Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations
Cedric Hermans, MD, MRCP (UK), PhD, Haemostasis and Thrombosis Unit, Division of Haematology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate, 10, 1200 Brussels, Belgium.
Tel.: +32 2 764 1740; fax: +32 2 764 8959;
Summary. Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80–90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10–14 days; for liver biopsy, 70–100%, 1–7 days; tonsillectomy: 90–100%, 5–11 days; indwelling venous access device insertion: 100%, 3–10 days; circumcision: 50–60%, 2–4 days; dental surgery: 30–50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better-designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.
Most surgical and invasive procedures can be performed safely in patients with haemophilia with factor replacement therapy. Country-specific consensus recommendations for substitutive therapy during these procedures have previously been published [1–8]. However, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. This gives rise to a widely acknowledged lack of consistency among treatment regimens for factor replacement therapy in patients with haemophilia undergoing invasive procedures.
Despite the existence of a large number of reports of the use of replacement therapy cover during invasive procedures in patients with haemophilia, few comprehensive reviews of published literature have so far been performed . Moreover, little data are available regarding the current management of invasive procedures, especially those employing the more recently introduced treatment practices such as continuous infusion or thromboprophylaxis in patients undergoing major orthopaedic surgery.
For these reasons, an extensive literature review of invasive procedures in patients with haemophilia A and B was conducted and a survey carried out to provide information on current practice in 26 European haemophilia centres representing 15 different countries. All survey participants were members of the European Haemophilia Therapy Standardisation Board (EHTSB), an established group of experienced haemophilia centre-based physicians who are responsible for treating a total of 3633 people with severe haemophilia. The aim was to provide a comprehensive overview of existing data that would be invaluable in assessing current practices and identifying areas of controversy and unresolved issues as well as topics for future research. Data that accrued from the literature and the survey, as well as the clinical experience of the treaters, served as a platform for extensive discussions within the network of the EHTSB to develop consensus recommendations for replacement therapy.
Materials and methods
A comprehensive review was performed of published evidence regarding replacement therapy for invasive surgical procedures in patients with haemophilia. This included major procedures (orthopaedic surgery including synovectomy) and minor surgery [tonsillectomy, central venous access device (CVAD) insertion, circumcision, dental surgery, liver biopsy]. For each procedure, the literature review was conducted by physicians of the EHTSB. Relevant papers were identified using a Pub-Med search and data were reviewed using a standard protocol. The following information was collected: study reference, year of publication, year of study, level of evidence (rated as 1: high-quality meta analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias; 2: high-quality systematic reviews of case control or cohort studies. High-quality case control or cohort studies with a very low risk of confounding or bias with a high probability that the relationship is casual; 3: non-analytical studies, e.g. case reports, case series and 4: expert opinion), sample size, severity and type of haemophilia, study design (pre-registration, post registration, observational, case-control, retro- or prospective, single centre and multiple centre), type of concentrate (plasma-derived, recombinant, degree of purity and brand), dosage (U kg−1), level of factor aimed for, level of factor achieved, mode of administration (continuous infusion vs. bolus infusion), duration of treatment, complications, outcome and special comments. A critical analysis of relevant papers was then undertaken.
Treatment practices were surveyed by questionnaires related to clinical cases illustrating common invasive procedures, including major orthopaedic surgery (knee replacement), liver biopsy (performed by the transjugular route), circumcision, CVAD (Port-A-Cath®; Smiths Medical International Limited, Kent, UK) insertion, tonsillectomy and dental extraction in patients with severe haemophilia. Information was collected regarding target levels of clotting factors, duration of treatment, treatment modality [continuous infusion vs. bolus, use of DDAVP (deamino d-arginine vasopressin or desmopressin)], peri-operative management including pharmacokinetic evaluation, 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. The average number of haemophilia patients per centre was 241 (range 45–613). The average number of procedures per year per centre was between 2 and 5 for major orthopaedic surgery and liver biopsy, between 6 and 10 for minor surgery and more than 10 for dental surgery. Most respondents were from Comprehensive Care Centres and followed written guidelines for replacement therapy during surgery.
Literature review. Thirty-five clinical studies were reviewed [10–44] (Table 1). Eight studies were considered to have reached level of evidence 2 and 27 studies up to level 3. Nine studies were multicentre and six were case–control studies with at least historical controls. In total, 1114 patients underwent 1328 major surgical procedures (707 orthopaedic surgeries) including patients with severe, moderate and mild haemophilia A (862) and haemophilia B (241). Surgery was performed using different types of plasma-derived and recombinant factor concentrates. In nine studies, tranexamic acid was used as adjunct therapy. Twenty-three studies used bolus infusion and 16 studies continuous infusion (five studies used both regimens). A small proportion of major surgical procedures (218/1328 or 16.4%) were managed by continuous infusion.
Table 1. Major surgery in patients with haemophilia: literature review of replacement therapy.
|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|
Factor levels were not available in four of the studies. Considering the other 31 studies, the preoperative target factor levels for haemophilia A and B were >90% in 11 studies, >80% in 15 and >50–70% in five. Thus the majority of studies (26/31) aimed at values >80%. In the 27 studies that addressed postoperative trough levels for the first week, values were >70% in eight studies, >50% in 11 and >20–30% in eight. For the second week, data were available in 18 studies and levels were >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 days in six and up to 28 days or longer in further six studies. Bleeding complications occurred in 131/1328 or 10% of major surgical procedures; most of them (96/131 or 73.3%) were in the 714 procedures included in the papers published before 1990. During the above time period, there were two cases of fatality related to bleeding complications.
No reliable correlation between postoperative bleeding and target factor level emerged. Local phlebitis was observed in a limited number of patients treated with continuous infusion (25/218). No publication recommended thromboprophylaxis with anticoagulants.
Survey. A target factor level of at least 80% was reported by all centres prior to major orthopaedic surgery (Table 2) which is similar to published practice. In contrast to the details reported in the literature, according to which continuous infusion was employed in only 16% of the procedures, this infusion technique was used in procedures performed in nearly half of the centres. In most centres, 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 the immediate postoperative period (from day 1 to 5) and around 60% in the late postoperative period (from day 6 to 14) – values that are higher than published targets. The duration of postoperative replacement therapy ranged from 12 to 14 days. When continuous infusion was used, the factor level was maintained at 80% during the first five postoperative days and decreased to 30–40% or 50–60% between days 6 and 14. Before major orthopaedic surgery, pre-operative pharmacokinetic evaluation was performed in one-third of the centres and the recovery measured in more than half of them. Thromboprophylaxis with low-molecular-weight heparin is used in more than half, and antifibrinolytic treatment in more than two-thirds, of the centres.
Table 2. European survey of replacement therapy for invasive procedures in haemophilia.
| Pre-operative|| ||81||19|| ||0|
| Pre-operative|| ||81||19|| ||0|
| Postoperative||1–3||25||62.50|| ||12.50|
|>7|| || ||6||94|
| Pre-operative|| ||100|| || ||0|
| Postoperative||1–3||69||31|| ||0|
| Pre-operative|| ||87.50||12.50|| ||0|
| Postoperative||1–3||50||50|| ||0|
| Pre-operative|| ||77||14||9||0|
| Pre-operative|| ||32||59||9||0|
| Pre-operative|| ||100|| || || |
| Postoperative||1–5 (bolus)||85||15||0||0|
Literature review. Four papers reporting data on replacement therapy for synovectomy published between 2000 and 2003 were identified [45–48]. The level of evidence was 3 or 4. These four studies involved 158 patients undergoing 197 different procedures. Factor replacement always included a loading dose, ranging from 15 to 50 IU kg−1 in patients with haemophilia A and from 30 to 90 IU kg−1 in patients with haemophilia B, aiming at factor levels between 30–100% and 30–90%, respectively. Subsequent replacement therapy was either short (repeated bolus at full dose 8–12 h later and at half-dose on day 2) or prolonged for 8 weeks using a prophylactic regimen (20 IU kg−1 three times per week – 2 weeks and 15 IU kg−1 two times per week – 6 weeks for haemophilia A and 30 IU kg−1 three times per week – 2 weeks and 25 IU kg−1 two times per week – 6 weeks for haemophilia B). No bleeding complications were reported.
Survey. A target level of factor VIII (FVIII) between 80% and 100% was reported by 87.5% of the centres (Table 2). Continuous infusion for this procedure was considered as an option by 62.5% of the treaters. Treatment was continued for more than 7 days in a majority of the centres. Antifibrinolytics were used in 56% of the centres.
Literature review. A total of 26 papers published between 1977 and 2007 were reviewed [49–74] (Table 3). These studies included 778 procedures performed in 713 patients (Haemophilia A: 526; Haemophilia B: 68; unspecified: 119). Among these patients, 278 had severe haemophilia. Although the review criteria did not include patients with inhibitors, one study reported the inclusion of one patient with inhibitors. Patients co-infected with HIV were not excluded unless they were severely immunosuppressed. The following types of procedures were performed: percutaneous liver biopsy (11 studies), biopsy under laparoscopy (two studies) and transjugular liver biopsy (seven studies). The replacement therapy protocol did not vary in most studies with a pre biopsy target level of FVIII of 100% in most studies. Intermittent bolus infusions every 12 h were usually given after the procedure. Continuous infusion was also used in some patients (four studies). The post biopsy target levels were 70–100% for the first 24 h, 50–70% for 24–48 h, and >50% for 48–72 h. When the replacement therapy was extended for 5–7 days, target levels were >30%. The duration of in-hospital stay ranged from 4 h to 7 days. For patients discharged early, treatment was continued at home. Concomitant use of antifibrinolytics was reported in two studies. All studies except one reported bleeding risk similar to non-haemophilic patients (0.5%). The incidence of complications and the factor requirements did not differ among the various methods.
Table 3. Liver biopsy in patients with haemophilia: literature review of replacement therapy.
|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)|
|Dawson MA||2005||72||3||sc||5||4||1||1||5||Transjugular||100%||100% (24 h) – >50% (48 h)||No||No bleed|
|Detrait M||2007||73||3||sc||9||9||0||6||9||Transjugular||100%||80–100% (24 h) then 50%||No||No bleed|
|Sterling RK||2007||74||3||sc||29||24||5|| ||29||Percutaneous||100%||50–30% (24 h)–50% (24–72 h) (HA)|
50% (during 72 h) (HB)
|Total||713||526||68||285||778|| || || || ||12 bleeds|
Survey. The target factor level before transjugular biopsy was between 80% and 100% in 77% of the centres (Table 2). Bolus infusions were used in two-third of the participants. Post biopsy, the factor level was maintained above 80% in 45% of the centres, or between 40% and 70% in 45%. There was wide variation among the centres, although the duration of treatment was usually between 2 and 3 days in 10 out of the 18 centres.
Three invasive procedures (tonsillectomy, circumcision and CVAD insertion) commonly performed in children with haemophilia were addressed in the survey.
Literature review. Only three studies involving tonsillectomy published between 1985 and 1996 were identified [75–77] (Table 4). All were single-centre, retrospective studies and only included 24 patients. The level of evidence was 3. The target factor level preoperatively varied between 80% and 100%. Replacement therapy was maintained for 5–11 days in combination with antifibrinolytics. Only one patient developed a bleeding episode postoperatively.
Table 4. Tonsillectomy and circumcision in patients with haemophilia: literature review of replacement therapy.
|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|| || || || || || || || || |
Survey. In agreement with the published data, all participants would aim for a factor level between 80% and 100% (Table 2). Interestingly, 33% of participants would consider the use of continuous infusion. Treatment would be continued for 1–3 days in 69% of the centres aiming at levels of 80–100% and for 4–7 days in 75% of centres. Fifty per cent of treaters would however consider replacement therapy of more than 7 days duration. Antifibrinolytics were used in 94% of the centres.
Literature review. Six studies involving circumcision published between 1992 and 2004 were reviewed [78–83] (Table 4). Four were retrospective and two prospective; the level of evidence was 3 in five studies and 2 in one. These studies included 163 patients. Replacement therapy with factor concentrate was used in five studies. In one study, antifibrinolytics were used alone. The factor level before the procedure was only reported in two studies where it was between 30% and 60%. Adjuvant haemostatic agents (fibrin glue or antifibrinolytics) were used in most studies. Postoperatively, replacement therapy was continued for 2–8 days. Bleeding complications were reported postoperatively in three studies with a frequency up to 50%.
Survey. In 81% of the centres, the target factor level before circumcision was between 80% and 100% (Table 2). Use of continuous infusion was considered a treatment option by 12.5% of the respondents. Treatment was continued for 1–3 days in 75% of the centres aiming at levels of 50% on average and for 4–7 days in 44% centres. Only 66% of the treaters consider longer treatment to be appropriate. Antifibrinolytics were used in 69% of the centres.
Literature review. Fifteen studies involving Port-A-Cath® insertion and published between 1992 and 2004 were reviewed [84–98] (Table 5). Eleven studies were retrospective. The level of evidence was 3 in 11 studies and 2 in two studies. The studies involved 256 patients who underwent 347 procedures. Seventy patients had inhibitors. For patients treated with FVIII or FIX concentrates, the target level before surgery reported in eight studies was more than 90%. Replacement therapy was maintained for a variable period ranging from 2 to 10 days. Bleeding complications were reported following 34 procedures.
Table 5. Port-A-Cath® insertion in patients with haemophilia: literature review of replacement therapy.
|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 μg 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 μg kg−1|| || ||5||Mild haematoma at the site of insertion||Use of TA.|
|Bollard CM||2000||95||3||14 severe (5 INH)/23 procedures||O, R, SC||Various||50–100||NA||NA||3–5||Four haematomas (17% of procedures)||Indications for PAC: prophylaxis 11 cases, ITI 2 cases|
|McMahon C||2000||96||3||46 severe (8 INH)/77 procedures (74 PAC)||R||NA|| ||NA||NA||NA||NA||Indications for PAC: prophylaxis 34 cases, ITI 12 cases|
|Morado M||2001||97||3||15 (moderate and severe with INH)/34 procedures||O, R, SC||aPCC or rFVIIa||100 U kg−1 (aPCC)/120 μg kg−1 (rFVIIa)||NA||NA||NA||2 Haematomas out of 6 ports||Only 6 ports|
|Valentino LA||2004||98||2||256 patients/347 procedures 70 INH||Review|| || ||100|| ||3–8|| || |
Survey. Target FVIII level was between 80% and 100% in 81% of the centres (Table 2). Use of continuous infusion was considered an option by 12.5% of the treaters. Treatment was continued for 1–3 days in 62.5% of the centres aiming at levels of 50% on average and for 4–7 days in 31% of the centres. Antifibrinolytics were used in 69% of the centres.
Literature review. Twenty-one studies involving dental surgery published between 1965 and 2006 were identified [99–119] (Table 6). The level of evidence was 1 in two studies and one subgroup in another study. Ten studies were level 2 evidence and nine were level 3.
Table 6. Dental extraction in patients with haemophilia: literature review of replacement therapy.
|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 treatment|
|Arm 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)|
|Arm 2: factor replacement 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)|
| || || || || || || ||Arm 3: factor replacement 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)|
|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|
|Arm 2: factor replacement 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|
|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 benefit|
|Arm 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 benefit|
|Arm 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|
|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|| || || || |
Several studies were randomized. A total of 1124 patients underwent 1470 surgical dental procedures. Clotting factor was used in 15 studies, fibrin glue in 10 studies and antifibrinolytic agents in 17 studies. The factor level before extraction was 50% in most studies. The duration of replacement therapy varied between 5 and 7 days.
Survey. Factor VIII was given in all patients in order to raise the FVIII level to between 60% and 80%. Treatment was repeated in one-third of the centres. Antifibrinolytics were given to all patients for a period ranging from 5 to 10 days.
Although numerous reports of the use of replacement therapy with clotting factor concentrates in patients with haemophilia undergoing different kinds of surgical procedures have been published, no comprehensive review of the literature has so far been performed. It is noticeable that the most recently published international treatment recommendations and guidelines of replacement therapy in haemophilia are not supported by a comprehensive literature review. This article aims to address this gap in the literature by providing an original and comprehensive literature review as well as a survey of current practice among a large group of European haemophilia treaters.
Interesting conclusions can be drawn from the literature review. It is evident that there is a lack of robust data, as, with the exception of two studies in dental surgery, no randomized controlled trials of replacement therapy were identified. For the remaining studies reviewed, the level of evidence was rated as 2, but more frequently 3. Thus, the body of evidence we have is founded on studies, most of which have significant methodological limitations. Procedures such as tonsillectomy and circumcision are commonly performed yet are poorly represented in the literature; only nine of the 110 papers considered these operations. Additional limitations are the very small patient numbers included in the majority of studies and the fact that many reports do not provide detailed information regarding the levels of clotting factor achieved or the duration of replacement. The percentage of bleeding complications and the magnitude of blood losses are not systematically reported so that minimal haemostatic levels cannot be clearly derived from our review of the literature.
With the exception of a single study performed in India , there has been no attempt during the last three decades to test the haemostatic efficacy of using lower factor levels. This observation can to some extent be accounted for by the fact that most studies were performed in developed countries (Europe and USA) where the availability of clotting factor concentrates is greater and where there has been a tendency to aim for higher target levels and to use higher doses of factor concentrates in surgical procedures over the last few decades.
The survey conducted among a large group of treaters caring for several thousands of haemophilia patients has provided invaluable information on treatment practices including target factor levels, duration of treatment and use of certain treatment modalities such as continuous infusion and thromboprophylaxis in the postoperative course of major orthopaedic surgery. The survey highlights much heterogeneity in practice consistent with the wide range of treatment regimens reported in the literature. However, it was interesting that for most procedures reviewed, there was a good agreement between published data and current treatment practices in terms of intensity and duration of replacement therapy. For dental care, however, the prescribed treatment regimens revealed by the survey are usually more intensive and target higher factor levels than those reported in the literature. Continuous infusion appears to be used in nearly half of the patients undergoing major orthopaedic surgery in the survey centres, suggesting that the extent of the clinical experience and use of this treatment modality is greater than what the published literature would suggest.
Because of the limitations discussed and the very limited number of randomized controlled trials, no well-supported recommendations can be made regarding optimal factor levels and duration of replacement therapy for patients with haemophilia undergoing invasive procedures. However, data accrued in the literature and the survey, as well as the clinical expertise of the treaters involved in the group, have served as a platform for extensive discussion within the network of the EHTSB and the development of consensus recommendations for replacement therapy. Consensus was reached on the following recommendations and the level of evidence for each of these is given in parenthesis (Table 7):
Table 7. Grading of recommendations and levels 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|
- 1In 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 above 50% in the first postoperative week and above 30% in the late postoperative period (grade C, level IV). Continuous infusion appears safe and effective and the use of antifibrinolytic agents and thromboprophylaxis could be considered in certain settings.
- 2In patients undergoing liver biopsy, the preoperative factor level should be above 80% and replacement therapy should be continued for at least 3 days (grade B, level III). The biopsy method should be selected depending on the local experience.
- 3Replacement therapy is required for children undergoing surgical procedures such as tonsillectomy, CVAD insertion and circumcision (grade B, level III). The preoperative factor level should be above 80% and replacement therapy should be continued for 7–10 days after tonsillectomy and at least 3 days after CVAD insertion (grade B, level III). For circumcision, a target level of 80% and continuation of replacement therapy during 3–4 days are recommended (grade C, level IV). Adjunctive treatment with antifibrinolytics and/or fibrin glue should be considered (grade B, level IV).
- 4For patients undergoing dental extraction, replacement with clotting concentrate is recommended with a minimal factor level of 50% (grade B, level IV). Antifibrinolytic therapy is recommended for 7 days (grade A, level I). Adjunctive treatment with fibrin glue should be considered (grade B, level IV).
In conclusion, this study provides both a comprehensive review of the available literature and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; this review highlights the need for robust future studies on the incidence, type and magnitude of bleeding complications in patients with haemophilia undergoing invasive procedures and comparing them with bleeding events in non-haemophilic patients. Within the constraints discussed, treatment recommendations are provided, which reflect the literature, current practice and the clinical experience of the EHTSB. Better-designed studies using standardized protocols, as well as patient registries, are however needed in order to define minimal haemostatic levels and optimal durations of treatment.
The European Therapy Standardisation Board consists of the following members and European haemophilia centres: Alessandro Gringeri, Milan, Italy; Ana Villar and Marta Morado, Madrid, Spain; Angelika Batorova, Bratislava, Slovakia; Angiola Rocino, Napoli, Italy; Anastasia Karafoulidou, Athens, Greece; Barry White, Dublin, Ireland; Carmen Altisent, Barcelona, Spain; Cedric Hermans, Brussels, Belgium; Chantal Rothschild, Paris, France; H. Marijke van den Berg, Utrecht, the Netherlands; Géraldine Lavigne Lissalde, Montpellier, France; Gerry Dolan, Nottingham, UK; Herve Chambost, Marseille, France; Jan Astermark, Malmö, Sweden; Jerzy Windyga, Warsaw, Poland; Lorenzo Giovanni Mantovani, Napoli, Italy; Manuela Fraga, Porto, Portugal; Mario Schiavoni, Bari, Italy; Mario von Depka, Hannover, Germany; Michael Richards, Leeds, UK; Philippe de Moerloose, Geneva, Switzerland; Rosario Pérez Garrido, Seville, Spain; Riitta Lassila, Helsinki, Finland; Robert Klamroth, Berlin, Germany; Thierry Lambert, Paris, France.
Barry White has received an unrestricted educational grant from Baxter and NovoNordisk. The other authors stated that they had no interests which might be perceived as posing a conflict or bias.