3 Management during surgery
1 Which patients require substitution therapy during surgery?
As previously stated, the correlation between FVII levels and risk of bleeding in FVII deficiency is very weak. In one retrospective study where substitution was only given if a severe bleeding phenotype was present (irrespective of FVII level), bleeding complications were present in 15.3% of performed operations [1]. Bleeding frequency was not increased in “high-risk” operations (assessed by the surgeon) and the highest bleeding frequency was observed in tonsillectomy, hernia and circumcision (20, 25 and 40% respectively). History of trauma induced excessive bleeding and frequent nosebleeds predicted risk of bleeding, but bleeding during previous surgery did not. A ROC analysis made from these data determined that a FVII level below 7% would justify replacement therapy during surgery [1].
2 What hemostatic therapy should be used?
Currently rFVIIa is recommended as first line therapy since it is highly effective, has few adverse events and low risk of virus transmission. However, no direct comparisons between available treatment options exists. Historically prothrombin complex concentrate (PCC) and pdFVII have also been applied [2]. Tranexamic acid has been found to reduce perioperative blood loss and transfusion requirements in hip and knee replacement, and concomitant treatment with rFVIIa in recently published case series did not lead to thrombotic complications [3,4].
3 What dose of rFVIIa?
The STER (Seven Treatment Evaluation Registry) committee evaluated 41 operations where rFVIIa was administered to patients with FVII levels below 20% [1]. In line with the previous recommendations they identified a minimum dose of rFVIIa of 13 µg/kg administered at least 3 times in order to prevent bleeding complications [5]. In a recent report of five patients undergoing orthopedic surgery a dose of 18-37 µg/kg three times daily was used with no bleeding or thrombotic complications [6]. In the MARACI study, 51 surgeries in patients with FVII levels <10% was evaluated. In 24/51 surgeries rFVIIa was given as repeated doses of 15-30 µg/kg, while in 11 surgeries a first full-loading dose was followed by half-dose infusions. Excessive bleeding occurred in only two cases (4%), one related to the surgery and one corresponding to a bleed at day 7 after tonsillectomy [7].
Cardiac surgery inflicts further complexity due to the need of systemic administration of heparin and institution of cardiopulmonary bypass thus, higher and more frequent dosing might be needed [8,9].
The short half-life of rFVIIa necessitates repeated bolus injections [10]. It was recently shown that by administering rFVIIa as continuous infusion the amount of rFVIIa and hence medication costs could be reduced by 70–90% when compared to expected costs of bolus injections [11]. No prospective randomized trials comparing bolus injections with continuous infusion of rFVIIa have been performed, but both approaches appear safe and efficacious.
4 Recommendations for management during major surgery
4.1 rFVIIa replacement using bolus injections
Shortly before start of surgery, rFVIIa 15-30 µg/kg is administered depending on type of surgery. The dose is rounded up or down to closest vial size to avoid waste of product.
This dose is given every 6 hours for the first 24 hours. The first postoperative day the same dose is given every 8 hours and the second postoperative day every 12 hours. The dose is thereafter tapered depending on type of surgery and occurrence of bleeding complications.
4.2 rFVIIa replacement using continuous infusion
An intravenous bolus injection of 0.6 mg from a vial of 1 mg, is given immediately before the start of the surgery, followed by continuous infusion. The rFVIIa, given by continuous infusion, is prepared by diluting 5.4 mg NovoSeven (of a 5 mg vial and the remaining 0.4 mg from an already opened vial) in 50 mL sterile water to a final concentration of 108 µg mL). The reconstituted rFVIIa is delivered at an infusion rate of 15 mL per 24 hours (h), corresponding to approximately 0.9 µg/kg/h, for the first 3 days. The medication cassette should be prepared to last for 24–72 h, as rFVIIa activity previously has been reported to be preserved at room temperature for at least 3 days. To avoid local thrombophlebitis at the infusion site, a parallel infusion with saline at 20 mL/h should be administered.
4.3 Tranexamic acid
Just before start of surgery tranexamic acid is given at 10 mg/kg iv. The dose is repeated after 4 hours. Tranexamic acid is then given orally at 20-25 mg/kg x 3-4 times daily for 4-7 days.
4.4 Laboratory monitoring of treatment
Plasma levels of FVII are measured once daily weekdays. The target range of FVII:C is 0.5–0.8 IU/mL when receiving the bolus dose, and 0.3–0.4 IU/mL when receiving the maintenance continuous treatment during the first days after surgery.
4.5 Thromboprophylaxis
The risk for venous thromboembolism (VTE) is considered low after factor replacement therapy in rare bleeding disorders, and thromboprophylaxis is therefore not routinely recommended [12].
4.6 Recommendation for factor substitution therapy during major surgery
Substitution therapy should only be given to high-risk patients defined as:
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5 Management of minor surgery and procedures
5.1 Bleeding complications in minor surgery
The risk of bleeding complications in minor surgery, diagnostic interventions and dental procedures have been systematically documented in one study [1] comprising 83 unrelated patients with FVII deficiency (FVII:C levels: 0.6 – 35 %) that underwent 157 procedures, without coagulation factor replacement. Bleeding complications were seen in 15 % of procedures performed. This includes dental extractions (10/52 patients), nose-throat procedures (4/22 patients), circumcision (2/5 patients), abdominal hernia repair (2/8 patients) cesarean section (1/6 patients), breast surgery (1/4 patients), haemorrhoid operation (1/1 patients), episiotomy (1/2 patients), elective induced abortion (1/10) and GI-endoscopy (1/3) [1].
5.2 Recommendations for rFVIIa replacement and tranexamic acid during minor surgery and procedures
Please see Appendix A for suggested treatment regimens in specific minor surgery and procedures.