Surgery in patients with hemophilia carries a high risk of bleeding and represents one of the most challenging areas in hemophilia care. Most surgical and invasive procedures can be performed safely in patients with hemophilia with factor replacement therapy (intravenous infusion of the deficient factor at the appropriate dose during the adequate period of time). Despite the risk, the results of orthopedic surgery in patients with hemophilia are good; however, a favorable outcome depends on coordination between multidisciplinary team members. It is also crucial to ensure that orthopedic procedures in hemophilia patients are conducted in specialized centers by an experienced team [11].

The optimal level and duration of replacement therapy needed to prevent bleeding complications have not been established yet. Hermans et al., on behalf of the European Hemophilia Therapy Standardization Board, published a review article about replacement therapy for invasive procedures in patients with hemophilia [12]. They reviewed 35 clinical studies regarding replacement therapy for major invasive procedures. The preoperative target factor levels for hemophilia A and B were in 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 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 131/1,328 or 10 % of major surgical procedures, most of them in the papers published before 1990.

As part of this comprehensive task, Hermans et al. also performed a survey in 26 European Hemophilia Comprehensive Care Centers, representing 15 different countries to develop consensus recommendations for replacement therapy [12]. All centers prior to major orthopedic surgery reported a target factor level of at least 80 %. In contrast to the literature, continuous infusion (CI) was used in procedures performed in nearly half of the centers. In most centers, factor levels were maintained above 80 % in the postoperative period. With bolus infusion (BI), 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 CI 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 orthopedic surgery, preoperative pharmacokinetic evaluation was performed in one-third of the centers and the recovery measured in more than half of them. Thromboprophylaxis with low-molecular-weight heparin was used in more than half, and antifibrinolytic treatment in more than two-thirds, of the centers [12].

Regarding synovectomy, Hermans et al. found four papers [12]. These four studies involved 158 patients undergoing 197 different procedures. Factor replacement always included a loading dose, ranging from 15 to 50 IU/kg in patients with hemophilia A and from 30 to 90 IU/kg in patients with hemophilia 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 three times per week – 2 weeks and 15 IU/kg two times per week – 6 weeks for hemophilia A and 30 IU/kg three times per week – 2 weeks and 25 IU/kg two times per week – 6 weeks for hemophilia B). No bleeding complications were reported. The survey from European Hemophilia Comprehensive Care Centers concluded that a target level of factor VIII (FVIII) between 80 % and 100 % was reported by 87.5 % of the centers. CI 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 centers. Antifibrinolytics were used in 56 % of the centers. Our protocol for hemostatic cover in orthopedic surgery is shown in table 2.2.

In conclusion, in major orthopedic surgery the preoperative factor levels should be 80–100 %, and in the postoperative period the minimal factor level should be above 50 % in the first week and 30 % in the late postoperative period. Nevertheless, the World Federation of Hemophilia (WFH) guidelines for perioperative plasma factor VIII levels recommend a preoperative level of 120 %, tapering down to 50 % at 14 days. In addition, a very interesting report from Wong et al. supports the fact that maintaining a high level of clotting factor replacement therapy (at least 80 % factor replacement over the first two postoperative weeks) throughout wound healing can result in lower infection rates, comparable to that of total knee arthroplasty (TKA) in patients without hemophilia [13].

Most hemophilia centers use bolus infusion (BI) to replace coagulation factors for surgery [14]. Continuous infusion (CI) therapy was described initially in 1970 by McMillan et al. [15]. The idea was to maintain stable FVIII levels without the deep troughs that regularly accompany BI and expose the patient to the risk of bleeding (Fig. 2.1). However, it did not receive much attention because of technical issues related to the volumes required for infusion and concerns about the stability FVIII at room temperature and the potential for sepsis. Later it was observed that most FVIII concentrates are stable after reconstitution at room temperature for several days or even weeks [16, 17] and can be infused in small volumes of concentrated solution (with the addition of heparin to prevent local thrombophlebitis) via minipumps [18–20] to make CI a more accessible therapy.

Martinowitz et al. described the most accepted method in hemophilia centers [18]. This method employs pharmacokinetic dosing and takes advantage of decreasing clearance of coagulation factor during CI. The simple protocol for this method is based on the following principles [18]:

CI is a safe mode of treatment, more cost effective, and should be the treatment of choice for major surgery in hemophilia patients [18]. Batorova and Martinowitz reported a reduction in the bleeding rates and FVIII dosage (36 %) compared with the use of BI [14].