Replacement therapy for invasive procedures in patients with haemophilia: literature review,...

REVIEW ARTICLE

Replacement therapy for invasive procedures in patientswith haemophilia: literature review, European survey andrecommendations

C. HERMANS,* C. ALTISENT,� A. BATOROVA,� H. CHAMBOST,§ P. DE MOERLOOSE,–

A. KARAFOULIDOU,** R. KLAMROTH,�� M. RICHARDS,�� B. WHITE§§ and G. DOLAN–– on

behalf of THE EUROPEAN HAEMOPHILIA THERAPY STANDARDISATION BOARD

*Haemostasis – Thrombosis Unit, Division of haematology, Cliniques Universitaires Saint-Luc, Universite Catholique de

Louvain, Bruxelles, Belgium; �Unitat d’Hemofilia, Hospital Vall d’Hebron, Barcelona, Spain; �National Haemophilia

Centre, Department of Hematology and Blood Transfusion, University Hospital, Bratislava, Slovak Republic; §Service

d’Hematologie Pediatrique, Hopital de la Timone, Marseille, France; –Unite d’Hemostase, Hopitaux Universitaires de

Geneve, Geneva, Switzerland; **Second Blood Transfusions’ Reference Centre for Bleeding disorders, Laikon General

Hospital, Athens, Greece; ��Vivantes – Klinikum in Friedrichhain Klinik fuer Innere Medizin Haemophiliezentrum, Berlin,

Germany; ��Paediatric Haematology Department, Children’s Day Hospital, St James University Hospital, Leeds, UK;

§§National Centre for Inherited Coagulation Disorders, St James’s Hospital and Trinity College, Dublin, Ireland; and

––Queen’s Medical Centre, University Hospital, Nottingham, UK

Summary. Although most surgical and invasiveprocedures can be performed safely in patientswith haemophilia, the optimal level and durationof replacement therapy required to prevent bleed-ing complications have not been established con-clusively. For providing more insight into optimaltherapy during invasive procedures, a literaturereview of surgical procedures in patients withhaemophilia was conducted. Concomitantly, cur-rent practice was surveyed in 26 EuropeanHaemophilia Comprehensive Care Centres, repre-senting 15 different countries. The review identified110 original papers published between 1965 and2007. Of these, only two studies were randomizedcontrolled trials. Target levels and the duration ofreplacement therapy in the published studies wereas follows. For major orthopaedic surgery: preop-erative targets were 80–90%; postoperative targetsshowed a high degree of variation, with troughlevels ranging from 20% to 80%, duration

10–14 days; for liver biopsy, 70–100%, 1–7 days;tonsillectomy: 90–100%, 5–11 days; indwellingvenous access device insertion: 100%, 3–10 days;circumcision: 50–60%, 2–4 days; dental surgery:30–50%, single treatment. With the exception ofdental surgery, current practice in Europe, asassessed by the survey, was largely in agreementwith published data. In conclusion, this studyprovides both a comprehensive review and a largesurvey of replacement therapy in patients withhaemophilia undergoing invasive procedures; thesedata have informed the consensus practical treat-ment recommendations made in this paper. Thisstudy highlights the need for better-designed studiesin order to better define minimal haemostatic levelsof replacement therapy and optimal treatmentduration.

Keywords: haemophilia, invasive procedures, recom-mendations, replacement therapy, survey

Introduction

Most surgical and invasive procedures can beperformed safely in patients with haemophilia withfactor replacement therapy. Country-specific con-sensus recommendations for substitutive therapyduring these procedures have previously beenpublished [1–8]. However, the optimal level and

Correspondence: Cedric Hermans, MD, MRCP (UK), PhD, Hae-

mostasis and Thrombosis Unit, Division of Haematology, Cli-

niques Universitaires Saint-Luc, Avenue Hippocrate, 10, 1200

Brussels, Belgium.

Tel.: +32 2 764 1740; fax: +32 2 764 8959;

e-mail: [email protected]

Accepted after revision 5 November 2008

Haemophilia (2009), 15, 639–658 DOI: 10.1111/j.1365-2516.2008.01950.x

� 2009 Blackwell Publishing Ltd 639

duration of replacement therapy required to preventbleeding complications have not been establishedconclusively. This gives rise to a widely acknowl-edged lack of consistency among treatment regimensfor factor replacement therapy in patients withhaemophilia undergoing invasive procedures.Despite the existence of a large number of reports

of the use of replacement therapy cover duringinvasive procedures in patients with haemophilia,few comprehensive reviews of published literaturehave so far been performed [9]. Moreover, little dataare available regarding the current management ofinvasive procedures, especially those employing themore recently introduced treatment practices suchas continuous infusion or thromboprophylaxis inpatients undergoing major orthopaedic surgery.For these reasons, an extensive literature review of

invasive procedures in patients with haemophilia Aand B was conducted and a survey carried out toprovide information on current practice in 26 Euro-pean haemophilia centres representing 15 differentcountries. All survey participants were members ofthe European Haemophilia Therapy StandardisationBoard (EHTSB), an established group of experiencedhaemophilia centre-based physicians who are respon-sible for treating a total of 3633 people with severehaemophilia. The aim was to provide a comprehen-sive overview of existing data that would be invalu-able in assessing current practices and identifyingareas of controversy and unresolved issues as well astopics for future research. Data that accrued from theliterature and the survey, as well as the clinicalexperience of the treaters, served as a platform forextensive discussions within the network of theEHTSB to develop consensus recommendations forreplacement therapy.

Materials and methods

Literature review

A comprehensive review was performed of publishedevidence regarding replacement therapy for invasivesurgical procedures in patients with haemophilia. Thisincluded major procedures (orthopaedic surgeryincluding synovectomy) and minor surgery [tonsillec-tomy, central venous access device (CVAD) insertion,circumcision, dental surgery, liver biopsy]. For eachprocedure, the literature review was conducted byphysicians of the EHTSB. Relevant papers wereidentified using a Pub-Med search and data werereviewed using a standard protocol. The followinginformation was collected: study reference, year ofpublication, year of study, level of evidence (rated as 1:

high-quality meta analyses, systematic reviews ofrandomized controlled trials (RCTs), or RCTs with avery low risk of bias; 2: high-quality systematicreviews of case control or cohort studies. High-qualitycase control or cohort studies with a very low risk ofconfounding or bias with a high probability that therelationship is casual; 3: non-analytical studies, e.g.case reports, case series and 4: expert opinion), samplesize, severity and type of haemophilia, study design(pre-registration, post registration, observational,case-control, retro- or prospective, single centre andmultiple centre), type of concentrate (plasma-derived,recombinant, degree of purity and brand), dosage(U kg)1), level of factor aimed for, level of factorachieved, mode of administration (continuous infu-sion vs. bolus infusion), duration of treatment, com-plications, outcome and special comments. A criticalanalysis of relevant papers was then undertaken.

Survey

Treatment practices were surveyed by questionnairesrelated to clinical cases illustrating common invasiveprocedures, including major orthopaedic surgery(knee replacement), liver biopsy (performed by thetransjugular route), circumcision, CVAD (Port-A-Cath�; Smiths Medical International Limited, Kent,UK) insertion, tonsillectomy and dental extractionin patients with severe haemophilia. Information wascollected regarding target levels of clotting fac-tors, duration of treatment, treatment modality [con-tinuous infusion vs. bolus, use of DDAVP (deaminod-arginine vasopressin or desmopressin)], peri-opera-tive management including pharmacokinetic evalua-tion, use of a central line, monitoring of factor levels,use of antifibrinolytics and thromboprophylaxis.The total number of haemophilia patients followed

up by the participating centres was 3633. Theaverage number of haemophilia patients per centrewas 241 (range 45–613). The average number ofprocedures per year per centre was between 2 and 5for major orthopaedic surgery and liver biopsy,between 6 and 10 for minor surgery and more than10 for dental surgery. Most respondents were fromComprehensive Care Centres and followed writtenguidelines for replacement therapy during surgery.

Results

Major surgery

Literature review. Thirty-five clinical studies werereviewed [10–44] (Table 1). Eight studies wereconsidered to have reached level of evidence 2 and

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Table 1. Major surgery in patients with haemophilia: literature review of replacement therapy.

First author Year References

Level of

evidence

All

(n)

A

(n)

B

(n)

Major

surgery

all (n)

Orthopaedic

surgery (n)

Bolus

infusion

(n)

Continuous

infusion

(n)

Factor

level, pre-

operative

(%)

Factor level,

1st week

postoperative

(%)

Factor

level, 2nd week

postoperative

(%)

Duration

of treatment

(days)

Antifibrinolytics

(yes/no)

Outcome

bleeds (n)

Phlebitis

(n)

Nilson IM 1977 10 3 (sc, uc) 77 61 16 108 53 108 0 >90 >30–40 >10–20 14–28 Yes 4 0

Krieger JN 1977 11 3 (sc, uc) 31 25 6 58 18 58 0 100 60 40 5–12 No 3 0

Rudowski WJ 1981 12 3 (sc, uc) 101 85 16 121 33 121 0 >50 >50 NA NA NA 11 NA

Willert HG 1983 13 3 (sc, uc) 18 16 2 18 18 18 0 >60 50 50 NA No 0 0

Kasper CK 1985 14 3 (sc, uc) 163 163 0 350 194 350 0 >80 50 50 14 NA 72 0

Brown B 1986 15 3 (sc, uc) 22 18 4 23 0 23 0 100 50 25 7–14 NA 4 0

Kitchens CS 1986 16 3 (sc, uc) 36 30 6 36 NA 36 0 >80 NA NA 5–18 NA 2 1

Martinowitz U 1992 17 3 (sc, hc) 25 25 0 25 NA 11 14 >80 >50 >30 7–14 Yes 0 0

Schulman S 1994 18 3 (sc, hc) 12 12 0 12 10 0 12 >80 >50 >30 4–18 Yes 0 5

Bushan V 1994 19 3 (sc, uc) 37 32 5 26 14 26 0 80/

50–80

20–40/

15–30

20–40/

15–30

10 No 7 NA

Lofqvist T 1996 20 3 (sc, uc) 66 53 13 98 98 98 0 100 >30–40 >10–20 14–28 Yes 1 0

Hay CR 1996 21 3 (sc, uc) 24 24 0 21 20 0 21 100 80 NA 5 (CI) No 0 0

Shapiro AD 1997 22 2 (mc, uc) 74 0 74 34 24 34 0 >60 >30 NA 10 No 0 0

White GC 1997 23 2 (mc, uc) 13 13 0 9 5 NA NA NA NA NA NA NA 0 NA

Srivastava A 1998 24 3 (sc, uc) 18 11 7 20 14 20 0 >80/

>60

>20–40/

>15–30

>15–30/

>10–20

11 No 1 0

Heeg M 1998 25 3 (sc, uc) 9 8 1 12 12 12 0 >100 >50 >25 14 No 1 0

Campbell PJ 1998 26 3 (sc, hc) 21 18 0 18 18 8 10 100 >80 NA 13–17 No 8 1

Gosh J 1998 27 3 (sc, uc) 16 12 4 7 2 7 0 >60 >30 NA 10 Yes 2 0

Negrier C 1998 28 3 (sc, uc) 13 9 4 13 10 0 13 >80 >80 >50 9–22 No 0 0

Tagariello G 1999 29 3 (sc, hc) 15 14 1 11 9 0 11 >80 >70/>40 >40/>20 10 Yes 0 2

Rochat C 1999 30 3 (sc, hc) 5 5 0 5 5 0 5 >80 >50 NA 5 (CI) No 0 5

Scharrer I 2000 31 2 (mc, uc) 15 15 0 8 4 8 0 NA NA NA 12 No 0 0

Batorova A 2000 32 2 (sc, c) 40 40 0 43 31 18 25 >80 >50 >30 12 Yes 3 4

Bastounis E 2000 33 3 (sc, uc) 65 43 15 58 6 58 0 >80 >30 >30 14 No 2 0

Chowdary P 2001 34 3 (sc, uc) 6 0 6 5 3 0 5 >80 >80 NA 3–10 No 0 2

Scharrer I 2002 35 2 (mc, uc) 22 22 0 13 7 13 0 NA NA NA 12–26 No 0 0

Mishra V 2002 36 3 (sc, uc) 9 6 2 8 8 0 8 >90 >50–70 >30 9 Yes 0 0

Ragni MV 2002 37 2 (mc, uc) 26 0 26 23 11 14 9 >80 NA NA 10–20 No 0 1

Dingli D 2002 38 3 (sc, uc) 28 28 0 35 25 0 35 >80 >80 >50 6 (CI) No 5 0

Hoots WK 2003 39 2 (mc, uc) 28 0 28 25 21 0 25 >90 >70 NA 6 (CI) No 0 3

Evans G 2003 40 3 (sc, uc) 4 0 4 5 5 0 5 >90 >70 NA 3–54 No 1 0

Lusher JM 2003 41 2 (mc, uc) 42 42 0 48 NA 48 0 >70 NA NA NA NA 0 0

Wolf DM 2004 42 3 (mc, uc) 8 8 0 5 5 5 0 >90 NA NA 9–21 NA 0 0

Stieltjes N 2004 43 3 (mc, uc) 16 16 0 18 15 0 18 NA NA NA 5–21 Yes 4 1

Lee V 2004 44 3 (sc, uc) 9 8 1 9 9 7 2 >80 >30 >10–20 5–44 No 0 0

1114 862 241 1328 707 1101 218 131 25

CI, continuous infusion; hc, historical controls; mc, multi-centre; NA, not available; sc, single centre; uc, uncontrolled.

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27 studies up to level 3. Nine studies were multicen-tre and six were case–control studies with at leasthistorical controls. In total, 1114 patients underwent1328 major surgical procedures (707 orthopaedicsurgeries) including patients with severe, moderateand mild haemophilia A (862) and haemophilia B(241). Surgery was performed using different types ofplasma-derived and recombinant factor concentrates.In nine studies, tranexamic acid was used as adjuncttherapy. Twenty-three studies used bolus infusionand 16 studies continuous infusion (five studies usedboth regimens). A small proportion of major surgicalprocedures (218/1328 or 16.4%) were managed bycontinuous infusion.Factor levels were not available in four of the

studies. Considering the other 31 studies, thepreoperative target factor levels for haemophiliaA and B were >90% in 11 studies, >80% in 15and >50–70% in five. Thus the majority of studies(26/31) aimed at values >80%. In the 27 studiesthat addressed postoperative trough levels for thefirst week, values were >70% in eight studies,>50% in 11 and >20–30% in eight. For the secondweek, data were available in 18 studies and levelswere >50% in four, >30% in seven and >10–20%in seven.Duration of treatment in the 31 studies varied

from 5 to 14 days in 19 of the studies, 15–21 daysin six and up to 28 days or longer in further sixstudies. Bleeding complications occurred in 131/1328 or 10% of major surgical procedures; mostof them (96/131 or 73.3%) were in the 714procedures included in the papers published before1990. During the above time period, there weretwo cases of fatality related to bleeding complica-tions.No reliable correlation between postoperative

bleeding and target factor level emerged. Localphlebitis was observed in a limited number ofpatients treated with continuous infusion (25/218).No publication recommended thromboprophylaxiswith anticoagulants.

Survey. A target factor level of at least 80% wasreported by all centres prior to major orthopaedicsurgery (Table 2) which is similar to publishedpractice. In contrast to the details reported in theliterature, according to which continuous infusionwas employed in only 16% of the procedures, thisinfusion technique was used in procedures per-formed in nearly half of the centres. In mostcentres, factor levels were maintained above 80%in the postoperative period. With bolus infusion,two infusions per day were administered in order

to maintain trough levels above 80% during theimmediate postoperative period (from day 1 to 5)and around 60% in the late postoperative period(from day 6 to 14) – values that are higher thanpublished targets. The duration of postoperativereplacement therapy ranged from 12 to 14 days.When continuous infusion was used, the factorlevel was maintained at 80% during the first fivepostoperative days and decreased to 30–40% or50–60% between days 6 and 14. Before majororthopaedic surgery, pre-operative pharmacokineticevaluation was performed in one-third of thecentres and the recovery measured in morethan half of them. Thromboprophylaxis withlow-molecular-weight heparin is used in more than

Table 2. European survey of replacement therapy for invasive

procedures in haemophilia.

Procedure

Duration

of

treatment

(days)

Replacement therapy

Target FVIII levels in % No

treatment

(%)80–100% 40–70% 20–40%

Circumcision

Pre-operative 81 19 0

Postoperative 1–3 19 75 6 0

4–7 44 31 25

>7 6 94

CVAD insertion

Pre-operative 81 19 0

Postoperative 1–3 25 62.50 12.50

4–7 6 31 12.50

>7 6 94

Tonsillectomy

Pre-operative 100 0

Postoperative 1–3 69 31 0

4–7 25 75 0

>7 25 25 50

Surgical synovectomy

Pre-operative 87.50 12.50 0

Postoperative 1–3 50 50 0

4–7 19 69 12.00 0

>7 50 25 25

Liver biopsy

Pre-operative 77 14 9 0

Postoperative 45.50 45.50 9 0

Dental extraction

Pre-operative 32 59 9 0

Knee arthroplasty

Pre-operative 100

Postoperative 1–5

(bolus)

85 15 0 0

6–14

(bolus)

7 71 22 0

1–5 (CI) 66 34 0 0

6–14

(CI)

0 58 42 0

CVAD, central venous access device; CI, continuous infusion.



Table 3. Liver biopsy in patients with haemophilia: literature review of replacement therapy.

First author Year References

Level

of

evidence Design

Number

of

patients HA HB

Number

with severe

disease

Number

of

procedures

Method

of liver

biopsy

Factor level

prebiopsy

(%)

Factor level post

biopsy and duration

of replacement

Use of

antifibrinolytics Outcome

Lesesne HR 1977 49 3 sc 6 6 6 Percutaneous 100 72 h No NA

Preston FE 1978 50 3 sc 8 8 8 8 Percutaneous 100 72 h No NA

White GC 1982 51 3 sc 15 15 15 15 NA NS 72 h No NA

Aledort LM 1985 52 mc 115 90 126 NA NS NA No Two deaths

Hay CRM 1987 53 3 sc 34 32 2 24 43 NA NA NA No No bleed

Makris M 1991 54 3 sc 77 66 11 43 99 NA NA NA No No bleed

Ahmed MM 1996 55 3 sc 50 50 50 Percutaneous 100 48 h No No bleed

(pain, 2)

Hanley JP 1996 56 3 sc 22 22 22 Laparoscopy 100 (A)

70 (B)

50–100% (48 h)

(HA)/50–70%

(48 h) (HB)

No No bleed

Wong VS 1997 57 3 sc 35 35 35 Percutaneous 100 50% (36 h) –

CI in 5 patients/

2–4 days in hospital

NA No bleed

Gupta R 1997 58 3 sc 6 5 1 5 6 Transjugular 80–100 24 h in hospital No No bleed

Fukuda Y 1998 59 3 sc 36 28 5 36 Percutaneous NA 50% loading

dose (24–48 h)

No No bleed

Adamowicz A 1999 60 3 sc 13 13 NA 100 (A)

80 (B)

100% (HA) 80%

(HB) (12–24 h)/

50% (24–48 h)

No No bleed

Farell RJ 1999 61 3 sc 5 5 5 Percutaneous 100 CI (4 U Kg)1 h)1)

(48 h)

No No bleed

McMahon C 2000 62 3 sc 17 13 4 10 21 Percutaneous 100 100% (48–72 h) 4 proc No bleed

Venkataramani A 2000 63 3 sc 12 9 3 5 12 Percutaneous 100 >50% (24–48 h)/

CI >30% (7 days)

No Bleed (1)

Shields PL 2000 64 3 sc 21 21 NA NA NA NA No bleed

Lethagen S 2001 65 3 sc 27 24 3 11 39 Percutaneous 100 100% (48 h)/

2 days in hospital

Yes No bleed

Delladetsima J 2002 66 3 sc 24 24 25 Percutaneous 100 NA NA No bleed

Denzer U 2003 67 3 sc 1 1 Mini Laparoscopy NA NA NA

Dimichele DM 2003 68 3 sc 10 9 1 8 10 Transjugular >70 >70% (24 h)/

>50% (24–72 h)/

>30% (4–5 days)

No No bleed

(pain, 3)

Stieltjes N 2004 69 3 sc 69 60 21 45 88 Transjugular NS 20 U kg)1 per 8–12 h

(48 h) (HA)/60 U kg)1

per 8–12 h (48 h) (HB)

No Bleed (4)

Saab S 2004 70 3 sc 11 9 2 7 11 Transjugular 100 72 h No No bleed

Shin J 2005 71 3 mc 56 47 9 7 65 TJLB (64), Femoral (1) 75% half-dose 12–24–48 h No Bleed (7)

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half, and antifibrinolytic treatment in more thantwo-thirds, of the centres.

Synovectomy

Literature review. Four papers reporting data onreplacement therapy for synovectomy publishedbetween 2000 and 2003 were identified [45–48].The level of evidence was 3 or 4. These four studiesinvolved 158 patients undergoing 197 differentprocedures. Factor replacement always included aloading dose, ranging from 15 to 50 IU kg)1 inpatients with haemophilia A and from 30 to90 IU kg)1 in patients with haemophilia B, aimingat factor levels between 30–100% and 30–90%,respectively. Subsequent replacement therapy waseither short (repeated bolus at full dose 8–12 h laterand at half-dose on day 2) or prolonged for 8 weeksusing a prophylactic regimen (20 IU kg)1 three timesper week – 2 weeks and 15 IU kg)1 two times perweek – 6 weeks for haemophilia A and 30 IU kg)1

three times per week – 2 weeks and 25 IU kg)1 twotimes per week – 6 weeks for haemophilia B). Nobleeding complications were reported.

Survey. A target level of factor VIII (FVIII) between80% and 100% was reported by 87.5% of thecentres (Table 2). Continuous infusion for this pro-cedure was considered as an option by 62.5% of thetreaters. Treatment was continued for more than7 days in a majority of the centres. Antifibrinolyticswere used in 56% of the centres.

Liver biopsy

Literature review. A total of 26 papers publishedbetween 1977 and 2007 were reviewed [49–74](Table 3). These studies included 778 proceduresperformed in 713 patients (Haemophilia A: 526;Haemophilia B: 68; unspecified: 119). Among thesepatients, 278 had severe haemophilia. Although thereview criteria did not include patients with inhibi-tors, one study reported the inclusion of one patientwith inhibitors. Patients co-infected with HIV werenot excluded unless they were severely immuno-suppressed. The following types of procedures wereperformed: percutaneous liver biopsy (11 studies),biopsy under laparoscopy (two studies) and tran-sjugular liver biopsy (seven studies). The replacementtherapy protocol did not vary in most studies witha pre biopsy target level of FVIII of 100% inmost studies. Intermittent bolus infusions every12 h were usually given after the procedure.Continuous infusion was also used in some patientsT

able

3.Continued.

First

author

Year

References

Level

of

evidence

Design

Number

of

patients

HA

HB

Number

withsevere

disease

Number

of

procedures

Method

ofliver

biopsy

Factorlevel

prebiopsy

(%)

Factorlevel

post

biopsy

andduration

ofreplacement

Use

of

antifibrinolytics

Outcome

Daw

sonM

A2005

72

3sc

54

11

5Transjugular

100%

100%

(24h)

–>50%

(48h)

No

Nobleed

DetraitM

2007

73

3sc

99

06

9Transjugular

100%

80–100%

(24h)

then

50%

No

Nobleed

SterlingRK

2007

74

3sc

29

24

529

Percutaneous

100%

50–30%

(24h)–50%

(24–72h)(H

A)

50%

(during

72h)(H

B)

No

Nobleed

Total

713

526

68

285

778

12bleeds

CI,continuousinfusion;HA,haem

ophilia

A;HB,haem

ophilia

B;NA,notavailable;TJLB,transjugularliver

biopsy.



(four studies). The post biopsy target levels were70–100% for the first 24 h, 50–70% for 24–48 h,and >50% for 48–72 h. When the replacementtherapy was extended for 5–7 days, target levelswere >30%. The duration of in-hospital stayranged from 4 h to 7 days. For patients dischargedearly, treatment was continued at home. Concomi-tant use of antifibrinolytics was reported in twostudies. All studies except one reported bleeding risksimilar to non-haemophilic patients (0.5%). Theincidence of complications and the factorrequirements did not differ among the variousmethods.

Survey. The target factor level before transjugularbiopsy was between 80% and 100% in 77% of thecentres (Table 2). Bolus infusions were used in two-third of the participants. Post biopsy, the factor levelwas maintained above 80% in 45% of the centres, orbetween 40% and 70% in 45%. There was widevariation among the centres, although the durationof treatment was usually between 2 and 3 days in 10out of the 18 centres.

Paediatric surgery

Three invasive procedures (tonsillectomy, circumci-sion and CVAD insertion) commonly performed inchildren with haemophilia were addressed in thesurvey.

Tonsillectomy

Literature review. Only three studies involving ton-sillectomy published between 1985 and 1996 wereidentified [75–77] (Table 4). All were single-centre,retrospective studies and only included 24 patients.The level of evidence was 3. The target factor levelpreoperatively varied between 80% and 100%.Replacement therapy was maintained for 5–11 daysin combination with antifibrinolytics. Only onepatient developed a bleeding episode postopera-tively.

Survey. In agreement with the published data, allparticipants would aim for a factor level between80% and 100% (Table 2). Interestingly, 33% ofparticipants would consider the use of continuousinfusion. Treatment would be continued for 1–3 days in 69% of the centres aiming at levels of80–100% and for 4–7 days in 75% of centres. Fiftyper cent of treaters would however consider replace-ment therapy of more than 7 days duration. Antifib-rinolytics were used in 94% of the centres.

Circumcision

Literature review. Six studies involving circumcisionpublished between 1992 and 2004 were reviewed[78–83] (Table 4). Four were retrospective and twoprospective; the level of evidence was 3 in fivestudies and 2 in one. These studies included 163patients. Replacement therapy with factor concen-trate was used in five studies. In one study,antifibrinolytics were used alone. The factor levelbefore the procedure was only reported in twostudies where it was between 30% and 60%.Adjuvant haemostatic agents (fibrin glue or antifib-rinolytics) were used in most studies. Postopera-tively, replacement therapy was continued for2–8 days. Bleeding complications were reportedpostoperatively in three studies with a frequencyup to 50%.

Survey. In 81% of the centres, the target factorlevel before circumcision was between 80% and100% (Table 2). Use of continuous infusion wasconsidered a treatment option by 12.5% of therespondents. Treatment was continued for 1–3 daysin 75% of the centres aiming at levels of 50% onaverage and for 4–7 days in 44% centres. Only66% of the treaters consider longer treatment to beappropriate. Antifibrinolytics were used in 69% ofthe centres.

Port-A-Cath� insertion

Literature review. Fifteen studies involving Port-A-Cath� insertion and published between 1992 and2004 were reviewed [84–98] (Table 5). Eleven stud-ies were retrospective. The level of evidence was 3 in11 studies and 2 in two studies. The studies involved256 patients who underwent 347 procedures. Sev-enty patients had inhibitors. For patients treated withFVIII or FIX concentrates, the target level beforesurgery reported in eight studies was more than90%. Replacement therapy was maintained for avariable period ranging from 2 to 10 days. Bleedingcomplications were reported following 34procedures.

Survey. Target FVIII level was between 80% and100% in 81% of the centres (Table 2). Use ofcontinuous infusion was considered an option by12.5% of the treaters. Treatment was continued for1–3 days in 62.5% of the centres aiming at levels of50% on average and for 4–7 days in 31% of thecentres. Antifibrinolytics were used in 69% of thecentres.

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Table 4. Tonsillectomy and circumcision in patients with haemophilia: literature review of replacement therapy.

Procedure

First

author Year References

Level

of

evidence

Number

of

patients

Severity of

haemophilia

Study

design

Type of

concentrate

Dose

(IU kg)1)

Factor

level aimed

at (%)

Factor level

achieved

(%)

Duration of

treatment

(days)

Outcome

(early

outcome)

Special

comments

Tonsillectomy Thach T 1985 75 3 9 Mild,

moderate,

severe

SC, R NA 40–50 80 initially

then 30–50

NA 9–11 No

complication

Tonsillectomy Prinsley P 1993 76 3 5 Mild,

moderate,

severe

SC, R NA NA 90–100

then >50

90–100 5–7 1 epistaxis at

day 9 (FVIII

level at 40%)

Use of TA

until day 7

Tonsillectomy Conlon B 1996 77 3 10 Mild,

moderate,

severe

SC, R NA NA 90–100 90–100 10 No

complication

Use of TA

until day 7

Circumcision Martinowitz

U

1992 78 3 10 Severe

only

SC,

R, 0

NA NA NA NA NA 3 secondary

bleeds (2 required

replacement

therapy),

FG useful

Use of TA

and FG. No

replacement

therapy

Circumcision Kavakli K 1997 79 3 4 Severe

only

SC,

R, O

Branded

Plasma

FVIII

products

NA 50–60 50–60 4 No

complication

Use of TA

and FG

Circumcision Avanoglu A 1999 80 2 22 NA C, P bolus or

CI (4 U

Kg)1 h)1)

NA NA 2–4 Reduction of

substitutive

therapy by

adjunction

of FG

Circumcision Shittu OB 2001 81 3 70 Mild,

moderate,

severe

SC,

R, O

None NA NA NA NA 52.1% bleeds

Circumcision Zulfikar B 2003 82 3 56 Mild,

moderate,

severe

SC,

R, O

NA 20–30 NA 30–40

(1–4 days)/

20–30

(5–7 days)/

10–20

(8–12 days)

No major bleed,

five transient

bleeds, one

delayed

haematoma

Prolonged

replacement

therapy with

low dose.

Use of TA

Circumcision Karaman

MI

2004 83 3 45 Mild,

moderate,

severe

P NA 25–40 NA NA 7–18 Five minimal

bleeds

231

C, controlled; CI, continuous infusion; FG, fibrin glue; NA, not available; SC, single centre; R, retrospective; O, observational; P, prospective; TA, tranexamic acid.

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Table 5. Port-A-Cath� insertion in patients with haemophilia: literature review of replacement therapy.

First author Year Reference

Level of

evidence

Sample Size

(number of

patients and

severity)

Study

design

Type of

concentrate

Dose (IU

kg)1)

Level

aimed

at (%)

Level

achieved

(%)

Duration

of treatment

(days)

Outcome

(early

outcome)

Special

comments

Ljung R 1992 84 3 12 severe

haemophilia A

O, R, SC NA 40–50 NA NA NA Two mild

haematomas

Use of TA

Girvan DP 1994 85 3 9 severe for 11

procedures (4 PAC

vs. 7 external

devices)

O, R, SC NA 90–100 100 7 Two cases of

minor bruising

Liesner RJ 1995 86 3 23 severe (6 INH)/

27 procedures

R, 2

centres

High purity.

INH (6):

5 PorcFVIII,

1 rFVIIa

45–108 >75 5–7 27% complication

rate

(6/23 with 3 bleeds,

2 new inhibitors,

1 allergy)

Blanchette

VS

1996 87 3 19 (1 moderate

and 18 severe,

3 INH)/23 PAC

O, R, SC PorcFVIII

or aPCC

for INH

NA 100 90–100 7 No complication 13 prophylaxis/

2 ITI/4 other

indications

Smith OP 1996 88 3 3 severe haemophilia

A INH/4 procedures

O, R, SC rFVIIa 90 lg kg)1 NA NA 2 No complication Use of TA. Ports

represented

2 out of the

4 procedures

Perkins JL 1997 89 3 32 severe (7 INH)/

36 procedures

O, R, SC NA NA 100 NA 5–10 No complication

Warrier I 1997 90 3 22 severe (11 INH)/

35 procedures

O, R, SC PorcFVIII

or rFVIIa

for INH

50–100 80–90 NA 5–7 Mild bleeds in five

patients (14%

of procedures)

9 cases for ITI

Santagostino

E

1998 91 2 15 moderate and

severe (2 INH)

O, P, UC, SC Recombinant

FVIII or rFVIIa

70–80 80–90 80–90 6 1 case with

haematoma at

day 7 and inhibitor

at day 14

Indications for

PAC:

prophylaxis 13

cases, ITI 2 cases

Miller K 1998 92 3 45 (3 moderate,

42 severe) (8 INH)/

49 procedures

(41 PAC)

O, R, 2

centers

NA NA 100 >30–40 3–10 No major

complication.

11 minor

haematomas

(22% of procedures)

Indications for

PAC: prophylaxis

26 cases,

ITI 8 cases

Van Den

Berg HM

1998 93 4 Review 100 NA 5–7 NA

Montoro

JB

1998 94 3 1 severe hemophilia

A (INH)

case

report

rFVIIa

(Continuous

Infusion)

90 lg kg)1 5 Mild haematoma at

the site of insertion

Use of TA.

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Dental surgery

Literature review. Twenty-one studies involvingdental surgery published between 1965 and 2006were identified [99–119] (Table 6). The level ofevidence was 1 in two studies and one subgroup inanother study. Ten studies were level 2 evidenceand nine were level 3.Several studies were randomized. A total of 1124

patients underwent 1470 surgical dental proce-dures. Clotting factor was used in 15 studies, fibringlue in 10 studies and antifibrinolytic agents in 17studies. The factor level before extraction was 50%in most studies. The duration of replacementtherapy varied between 5 and 7 days.

Survey. Factor VIII was given in all patients inorder to raise the FVIII level to between 60% and80%. Treatment was repeated in one-third of thecentres. Antifibrinolytics were given to all patientsfor a period ranging from 5 to 10 days.

Discussion

Although numerous reports of the use of replace-ment therapy with clotting factor concentrates inpatients with haemophilia undergoing differentkinds of surgical procedures have been published,no comprehensive review of the literature has so farbeen performed. It is noticeable that the mostrecently published international treatment recom-mendations and guidelines of replacement therapyin haemophilia are not supported by a comprehen-sive literature review. This article aims to addressthis gap in the literature by providing an originaland comprehensive literature review as well as asurvey of current practice among a large group ofEuropean haemophilia treaters.Interesting conclusions can be drawn from the

literature review. It is evident that there is a lack ofrobust data, as, with the exception of two studiesin dental surgery, no randomized controlled trialsof replacement therapy were identified. For theremaining studies reviewed, the level of evidencewas rated as 2, but more frequently 3. Thus, thebody of evidence we have is founded on studies,most of which have significant methodologicallimitations. Procedures such as tonsillectomy andcircumcision are commonly performed yet arepoorly represented in the literature; only nine ofthe 110 papers considered these operations. Addi-tional limitations are the very small patient num-bers included in the majority of studies and thefact that many reports do not provide detailedT

able

5.Continued.

First

author

Year

Reference

Level

of

evidence

Sample

Size

(number

of

patients

and

severity)

Study

design

Typ

eof

concentrate

Dose

(IU

kg)

1)

Level

aim

ed

at(%

)

Level

achieved

(%)

Duration

oftreatm

ent

(days)

Outcome

(early

outcome)

Special

comments

Bollard

CM

2000

95

314severe(5

INH)/

23procedures

O,R,SC

Various

50–100

NA

NA

3–5

Fourhaem

atomas

(17%

ofprocedures)

Indications

forPAC:

prophylaxis11

cases,ITI2cases

McM

ahon

C

2000

96

346severe(8

INH)/

77procedures(74PAC)

RNA

NA

NA

NA

NA

Indications

forPAC:

prophylaxis

34cases,

ITI

12cases

Morado

M

2001

97

315(m

oderate

andsevere

withIN

H)/34procedures

O,R,SC

aPCC

or

rFVIIa

100U

kg)1

(aPCC)/120lg

kg)1(rFVIIa)

NA

NA

NA

2Haem

atomas

outof6ports

Only

6ports

Valentino

LA

2004

98

2256patients/

347procedures70IN

H

Review

100

3–8

APCC,activated

prothrombin

complexconcentrate;IN

H,inhibitor;

ITI,im

munotolerance;NA,notavailab

le;O,observational;P,prospective;

PAC,Port-A

-Cath;R,retrospective;

sc,

single

centre;

TA,tranexamic

acid;uc,

uncontrolled.



Table 6. Dental extraction in patients with haemophilia: literature review of replacement therapy.

First


Level

of

evidence

Number

of

patients Procedures

Study

design

% of

procedures

on severe

patients Study arms

Bleeds in

each arm

Haemostatic

treatment Comments

Part 1

Biggs R 1965 99 3 38 43 SC, O, R 85 Arm 1: single extraction,

5 days of treatment

0/8 bleeds F High bleed rates

despite prolonged

treatmentArm 2: 2–9 extractions,

5–10 days of treatment

9/13 bleeds

Arm 3: >9 extractions,

8–12 days of treatment

7/13 bleeds

Tavenner

RWH

1968 100 2 30 61 SC, CC, R 47 No factor replacement.

EACA 6 g 4-hourly

pre-operative until

discharge FG and suture

7/30 bleeds

(6/7 with

severe disease)

EACA (s), FG FG, EACA and

suture effective

in mild disease

Walsh PN 1971 101 2 18 18 SC, CC, R 53 Arm 1: factor replacement

target level 50% during

7–10 days + EACA

6 g qds during 10 days

7/18 bleeds F, EACA (s)

Arm 2: factor replacement

target level 50% during

7–10 days

7/20 bleeds

101 1 31 31 MC, RCT 39 Arm 1: factor replacement

target level 50% + EACA

(s) 6 g qds during 7–10 days

3/15 bleeds F, EACA (s) EACA is effective

(level 1 evidence)


target level 50%

14/16 bleeds

Forbes CD 1972 102 1 28 32 SC, RCT, DB 47 Arm 1: plasma + TA

1 g tds during 5 days

2/16 bleeds Plasma, TA (s) TA is effective

(level 1 evidence)

Arm 2: plasma 11/16 bleeds

Tavenner

RWH

1972 103 2 21 51 SC, CC, R 41 No factor replacement.

TA (s) 1.5 g qds pre-operative

until discharge. FG and suture

5/51 bleeds

(5 with severe

disease)

FG, TA (s) Fibrin glue, TA (s)

and suture effective

in mild disease

Ramstrom G 1975 104 2 52 97 SC, CC, R 40 Arm 1: factor replacement

target level 30–50%

pre-operative, 25–30

during 2–3 days, 12–25%

during 6–10 days

23/27(9/23

prolonged

or severe)

F, TA (s) Antifibrinolytics and

local haemostasis

are of benefit

Arm 2: similar to arm 1 except

many patients received a single

pre-operative bolus to 20–30%.

TA 1 g tds (duration not stated)

10/30 (0/10

severe or

prolonged)


target level 8–10% pre-

operative + TA (s) 1 g tds

during 7 days + local

haemostatics (surgical/

acrylic plates)

4/27 (0/4

severe or

prolonged)

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Table 6. Continued.

First


Level

of

evidence

Number

of

patients Procedures

Study

design

% of

procedures

on severe

patients Study arms

Bleeds in

each arm

Haemostatic

treatment Comments

Kaneda T 1981 105 3 74 98 SC, O, R NA Factor

replacement

until

haemostasis

achieved

12% (3.5–25%)

for haemostasis

F Factor level of 25%

may be adequate

Suzuki M 1983 106 3 9 13 SC, O, R 70 Thrombin and

packing.

No factor

replacement

therapy.

3/13 bleeds FG Local thrombin

generation

is important

Steinberg

SE

1984 107 3 16 19 SC, O, R 44 In 11 patients, FVIII

increased to 20% and FIX

to 10% pre-operative.

8 patients (4 severe) had

no pre-operative treatment.

Thrombin was given

when necessary.

7/19 bleeds F High bleed rate

in absence of

antifibrinolytic

therapy,

FG and factor

concentrate.

Baudo F 1985 108 3 29 29 SC, O, R 45 FG, collagen and suture 8/29 (7/13

with severe

disease)

FG FG and suture

may prevent bleeding

in mild disease but

bleeding rate is high

in severe disease.

Stajcic Z 1985 109 2 43 43 SC, CC 51 Arm 1: factor replacement

with 10–20 U kg)1 FVIII +

EACA (s) 6 g qsd during

6–10 days

0/13 bleeds F, EACA Antifibrinolytics

are of benefit


as for arm 1 (pre-operative) +

FVIII (? Dose) (postoperative) +

EACA (locally) during 1 day

5/11 bleeds

Arm 3: factor replacement as

for arm 1 (pre-operative) +

EACA (locally) during day 1 +

EACA (s) 6 g qds during

6–10 days

5/11 bleeds

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Table 6. Continued.

First


Level

of

evidence

Number

of

patients Procedures

Study

design

% of

procedures

on severe

patients Study arms

Bleeds in

each arm

Haemostatic

treatment Comments

Sindet-

Pedersen S

1986 110 2 40 54 SC, O, R 62 Arm 1: factor replacement

target level 60–70%

pre-operative + TA (s)

37–123 mg kg)1 per day

during 3–6 days. Some post

treatment was given as some

patients were on prophylaxis

13/27 F, TA (s

and locally)

TA mouth wash

appears to add benefit

to TA (s).Factor level

of 10% preop level is

inadequate in

severe disease.

Arm 2: as for arm 1 +

TA (mouth wash) during

5–7 days

0/12 bleeds

Arm 3: Factor replacement

with median preop level

of 13% (10–22%).

If baseline factor level >10%,

no treatment plus TA (s)

72–106 mg kg)1 per day

during >6 days + TA (mouth

wash) during 5 days at least

6/15 bleeds

Baudo F 1988 111 2 59 91 SC, O, R 60 Arm 1: FG 11/63 bleeds FG, TA (s) Antifibrinolytics are

of benefitArm 2: FG + TA (s)

1 g tds during 7 days

0/28 bleeds

Ramtsrom

G

1989 112, 104 2 87 228 SC, O 41 Arm 1: Factor replacement

target level 8–10% pre-

operative + TA (s) 1 g tds

during 7 days plus local

haemostasis, acrylic plates

or suturing of flap.

5/162 bleeds F, TA

Arm 2: Similar but time

period 1972–1973 and

reported in arm 3 in

reference 104

Rakocz M 1993 113 2 37 37 SC, CC, R 100 Arm 1: FG 9/12 bleeds FG, TA (locally) Antifibrinolytics

are of benefitArm 2: FG + TA (mouth

wash) qds during 10 days

3/25 bleeds

Waly NG 1995 114 1 24 24 SC Arm 1: replacement therapy +

TA (s)

75% bleeds F, TA (locally) TA mouth wash

effective

Arm 2: replacement therapy +

TA (s) + TA (mouth wash)

8.4% bleeds

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Table 6. Continued.

First


Level

of

evidence

Number

of

patients Procedures

Study

design

% of

procedures

on severe

patients Study arms

Bleeds in

each arm

Haemostatic

treatment Comments

Zanon E 2000 115 2 261 261 SC, CC, R 45 Arm 1: factor replacement

target level 30% pre-operative,

TA (s) 20 mg kg)1 pre-

operative then tds during

7 days, FG and suture

2/77 bleeds F, FG, TA (s) FG and 30% factor

rise is effective.

Arm 2: standard extraction

in healthy controls. 117/

184 had suture

1/184 bleeds

Piot B 2002 116 3 45 51 SC, O, R 20 Factor level 50% pre-

operative and 24 h

postoperative and TA (s)

20 mg kg)1 tds during 8 days

0/51 F, TA (s) 50% factor rise

pre-operative and

24 h postoperative +

TA (s) 8 days is effective

Frachon X 2005 117 3 16 19 SC, O, R 36 Factor replacement preop

with 50 IU kg)1 FVIII in

patients with severe haemophilia

A. DDAVP in patients with

mild haemophilia A. Local

haemostasis (FG, suturing).

TA locally for 3 days

6/19 bleeds F, FG, TA

(locally)

Single treatment with

factor not effective

in all cases

Franchini M 2005 118 3 135 139 MC, O, R 38 Factor replacement or DDAVP

aiming at 50% pre-operative

with systemic and local

antifibrinolytics

7/139 bleeds F, FG, TA (s)

and locally

Factor replacement

plus antifibrinolytics

is safe and effective

Correa ME 2006 119 3 31 31 SC, O, R 25 FG, EACA (s) during 7 days 6/31 bleeds FG, EACA (s)

1124 1470 989

CC, case–control; DB, double blind; EACA, epsilon-aminocaproic acid; F, factor; FG, fibrin glue; MC, multi-centre; O, observational; P, prospective; R, retrospective; RCT, randomized controlled

trial; SC, single centre; TA, tranexamic acid.

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information regarding the levels of clotting factorachieved or the duration of replacement. Thepercentage of bleeding complications and the mag-nitude of blood losses are not systematicallyreported so that minimal haemostatic levels cannotbe clearly derived from our review of the literature.With the exception of a single study performed

in India [24], there has been no attempt during thelast three decades to test the haemostatic efficacyof using lower factor levels. This observation canto some extent be accounted for by the fact thatmost studies were performed in developed coun-tries (Europe and USA) where the availability ofclotting factor concentrates is greater and wherethere has been a tendency to aim for higher targetlevels and to use higher doses of factor concen-trates in surgical procedures over the last fewdecades.The survey conducted among a large group of

treaters caring for several thousands of haemophiliapatients has provided invaluable information ontreatment practices including target factor levels,duration of treatment and use of certain treatmentmodalities such as continuous infusion and throm-boprophylaxis in the postoperative course of majororthopaedic surgery. The survey highlights muchheterogeneity in practice consistent with the widerange of treatment regimens reported in the litera-ture. However, it was interesting that for mostprocedures reviewed, there was a good agreementbetween published data and current treatment prac-tices in terms of intensity and duration of replace-ment therapy. For dental care, however, theprescribed treatment regimens revealed by the surveyare usually more intensive and target higher factorlevels than those reported in the literature. Contin-uous infusion appears to be used in nearly half of thepatients undergoing major orthopaedic surgery inthe survey centres, suggesting that the extent of theclinical experience and use of this treatment modalityis greater than what the published literature wouldsuggest.Because of the limitations discussed and the very

limited number of randomized controlled trials, nowell-supported recommendations can be maderegarding optimal factor levels and duration ofreplacement therapy for patients with haemophiliaundergoing invasive procedures. However, dataaccrued in the literature and the survey, as well asthe clinical expertise of the treaters involved in thegroup, have served as a platform for extensivediscussion within the network of the EHTSB andthe development of consensus recommendationsfor replacement therapy. Consensus was reached

on the following recommendations and the level ofevidence for each of these is given in parenthesis(Table 7):1. In patients undergoing major orthopaedic

surgery, including open surgical synovectomy,preoperative factor levels should be 80–100%(grade B, level III). In the postoperative period,minimal factor levels should be maintained above50% in the first postoperative week and above30% in the late postoperative period (grade C,level IV). Continuous infusion appears safe andeffective and the use of antifibrinolytic agentsand thromboprophylaxis could be considered incertain settings.

2. In patients undergoing liver biopsy, the preoper-ative factor level should be above 80% andreplacement therapy should be continued for atleast 3 days (grade B, level III). The biopsymethod should be selected depending on the localexperience.

3. Replacement therapy is required for childrenundergoing surgical procedures such as tonsillec-tomy, CVAD insertion and circumcision (grade B,level III). The preoperative factor level should beabove 80% and replacement therapy shouldbe continued for 7–10 days after tonsillectomyand at least 3 days after CVAD insertion (grade B,level III). For circumcision, a target level of 80%and continuation of replacement therapy during3–4 days are recommended (grade C, level IV).Adjunctive treatment with antifibrinolytics and/orfibrin glue should be considered (grade B, levelIV).

Table 7. Grading of recommendations and levels of evidence.

Grade Level Type of evidence

A Ia Evidence obtained from meta-analysis

of randomized studies

A Ib Evidence obtained from at least one

randomized controlled trial

B IIa Evidence obtained from at least one well

designed controlled study without

randomization

B IIb Evidence obtained from at least one

other type of well-designed quasi-

experimental study

B III Evidence obtained from well-designed

non-experimental descriptive

studies, such as comparative studies,

correlation studies and case-control studies

C IV Evidence obtained from expert committee

reports or opinions and/or clinical experience

of respected authorities



4. For patients undergoing dental extraction,replacement with clotting concentrate is recom-mended with a minimal factor level of 50%(grade B, level IV). Antifibrinolytic therapy isrecommended for 7 days (grade A, level I).Adjunctive treatment with fibrin glue should beconsidered (grade B, level IV).In conclusion, this study provides both a compre-

hensive review of the available literature and a largesurvey of replacement therapy in patients withhaemophilia undergoing invasive procedures; thisreview highlights the need for robust future studieson the incidence, type and magnitude of bleedingcomplications in patients with haemophilia under-going invasive procedures and comparing them withbleeding events in non-haemophilic patients. Withinthe constraints discussed, treatment recommenda-tions are provided, which reflect the literature,current practice and the clinical experience of theEHTSB. Better-designed studies using standardizedprotocols, as well as patient registries, are howeverneeded in order to define minimal haemostatic levelsand optimal durations of treatment.

Acknowledgements

The European Therapy Standardisation Boardconsists of the following members and Europeanhaemophilia centres: Alessandro Gringeri, Milan,Italy; Ana Villar and Marta Morado, Madrid, Spain;Angelika Batorova, Bratislava, Slovakia; AngiolaRocino, Napoli, Italy; Anastasia Karafoulidou, Ath-ens, Greece; Barry White, Dublin, Ireland; CarmenAltisent, Barcelona, Spain; Cedric Hermans, Brus-sels, Belgium; Chantal Rothschild, Paris, France;H. Marijke van den Berg, Utrecht, the Netherlands;Geraldine Lavigne Lissalde, Montpellier, France;Gerry Dolan, Nottingham, UK; Herve Chambost,Marseille, France; Jan Astermark, Malmo, Sweden;Jerzy Windyga, Warsaw, Poland; Lorenzo GiovanniMantovani, Napoli, Italy; Manuela Fraga, Porto,Portugal; Mario Schiavoni, Bari, Italy; Mario vonDepka, Hannover, Germany; Michael Richards,Leeds, UK; Philippe de Moerloose, Geneva, Switzer-land; Rosario Perez Garrido, Seville, Spain; RiittaLassila, Helsinki, Finland; Robert Klamroth, Berlin,Germany; Thierry Lambert, Paris, France.

Disclosures

Barry White has received an unrestricted educationalgrant from Baxter and NovoNordisk. The otherauthors stated that they had no interests which mightbe perceived as posing a conflict or bias.

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Replacement therapy for invasive procedures in patients with haemophilia: literature review,...

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