Comparison of continuous infusion versus bolus injection of factor concentrates for blood management after total knee arthroplasty in patients with hemophilia

Blood management has been an issue in perioperative care in general TKA and especially in hemophilia, inappropriate perioperative blood management in the hip and knee arthroplasty is the most important cause of affecting the clinical outcome [1‐4]. Control of bleeding episodes, and the management of perioperative bleeding in patients with hemophilia, is attained via the administration of plasma-derived or recombinant coagulation factors. Most often, these factors are given at regular intervals as a bolus injection (BI) to attain hemostasis [5]; however, there has been growing interest in the use of continuous infusions (CI) of clotting factors during major surgery to maintain constant factor concentrations, thus reducing the risk of bleeding caused by overly low factor trough levels [5‐8]. Compared with BI, the CI method is believed to reduce the total FVIII dose required and also the incidence of severe bleeding events. However, there has been paucity in the literature regarding comparison between these two different methods of coagulation factor replacement for major surgery in patients with hemophilia. Therefore, we questioned whether CI has superiority in terms of perioperative bleeding control and consumption of FVIII following TKA. This study was performed to explore the effectiveness and safety of CI in hemophilia A patients that underwent TKA, by comparing CI with BI.

This prospective study involved 42 TKAs performed in 31 patients with severe hemophilia A, admitted to undergo TKA by a single institute. The inclusion criteria were severe hemophilia A (FVIII: C < 1%), more than 150 exposure days (EDs) to any FVIII product before enrolment, no previous history of inhibitors, and good compliance. Each group consisted of 21 cases. Since this disease entity is rare compared to primary osteoarthritis, we assumed that the same infusion protocol in consecutive patients would be better to manage in hemophilia teams. The BI protocol was applied to the former half of the cases in the period between July 2010 and December 2013 and the CI protocol was applied to the latter half of cases during the period between January 2014 and July 2016.

Postoperative hemorrhagic complications in hemophilia patients are quite common and may lead to serious consequences after TKA [10‐13]. In patients with hemophilia, coagulation factor concentrates can be administered by way of CI or BI as the perioperative blood management [14]. While several studies have shown that the CI method is safe and effective due to maintaining constant level of the coagulation factor in the blood during the perioperative periods [15‐17], most studies practically have utilized a simple BI method [2, 12, 18]. Furthermore, no comparative study regarding CI and BI methods following total joint replacement for of hemophilia could be found. Therefore the authors attempted to evaluate whether the CI could show efficacy and advantages compared to the BI especially undergoing a relatively common major surgery, such as TKA by way of prospective comparative study. We confirmed that CI could lead to a significant decrease in both postoperative hemoglobin drop and drained blood volume following TKA.

CI has been established that coagulation factor concentrates are stable and microbiologically safe at room temperature [19, 20]. Moreover, it has been known that Cl is a cost-effective drug delivery approach, compared with BI [6, 21]. In this study, the average consumption of coagulation factor concentrates with CI for 5 days was 604.03 ± 112.84 IU/kg, in comparison with 467.85 ± 1.16 IU/kg of BI for the same period after undergoing TKA. There was a discrepancy in our results vis-à-vis the theoretically-advantageous aspect of CI. The discrepancy seems to be coming from the dissimilar BI protocols implemented by different institutions. In this study, the target peak level of factor concentrates administered via BI was 100% at Day 0–3 and 80% at Day 4–6. This regimen required a less amount of factor concentrates than other regimens as reported from various centers [22‐26]. Unlike CI that maintains the peak level for 24 h a day, BI achieves the peak level only for a certain duration of just injected time. Afterward, the FVIII levels, given by BI, continue to decline for the half-life of FVIII, 8–12 h, until FVIII level rises after administration of a dose to reach the peak level again. The fact of the matter is that the peak level using a BI method is maintained not 100%, but just 75% for 3 days, in comparison with the conception applicable to CI method. Therefore, the total factor dose administered by BI might be lesser than that of CI, which would maintain the peak level 100% throughout the 24 h-duration. However, the presumption is that the inability to maintain the peak level for 100% of the time would lead to the inferior results of BI, as shown by the decline in hemoglobin level or blood drainage volume, as well as by the increased frequency of blood infusion. Furthermore, a less dose of factor concentrates was administered via BI in this same regimen, in comparison with hemophilia patients who had undergone total hip arthroplasty [9]. This would be the rationale behind CI showing greater consumption of FVIII than BI in this investigation. Further study on various protocols, including cost-effectiveness, is necessary.

The initial concern for prolonged CI was focused on factor stability and safety when the products were kept at room temperature for some period of time [27]. However, such a concern has been addressed in several articles [19, 20, 23]. The potential for inhibitor development has been a recent issue in the context of CI; as such development renders FVIII replacement therapy ineffective and makes it difficult to control bleeding [14, 28, 29]. At the end of our study, we found that no patient had developed inhibitors of FVIII. However, at the time of enrollment, all subjects had over 150 EDs FVIII with no history of prior development of inhibitors were taken. Other studies also reported that inhibitors were absent in previously treated patients who underwent CI during surgery [22].

Another issue with CI is a thromboembolism. Recent reviews on CI found that venous thrombosis developed in 1.39%–3.8% of patients who had received FVIII via CI during various surgeries [16, 30]. In this study, no symptomatic thrombotic event was noted, although we did not use chemoprophylaxis. Also, neither saline dilution nor heparin addition was not carried out during the CI. The suggestion is that CI would not increase the risk of postoperative thrombosis. No saline dilution was prepared for CI in this study, while the syringe was changed at 8 h intervals. CI was carried out at the infusion rate of 4 IU/kg/h of clotting factor concentrates.

In current study, the patients in the BI group showed a significant drop in hemoglobin levels after TKA. Moreover, there was a significant difference between the CI and BI groups in drained blood volume for postoperative 24 h. The frequency number of postoperative transfusions given by BI was larger than that provided by CI. Meanwhile, the patient age and body mass index before surgery were not similar between these two groups. During the investigational period, the study was conducted in sequence of patient’s hospital admission. The difference of the mean ages of these two groups might inadvertently contribute to bias. It appears to be an issue, attributing to the scarcity of the disease and that of patients. How this may affect the bleeding management of patients with hemophilia remains unclear, but the difference between the two groups was the limitation in this study. Another limitation of this study was the fact that it had not been a randomized study. However, it was prospectively designed and followed up. Finally, this study was carried out among patients in Asian population and there could be ethnic differences. Further study regarding Western population would be interesting.

Good control of hemostasis could be achieved using either infusion method during the perioperative period of TKA in patients with hemophilia. However, CI seems more tolerable and effective than BI to reduce perioperative blood loss in these cohorts undergoing TKA.