The role of recombinant factor VIIa for obstetric block in women with severe factor XI deficiency

Summary. Regional blocks like spinal, epidural and combined spinal epidural (CSE) are relatively contraindicated in individuals with bleeding disorders. Consequently pregnant women with severe factor XI (FXI) deficiency are often denied this option during labour and caesarean section. We describe three women with severe FXI deficiency in whom regional block was performed with low‐dose recombinant factor VIIa (rFVIIa) for their operative procedures during delivery. All women achieved haemostasis and had uncomplicated regional block, delivery and surgical procedures. The point of care device – rotational thromboelastometry (ROTEM) was used to monitor the patients’ coagulation and determine the dose of rFVIIa to achieve in vitro haemostasis in these women that was then subsequently used in vivo. Low‐dose rFVIIa seems to be effective and safe in the management of delivery and enables provision of regional blocks in women with severe FXI deficiency.     

Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors

Summary.  Severe FXI deficiency is a rare injury-related bleeding disorder. In patients with FXI inhibitors, surgeries may be treated using recombinant activated factor VII; however, treatment safety is a major concern and the best dosing regimen as well as mode of administration is still to be defined. We describe four patients with severe factor XI deficiency and inhibitors to FXI, undergoing eight (four major) surgical procedures treated with continuous infusion of rFVIIa. Following acute MI that evolved after surgery of our first patient, all other patients were treated with low-dose bolus rFVIIa followed by low-dose continuous infusion of rFVIIa. Haemostasis was successfully achieved and no further thrombotic complications occurred. To support our clinical results ex-vivo thromboelastography studies were performed, demonstrating the differences of clot formation and lysis between patients with FXI deficiency and healthy controls and suggesting that low-dose rFVIIa corrects coagulation similarly to high-dose rFVIIa in FXI deficiency. Recombinant FVIIa at low doses may effectively induce haemostasis and seems to be a safe treatment mode in patients with FXI deficiency and inhibitors undergoing surgeries.     

Recombinant factor VIIa to prevent surgical bleeding in factor XI deficiency

Summary.  Factor XI (FXI) deficiency is associated with bleeding after invasive procedures. Risks of human plasma-derived FXI replacement products include transfusion transmitted infection, thrombosis and fluid overload. This study was designed to test the hypothesis that recombinant factor VIIa (rFVIIa) is an effective haemostatic agent in patients with FXI deficiency undergoing surgery. Fourteen FXI deficient patients [five severely deficient (FXI:C <20 U dL⁻¹) and nine partially deficient (FXI:C 20–70 U dL⁻¹] received rFVIIa to prevent surgical bleeding during five major, four minor and six dental procedures. Minor surgical and dental procedures were covered with two doses of rFVIIa (90 μg kg⁻¹ i.v.), the first pre-operatively and the second 4 h postoperatively. Major surgery was covered with 90 μg kg⁻¹ i.v. two hourly for the first 24 h and four hourly for the second 24 h. Oral tranexamic acid was given for 7 days postoperatively. Effective haemostasis was observed in all cases and no alternative haemostatic agents or blood transfusions were required. Three adverse events were recorded; an acute cerebrovascular accident in a patient with a history of cardiovascular disease, an allergic reaction and local phlebitis. In this study, rFVIIa was an effective alternative to plasma-derived FXI replacement for the prevention of surgical bleeding in FXI deficient patients but rFVIIa may not be suitable for patients with pre-existing risk factors for thrombosis.     

Response to desmopressin of factors XI, X and V in patients with factor VIII deficiency and von Willebrand disease

Desmopressin [1-deamino-8-d-arginine vasopressin (DDAVP)] has been successfully used in the treatment of type 1 von Willebrand disease (VWD) and mild haemophilia A (MHA). Data suggest that DDAVP can increase factor XI (FXI) plasma levels and may represent an effective treatment for mild FXI deficiency. We assessed the DDAVP response of FXI coagulant activity (FXI:C), FXI antigen (FXI:Ag), factor V coagulant activity (FV:C), and factor X coagulant activity (FX:C) in 33 individuals with VWD or MHA. DDAVP did not produce a clinically significant increase in FXI:C, FXI:Ag, FX:C or FV:C in any patient. The mean +/- SD FXI:C pre-DDAVP (time 0) and at 1 h post-DDAVP was 90.7 (+/-22.9) U/dl and 92.1 (+/-20.9) U/dl, respectively. The mean (+/-SD) FXI:Ag at time 0 and 1 h was 92.2 (+/-20.1) U/dl and 89.9 (+/-21.3) U/dl, respectively. There was a small reduction at 1 h post-DDAVP in both FV:C, from 101.8 (+/-20.9) U/dl to 97.2 (+/-21.4) U/dl (P < 0.001), and FX:C from 103 (+/-19.5) U/dl to 98.8 (+/-18.7) U/dl (P < 0.001). No significant increase in FXI:C, FXI:Ag, FV:C or FX:C levels was seen at 4 h post-DDAVP. This study failed to demonstrate a clinically significant increase in the levels of FXI, FX or FV following administration of DDAVP.     

Experience with recombinant-activated factor VII in 30 patients with congenital factor VII deficiency

Recombinant-activated factor VII (rFVIIa) represents a therapeutic advance for the treatment and prevention of haemorrhage in patients with the rare bleeding disorder, congenital FVII deficiency. Thirty-nine cases of the use of rFVIIa in 30 patients with congenital FVII deficiency were identified from the international, internet-based registry haemostasis.com, which is a repository of case reports on the investigational use of rFVIIa that have been voluntarily submitted by physicians worldwide. These registry data have limitations compared with clinical-trial data but give valuable insights into a treatment for a rare disease that is virtually impossible to assess in conventional clinical trials. rFVIIa was used in: elective surgery (13 cases); haematoma (9 cases); emergency surgery (6 cases); epistaxis (4 cases); menorrhagia (2 cases); cover during childbirth (2 cases); disseminated intravascular coagulation (1 case; premature infant); removal of intradermal stitches (1 case); and haematuria (1 case). In 22/39 cases, rFVIIa was used prophylactically. Total dose and dosing schedules varied; median individual dose was 13.3 mug/kg body weight (bw) (range 1.2-223.8 mug/kg bw), median total dose was 38 microg/kg bw (range 1.2-758 microg/kg bw) and median number of doses was 3 (range 1-55). rFVIIa was generally associated with bleeding cessation or markedly reduced bleeding. Two adverse events were reported, but neither was regarded as being related to rFVIIa. These 39 cases support data confirming the safety and efficacy of rFVIIa in its EU-licensed indications, including that for preventing and/or controlling haemorrhage in patients with congenital FVII deficiency.     

Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry

Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg(-1) every 2-3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90-300 mcg kg(-1). High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100-150, 150-200 and >200 mcg kg(-1). Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1-55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg(-1) (range: 40-4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P < 0.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100-150, 0% for 150-200, <1% for >200 mcg kg(-1) dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346 mcg kg(-1) appear to be well-tolerated. Additionally, rFVIIa doses >200 mcg kg(-1) appear to significantly increase efficacy (97% in the high-dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high-dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.     

Prophylaxis with recombinant-activated factor VII (rFVIIa) for minimally invasive surgery in a patient with congenital factor VII deficiency: a case report with a single-low dose of rFVIIa

Congenital factor VII deficiency is a rare autosomal-recessive disorder and surgery in patients with factor VII deficiency has been reported to be endangered by intraoperative or postoperative bleeding, unless a replacement therapy is used. In this paper, we report a successful prophylaxis with single and low dose rFVIIa (12.5 microg kg(-1)) in a 22-year-old homozygote factor VII deficient patient who underwent laparoscopic gynecologic surgery. Minimally invasive surgeries, such as laparoscopic surgery, could be safely performed in patients with congenital factor VII using single and low dose rFVIIa combined with vigilant clinical observation and laboratory examination.     

Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres

Many patients with haemophilia develop inhibitors to factor VIII and require bypassing agents to provide haemostatic cover for limb- or life-threatening bleeding episodes. Due to the reduced risk of blood-borne pathogen transmission with recombinant products, on-demand recombinant factor VIIa (rFVIIa; NovoSeven is the treatment of choice for children with inhibitors. In haemophiliac patients without inhibitors, primary prophylaxis has been clinical practice for several years. This paper summarises 13 case histories of rFVIIa secondary prophylaxis for haemophilia patients with inhibitors. This was a retrospective survey of adult and paediatric severe haemophilia patients with inhibitors treated with rFVIIa from ten European Haemophilia Centres. There was a wide variation in administered rFVIIa dose, from 200-250 microg kg(-1) per week to 220 microg kg(-1) daily. In many cases, this was lower than the recommended on-demand dose of rFVIIa. In 12/13 cases, prophylaxis with rFVIIa considerably reduced the number of bleeding episodes compared with previous treatment. Eight/nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life (QoL), all were improved, much improved, or significantly improved. In haemophilia patients with inhibitors, prophylaxis with rFVIIa is highly effective in reducing the number of bleeding episodes and results in good patient compliance and improved QoL. Randomised controlled trials are needed to confirm these findings. Results of a recently completed clinical trial on secondary prophylaxis with rFVIIa in frequently bleeding haemophilia patients with inhibitors are expected in late 2006.     

Use of recombinant factor VIIa in the management of severe bleeding episodes in patients with Bernard–Soulier syndrome

Bernard–Soulier syndrome (BSS) is a rare congenital platelet disorder characterized by defective platelet adhesion and manifested by spontaneous and often profuse bleeding. Recombinant factor VIIa (rFVIIa) is a haemostatic agent licensed for the treatment of bleeding episodes in patients with haemophilia and inhibitors, which may represent a low-risk alternative to existing therapies in the management of patients with BSS. Here, we describe the use of rFVIIa for the treatment of three severe bleeding episodes in two patients with BSS. Data were extracted by automated searching of the international, Internet-based registry . Patient 1, a 24-year-old woman, was admitted with severe epistaxis and hypotension. The diagnosis of BSS was confirmed by macrothrombocytopenia, absence of ristocetin-induced platelet agglutination (RIPA) and absence of glycoprotein (GP) Ibα and IX on the platelet surface. Epsilon aminocaproic acid (EACA; two 50-mg/kg doses), packed red blood cells (PRBCs, 2 U) and platelets (30 U) failed to control the bleeding and, after 13 h, three bolus doses of rFVIIa (90 μg/kg body weight) and a third dose of EACA were administered; bleeding stopped after the third dose of rFVIIa. Patient 2, a 15-year-old girl, initially presented with severe menorrhagia. A lack of RIPA and severe deficiency of GPIbα on the platelet surface confirmed the diagnosis of BSS. EACA and fresh-frozen plasma did not control the haemorrhage, but two bolus doses of rFVIIa (98 μg/kg body weight) resulted in a marked decrease in bleeding. On second admission, patient 2 had severe epistaxis and mild menorrhagia. Two rFVIIa doses (98 and 122.5 μg/kg body weight) were given, and the bleeding stopped. No adverse events were reported in these cases. These three admissions highlight the potential of rFVIIa for the treatment of severe bleeds in patients with BSS.     

The use of recombinant activated factor VII in the circumcision operation in the case of a congenital factor VII deficiency.

Congenital factor VII deficiency is a rare autosomal recessive hemorrhagic disorder and surgery is normally the cause of excessive bleeding. In this report, we describe the first case with congenital factor VII deficiency admitted to our clinics for the sunnet operation (circumcision), in which recombinant activated factor VII (rFVIIa; NovoSeven) was used to manage the bleeding. The patient was an 8-year old boy with moderate factor VII deficiency (factor VII level, 4%), and rFVIIa was administered at a dose of 20 microg/kg per dose during the circumcision operation. The same dose was repeated at 2, 4, 6, 9, 12, 15, 18, 21 and 24 h post operation. The circumcision operation could therefore be safely performed in patients with congenital factor VII using rFVIIa.     

Controlling acute bleeding episodes with recombinant factor VIIa in Haemophiliacs with inhibitor: continuous infusion and bolus injection

The efficacy of recombinant activated factor VII (rFVIIa, NovoSeven) in five Haemophiliacs (four Haemophilia A, one Haemophilia B), with high inhibitors ranging from 70 to 1900 Bethesda units, was evaluated. The treatment regimen was divided into two groups: group I, continuous infusion of 16.5 microg h-1 kg-1 body weight (bw) after the initial bolus of 90 microg kg-1 bw in three episodes of severe bleeding and group II, bolus injection 80-150 microg kg-1 bw every 3 hours for a maximum of four doses in six haemarthroses. The bleeding was effectively controlled within 1 to 48 h in five of nine bleeding episodes. One patient in group I, who had active arterial bleeding requiring sutures, had an ineffective response and three patients in group II had partially effective responses because the rFVIIa was given after the onset of bleeding at 36, 44 and 72 h, respectively. The prothrombin time was shortened and the FVII:C levels were successfully achieved at approximately 10 U mL-1. The continuous infusion reduced the total dose of rFVIIa by 50%. Recurrent bleeding episodes were found in three patients; two occurred at the same site after ceasing rFVIIa for 51 h and while receiving rFVIIa at 144 h and one occurred at a new site after ceasing rFVIIa for 12 h. Our experience would suggest that rFVIIa is effective in controlling acute bleeding episodes in Haemophiliacs with high inhibitors either by continuous infusion or bolus injection.     

Sequential treatment with bolus and continuous infusion of recombinant factor VIIa for hip arthroplasty in a patient with haemophilia A and inhibitor

We describe a total arthroplasty of the hip in a 40-year-old male patient with haemophilia A and a high-titre inhibitor to factor VIII, treated with rFVIIa. The patient received sequential therapy first as bolus in the early postoperative phase in order to obtain appropriate haemostasis and then as continuous infusion with lower doses to avoid frequent episodes of bleeding without a higher consumption of product. After an initial dose of 150 micro g kg-1 for the first five days after surgery, we used bolus doses of 120-90 micro g kg-1 every 2.5-3 h, achieving plasma FVII:C levels above 40 U mL-1. We then continued with continuous infusion at decreasing doses 15-7 micro g kg-1 h-1 for 12 days (FVII:C 19-7 U mL-1). There were no bleeding complications nor signs of clotting activity. The rehabilitation programme was continued without prophylactic treatment. The total consumption of rFVIIa was 6.3 mg kg-1, implying a saving of at least 30% of the product with respect to previous publications.     

Clinical usefulness of desmopressin for prevention of surgical bleeding in patients with symptomatic heterozygous factor XI deficiency

Heterozygous factor XI (FXI) deficiency is sometimes associated with a significant bleeding tendency. Fresh frozen plasma or FXI concentrates are the mainstay of treatment in patients with a clear bleeding history, especially prior to surgery. However, these treatments are not completely free of risk. Furthermore, thrombosis has been reported in patients with FXI deficiency infused with FXI concentrate. No data are available on the possible efficacy of desmopressin in these patients.   Two patients with a clear bleeding history associated with FXI deficiency and no additional haemostatic defects agreed to be treated with desmopressin before carpal tunnel surgery and dental extraction. The reduced basal FXI activity and antigen levels slightly increased after infusion, reaching borderline values. No bleeding was observed after surgical procedures.   Desmopressin treatment seems a reasonable and useful choice in symptomatic, heterozygous FXI-deficient patients, thus reducing the cost of treatment, the risk of transmission of blood-borne viruses, and of thrombosis.     

Congenital factor VII deficiency: therapy with recombinant activated factor VII – a critical appraisal

Congenital factor VII (FVII) deficiency is a rare bleeding disorder with high phenotypic variability, and optimal management has yet to be determined. Treatment has traditionally involved FVII replacement therapy using fresh frozen plasma, prothrombin complex concentrates or plasma-derived FVII concentrates. Recombinant activated FVII (rFVIIa, NovoSeven(R)), the first recombinant treatment option, has recently been approved in the European Union for use in congenital FVII deficiency, but has been available on an emergency and compassionate use basis since 1988. In FVII deficiency, rFVIIa serves as substitution therapy as it provides the physiological ligand (FVIIa) for tissue factor, its receptor exposed at the site of vascular injury. This paper provides an overview of published and unpublished experience with rFVIIa in patients with congenital FVII deficiency from the NovoSeven compassionate and emergency use programmes (1988-99) and of independent reports in the literature. Recombinant FVIIa has been reported to provide effective haemostasis in patients of all ages and in a range of bleeding situations, including acute central nervous system/life-threatening bleeding episodes (15 episodes in 12 patients), non-life-threatening bleeding episodes (>32 episodes in 17 patients), surgery (>40 interventions in 25 patients) and childbirth (three women). Preliminary reports suggest that it may also be effective prophylactically. The risk of thrombosis in FVII-deficient patients treated with rFVIIa is unknown, as is the occurrence of inhibiting antibodies. A postlicensure pharmacovigilance registry (Seven Treatment Evaluation Registry) has been set up to continue to monitor the efficacy and safety (including alloantibody development) of rFVIIa in patients with FVII deficiency.     

Use of recombinant factor VIIa to treat persistent bleeding following dental extractions in two cirrhotic patients

BACKGROUND AND OBJECTIVES: A single dose of recombinant factor VIIa (rFVIIa) has been shown to be effective and safe in correcting the prothrombin time (PT) in cirrhotic patients, but no clinical data exists demonstrating its efficacy in arresting active bleeding. MATERIALS AND METHODS: rFVIIa was used in two cirrhotic patients for persistent bleeding following dental extractions despite repeated treatment at the wound site and, in one case, repeated administrations of fresh-frozen plasma (FFP). RESULTS: Bleeding stopped promptly in both patients after administration of rFVIIa. However, bleeding recurred in the patient who had not received concomitant treatment at the extraction sites. No recurrence of bleeding was observed in the second patient, who underwent local treatment 15 min after rFVIIa. CONCLUSIONS: Recombinant factor VIIa arrested bleeding after dental extractions in two cirrhotic patients who had been unsuccessfully treated with FFP. However, additional local treatment is needed to limit the risk of recurrence as a result of the short half-life of rFVIIa.     

Recombinant factor VIIa enhances platelet deposition from flowing haemophilic blood but requires the contact pathway to promote fibrin deposition

In prior microfluidic studies with haemophilic blood perfused over collagen, we found that a severe deficiency (<1% factor level) reduced platelet and fibrin deposition, while a moderate deficiency (1–5%) only reduced fibrin deposition. We investigated: (i) the differential effect of rFVIIa (0.04–20 nm ) on platelet and fibrin deposition, and (ii) the contribution of the contact pathway to rFVIIa‐induced haemophilic blood clotting. Haemophilic or healthy blood with low and high corn trypsin inhibitor (CTI, 4 or 40 μg mL^?1) was perfused over collagen at an initial venous wall shear rate of 100 s^?1. At 100 s^?1 wall shear rate, where FXIIa leads to thrombin production without added tissue factor, FXI‐deficient blood (3%) or severely FVIII‐deficient blood (<1%) produced no fibrin at either CTI level. Whereas rFVIIa potently enhanced platelet deposition, fibrin generation was not rescued. Distinct from the high CTI condition, engagement of the contact pathway (low CTI) in moderately FVIII‐deficient (3%) or moderately FIX‐deficient blood (5%) resulted in enhanced platelet and fibrin deposition following 4 nm rFVIIa supplementation. In mildly FVIII‐deficient blood (15%) at <24 h since haemostatic therapy, rFVIIa enhanced both platelet and fibrin generation in either CTI condition although fibrin was produced more quickly and abundantly in low CTI. For tissue factor‐free conditions of severe haemophilic blood clotting, we conclude that rFVIIa reliably generates low levels of ‘signaling’ thrombin sufficient to enhance platelet deposition on collagen, but is insufficient to drive fibrin polymerization unless potentiated by the contact pathway.     

Continuous infusion of recombinant activated factor VII during caesarean section delivery in a patient with congenital factor VII deficiency

Recombinant activated factor VII (rFVIIa) can be used as an alternative therapy in patients with FVII deficiency. However, as the drug has a very short half-life, continuous infusion could be a meaningful administration modality. We report the case of a 30-year-old woman with moderate FVII deficiency and human immunodeficiency virus infection who underwent a caesarean section delivery. She was treated with a continuous infusion of rFVIIa and did not suffer any bleeding complication. The continuous infusion of rFVIIa was a safe and effective therapeutic approach for our patient, maintaining her levels of FVII:C and avoiding bleeding during caesarean section and afterwards.     

Factor VIIa in the treatment of haemophilia

Recombinant FVIIa is being developed for treatment of haemophiliacs with antibodies against FVIII/FIX. rFVIIa was shown to be haemostatically active in haemophilia A and B dogs as well as in 20 haemophilia patients (one haemophilia B and 19 haemophilia A patients). Thirteen patients were treated for life-threatening bleedings and nine at surgery (dose: 60-90 micrograms/kg q 3-4 h). One patient underwent synovectomy in a knee joint under the cover of rFVIIa as the sole coagulation factor without any problems. One patient with FXI deficiency was successfully treated at an orchidectomy. The haemophilia B patient was treated in association with a compartment syndrome (surgical fasciotomy) with a complete haemostasis. He later uneventfully underwent skin grafting. Two CNS bleeds, a severe mouth bleed were treated as well as an extensive nasopharyngeal bleed in a patient with an acquired inhibitor against FVIII. Shortening of the prothrombin time as well as of the APTT was seen. No side-effects were observed. It is speculated whether FVIIa in complex with not only tissue factor but also phospholipids exposed at the site of injured cells directly activates FXa and thereby the final common pathway of the coagulation cascade.     

Treatment with recombinant activated factor VII in a patient with hemophilia A and an inhibitor: advantages of administration by continuous infusion over bolus intermittent injections.

Recent studies have shown that treatment with a continuous infusion of recombinant activated factor VII (rFVIIa) is far more convenient than administration by bolus intermittent injections and may allow a substantial reduction in the dose. We present the case of a 26-year-old patient with hemophilia A, who had a high-titer inhibitor to both human and porcine factor VIII, and who had recently been admitted to hospital because of a bilateral severe ilio-psoas hematoma. Two subsequent courses of treatment with rFVIIa by bolus intermittent injection showed only a partial efficacy. A further administration of rFVIIa was therefore carried out using a continuous infusion regimen that proved to be fully efficacious. During the continuous infusion course levels of factor VII coagulant activity were in the range 18.2-5.2 U/ml, while the prothrombin time, expressed as an International Normalized Ratio, remained within the range 0.57-0.71. The continuous infusion, compared with the administration of the bolus intermittent infusion, reduced the amount of rFVIIa required by approximately 40-50%. Statistical analysis demonstrated that there was a strong positive correlation between the rate of infusion of rFVIIa and levels of factor VII coagulant activity (r = +0.941; P < 0.001), and a very significant negative correlation between levels of factor VII coagulant activity and prothrombin time values (r = -0.897; P < 0.001). In accordance with previous findings, our experience confirms that, when prolonged therapy is required, treatment with rFVIIa by continuous infusion is more convenient than administration of bolus intermittent injections, and may allow the saving of a large amount of drug. Moreover, we suggest potential additional advantages of the continuous infusion regimen over bolus intermittent injections, such as a better efficacy and a stronger correlation between prothrombin time and factor VII coagulant activity levels.     

Recombinant, activated factor VII for surgery in factor VII deficiency: a prospective evaluation - the surgical STER

Excessive bleeding represents a major complication of surgical interventions and its control is especially relevant in patients with Congenital Bleeding Disorders (CBD). In factor VII (FVII) deficiency, scanty data on surgery is available to guide treatment strategies. The STER (Seven Treatment Evaluation Registry) is a multi-centre, prospective, observational, web-based study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Forty-one surgical operations (24 'major' and 17 'minor') were performed in 34 subjects with a carefully characterized FVII deficiency under the coverage of recombinant activated Factor VII (rFVIIa). Bleeding occurred during three major interventions of orthopaedic surgery, but rFVIIa was given at very low dose in each case. An antibody to FVII was observed in one patient who underwent a multiple dental extraction. No thromboses were reported during the 30-d follow up period. Replacement therapy with rFVIIa proved effective when suitable doses were used, which, during the period of maximum bleeding risk (the day of operation), were calculated (Receiver Operated Characteristic analysis) to be of at least 13 μg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.