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F. Bernardi and G. Mariani et al.
Replacement therapy and prophylaxis
Replacement therapy (RT) options are determined by: the rarity of the disorder; the availability and supply of products and the economic and geographical factors. These include: i) recombinant FVIIa (rFVIIa), ii) plasma- derived FVII (pdFVII), iii) fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC). In the STER prospective trial (comprising 312 RT) most therapies were carried out with rFVIIa (78%), the remaining with FFP (10%), pdFVII concentrates (10%%) and PCC (2%).
Based on the modest catalytic activity of FVIIa in the absence of TF, the therapeutic/prophylactic use of FVIIa and rFVIIa (initially proposed for bleeding diathesis other than FVII deficiency) represents a therapeutic milestone8 and distinguishes replacement therapy in FVII deficiency from that in the other coagulation defects (Table 1). Although in FVII deficiency rFVIIa is employed (Figure 1A) at doses (Table 3) much lower than those needed for patients with FVIII inhibitors, supraphysiological FVIIa concentrations are also produced in plasma of FVII defi- cient subjects.
It is still a matter of debate whether rFVIIa acts through the binding with TF, provided by microparticles shed into the circulation following diverse stimuli, or binds at high concentration66 to anionic phospholipids exposed on activated platelets, thus directly activating FX to FXa. FXa would in turn generate thrombin, bypass- ing the tenase complex. It is tempting to speculate that the physiological FVIIa-TF function (Figure 3) prevails at the rFVIIa doses used in FVII deficiency and in the pres- ence of normal FVIII levels. rFVIIa easily diffuses into the extravascular spaces where it could be retained for extended time periods. As supported by pharmacokinet- ic studies,67 rFVIIa prolongs its pharmacological effects at low concentration, in accordance with the hypothesis of physiological binding to TF.
rFVIIa has a very good safety-to-efficacy ratio.46 One- day therapy with ‘intermediate’ doses of rFVIIa can be effective and safe for the treatment of most of sponta- neous bleeds as well as for minor surgery and invasive procedures (Table 3). Replacement with rFVIIa is also effective to prevent bleeding in major surgical proce- dures.46
The large volume of the infusions and the limited availability make pd-FVII concentrates less appealing. Currently, the average pd-FVII dosages used are 15–20 IU/kg for mucosal bleeding, and 30–40 IU/kg for severe or life-threatening hemorrhages.
Although FFP is easily available in developing coun- tries, its effectiveness is limited owing to the high risk of fluid overload and the consequent need for slow infu- sions.
In the case of mild mucosal bleeds (epistaxis, mild menorrhagia) tranexamic acid and hormones are current- ly considered.
Anti-fibrinolytic agents are contraindicated in hema- turia, and may trigger thrombosis in association to PCC. Prophylaxis is warranted for patients with the most severe bleeding picture and should be prescribed from childhood or soon after the first bleeding event.45,68 Effective prophylaxis schedules have been reported for
rFVIIa68,69 and pdFVII concentrates.70
Treatment complications
Inhibitors to FVII are a rare (1-2%)71 complication that
occurs mainly in severely deficient patients, particularly in children younger than 1 year on prophylaxis. We observed only high responders (>5 BU Bethesda Unit)71, and in the presence of a high-titer inhibitor to FVII treatment becomes a problem.71
At variance with the homologous deficiency of FIX (F9, HB), complete homozygous gene deletions that predis- pose to FIX inhibitors have never been detected in FVII deficiency (Table 1),5,12 and FVII inhibitors have never been shown to be complicated by allergic reactions.
Paradoxically, a dozen of cases with FVII deficiency and thrombosis have been reported. Surgical interventions and/or replacement therapies had a close temporal rela- tionship with thrombotic episodes, but apparently spon- taneous events were also reported.68,72 Different replace- ment therapies were associated with the thrombotic events: PCC (three cases), rFVIIa (three cases), pdFVII (two cases), FFP (one case), no replacement (three cases).72 This suggests that FVII deficiency does not seem to offer pro- tection from strong thrombosis risk factors such as sur- gery/high dose radiotherapy.
Women with factor VII deficiency
Autosomally transmitted RBD occur as frequently in women as in men, but women may experience more bleeding than men because gynecological and obstetric challenges to hemostasis add an important burden to the background bleeding related to the hemostatic defect. Menstruation and ovulation are associated with an increased risk of bleeding, as are pregnancy and delivery.73 While in normal and heterozygous women FVII plasma levels rise during pregnancy, no such increase is observed in women with a severe homozygous deficiency. As a consequence, symptomatic women with FVII deficiency may continue to bleed during pregnancy and postpartum. In a large study (234 women with FVII deficiency),74 men- orrhagia during the reproductive age occurred in half of the cases, and in 12% represented the first bleed. Further, frequent gynecological problems, such as uterine fibroids, were diagnosed earlier because of the hemostatic defect. Although FVIIc was an important predictor of gynecolog- ical bleeding, other determinants including endocrine pathologies may also play a role.
For severe menorrhagia, management has been moved from hemostatic agents like tranexamic acid, oral contra- ceptives and intra-uterine devices, to replacement therapy and prophylaxis with effective single- or multiple-dose schedules.68,73,74 This will hopefully change clinical practice that, until recently, included surgical approaches such as endometrial ablation or hysterectomy.
Therapeutics in development
The first attempts to improve rFVIIa activity through mutagenesis, or its half-life in plasma by glycoPEGylation, have increased FVII antigenicity. Longer-acting FVIIa has been tested in different recombinant preparations, which are currently in clinical trials (reviewed in Menegatti et al.)75: i) addition of a c-terminal peptide76 potentially suit- able for subcutaneous administration that led to pro- longed pharmacodynamics effects, ii) an Fc receptor-fused rFVIIa that displayed a 5-fold longer plasma half-life and iii) an albumin-fused rFVIIa molecules that showed improved features compared to rFVIIa (2- to 3-fold longer half-life and 4- to 8-fold lower clearance) in patients with congenital FVII deficiency.77 Recently, an engineered albu-
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haematologica | 2021; 106(2)