~ 25# Antithrombin +
(Kedrion) defi-ciency chromatography (TNBP/Tween 80)+dry heat FX ~ 20# Heparin added
100 °C, 30 min
©

WILFACTIN VWD Adsorption Solvent/detergent >50 Albumin added

(LFB, distributed on aluminium (TNBP/Polysorbate FVIII + (<10 UI/100 RCo)
by Kedrion) hydroxide gel; 80)+nanofiltration
ion exchange (35 nm pore size filter)+
chromatography; dry heat 80 °C, 72 h
affinity
chromatography
*The product is not licensed in Italy, but is available by direct import after specific authorisation by the AIFA. ^mg fibrinogen/mg total protein;
°In compliance with current EMA guidelines (the cells used for production are fungi, with fermentation medium free of animal or human components);
#IU/mL of reconstituted product.

current purification methods is estimated to range 3.2 Inhibitor development

from 100,000 to more than 1,000,000 times31,32. In
conclusion, all these measures have contributed to
improve the infectious safety of therapeutic products
for haemophilic syndromes and there is no doubt that
both the plasma-derived and recombinant concentrates
currently available have a very good safety profile.
The development of alloantibodies directed against
the exogenous coagulation factor given as replacement
therapy and usually interfering with its clotting activity
(inhibitors) is today the most serious complication
of haemophilia treatment. Inhibitor formation makes
replacement treatment ineffective, preventing patients

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from receiving long-term prophylaxis and exposing
them to an increased risk of mortality, morbidity and
disability with a tremendous impact on their quality
of life33-35. The occurrence of inhibitors is much rarer
in haemophilia B, in which it is often associated with
the presence of large deletions in the F9 gene36, but in
about half of patients with haemophilia B and inhibitors
severe allergic reactions in association with treatment
with products containing FIX further complicate the
therapeutic management37.
Long-term prospective studies in PUPs and
previously treated patients (PTPs) have allowed the
incidence of inhibitors in haemophilia A to be assessed38.
Inhibitors develop in approximately one third of PUPs
with severe haemophilia A, usually within the first 10-15
days of exposure. The inhibitor risk is greatly reduced
in PTPs exposed to FVIII concentrates for more than
50-150 days38, but it never disappears, persisting even in
the elderly although to a lesser extent39. The mechanisms
responsible for this complication are still only partially
understood. Studies in PUPs have identified several
risk factors, both genetic (ethnicity, null mutations in
the F8 gene, major histocompatibility complex [MHC]
genotype, polymorphisms of immunoregulatory genes)
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and related to treatment, which indicate a complex multi-
factorial pathogenesis40,41. The source of replacement
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products (plasma-derived or recombinant) has been
suggested to be implicated in these mechanisms.
However, experimental studies 42,43, cohort studies
in PUPs44-46 and several systematic reviews of the
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literature38,47,48, including the meta-analysis conducted
by AICE10, did not provide conclusive results about
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a possible difference between FVIII concentrates of
different source or among the various generations of
rFVIII products in determining the risk of inhibitor
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development.
The persistent state of uncertainty regarding this issue
was the reason for conducting a clinical randomised
©
controlled trial (SIPPET, Survey of Inhibitors in Plasma-
Product Exposed Toddlers)49, currently in progress,
which was specifically designed to assess whether
recombinant and VWF-containing plasma-derived
FVIII products are equally immunogenic. Pending the
results of this study, prospective data, collected as part
of the EUHASS monitoring programme, are available.
No significant difference in inhibitor incidence
following exposure to plasma-derived or recombinant
FVIII concentrates has been found in the first 4 years
of observation50, although this finding needs further
confirmation in a larger number of cases and during a
longer follow-up period. In addition, the results of the
RODIN study51, a prospective multicentre study aimed
at identifying the risk factors of inhibitor development
in PUPs with severe haemophilia A during the first
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Rocino A et al
75 days of exposure, failed to show any difference in
inhibitor rates between patients treated with recombinant
or plasma-derived concentrates. This study did show
a 1.6 times higher risk of inhibitor development in
PUPs treated with second-generation full-length rFVIII
compared to those treated with a third-generation full-
length rFVIII51. However, once again, additional studies
are required to confirm this observation which does
not seem to be attributable to any known biological
mechanism and is not supported either by evidence
arising from the European surveillance50 or by the most
recent meta-analysis of prospective studies conducted
in PUPs exposed to FVIII concentrates of different
sources10.
Regarding inhibitor development in PUPs with
haemophilia B37 and patients with type 3 VWD52, there is
currently no scientific evidence supporting any particular
association with the type of product used for replacement
l
therapy. For both these CBD, the most important risk
Sr
factor is the type of gene mutation determining the
severity of the disease. However, no study has so far
investigated the role of factors other than gene mutations
i
iz
in influencing the risk of developing inhibitors in these
two diseases.
PTPs with haemophilia are considered the
most appropriate population for evaluating the
immunogenicity of different products53. In fact, it is
believed that PTPs have already acquired immunological
tolerance. Several studies and systematic reviews of
the literature38,54,55 have evaluated the incidence of de
novo inhibitors in PTPs, who underwent a switch from
a plasma-derived to a recombinant product. According
to a recent meta-analysis evaluating 33 independent
cohorts (total patients: 4,323), the estimated inhibitor
incidence was 3 (95 % CI 1-4) per 1000 patients/year
and no specific risk factors, including the type of factor
concentrate, were identified55. Thus, available evidence
does not support a significant risk of de novo inhibitors in
PTPs switched from a plasma-derived to a recombinant
FVIII product and from one recombinant FVIII product
to another56-58. Nevertheless, it is always advisable to
monitor each patient carefully every time a new product
is introduced into clinical practice. Indeed, rare adverse
events may not be observed in licensing clinical trials
since these are generally of restricted duration and
involve a limited number of patients. The need for
careful inhibitor monitoring in PTPs is also supported
by the residual, although low, inhibitor risk that these
patients carry throughout their life39.
3.3 Thrombogenicity
Albeit rarely, the use of activated factor concentrates
(activated prothrombin complex concentrates [APCC]
and recombinant activated factor VII [rFVIIa]) in
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Italian principles for haemophilia treatment
haemophilia patients with inhibitor has been associated
with the occurrence of thrombotic complications,
including deep vein thrombosis, pulmonary embolism,
disseminated intravascular coagulation and myocardial
infarction59-61. It is believed that these complications are
due to the presence of activated coagulation factors in the
concentrates. The thrombotic risk is related to the dose
used, the duration of treatment and the combination of
other risk factors, such as surgery, prolonged bed-rest,
liver disease, cardiovascular and metabolic disorders,
and active infections, which increase the propensity of
patients to the development of thrombotic events. By
similar mechanisms and inducing abnormally high FX
and FVII levels, prothrombin complex concentrates
(PCC) used in the past in haemophilia B patients
were associated with a thromboembolic risk62, while
modern PCC do not contain activated clotting factors63.
The currently available plasma-derived purified FIX
concentrates contain minimal traces of other coagulation
factors and their safety profile has been supported by
studies aimed at detecting any signs of activation of the
coagulation system64,65 In addition, a recent systematic
review of prospective studies published after 1990 did
not reveal any major arterial or venous thrombotic
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complication in 748 haemophilia B patients treated
with seven different FIX concentrates, reporting only
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11 minor events (superficial thrombophlebitis), almost
always in association with continuous infusion and
invasive procedures66. Cases of thrombosis and signs of
activation of the coagulation system were also described
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following the use of FXI concentrate, although in the
presence of other risk factors67, as well as in association
M
with fibrinogen replacement therapy in patients with
congenital fibrinogen deficiency 68. However, the
intrinsic susceptibility of patients affected by the latter
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defect towards the occurrence of venous and arterial
thrombotic events is well recognised69.
The rate of reported thrombotic complications in
©
haemophiliacs with inhibitor has been estimated to be as
low as one case per 3.87×105 standard-dose infusions of
rFVIIa70 and 8.4×105 infusions of APCC71. Nevertheless,
close monitoring of tests of coagulation activation is
recommended in patients receiving intensive treatment
(high doses and/or prolonged) with bypassing agents,
especially in the presence of thrombotic risk factors.
Even repeated infusions of VWF/FVIII concentrates
given to patients with VWD at close intervals for the
treatment of severe bleeding or after surgery may result
in an increased risk of venous thromboembolism, due
to the achievement of persistently high (>150%) FVIII
plasma levels, especially in patients with additional
risk factors72. However, the aforementioned systematic
review of prospective studies published after 1990,
along with five episodes of superficial thrombophlebitis,
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showed only two documented venous thromboembolic
complications in 361 VWD patients treated with nine
different products following over 8,000 concentrate
infusions66. In both cases, treatment for surgery for more
than 10 days in association with high levels of circulating
FVIII, was reported. By contrast, no arterial or venous
thrombotic episodes, with the exception of two episodes
of superficial thrombophlebitis, were recorded in over
4,400 haemophilia A patients treated with 15 different
FVIII concentrates (9 plasma-derived containing VWF
and 6 recombinant)66. These observations indicate
the need for close monitoring of replacement therapy
in patients with VWD, taking into account the VWF
and FVIII content in the products used, and the use of
thromboprophylaxis in patients undergoing surgery and/
or with concomitant thrombotic risk factors.
4. Recommendations for treatment of congenital
l
bleeding disorders
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4.1 General recommendations
4.1.1 Vaccinations
All patients with CBD who may require treatment
i
iz
with blood products should be immunised against
HBV7. In Italy, HBV vaccination is scheduled by law
since 1991 for all infants within the first year of life.
Anti-HBs antibody titre should be periodically checked
in CBD patients, in order to administer booster doses if
needed. HBV vaccination is also suggested in all family
members or caregivers involved in home treatment of
HBsAg-positive patients. As regards hepatitis A viurs,
although recommendations vary among different groups
of experts, vaccinations against this virus may be still
advisable73,74, especially for those patients with rare
CBD who are candidates for the use of plasma-derived
concentrates and/or SD virally inactivated plasma.
4.1.2 Coagulation factor concentrates
Licensed specific coagulation factor concentrates
are the products of choice for replacement treatment of
patients with CBD. Non-licensed products should be
used only in the frame of clinical trials. When specific
concentrates are not available/licensed in Italy, the use
of virally inactivated replacement products is always
recommended. In patients on replacement treatment with
factor concentrates, frequent product changes should
be avoided in the absence of rigorous clinical reasons,
in order to preserve pharmacovigilance and patients'
adherence to treatment75. When clinically indicated,
patients with mild CBDs should be treated with synthetic
haemostatic agents (tranexamic acid, desmopressin), in
order to limit the exposure to biological (plasma-derived
and recombinant) replacement products.
In all cases, it is recommended that the patient
and/or his/her parents/tutors receive detailed and
583

clear information concerning the available therapeutic
approaches and replacement products, in order to
achieve shared decisions and the written informed
consent for treatment and the choice of the product.
According to the Italian legislation, written informed
consent by the patient or his/her tutor is mandatory
for treatment with blood components or derivatives,
including plasma-derived factor concentrates, and
must be recorded in the patient's file. However, it is
advisable to obtain written informed consent even in
the case of treatment with recombinant products. In this
respect, disease-specific forms have been prepared by
AICE for approval of reference ethical committees of
each HTC. Moreover, licensed product indications and
dosages should be adopted, unless available clinical
and literature data support non-licensed indications or
therapeutic approaches. This is the case for the use of
FVIII and FIX concentrates in ITI regimens. In spite
of the unanimous recognition of ITI as the first-choice
treatment for patients with persistent inhibitors76-78,
no available concentrate is currently licensed for ITI.
However, as recently pointed out by the European
Medicines Agency (EMA)79, clinical data concerning the
use for ITI regimens are being reported in the product
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files. Moreover, in March 2014, ITI with FVIII and
FIX plasma-derived and recombinant concentrates was
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approved in Italy by the AIFA among new indications
from consolidated clinical use on the basis of literature
evidence, thus enabling regular prescription and
reimbursement by the national healthcare system of all
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licensed FVIII/FIX concentrates80. In order to collect
further data about predictors of success and optimal cost-
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effective ITI regimens, we suggest enrolling patients in
the ongoing Italian ITI Registry81. Similarly, although
prophylaxis regimens in inhibitor patients are currently
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licensed only for APCC, it is considered that available
literature data82-86 document the benefits and support
the use of such regimens even for rFVIIa, as reported
©
in detail in the Specific Recommendations.
4.1.3 Choice of the product
The choice of type of product for replacement
treatment in patients with haemophilia A and B must
rely on rigorous efficacy and safety data. All currently
available plasma-derived and recombinant FVIII and
FIX concentrates have been shown to be highly effective
in clinical studies reporting that the large majority of
bleeding episodes were successfully treated with one or
two infusions87-99. However, no study has yet compared
the efficacy of different (source or brand) products.
The risk of inhibitor development remains the most
challenging open issue in treatment with concentrates,
particularly in patients with severe haemophilia A.
Nevertheless, according to the recent AICE survey
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Rocino A et al
among the Directors of Italian HTCs, the majority
of respondents (80%) are still more concerned by
infectious safety of factor concentrates than by their
immunogenicity11. Indeed, recombinant concentrates were
almost unanimously indicated (95%) as the products of
choice for PUPs and preferred by 75% of the respondents
for PTPs not affected by blood-borne infections. However,
while awaiting more rigorous evidence concerning the
inhibitor risk of different products, it is recommended that
all patients, in particular PUPs, participate in long-term
pharmacovigilance programmes20 or ongoing clinical
trials addressing this issue.
As regards pathogen safety, although no biological
product can guarantee the absence of risk, AICE
considers that the lack of transmission of any infectious
agent by recombinant products, since their introduction
into the market, fulfils the main requirement for safety,
as recently claimed by the large majority of physicians11
l
and patients100 in Italy. The participation of all patients
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in long-term pharmacovigilance programmes is
recommended also with regards to pathogen safety20,101.
In this respect, continuing replacement treatment
i
iz
with the same product should be favoured in order to
make surveillance easier and to preserve adherence to
treatment, which significantly contributes to the clinical
efficacy of products75,101.
On the whole, the choice of the product must derive
predominantly from thorough and clear discussion of
available literature data, including all still debated issues,
between the HTC physicians and patients or their tutors.
In the frame of such a careful assessment, the active
involvement of the latter is a prerequisite for signing
the informed consent to the choice of product for their
own replacement treatment.
On this background, AICE substantially confirms the
previously published recommendations for the choice
of products7, updating them as follows:
- recombinant concentrates are the products of choice
for treatment of PUPs, minimally treated patients
and PTPs exclusively exposed to recombinant
concentrates;
- recombinant concentrates are the products of choice
for treatment of HIV-positive patients with clinical
signs of immune deficiency, because they could be
at risk of infection from Parvovirus or other potential
blood-borne, still unknown, pathogens;
- recombinant concentrates are the products of choice
for treatment of PTPs exposed to plasma-derived
concentrates, who have not been infected by HCV
or who have cleared the virus spontaneously or after
antiviral treatment; if these patients are currently
treated with a plasma-derived product, they can
continue on the same product, according to the
decision shared with the HTC physician;
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
Italian principles for haemophilia treatment
- PTPs exposed to plasma-derived concentrates who
have chronic HCV infection (HCV-RNA virus
positive) or are HIV-positive without signs of
immune deficiency, can continue on currently used
plasma-derived or recombinant products, according
to the decision shared with the HTC physician.
Continuous and careful surveillance of both
inhibitor development and pathogen safety is always
recommended, in all patients, including PTPs, and in
particular, when products are changed.
These recommendations on the choice of products
also apply in other settings of CBD when both
plasma-derived and recombinant concentrates are
available.
4.1.4 Desmopressin (DDAVP, desamino-8-D-
arginine-vasopressin)
DDAVP is the first-choice treatment in all responsive
patients with mild/moderate haemophilia A and
mild VWD, since it is effective, free of risk of viral
transmission and inexpensive72,102. However, individual
responsiveness to DDAVP should be evaluated by
measuring FVIII levels (and VWF ristocetin cofactor in
VWD patients) 1 and 4 hours after administration72,103,104.
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Treatment effectiveness should be monitored in
particular in the case of prolonged treatment with
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repeated doses (i.e. surgery). Indeed, tachyphylaxis may
occur in mild haemophiliacs, leading to progressive
reduction of post-infusion FVIII105. Because of the risk
of water retention, hyponatraemia and, consequently,
TI
seizures, close monitoring of diuresis and electrolytes is
recommended, particularly in children below the age of
M
2 years106. Due to the risk of hypotension and reported
vascular complications107, caution is also suggested in
elderly patients and in those with cardiovascular disease
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or other risk factors for thrombosis. In haemophilia
carriers with low FVIII levels and in women with VWD,
DDAVP can be safely used as haemostatic treatment
©
during invasive procedures in the first trimester of
pregnancy108 or at delivery109,110.
4.1.5 Tranexamic acid
The synthetic lysine analogue tranexamic acid
prevents plasminogen activation into plasmin through
competitive and reversible binding to its fibrin site.
It is able to accumulate in extracellular spaces and
can be particularly effective in the presence of high
concentrations of tissue plasminogen activators,
as observed in mucous membranes 111. Tranexamic
acid is, therefore, widely used in mucosal bleeding
and for the prevention and treatment of bleeding in
dental procedures, possibly combined with DDAVP
in responsive patients 111-113. Tranexamic acid may
also be used in association with rFVIIa114, whereas
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the association with PCC or APCC is usually avoided
because of the risk of thromboembolic complications.
However, recent data from a small cohort of patients
support an effective and safe use of tranexamic acid
in inhibitor patients receiving APCC for the treatment
of bleeding or undergoing invasive procedures 115.
The agent remains contraindicated in patients with
thromboembolic diseases and must be avoided in the
case of haematuria116,117. For dental procedures, patients
should receive tranexamic acid mouth-washes112,113.
4.1.6 Fibrin glue
This agent is employed to facilitate local haemostasis
in patients with congenital or acquired bleeding
disorders, in particular during surgical interventions,
and in patients with bleeding complications118.
4.2 Specific recommendations
l
4.2.1 Haemophilia A
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Treatment regimens
On-demand replacement treatment is based on FVIII
administration at doses reflecting the type and severity
i
iz
of bleeding episodes. Table VI reports FVIII doses to
be used for the treatment of acute bleeding episodes
and prophylaxis of bleeding during surgery and in the
post-operative period. Both treatment of bleeding and
management of surgery require close monitoring of the
individual response to replacement therapy, in order to
determine whether expected in vivo recovery and trough
factor levels are achieved and maintained. FVIII levels
are usually measured by the one-stage clotting assay or,
less frequently, the chromogenic assay, using calibration
against the World Health Organisation (WHO) plasma
standard. In patients treated with the B-domain
deleted rFVIII concentrate (ReFacto AF®, Pfizer), a
specific standard provided by the manufacturer119, or,
alternatively, the chromogenic assay, should be used.
Consistent with recommendations from the WHO,
WFH, the European Principles of care8,9,120 and a series
of national scientific societies, in spite of a later diffusion
of prophylaxis in Italy with respect to other countries
in Northern Europe, primary prophylaxis, started at an
early age, is now the regimen of choice for treatment
of children with severe haemophilia, largely adopted in
Italian HTCs11. This treatment approach is based on data
from retrospective121 and prospective122 cohort studies
and from two randomised controlled trials123,124, clearly
documenting the advantages of primary/early secondary
prophylaxis in preventing bleeding and reducing its
long-term deleterious effects on joint morbidity and
quality of life. Primary prophylaxis is started usually after
no more than one large joint bleed and before 3 years of
age, as a regular continuous treatment consisting of 25-40
IU/kg FVIII concentrate infusions three times per week
585
 Rocino A et al

Table VI - Recommended FVIII and FIX doses for treatment of haemophilia A and B.
Clinical condition Haemophilia A Haemophilia B Treatment duration2
FVIII dose1 FIX dose1 (days)
(IU/kg) (IU/kg)
Mild/moderate haemarthroses or haematomas 20-30 40-60 1-2
Severe haemarthroses or haematomas (iliopsoas or
deep muscles with neurovascular compression)
Initial treatment 40-50 60-80 1-2
Maintenance 20-30 30-60 5-7
CNS/spinal cord haemorrhage
Gastrointestinal haemorrhage
Throat/neck3
Initial treatment 50-100 50-100 1-7
Maintenance 20-30 20-40 8-21
Renal haemorrhage 20-30 30-40 5-7
Moderate head injury 30-50 40-60 2-5
Severe head injury 50-100 50-100
Major surgery4 50-100 50-100 7-15
Minor surgery5 30-40 50-80 1-5

l
CNS: central nervous system. 1Both in the treatment of bleeding episodes and in the management of surgery, is always indicated a careful monitoring

Sr
of individual clinical response and trough levels of circulating FVIII/FIX before the next infusion. Post-infusion plasma FVIII/FIX measurements (in
vivo recovery) are often necessary in order to verify that the levels expected, in relation to the dose administered, are actually achieved. 2The duration of
treatment should be evaluated in relation to the clinical course, but in any case until the complete resolution of the haemorrhage. 3Bleeding with risk of
airway compression. 4Pre-operative dosage. The haemostatic coverage after surgery is maintained for 7-15 days with FVIII/FIX doses to ensure plasma

i
levels higher than 40-50%. 5Pre-operative dosage. The haemostatic coverage after surgery is maintained for 1-5 days depending on the type of surgical
iz
procedure, with FVIII/FIX doses to ensure plasma levels higher than 40-50%.
rv
on non-consecutive days, or every other day. Individual of their bleeding phenotype and individual needs127-129.
monitoring of clinical response is always recommended, While awaiting further studies clarifying the risk-benefit
Se

with careful assessment of bleeding episodes and, in ratio and long-term outcomes of changing prophylaxis
particular, of joint status, in order to adjust the prophylaxis regimens in young-adult patients treated with full primary
schedule. In this respect, measurement of FVIII trough prophylaxis, it is recommended that patients' bleeding
TI

levels (48-72 hours after the last infusion and before frequency and joint status are carefully assessed, when
the next administration) can be useful for tailoring the considering such regimen modifications. In any case the
dose of prophylaxis, with the aim of achieving FVIII clinical choice must rely on a shared decision with the
M

levels always >1-2 IU/dL. In order to facilitate the patient, taking into account his clinical conditions and
early implementation of prophylaxis in children with individual needs, in terms of lifestyle, work and social
SI

venous access problems, escalating dose regimens in participation.

which prophylaxis is started with a once weekly infusion Increasing data support clinical benefits of tertiary
schedule are being increasingly used, even in Italian HTCs. prophylaxis regimens, started in adolescent and adult
©

The infusion frequency is then increased on the basis of
clinical needs and bleeding frequency, in parallel with
the training of caregivers enabling home treatment125,126.
It is recommended that the clinical follow-up of patients
on these regimens should be even more careful, since
long-term outcomes are still unknown and there are no
comparisons with full-dose regimens. With the aim of
increasing the knowledge about long-term outcomes
in this setting, it is recommended that patients' clinical
follow-up data are collected in the national database
and/or prospective national or international ad hoc studies.
Whether primary prophylaxis should be continued
lifelong or patients can safely modify prophylaxis
regimens in adulthood is still debated, also among Italian
HTC physicians. According to the few available studies, it
is likely that regular prophylaxis can be withdrawn or the
intensity of treatment reduced in some patients, because
patients with the aim of reducing the clinical impact of
haemophilic arthropathy, thus improving quality of life.
The advantages of such regimens are documented by
retrospective130 and prospective studies131,132, including
the first-year analysis of a 3-year randomised controlled
trial comparing prophylaxis vs on-demand treatment133.
These studies consistently show the significant reduction
of bleeding frequency in patients on secondary/tertiary
prophylaxis, with the annual rate of joint bleeding being
as low as one or two. Prospective data on long-term
outcomes in this setting are still lacking. However,
encouraging results have been preliminarily reported
from an Italian prospective study (POTTER), recently
concluded after the patients had been followed up for
a median of 5.4 years134. Available evidence does not
enable tertiary prophylaxis to be recommended for
all adult patients with severe haemophilia, whereas

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586

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Italian principles for haemophilia treatment
secondary prophylaxis is recommended for adolescents
previously treated on-demand, in order to reduce
bleeding frequency and the negative impact on their
quality of life. For patients older than 18 years treated
on demand, it is suggested that the treatment regimens
are individualised according to a careful assessment
of bleeding phenotype, together with an evaluation
of the patient's needs in terms of lifestyle, work and
social participation. This view was largely shared by
Italian HTC physicians in the recent AICE survey,
as nearly 90% of those interviewed consider the use
of prophylaxis in adolescent and adult patients with
a severe clinical phenotype11. Again, with the aim of
increasing our knowledge about long-term outcomes
in this setting, data on clinical follow-up, quality of life
and factor concentrate consumption from all patients
on secondary/tertiary prophylaxis should be collected
in the national database.
4.2.2 Haemophilia A with inhibitors
The therapeutic approach in haemophilia with
inhibitors requires highly specific expertise; patients
with inhibitors should, therefore, be managed exclusively
in HTCs, as also recommended by national and
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international guidelines8,9,76-78,135,136. These documents
extensively discuss treatment strategies and current
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management of inhibitor patients, which is not the aim of
these general principles of haemophilia care. However,
some recommendations for the management of patients
with inhibitors are summarised here.
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Inhibitor eradication
M
Treatment of patients with inhibitors should be
primarily aimed at inhibitor eradication, in order to
prevent, or at least reduce, the negative impact of
SI
persistent inhibitors on patients' morbidity and quality of
life34,35,137. ITI through regular, prolonged, often high-dose
FVIII administration is the only therapeutic approach
©
proven to eradicate or reduce the neutralising inhibitor
activity and restore the efficacy of FVIII replacement
treatment138,139. ITI is recommended in all patients with
severe haemophilia A and high-responding inhibitors
by the WFH guidelines8, the European principles of
haemophilia care9, international guidelines and expert
panels76-78,136 and is largely adopted in Italian HTCs11.
This approach should also be considered in patients
with persistent low-responding inhibitors, interfering
with standard-dose FVIII prophylaxis or on-demand
treatment76,77. The main candidates for ITI are children
with recent onset high-responding inhibitors in whom
early eradication can provide an optimal cost-utility
ratio in a long-term perspective140. To this purpose, ITI
should be started early after inhibitor detection, possibly
as soon as titres <10 BU/mL are measured. Such a low
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
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inhibitor titre at the time of starting ITI is associated
with higher success rates in all ITI Registries taking
into account this variable81,141,142. In addition, ITI should
be considered in selected patients with long-standing
inhibitors who have severe or recurrent episodes of
bleeding, as already reported in the literature141,142 and in
the AICE survey11, also taking into account that age and
time interval between inhibitor diagnosis and starting ITI
were not consistently recognised as predictors of success
in ITI studies, including the Italian PROFIT (Prognostic
Factors in Immune Tolerance) Registry81.
In addition to the selection of candidates for ITI
and identification of patients with good prognosis,
many issues concerning the optimal regimen (dose and
type of FVIII concentrate) and management of ITI are
still debated. Recently, an international randomised
trial in patients with a good prognosis failed to show
significantly different success rates between those
l
receiving a high-dose (200 IU/kg/day) or a low-dose (50
Sr
IU/kg thrice in week) ITI regimen143. However, this trial
was prematurely terminated because of a higher bleeding
frequency in patients on the low-dose ITI regimen. On
i
iz
this basis, the low-dose regimen should be avoided in
children139,143. On the other hand, daily ITI regimens using
intermediate FVIII doses (100 IU/kg/day) have been
reported in literature also by Italian clinicians81,144-146.
Although no direct comparison of such regimens with the
classical high-dose regimen is available, similar success
rates have been reported, particularly in children with a
good-prognosis profile145,146. Therefore, ITI can be started
with an intermediate dose (100 IU/kg/day) regimen and
the dose can be increased in the case of breakthrough
bleeding episodes or if high inhibitor peak titres
(≥200 BU/mL) are detected during the treatment. This
approach, also suggested by the UKHCDO guidelines78,
may contribute to improve cost-effectiveness and
cost-utility of ITI and is already frequently used in Italian
HTCs11. Nevertheless, high-dose regimens should be
preferred in patients with a poor prognosis in order to
improve the success rate77,139,141,147.
As to the type of FVIII concentrate, in vitro and
animal findings42,43, as well as uncontrolled clinical
studies 148-150, suggest that VWF-containing FVIII
concentrates may increase the likelihood of ITI success,
particularly in poor-prognosis patients. However,
similarly high success rates have been found even
in studies in which ITI was conducted exclusively
with rFVIII concentrates146,151,152, as well as in the
North-American and PROFIT registries, in which
most patients received such products81,142. With this
uncertainty, no recommendation can be expressed
concerning the type of product to be used for ITI in
adult patients, who should share the decision with
the HTC physician after a careful assessment of the
587

available information. On the other hand, in patients
undergoing ITI early after inhibitor development,
usually children on rFVIII concentrates, consistent with
expert recommendations76-78, the same product in use at
inhibitor development should be preferred. Alternatively,
another recombinant product with similar characteristics
could be used.
As regards definitions of ITI outcomes, there is
general agreement that complete ITI success implies
persistent inhibitor eradication in association with
normalisation of FVIII pharmacokinetics76-78,139,143. To
this aim, ITI should continue under the same regimen until
criteria for success or failure are fulfilled. In patients in
whom ITI fails, further ITI attempts should be considered,
in particular in the presence of a severe bleeding
phenotype and/or poor response to bypassing treatment76.
Switching to VWF-containing plasma-derived FVIII
products should be considered if a monoclonal or
recombinant FVIII product was given during first-line
ITI76-78. Indeed, some case series including second-line ITI
treatment show good success rates using VWF-containing
products149,150, although controlled studies comparing such
concentrates with VWF-devoid products are lacking. Case
reports and small series also suggest that the addition of
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immune-modulating/suppressive agents may increase the
chance of ITI success in patients in whom conventional
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ITI regimens have failed76-78,153. On the whole, the choice
for these second-line treatment options is based on the
physician's clinical experience and must be carefully
discussed with the patient or his tutors, clearly assessing
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the risk-benefit ratio.
For all patients undergoing ITI written informed
M
consent from the patient or his tutors should be obtained
and recorded in the patient's file. Moreover, enrolment
into ongoing clinical trials and the Italian ITI Registry is
SI
recommended, in order to maintain pharmacovigilance
and to collect data on controversial aspects of ITI.
©
Treatment of bleeding episodes
In addition to the type and severity of bleeding, the
choice of the therapeutic approach in patients with inhibitors
depends on the actual inhibitor titre and the anamnestic
response. Replacement treatment with FVIII concentrate
is the ideal approach78,135. However this is still possible,
by increasing FVIII doses, only in patients with low-
responding inhibitors and in high-responding inhibitors
with a low titre at the time of treatment. In these cases,
the initial bolus administered must include the FVIII dose
needed to neutralise circulating inhibitors and that required
to increase FVIII to haemostatic levels. FVIII treatment
should be continued by bolus infusions able to maintain
target FVIII levels until bleeding is controlled. As an
alternative, continuous FVIII infusion can be used, adjusting
the infusion rate according to the FVIII levels achieved.
588
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No other uses without permission
Rocino A et al
In patients with high inhibitor titres (>5 BU/mL) at
the time of treatment, the so-called bypassing agents
APCC and rFVIIa (Table III) represent the only available
approach for prevention and treatment of bleeding. The
efficacy of these two agents has been proven in clinical
studies, both in the setting of acute bleeding and surgery,
and during extensive use in clinical practice136,154-158.
However, clinical responsiveness to bypassing agents is
poorly predictable and no validated laboratory method
is currently available for monitoring their therapeutic
efficacy159,160 .
The choice of type of bypassing agent is based primarily
on the individual clinical responsiveness, together with
considerations on feasibility of home treatment. However,
the criteria for choosing the type of product (recombinant
versus plasma-derived) reported above for patients without
inhibitors also apply for bypassing agents in patients
with inhibitors, unless clinical unresponsiveness to either
l
product has been proven.
Sr
In patients with severe or recurrent bleeding and
development of target joints with deterioration of joint
status and quality of life, prophylaxis regimens with
i
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bypassing agents are being increasingly used, as also
agreed upon by 84% of the respondents to the AICE
survey11. A significant reduction of bleeding frequency
has been found in retrospective and prospective series
of patients treated with heterogeneous regimens using
both the bypassing products82,83,161,162. As regards the
APCC, these findings have been further confirmed
by two randomised trials showing that prophylaxis
results in significant reductions of total, joint and
target joint bleeding episodes163,164 and significantly
improves patients' quality of life165 compared with
on-demand treatment. A randomised trial comparing
two rFVIIa prophylaxis regimens also showed that
both a standard dose (90 μg/kg/day) and a high-dose
(270 μg/kg/day) regimen were able to reduce bleeding
rates significantly as compared to those in the previous
on-demand treatment period84. Taking these experiences
into account, prophylaxis with bypassing agents is
increasingly considered by expert recommendations and
guidelines78,86,136, particularly in patients with frequent
or severe bleeding (e.g. intracranial haemorrhage).
However, in patients waiting for ITI, rFVIIa should be
preferred in order to avoid the risk of anamnesis reported
in some patients receiving APCC166.
With the aim of increasing knowledge about
long-term outcomes in this setting, it is recommended
that patients receiving bypassing agent prophylaxis are
included in prospective studies and in the ad hoc AICE
Registry. It is also recommended that written informed
consent to the use of the specific bypassing agent according
to an on-demand and/or prophylaxis regimen is obtained
from each patient and recorded in the patient's file.
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
Italian principles for haemophilia treatment
4.2.3 Haemophilia B
The choice of FIX concentrate for replacement
therapy of patients with haemophilia B is based
on the considerations reported above (General
recommendations, 4.1.3). All currently available FIX
concentrates are highly effective for the treatment and
prophylaxis of bleeding episodes95-99. PCC should not
be used, since purified plasma-derived and recombinant
FIX concentrates are available.
The dose of FIX should be calculated according to
the type and severity of the haemorrhagic episode and
repeated until complete healing7,8. Recommended doses
for the treatment of several types of bleeding episodes,
during surgery and the post-operative period, are listed
in Table VI. As in haemophilia A, careful monitoring of
the individual clinical response and trough FIX levels
is recommended, both for treatment of acute bleeds and
for management of surgery.
Primary prophylaxis is generally conducted by
the administration of 40 IU/kg of FIX concentrate
on two non-consecutive days per week7,8. Monitoring
of individual clinical responses and measurement of
circulating FIX levels at least 72 hours after the previous
infusion are recommended. This allows personalisation
rv
of the dose in order to maintain trough FIX levels
above 1-2 UI/dL. Since this illness is less common
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than haemophilia A, fewer data on the effectiveness
of prophylactic treatment in haemophilia B have
been collected. Most information has, therefore, been
provided from studies in haemophilia A and transferred
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into the setting of haemophilia B. Nevertheless, with
regard to the indications for secondary and tertiary
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prophylaxis in adolescents and adults with haemophilia
B, the information and recommendations given for those
with haemophilia A should be considered, including
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suggestions for modulating primary prophylaxis
regimens in adult patients.
©
4.2.4 Haemophilia B with inhibitors
Inhibitors arise in about 3% of patients with
haemophilia B and more than 80% of them are
high-responding inhibitors37. Inhibitor development
is usually associated with large deletions or nonsense
mutations in the F9 gene, leading to the absence of
FIX antigen36,37. Such mutations can be associated with
severe allergic and anaphylactic reactions that occur after
exposure to any type of FIX concentrate and, typically,
concomitantly to inhibitor development 37,167. The
aetiology of such reactions is still unknown. In order to
identify patients at risk of inhibitor development as well
as of serious allergic and anaphylactic reactions, the gene
mutation responsible for the disease should be identified
in all newly diagnosed patients as soon as possible,
before the start of FIX replacement therapy. When
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
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treating patients at high risk of developing inhibitors,
the first 10-20 infusions of FIX concentrate should be
administered in a hospital setting, in order to guarantee
easier access to an intensive care unit37. Furthermore,
due to the great expertise required when treating patients
with haemophilia B with inhibitors, particularly in the
case of severe allergic and/or anaphylactic reactions,
these patients should be managed exclusively by HTCs.
ITI treatment is reported to be less effective in
eradicating inhibitors in haemophilia B patients. Data
from the North American Registry show that only 5/16
patients achieved immune tolerance and eradication
of the inhibitor. Additionally, 65% of patients suffered
adverse events during ITI, which often caused
discontinuation of the treatment142. Similarly, the ITI
success rate was only 15% in the ISTH Registry, with
38% of patients developing nephrotic syndrome during
treatment 168. For this reason, international expert
l
groups do not recommend ITI regimens in patients
Sr
with haemophilia B with inhibitors76-78. Nevertheless,
recent data collected in Italy on a low-dose ITI regimen
in five out of eight patients with inhibitors listed in the
i
iz
AICE database, interestingly show complete success
and inhibitor eradication in four cases169. However,
given the lack of data from a larger number of patients,
ITI in patients with haemophilia B with inhibitors is not
recommended but when ITI is attempted, precautions
suggested by international groups of experts76-78 should
be adopted.
4.2.5 Mild/moderate haemophilia with inhibitors
In recent years, increasing evidence has clarified
that anti-FVIII inhibitors develop in about 5-10%
of patients with mild/moderate haemophilia A170-172.
Unlike in severe haemophilia A, the risk of inhibitor
in moderate/mild haemophilia has been shown to
increase in parallel with the number of exposures
to FVIII and, frequently, inhibitors develop during
adulthood170-172, often following a period of intensive
treatment172,173. Therefore, inhibitor development must
be carefully monitored when such patients are exposed
to factor concentrates. Furthermore, some mutations are
likely to be associated with a higher risk of inhibitor
development172,173. In these patients, the risk of bleeding
can increase due to cross-reactivity between inhibitor
and the native FVIII synthesised by the patient, which
can lead to the reduction of circulating FVIII levels to
<1 IU/dL174. Due to the relative low number of inhibitors
in mild/moderate haemophilia, there is no strong
evidence that ITI should be systematically performed
in these patients On this basis, the following general
recommendations are provided:
- in order to identify patients carrying F8 mutations
thought to be at high risk of inhibitor development,
589

characterisation of the gene defect is recommended
in all patients with mild/moderate haemophilia A;
- in order to minimise the number of exposures to
FVIII concentrates, the use of DDAVP is encouraged
in patients with mild haemophilia A who successfully
respond to such treatment;
- inhibitor monitoring is recommended in patients
treated with FVIII concentrates, particularly after
intensive treatment due to severe bleeding or surgery;
- since great expertise is required in the management
of patients with mild or moderate haemophilia
A and inhibitors, these patients should be treated
exclusively in HTCs.
The possibility of adopting ITI protocols should be
considered in particular in patients with frequent bleeding
symptoms, although no evidence from literature suggests
any specific ITI regimen. If ITI is attempted, the patient
should be included in the AICE ITI Registry.
Currently, there is no evidence of inhibitor
development in mild haemophilia B, therefore inhibitor
testing is not required unless clinically indicated.
4.2.6 von Willebrand's disease
Available therapeutic options and recommendations
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for the treatment of VWD have been provided in
specific documents by the AICE72 and, recently by a
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European group of experts175. DDAVP is the first-choice
treatment for all patients responsive to this agent72,175,176.
The use of cryoprecipitate must be avoided, because
this product is not virally inactivated. In addition, the
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FVIII and VWF content of cryoprecipitate cannot be
standardised and its clinical use is less manageable than
M
commercial concentrates. When DDAVP is ineffective or
contraindicated, factor concentrates rich in VWF must
be used72,175. The characteristics of products available in
SI
Italy are described in Table I. These concentrates contain
different amounts of FVIII and VWF, and the appropriate
dosage should, therefore, be defined according to the
©
specific product characteristics. Insufficient or excessive
circulating levels of FVIII achieved with replacement
treatment can, in fact, lead to inadequate haemostatic
response or, on the contrary, to a potential risk of
thromboembolic events. A factor concentrate containing
almost exclusively purified VWF is specifically licensed
for the treatment of VWD patients177. The characteristics
of this product are summarised in Table V. Due to the very
low FVIII content, this concentrate should be mainly used
in patients unresponsive to DDAVP in circumstances such
as elective surgery and long-term prophylaxis, especially
if patients exhibit slightly reduced or normal FVIII
levels. On the other hand, this product is not considered
suitable for replacement therapy in emergency or urgent
medical conditions177. A recombinant VWF concentrate is
undergoing a clinical trial and no definite recommendation
590
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No other uses without permission
Rocino A et al
about its use can be made at present. Recombinant FVIII
concentrates do not contain VWF and, therefore, cannot
be used for the treatment of VWD patients, with the
exception of those with type 3 VWD with inhibitors
(about 5-10%)52. In these patients with bleeding episodes
uncontrolled by FVIII/VWF concentrates, rFVIIa and/
or platelet concentrates can be considered as additional
treatment options72,175. Some patients with severe VWD
(FVIII:C and/or VWF <5 IU/dL) can suffer from
frequent haemarthroses or spontaneous severe bleeding
episodes (in particular from the gastrointestinal tract).
Such patients can be candidates for secondary long-term
prophylaxis regimens, with excellent or good therapeutic
responses in most cases178-180. However, further studies
are needed to clarify the impact of such regimens on
patients' quality of life and to assess their long-term
cost-effectiveness and cost-utility72,175.
l
4.2.7 Fibrinogen deficiency
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Virally-inactivated fibrinogen concentrates are
the first-choice products for replacement treatment.
Although not registered in Italy, two products are
i
iz
available by direct importation with the authorisation of
AIFA (Table V). Alternatively, the product of choice is
virally-inactivated plasma manufactured from national
plasma from voluntary and habitual unpaid donors
throughout the network of Italian Transfusion Services.
When not available, preparations of commercial
S/D virally-inactivated plasma must be preferred to
fresh-frozen plasma and cryoprecipitate. Additionally,
AICE does not recommend the use of plasma preparations
virally inactivated by in-house methods because factor
concentrations in these products, including fibrinogen
content, cannot be standardised181. Virally-inactivated
plasma must be administered at doses of 15-20 mL/kg.
When infusing plasma, the risk of fluid overload should
be taken into account, in particular when fibrinogen
levels must be kept stable for several days (i.e., in the
case of surgery). In patients with afibrinogenaemia,
bleeding episodes must be treated with doses able
to increase and maintain circulating factor levels at
least up to 100 mg/dL (approximately 20-30 mg/kg of
concentrate), until adequate haemostasis is achieved.
The dose of concentrate can be subsequently reduced,
maintaining fibrinogen levels >50 mg/dL, until
complete resolution of bleeding. In the case of surgery,
fibrinogen levels of 50-100 mg/dL (approximately
20-30 mg/kg of concentrate) are usually effective
to provide adequate haemostasis. Early prophylaxis
in pregnant women with afibrinogenaemia, aiming
at maintaining fibrinogen levels of approximately
100 mg/dL, can help to prevent miscarriage or
placental abruption, both common complications in
such women69,182. Secondary prophylaxis can also be
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
Italian principles for haemophilia treatment
used in selected cases in order to prevent intracranial
haemorrhage or recurrent haemarthroses. Due to the
long half-life of fibrinogen (approximately 4 days),
infusions given once or twice a week should be
sufficient183. Patients with hypofibrinogenaemia or
afibrinogenaemia, even in the absence of replacement
therapy, may rarely experience venous and arterial
thrombotic complications, which are correlated with
increased thrombin activity, due to defective thrombin
binding capacity by fibrin 69. These situations are
extremely challenging and may require combined
treatment with fibrinogen concentrate and anticoagulant
agents184. Given the marked phenotypic heterogeneity
(asymptomatic, haemorrhagic, thrombotic,
haemorrhagic/thrombotic) of patients with
dysfibrinogenaemia, therapeutic approaches must take
into account patients' personal and family history and,
according to the clinical situation, may require treatment
with fibrinogen concentrate and/or anti-thrombotic
prophylaxis69. For further details on the treatment of
congenital fibrinogen defects, refer to the specific
guidelines183,.
4.2.8 Factor II and factor X deficiency
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Replacement therapy includes PCC at doses of
10-20 IU/kg, to be repeated as needed. Furthermore, a
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FX concentrate which also contains FIX, currently not
licensed in Italy, can be available by direct importation
after authorisation from AIFA. Alternatively, the
product of choice is S/D virally-inactivated plasma
TI
manufactured from national plasma from voluntary
and habitual unpaid donors throughout the network
M
of Italian Transfusion Services. When not available,
the above reported recommendations (4.2.7) on the
use of commercial S/D virally-inactivated plasma
SI
over plasma preparations virally inactivated by
in-house methods and, in particular, non-virally
inactivated products, also apply in this setting.
©
Doses of 15-20 mL/kg of virally-inactivated plasma
are suggested, with infusions repeated as needed.
Limited experience in seven patients (including
6 children) with severe FX deficiency demonstrated
the effectiveness of prophylactic infusions of a FX-rich
PCC (10-20 IU/kg), administered two to three times per
week in reducing the frequency of bleeding episodes185.
For further details about the treatment of congenital
FII or FX deficiency, refer to the specific guidelines183.
4.2.9 Factor V deficiency
A specific product for replacement treatment of
patients with FV deficiency is currently not available.
Therefore, the source of choice of replacement FV
is virally-inactivated fresh-frozen plasma. AICE
recommends the use of S/D virally-inactivated plasma
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
All rights reserved - For personal use only
No other uses without permission
manufactured from national plasma collected from
voluntary and habitual unpaid donors throughout the
network of Italian Transfusion Services. When not
available, the above reported recommendations (4.2.7)
on the use of commercial virally-inactivated plasma
over plasma preparations virally inactivated by in-house
methods and, in particular, non-virally inactivated
products, also apply in this setting. Severe bleeding
can be treated with 15-20 mL/kg of virally-inactivated
plasma, with infusions repeated according to clinical
needs. For further details on the treatment of congenital
FV deficiency, refer to the specific guidelines183.
4.2.10 Factor VII deficiency
A specific recombinant product containing
rFVIIa (NovoSeven®, Novo Nordisk) is registered
for replacement treatment of patients with FVII
deficiency. For treatment of bleeding episodes, doses
l
of 15-30 μg/kg are suggested, with infusions every
Sr
4-6 hours. A specific plasma-derived FVII concentrate
is also available (Table V), to be used according to the
severity of the deficiency and of the bleeding episode.
i
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Circulating FVII levels of 10-20 IU/dL are considered
sufficient for adequate haemostasis and can be achieved
and maintained by administering 30-40 IU/kg of
concentrate every 12 hours186.
Regarding the choice between recombinant and
plasma-derived products, the same considerations
previously reported in patients with haemophilia (i.e.,
the risk of pathogen transmission) apply in patients
with FVII deficiency (see General recommendations,
4.1.3). Also in this case, the choice of the concentrate
for replacement therapy must result from the thorough
and clear discussion of available scientific information
between the HTC physicians and patients or their tutors,
leading to their active involvement in a shared decision
and the granting of written informed consent.
Despite the short half-life of FVII (approximately
4 hours), prophylactic regimens with rFVIIa or
plasma-derived FVII concentrates, on alternate days and
at the same doses indicated for on-demand treatment,
has been shown to be effective in selected cases of
patients who experienced severe bleeding events (e.g.
intracerebral haemorrhage) or recurrent hemarthroses187.
Furthermore, secondary prophylaxis regimens can be
used to prevent disabling musculoskeletal complications
in patients with target joints. For further details on the
treatment of congenital FVII deficiency, refer to the
specific guidelines183.
4.2.11 Factor XI deficiency
No specific FXI concentrate is registered in Italy.
Nevertheless, direct import of a purified concentrate
(Table V) is possible with the authorisation of AIFA.
591

This concentrate must be used carefully when treating
patients at high risk of thrombosis, avoiding high
post-infusion FXI levels67. Alternatively, the replacement
product of choice is the S/D virally-inactivated plasma
manufactured using national plasma from voluntary and
habitual unpaid donors throughout the network of Italian
Transfusion Services. If this product is not available,
the above reported recommendations (4.2.7) on the use
of commercial virally-inactivated plasma over plasma
preparations virally inactivated by in-house methods
and, in particular, non-virally inactivated products, also
apply in this setting.
Replacement treatment is indicated for patients with
FXI levels <5 IU/dL who, usually, suffer from post-
traumatic or post-operative bleeding183. Recent studies,
however, show that the risk of haemorrhage can depend
on the type of surgery and the specific anatomical
site188. However, the bleeding risk is more difficult
to be predicted in patients with FXI levels between 5
and 50 IU/dL. In such cases, the bleeding history can
help to define indications for specific replacement
regimens, as demonstrated by cases of asymptomatic
pregnant women with severe FXI deficiency who
were successfully managed during delivery without
rv
receiving replacement therapy189. In contrast, in the
case of a negative or mild bleeding history, the use
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of tranexamic acid or DDAVP is indicated190, while
replacement therapy can be used if strictly indicated by
the clinical course. Tranexamic acid alone can also be
effective when performing dental extractions in patients
TI
with FXI levels <15 IU/dL191. For further information
on the treatment of congenital FXI deficiency, refer to
M
the specific guidelines188.
The risk of inhibitor development in patients with
severe FXI deficiency with homozygous type II mutation
SI
(E117stop) who have received plasma replacement
treatment should be taken into account. This mutation
is particularly common in populations of Jewish
©
origin192, and has also been reported in Italian patients193.
The identification of gene mutations in patients with
severe FXI deficiency (<1%) is recommended and
patients with homozygous E117 stop mutation should
be monitored closely as they are at risk of developing
anti-FXI inhibitors following replacement therapy with
plasma. The use of rFVIIa, at the same doses indicated
for FVII deficiency, has been reported to be effective for
the treatment of bleeding episodes in patients with FXI
inhibitors, even in association with tranexamic acid194.
4.2.12 Factor XIII deficiency
The available commercial plasma-derived concentrate
of FXIII (Table V) is not licensed in Italy. However,
this product can be directly imported following specific
authorisation from AIFA and used under the prescriber's
592
All rights reserved - For personal use only
No other uses without permission
Rocino A et al
responsibility. Alternatively, the replacement product of
choice is S/D virally-inactivated plasma manufactured
from national plasma collected from voluntary and
habitual unpaid donors throughout the network of Italian
Transfusion Services. If this product is not available,
the above reported recommendations (4.2.7) on the use
of commercial virally-inactivated plasma over plasma
preparations virally inactivated by in-house methods
and, in particular, non-virally inactivated products,
also apply in this setting. The recommended dosage of
virally-inactivated plasma is 15-20 mL/kg.
A recombinant FXIII concentrate (NovoThirteen®,
Novo Nordisk) which contains the A subunit of human
factor XIII produced in yeast cells (Saccharomyces
cerevisiae) has been licensed by the EMA for use in
patients aged >6 years. This product has recently been
licensed in Italy as well, but for prophylaxis only.
Given the long half-life of the FXIII and the risk of
l
life-threatening spontaneous bleeding, especially brain
Sr
haemorrhage, prophylactic treatment regimens is the
first choice for patients with severe deficiency (FXIII
<3 Ul/dL). Infusions are given every 3-4 weeks and the
i
iz
dosage and frequency of infusions are adjusted in order to
maintain the minimum FXIII level >3 IU/dL. Prophylaxis
should be considered in women of childbearing age, as
this treatment modality can prevent early miscarriage,
which commonly occurs in these patients195. For further
information on the treatment of congenital FXIII
deficiency, refer to the specific guidelines183.
4.2.13 Combined factor V and factor VIII deficiency
This extremely rare deficiency (about 200
patients reported in literature) is characterised by low,
although measurable, levels of both FV and FVIII
(5-20 IU/dL) and is usually associated with mucosal bleeding.
In approximately two-thirds of cases the molecular basis of
this disorder is a mutation in a gene located on chromosome
18, which encodes for the lectin mannose-binding protein,
LMAN1196. No specific replacement product is available
for this deficiency. Thus, when treating bleeding or in the
case of surgery, virally-inactivated fresh-frozen plasma
(15-20 mL/kg) must be infused in order to restore levels of
FV, combined with the administration of desmopressin and/
or FVIII concentrate replacing FVIII197. The above reported
recommendations (4.2.7) concerning the choice for virally-
inactivated plasma products also apply in this setting. For
further indications about the treatment of this deficiency,
refer to the specific guidelines183.
4.2.14 Combined deficiency of vitamin K-dependent
factors
This disorder consists of the deficiency of clotting
factors II, VII, IX and X, as well as of anticoagulant
proteins C and S. The residual levels of these
Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14
Italian principles for haemophilia treatment
vitamin K-dependent factors varies widely, from
<1 to 30 IU/dL. The molecular basis of the defect consists
of missense mutations in the γ-glutamyl carboxylase gene
(GGCX), which is located on chromosome 2, leading to
the production of a dysfunctional enzyme. In the case
of severe deficiency, early bleeding manifestations can
be observed during the neonatal period and include
umbilical cord bleeding and intracranial haemorrhages.
Nevertheless, in most patients symptoms are mild and
may be resolved by the administration of vitamin K198.
Four-factor PCC (20-30 IU/kg), which also contain
the natural coagulation inhibitors protein C and S, are
indicated for replacement therapy in the case of severe
bleeding. Alternatively, the replacement product of
choice is S/D virally-inactivated plasma, manufactured
from national plasma from voluntary and habitual unpaid
donors throughout the network of Italian Transfusion
Services, given at doses able to increase levels of
the deficient plasma factors at least at 15-20 IU/dL.
If this product is not available, the above reported
recommendations (4.2.7) on the use of commercial
virally-inactivated plasma over plasma preparations
virally inactivated by in-house methods and, in
particular, non-virally inactivated products, also apply
rv
in this setting. For further indications on the treatment
for this deficiency, refer to the specific guidelines183.
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Acknowledgements
The authors thank FedEmo and Fondazione
Paracelso for their comments and critical discussion
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of the contents of this manuscript and Baxter, Bayer,
Biotest, CSL Behring, Grifols, Kedrion, Novo Nordisk,
M
Octapharma and Pfizer for providing information on the
characteristics of their factor concentrates.
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The Authors declare no conflict of interest
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©
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hepatitis after transfusion of factor VIII in unfrequently
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treated patients. Br Med J 1983; 287: 1754-7.
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50129 Florence, Italy
e-mail: massimo.morfini@unifi.it

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Arianna Accorsi (Arezzo)
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hypo- and afibrinogenemia. Haemophilia 2009; 15: 533-7. - Anna Brigida Aru (Cagliari)
185) Auerswald G. Prophylaxis in rare coagulation disorders-factor - Chiara Biasoli (Cesena)
X deficiency. Thromb Res 2006; 118 (Suppl 1): S29-31. - Isabella Cantori (Macerata)
Se

186) Cohen LJ, McWilliams NB, Neuberg R, et al. Prophylaxis - Simone Cesaro (Verona)
and therapy with factor VII concentrate (human) immuno, - Carlo Ciabatta (Latina)
vapor heated in patients with congenital factor VII deficiency: - Raimondo De Cristofaro (Roma)
a summary of case reports. Am J Hematol 1995; 50: 269-76. - Grazia Delios (Ivrea)
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187) Napolitano M, Giansily-Blaizot M, Dolce A, et al. Prophylaxis - Giovanni Di Minno (Napoli)

in congenital factor VII deficiency: indications, efficacy and - Marco D'Incà (Reggio Emilia)
safety. Results from the Seven Treatment Evaluation Registry - Alfredo Dragani (Pescara)
(STER). Haematologica 2013; 98: 538-44.
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- Cosimo Pietro Ettorre (Bari)

188) Salomon O, Steinberg DM, Seligshon U. Variable bleeding - Fabio Gagliano (Palermo)
manifestations characterize different types of surgery in patients - Gabriella Gamba (Pavia)
with severe factor XI deficiency enabling parsimonious use of
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- Giorgio Gandini (Verona)

replacement therapy. Haemophilia 2006; 12: 490-3. - Paola Giordano (Bari)
189) Salomon O, Steinberg DM, Tamarin I, et al. Plasma replacement
- Gaetano Giuffrida (Catania)
therapy during labor is not mandatory for women with severe
- Paolo Gresele (Perugia)
©

factor XI deficiency. Blood Coagul Fibrinol 2005; 16: 37-41.

- Hamisa Jane Hassan (Roma, ISS)
190) Castaman G, Ruggeri M, Rodeghiero F. Clinical usefulness of
- Caterina Latella (Reggio Calabria)
desmopressin for prevention of surgical bleeding in patients
- Matteo Luciani (Roma)
with symtomatic heterolygous factor XI defieciency. Br J
- Maurizio Margaglione (Foggia)
Haematol 1996; 94: 168-70.
- Marco Marietta (Modena)
191) Berliner S, Horowitz I, Martinowitz U, et al. Dental surgery
- Maria Gabriella Mazzucconi (Roma)
in patients with severe factor XI deficiency without plasma
replacement. Blood Coag Fibrinol 1992; 3: 465-468. - Maria Messina (Torino)
192) Salomon O, Zivelin A, Livnat T, et al. Prevalence, causes, and - Angelo Claudio Molinari (Genova)
characterization of factor XI inhibitors in patients with inherited - Lucia Dora Notarangelo (Brescia)
factor XI deficiency. Blood 2003; 101: 4783-8. - Flora Peyvandi (Milano)
193) Zadra G, Asselta R, Tenchini ML, et al. Simultaneous - Gavino Piseddu (Sassari)
genotyping of coagulation factor XI type II and type III - Gina Rossetti (Trento)
mutations by multiplex real-time polymerase chain reaction to - Vincenza Rossi (Cosenza)
determine their prevalence in healthy and factor XI-deficient - Rita Carlotta Santoro (Catanzaro)
Italians. Haematologica 2008; 93: 715-21. - Mario Schiavoni (Scorrano)
194) Livnat T, Tamarin I, Mor Y, et al. Recombinant activated factor - Piercarla Schinco (Torino)
VII and tranexamic acid are haemostatically effective during - Maria Luisa Serino (Ferrara)
major surgery in factor XI-deficient patients with inhibitor - Annarita Tagliaferri (Parma)
antibodies. Thromb Haemost 2009; 102: 487-92. - Sophie Testa (Cremona)

Blood Transfus 2014; 12: 575-98 DOI 10.2450/2014.0223-14

598

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No other uses without permission