Factor VII Deficiency
As for all the other congenital bleeding disorders, replacement therapy is currently the only effective management option for FVII deficiency2,20,24 and is the main treatment for spontaneous bleeds, severe cases, surgical hemostasis, and for individuals with a bleeding history.37 Factor replacement therapy may also be used for prophylaxis in children with severe FVII deficiency.38
Besides plasma-derived FVII concentrates, other potential therapies for management of FVII deficiency include fresh frozen plasma (FFP), 4-factor prothrombin complex concentrates (PCCs), and recombinant FVIIa (rFVIIa). The latter is the only treatment supported by substantial research studies and is considered the first-line treatment option, if available.2,21,25
Treatment of FVII deficiency is characterized by the short in vivo half-life of FVII, low FVII recovery, and rapid FVII clearance, which is more evident in children.39 Because of these features, replacement regimens require frequent dosing.
FFP and PCCs were widely used in the past, but the risk of circulatory overload and the simultaneous administration of clotting factors other than FVII limit their use, primarily because of the risk of thrombotic complications.40 Plasma-derived concentrates of FVII (Provertin UM TIM3; 600 IU per 10 mL; Baxter) are effective at doses of 30–40 U/kg.40 The risk of blood-borne pathogen transmission with this product, although theoretically possible, is extremely low because of viral inactivation procedures.
Recombinant activated FVII (rFVIIa; Novoseven®; Novo Nordisk) is the most widely accepted therapeutic option for inherited FVII deficiency, both for spontaneous bleeding and in surgical settings.2,21,22 The recommended dosage of 15-30 µg/kg q4-6h is used to maintain FVII levels above 15%-20%.19,41,42,43
A new formulation of rFVIIa that is stable up to 25 ˚C has been tested in a randomized, double-blind trial that assessed equivalence with the original formulation in terms of safety, efficacy and pharmacokinetic parameters.44 Differences did exist in the determination of rFVIIa plasma levels, especially very low levels, when different assays were used.43 Repeated average doses of 20 µg/kg have been reported in a number of papers from the Seven Treatment Evaluation Registry (STER) to be effective in achieving hemostasis, but optimal treatment regimens have not been defined.29,30,37,38
Asymptomatic patients undergoing minimally invasive surgery, such as dental procedures, can be successfully treated with tranexamic acid given both orally or intravenously at the usual dosages.
Figure 4 shows a summary of the factor concentrates that are used for the treatment of FVII deficiency.
Figure 4. Overview of factor concentrates for the treatment of FVII deficiency.
Adapted from Mannucci PM, et al. Blood. 2004;104:1243-1252.
A recently published analysis of STER data focused on the treatment of ‘nonsurgical’ bleeding episodes (both spontaneous and traumatic).37 The data (Figure 5) showed that in the majority of cases, a single, intermediate dose of rFVIIa (60 µg/kg body weight) is sufficient to treat most of these bleeds.
Figure 5. STER data on the treatment for nonsurgical (spontaneous) bleeding episodes.
>Data from: Mariani G, et al. Thromb Haemost 2013;109:238-47.
Prophylactic regimens are not commonly used in FVII-deficient patients. Prophylaxis is mainly used in unweaned infants who are prone to severe and frequent bleeding.2,21,38 However, preliminary reports suggest that prophylaxis may also be effective in individuals experiencing menorrhagia with iron deficiency and in patients with recurrent hemarthrosis.20
Notwithstanding the very short half-life of FVIIa, several clinical reports have shown that prophylaxis is feasible even with low-intermediate dosage schedules (30 µg/kg body weight) 3 times per week.2 To prevent death and disability, prophylaxis should be considered mandatory in patients who have very severe bleeding, such as those presenting with CNS and gastrointestinal hemorrhage, hemarthrosis, or menorrhagia associated with low to very low FVIIc levels.38 In these patients, early diagnosis or prenatal diagnosis could allow for ‘true’ primary prophylaxis.
Treatment Related to Surgery
The STER registry prospectively collected data on the use of rFVIIa in surgery in FVII-deficient patients. Under coverage of rFVIIa, 41 surgeries (24 major surgeries, 17 minor surgeries) were performed in 34 patients who had residual FVIIc levels between <1% and 20%.30
Bleeding occurred during 3 major surgical procedures (all orthopedic). Low-dose rFVIIa was administered (single doses of ≥13 µg/kg; ≥3 administrations/day). No cases of thromboses were reported. One case of inhibitor development was reported. Due to the lack of bleeding events in the surgical follow-up period, a determination of an appropriate duration for replacement therapy was not possible.30
The data indicate that rFVIIa as replacement therapy is effective at suitable doses (single doses of ≥13 µg/kg; ≥ 3 administrations/day) during periods of maximum bleeding risk (surgery day), with no fewer than 3 doses administered on surgery day.
Minor surgery and invasive procedures
For uncomplicated minor surgical procedures, such as single dental extractions, catheter insertions, and endoscopic biopsies, the STER data indicate that 1-day therapy is sufficient with low-to-moderate doses of rFVIIa (25 µg/kg body weight) or plasma-derived FVII (median 18.5 IU/kg body weight). No bleeding or thrombotic events were reported, and one case of inhibitor development was identified.29
Longer-lasting replacement schedules and higher doses may be required for complicated interventions, such as multiple dental extractions complicated by gingivitis, and adenotonsillectomies.
A summary of suggested treatment strategies in the most common clinical settings is provided in Figure 6.
Figure 6. Suggested treatment strategies by age and type of bleeding at presentation.
Complications of Treatment
The development of inhibitors is one of the most serious complications of treatment. A centralized assessment of STER data identified 2 (1.9%) cases of inhibitor development among 115 patients severely affected by FVII deficiency,48 with 1 patient each developing inhibitors after rFVIIa or plasma-derived FVII treatment. Overall, 3 (1.3%) of 225 tested patients developed inhibitors.
None of the treated patients experienced allergic reactions during treatments, while 4 (1.35%) of 332 treatments were associated with development of thrombosis. These thrombotic events were always associated with a surgical procedure and replacement therapy.