Mechanism of action of factor VIIa in the treatment of coagulopathies

Recombinant factor VIIa (rFVIIa) has been developed for treatment of bleeding in patients with hemophilia who have inhibitors against factor VIII (FVIII) or FIX, and has been found to induce hemostasis during major orthopedic surgery. The use of rFVIIa treatment for hemophilia is a new concept and is based on the low-affinity binding of FVIIa to the surface of thrombin-activated platelets. Administration of pharmacologic doses of exogenous rFVIIa enhances thrombin generation on the platelet surface at the site of injury independently of the presence of FVIII or FIX. Pharmacologic doses of rFVIIa induce hemostasis not only in hemophilia patients, but also in patients with thrombocytopenia, functional platelet defects, and with profuse bleeding triggered by extensive surgery or trauma. The general mechanism of action of rFVIIa to induce hemostasis under these conditions may be its capacity to generate a tight fibrin hemostatic plug through increased thrombin generation. A tight fibrin plug will aid in resisting the overwhelming local release of fibrinolytic activity triggered by vast tissue damage occurring in extensive trauma. Local fibrinolytic activity also occurs in the gastrointestinal tract as well as during profuse postpartum bleeding. Pharmacologic doses of rFVIIa induce hemostasis in these cases also.     

Recombinant factor VIIa: its background, development and clinical use

PURPOSE OF REVIEW: To examine the development of recombinant FVIIa (rFVIIa); a new concept of inducing hemostasis. It was developed for use in hemophilia patients with inhibitors against FVIII or FIX with the vision to provide these patients with a therapeutical option to be used instead of FVIII or FIX. For the first time it was shown that pharmacological doses of FVIIa induced hemostasis. RECENT FINDINGS: Hemostasis was achieved by rFVIIa in major surgery (repeated doses) as well as in a home-treatment setting (one single injection) in severe hemophilia patients with inhibitors. A recent study indicates that rFVIIa may be useful as prophylaxis. In heavily bleeding nonhemophilia patients rFVIIa was shown to induce hemostasis. Pharmacological doses of rFVIIa enhance thrombin generation on activated platelets resulting in the formation of tight hemostatic fibrin plugs resistant against premature proteolysis. High doses of rFVIIa seem to be safe probably due to its localized effect. SUMMARY: Pharmacological doses of rFVIIa induce hemostasis in severe hemophilia and in nonhemophilia patients with profuse, heavy bleeding. rFVIIa enhances thrombin generation on activated platelets, thereby initiating the formation of strong, tight fibrin hemostatic plugs resistant to premature lysis. It also seems to be safe in high doses.     

Improved hemostasis with superactive analogs of factor VIIa in a mouse model of hemophilia A

It is currently debated whether the mechanism of action of therapeutic doses of recombinant factor VIIa (rFVIIa, Novo-Seven) relies on the tissue factor (TF)-independent activity of the enzyme. The present study was conducted to investigate the in vivo hemostatic effects of rFVIIa and 3 analogs thereof with superior intrinsic activity (FVIIaIIa, K337A-FVIIaIia, and M298Q-FVIIa) in mice with antibody-induced hemophilia A. A highly significant dose response was observed for the bleeding time and blood loss for each of the rFVIIa variants. The bleeding time and blood loss were normalized after administration of 10 mg/kg rFVIIa, 3 mg/kg K337A-FVIIaIia, and 3 mg/kg M298Q-FVIIa, indicating a potency of these FVIIa analogs 3-4 times above that of rFVIIa in FVIII-depleted mice. The different in vivo potencies of the various forms of FVIIa could not be explained by the pharmacokinetics. Histopathological evaluation of kidneys revealed no signs of treatment-related pathological changes even after treatment with the superactive variants. The fact that FVIIa analogs with enhanced intrinsic activity are more efficacious in the murine hemophilia A model strongly suggests that the TF-independent procoagulant activity of FVIIa contributes to its clinical hemostatic effect.     

Surgery in haemophilic patients with inhibitor: 20 years of experience

Summary.  Surgery in haemophilic patients with inhibitor against factor (F)VIII or FIX is high risk. Surgery may be performed with the administration of sufficiently high dose of FVIII in patients with low-response inhibitor or who, despite having a high response, present a low inhibitor titre at the time of surgery. The use of high doses of FX is more complicated in patients with a low-titre FIX inhibitor, as there is a high risk of anaphylactic reactions. In the case of patients with high-titre inhibitors, several treatments have been proposed, such as porcine FVIII, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrate (APCC). We present our 20 years' experience in the treatment and subsequent management of haemophilic patients with inhibitor in surgery and evaluate the results obtained with the products available for haemostatic control in 64 surgical procedures. The efficacy we obtained with FVIII is good in 100% of the cases described; we had no haemorrhagic complication (HC) in the 18 procedures in which it was used (three major and 15 minor surgery). With APCC we obtained excellent results with only one HC in a synoviorthesis in the form of bleeding and haematomas out of 32 procedures. Good results were obtained with rFVIIa with few haemorrhagic episodes. Thus, in major surgery there was one HC out of three cases. In minor surgery, greater efficacy was observed using extremely large doses of rFVIIa (≥ 120 mg kg⁻¹ 2h⁻¹) because of the shorter half-life of this factor in this type of patients.     

Severe acquired haemophilia A treated with recombinant factor VIIa

Acquired haemophilia can be associated with various conditions including pregnancy, autoimmune diseases and lymphoproliferative disorders, though often no underlying cause is found. It often presents with a rapid onset of muscle bleeding and involves the IgG antibody. It may be treated with human or porcine factor VIII (FVIII), prothrombin complex concentrates, factor IX (FIX) complex concentrates, factor VIIa (FVIIa) or by immunosuppression. We report a case of acquired haemophilia in a 40-year-old woman diagnosed following laparotomy. She was treated unsuccessfully using human FVIII and cryoprecipitate, porcine FVIII and FIX complex concentrate, before being treated with recombinant FVIIa (NovoSeven, Novo Nordisk). On treatment with recombinant FVIIa, bleeding stopped rapidly with no side-effects and the abdominal haematoma was evacuated with minimal post-operative bleeding.     

The treatment of bleeding in hemophilic patients with inhibitors with recombinant factor VIIa

Recombinant factor VIIa (rFVIIa) has proven efficacy in the treatment of patients with alloantibodies and autoantibodies to factors VIII and IX. More than 80% of over 2,000 reported bleeding episodes treated with rFVIIa have been controlled in a variety of clinical circumstances. Its theoretical lack of activation of the coagulation system prompted many clinicians to undertake elective surgical procedures using rFVIIa in addition to on-demand treatment of minor bleeding episodes. Hemostatic efficacy has been good for most of these surgical procedures, without serious adverse events. rFVIIa is considered a useful, safe, and effective treatment for bleeding in patients with anti-factor VIII (FVIII) and anti-factor IX (FIX) inhibitors. However, the optimal dose for various clinical situations has yet to be established and requires further investigation. Laboratory monitoring of treatment using plasma FVIIa measurements should be better standardized. Despite the relatively high cost of this new drug, rFVIIa represents a major therapeutic advance in the treatment of hemophilic patients with inhibitors.     

Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency

Inhibitors to factor VIII (FVIII) or IX (FIX) in patients with haemophilia A or B create a challenging problem for the treatment of these patients. Recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) is a realistic treatment option, owing to its specific mode of action and lack of immunogenicity. This was a multicentre, open-label, compassionate-use trial in patients with severe haemophilia A (FVIII:C < 1%) or B (FIX:C < 1%) with inhibitors, acquired antibodies to FVIII or FIX, or FVII deficiency (FVII:C < 5%), for whom alternative therapies had failed or were contraindicated. Patients received rFVIIa treatment for life- or limb-threatening bleeding episodes or for coverage during essential surgery. The mean rFVIIa dose was approximately 90 microg kg-1 for haemophilia A/B and acquired inhibitor patients, and 25 microg kg-1 for FVII-deficient patients. Efficacy data for 67 treatment episodes (45 bleeding episodes, 22 surgical procedures) are presented; seven patients were treated for a concurrent serious bleeding episode and surgical procedure. At the end of treatment, rFVIIa was effective or partially effective in 85% of serious bleeding episodes. During surgery, bleeding was assessed as none or less than or equivalent to normal in 91% of surgical procedures; postoperatively, 91% of procedures were associated with no or minimal oozing. During 60 separate treatment episodes, 26 adverse events (22 nonserious, four serious) were reported in 15 patients, during 17 bleeding episodes or surgical procedures. Only 10 were considered as having a possible, probable, or unknown relationship with rFVIIa; of these, fever (n=2) and thrombophlebitis (n=3) were the most common. There was no evidence of disseminated intravascular coagulation. In conclusion, rFVIIa is an effective, well-tolerated treatment for serious bleeding episodes and bleeding associated with surgical procedures in patients with severe haemophilia A/B with inhibitors, acquired inhibitors, or FVII deficiency.     

Trends in the utilization and wastage of coagulation factor concentrates: the application of a regional tracking programme

The Commission of Inquiry on the Blood System in Canada ('Krever Commission', 1997) recommended an active programme of surveillance for all blood products. To describe trends in the utilization of coagulation factor concentrates using a comprehensive factor tracking programme. Between 2001 and 2004 in the region of Southern Ontario, we prospectively tracked all coagulation factor concentrates that were distributed from the national blood supplier, issued by hospitals for inpatient use or for home infusions, infused at hospital facilities or at home and wasted. Discrepancies were reconciled by independent audits. Trends in the utilization of FVIII, FIX and FVIIa concentrates are reported. A total of 466 patients with inherited or acquired bleeding disorders were registered. Utilization of FVIII, FIX and FVIIa increased by an average of 13.7%, 33.2% and 34.2% per year respectively. Most FVIII and FIX infusions were administered at home while most FVIIa infusions were in hospital. The increase in FVIII and FIX usage was attributable to an increase in per-patient use, predominantly for prophylaxis. In total, 1.7% of coagulation factor concentrates was wasted during the study period, at a cost of over 1 million Canadian dollars. Utilization of coagulation factor concentrates increased steadily during the study period. A regional programme to track utilization is feasible and may be used to describe trends, assist planning, and reduce costs by minimizing wastage.     

A novel therapeutic approach combining human plasma-derived Factors VIIa and X for haemophiliacs with inhibitors: evidence of a higher thrombin generation rate in vitro and more sustained haemostatic activity in vivo than obtained with Factor VIIa alone

BACKGROUND AND OBJECTIVES: Therapy with recombinant Factor VIIa (rFVIIa) for haemophiliacs with inhibitors still has some unresolved problems, such as the requirement for frequent infusions of rFVIIa every 2-3 h to sustain haemostatic activity for an extended time-period and that the therapeutic dose of rFVIIa is not always predictable. In the present study, we searched for an effective combination of plasma-derived FVIIa with other blood coagulation factors, and demonstrated that a therapeutic approach combining plasma-derived FVIIa and Factor X (FX) was more useful for treating haemophiliacs with inhibitors than FVIIa alone. MATERIALS AND METHODS: The haemostatic effects of FVIIa and FX were evaluated in vitro and in vivo. In in vitro experiments we assessed the following: the ability to enhance the thrombin generation rate in a reconstituted blood coagulation model without Factor VIII (FVIII) or Factor IX (FIX); the ability to correct the activated partial prothrombin time (APTT) of FVIII-depleted plasma or FIX-depleted plasma; and the ability to correct the clotting time of haemophilia-like whole blood using thromboelastography (TEG). In in vivo experiments, the haemostatic activity of the combination treatment of FVIIa and FX was determined by measuring the bleeding time and TEG using a monkey haemophilia B model produced by the injection of anti-human FIX polyclonal antibodies. The degree of thrombogenicity of the combination was evaluated using the rabbit stasis model. RESULTS: The addition of FX to FVIIa dramatically enhanced the thrombin generation rate in the reconstituted blood coagulation model and corrected the prolonged APTTs of FVIII- and FIX-depleted plasmas to levels achieved by the replacement therapies. In contrast, the addition of prothrombin to FVIIa did not show such enhancing activity. Furthermore, FVIIa-induced whole blood clotting times in the FVIII- and FIX-inhibited states were also shortened by the addition of FX in a concentration-dependent manner. Finally, the co-administration of FVIIa (80 microg/kg) and FX (800 microg/kg) in a monkey haemophilia B model resulted in a more robust and persistent haemostatic effect on the secondary bleeding time and whole-blood clotting time of TEG than that of FVIIa alone. The results of rabbit stasis tests for evaluating the risk of thrombogenicity showed that the combination of FVIIa and FX was less thrombogenic than FEIBA. CONCLUSIONS: The present study demonstrated that the combination of FVIIa and FX appeared to have a higher and more sustainable haemostatic potential than FVIIa alone, and less thrombogenicity than FEIBA. A therapeutic approach combining FVIIa and FX could be a promising and novel approach to compensate for the disadvantages of rFVIIa and FEIBA for haemophiliacs with inhibitors.     

Management of haemophilic patients with inhibitors in major orthopaedic surgery by immunadsorption, substitution of factor VIII and recombinant factor VIIa (NovoSeven®): a single centre experience

Inhibitors of factor VIII or FIX in haemophilic patients are a common and serious complication associated with an increased risk of life-threatening bleeding during elective surgery. Substitution therapy fails to be effective, therefore an alternative treatment is needed. We have performed six major elective orthopaedic interventions in four patients with haemophilia A and inhibitors. A preoperative immunadsorbant therapy with Therasorb to eliminate inhibitors was successful in four cases, but during FVIII substitution inhibitors increased on day 4 to day 6 after surgery, leading to decreasing FVIII levels. Therefore, therapy was changed to recombinant FVIIa (rFVIIa; NovoSeven). Two interventions had to be covered with sole rFVIIa therapy as immunadsorbant therapy failed to be effective in one case and the need for acute intervention did not allow pretreatment in the other. We did not see increased bleeding during or after surgery when compared to our experience with non-inhibitor haemophilic patients. In conclusion, a preoperative decrease of inhibitors from immunadsorbant therapy, perioperative substitution of FVIII and changing treatment to rFVIIa when inhibitors are increased, is a safe and economic therapy for guaranteeing haemostasis in major elective orthopaedic surgery. On the contrary, sole therapy with rFVIIa allows immediate surgical intervention without a long hospital stay prior to surgery and a need for laboratory monitoring of inhibitor titres and FVIII levels. Our findings support data previously published.     

Monitoring rFVIIa 90 μg kg−1 dosing in haemophiliacs: comparing laboratory response using various whole blood assays over 6 h

Summary. Recombinant FVIIa is a haemostatic agent administered to patients with severe FVIII or FIX deficiency with inhibitors. Although rFVIIa is effective at stopping bleeding, a reliable assay to monitor its effect is lacking. To characterize the pharmacokinetics and global coagulation effects of rFVIIa for 6 h following a IV dose of 90 μg kg^?1. Ten non‐bleeding subjects with severe FVIII or FIX deficiency were infused with a single‐dose of rFVIIa 90 μg kg^?1 body weight and blood was collected before and at 0.5, 1, 2, 4 and 6 h postdose. Global haemostasis was characterized throughout the study utilizing whole blood analyses (Hemodyne HAS, TEG, ROTEM). The clearance and half‐life of factor FVII:C was estimated as 39.0 ± 8.8 mL h^?1 kg^?1 and 2.1 ± 0.2 h respectively. There was good inter‐assay agreement with respect to clot initiation parameters (R, CT and FOT) and these parameters all fell to a mean of approximately 9 min following rFVIIa dosing. The platelet contractile force (PCF) and clot elastic modulus (CEM) were positively correlated to FVII:C (P < 0.0001), and these parameters were dynamic throughout the 6‐h period. The MA and MCF did not correlate to FVII:C nor did they significantly change during the study. Prothrombin F1 + 2 significantly increased following rFVIIa dosing (P < 0.001), but remained steady throughout the study. There was no change in D‐dimer concentrations over time. The FOT, R and CT characterized clot initiation following rFVIIa dosing. The PCF and CEM were correlated to FVII:C and characterized the dynamics of platelet function and clot strength over the rFVIIa dosing interval. The clinical significance of these findings needs additional study.     

Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model

Hemophilia is treated by IV replacement therapy with Factor VIII (FVIII) or Factor IX (FIX), either on demand to resolve bleeding, or as prophylaxis. Improved treatment may be provided by drugs designed for subcutaneous and less frequent administration with a reduced risk of inhibitor formation. Tissue factor pathway inhibitor (TFPI) down-regulates the initiation of coagulation by inhibition of Factor VIIa (FVIIa)/tissue factor/Factor Xa (FVIIa/TF/FXa). Blockage of TFPI inhibition may facilitate thrombin generation in a hemophilic setting. A high-affinity (K(D) = 25pM) mAb, mAb 2021, against TFPI was investigated. Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa and improved clot formation in hemophilia blood and plasma. The binding epitope on the Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extensive overlap with the FXa contact region highlighting a structural basis for its mechanism of action. In a rabbit hemophilia model, an intravenous or subcutaneous dose significantly reduced cuticle bleeding. mAb 2021 showed an effect comparable with that of rFVIIa. Cuticle bleeding in the model was reduced for at least 7 days by a single intravenous dose of mAb 2021. This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option in hemophilia.     

An in-vitro assessment of tranexamic acid as an adjunct to rFVIII or rFVIIa treatment in haemophilia A

Haemophilia is characterised by defective thrombin generation, reduced clot stability and spontaneous bleeding. Treatment with factor VIII (FVIII) concentrate or bypassing agents (e.g. recombinant factor VIIa (rFVIIa)) is generally effective. Occasionally, haemostasis is not achieved, which may reflect a failure of factor concentrate to normalise clot stability. Tranexamic acid (TXA) is often used to aid haemostasis in surgery (e.g. joint replacements and dental procedures). Used routinely as an adjunct, it may enhance clot stability and allow effective, reliable, and cost-effective treatment at lower doses of factor concentrate. This study hypothesised that clot stabilising adjunct TXA is required in addition to factor substitution to normalise clot stability in whole blood from patients with severe haemophilia A. The in vitro effect of varying concentrations of recombinant FVIII or recombinant FVIIa and adjunct TXA on whole blood clot stability was measured by thromboelastometry. Coagulation was triggered by tissue factor and clots were challenged with tissue plasminogen activator. The area under the elasticity curve was the primary endpoint. High concentrations of FVIII and rFVIIa increased clot stability to levels that were not significantly different from controls (Mean ± SD: control 112,694?±?84,115; FVIII 78,662?±?74,126; rFVIIa 95,918?±?88,492). However, the response was highly variable between individuals and demonstrates why some patients show clinical resistance to treatment. Addition of TXA resulted in normalised clot stability in all individuals, even when combined with the lowest doses of factor concentrate. The results support the concept that a more efficient, reliable and cost effective treatment may be obtained if TXA is combined with factor concentrates to treat individuals with haemophilia.     

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.     

Recombinant Activated Factor VII in Patients at High Risk of Bleeding

Currently, recombinant activated factor VII (rFVIIa) (NovoSeven ® ) is indicated for the treatment of spontaneous and surgical bleeding in congenital haemophilia A and B patients with inhibitors to factors VIII (FVIII) and IX (FIX) >5 Bethesda units (BU) worldwide, and in patients with acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia in Europe. Until April 2003, almost three-quarters of a milion doses of rFVIIa have been administered proving its efficacy and excellent safety record. According to results from initial clinical trials and a large number of case reports, the rFVIIa may be effective not only in treating haemophilia patients but also in treatment of bleeding in patients on oral anticoagulation or heparin, patients with liver diseases, von Willebrand disease (vWD), thrombocytopenia, various platelet defects, congenital or acquired deficiency of FVII, and in subjects without any pre-existing coagulopathy with diffuse life-threatening bleeding triggered by surgery or trauma. This review will briefly summarize rFVIIa mode of action in haemostasis, the current clinical experience with rFVIIa and focus on the alternative use of rFVIIa in patients at the high risk of bleeding in both spontaneous cases and clinical trials reports. ? stasko@jfmed.uniba.sk     

Recombinant activated factor VII in patients at high risk of bleeding

Currently, recombinant activated factor VII (rFVIIa) (NovoSeven) is indicated for the treatment of spontaneous and surgical bleeding in congenital haemophilia A and B patients with inhibitors to factors VIII (FVIII) and IX (FIX) >5 Bethesda units (BU) worldwide, and in patients with acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia in Europe. Until April 2003, almost three-quarters of a milion doses of rFVIIa have been administered proving its efficacy and excellent safety record. According to results from initial clinical trials and a large number of case reports, the rFVIIa may be effective not only in treating haemophilia patients but also in treatment of bleeding in patients on oral anticoagulation or heparin, patients with liver diseases, von Willebrand disease (vWD), thrombocytopenia, various platelet defects, congenital or acquired deficiency of FVII, and in subjects without any pre-existing coagulopathy with diffuse life-threatening bleeding triggered by surgery or trauma. This review will briefly summarize rFVIIa mode of action in haemostasis, the current clinical experience with rFVIIa and focus on the alternative use of rFVIIa in patients at the high risk of bleeding in both spontaneous cases and clinical trials reports.     

Use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor

Treatment options during an acute hemorrhage for a hemophilic patient who has an inhibitor (antibody) to factor VIII (FVIII) are limited. If the inhibitor titer is high, even massive doses of FVIII are not sufficient to neutralize the antibody. Likewise, immunoadsorption techniques or plasmapheresis cannot remove enough antibody to permit treatment with FVIII. Allergic reactions and cross-reacting inhibitors complicate therapy with porcine FVIII. Prothrombin complex concentrates (PCC) may be effective but the mechanism is unclear. The theory that activated factor VII (FVIIa) is the active principle in PCC prompted our treatment of a patient with a recombinant FVIIa (rFVIIa) product (NOVO Industries). The patient presented with a large retropharyngeal hemorrhage and an initial inhibitor titer of 129 Bethesda units (BU). Despite Autoplex therapy (100U/kg), tracheal compression by the hematoma increased and asphyxiation was imminent. RFVIIa therapy (60 micrograms/kg) was substituted for Autoplex and nine doses were given without complication. The hemorrhage was controlled. By 18 hr breathing was normal and swallowing and speech were greatly improved. Clinically, the patient dramatically responded to rFVIIa. In addition, the purity, the lack of known infectious agents, and the ease of administration make rFVIIa a potentially attractive new therapy. Use of this product also promises to further our understanding of in vivo hemostasis.     

Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal

Acquired haemophilia is a rare bleeding disorder usually caused by the spontaneous formation of inhibitory antibodies to coagulation FVIII. The disease occurs most commonly in the elderly, and although acquired haemophilia may be associated with a variety of underlying conditions, up to 50% of reported cases are idiopathic. Treatment options have traditionally involved human FVIII or FIX replacement therapy (if the inhibitor titre allows), porcine FVIII or the use of activated pro-thrombin complex concentrates. Recombinant activated coagulation FVII (rFVIIa) was available on an emergency and compassionate use basis from 1988 to 1999 at sites in Europe and North America. It has been registered in Europe for use in treating acquired haemophilia since 1996 and has recently been licensed for this indication in the United States. By directly activating FX on the surface of activated platelets at the site of injury (thereby bypassing FVIII and FIX), rFVIIa can circumvent the actions of inhibitory antibodies present in acquired haemophilia patients. This paper provides an overview of experiences with rFVIIa for the treatment of acquired haemophilia from the NovoSeven compassionate and emergency use programmes (1989-1999), the Hemophilia and Thrombosis Research Society Registry, and independent published reports from January 1999 to September 2005. rFVIIa has been reported to provide safe and effective haemostasis as a first line therapy in patients of all ages for a variety of surgical and non-surgical bleeding situations.     

Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids

Recombinant factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors, as well for off-label treatment of severe bleeding in trauma and surgery. Effective bleeding control requires supraphysiological doses of rFVIIa, posing both high expense and uncertain thrombotic risk. Two major competing theories offer different explanations for the supraphysiological rFVIIa dosing requirement: (1) the need to overcome competition between FVIIa and FVII zymogen for tissue factor (TF) binding, and (2) a high-dose-requiring phospholipid-related pathway of FVIIa action. In the present study, we found experimental conditions in which both mechanisms contribute simultaneously and independently to rFVIIa-driven thrombin generation in FVII-deficient human plasma. From mathematical simulations of our model of FX activation, which were confirmed by thrombin-generation experiments, we conclude that the action of rFVIIa at pharmacologic doses is dominated by the TF-dependent pathway with a minor contribution from a phospholipid-dependent mechanism. We established a dose-response curve for rFVIIa that is useful to explain dosing strategies. In the present study, we present a pathway to reconcile the 2 major mechanisms of rFVIIa action, a necessary step to understanding future dose optimization and evaluation of new rFVIIa analogs currently under development.     

Cardiac tamponade in a patient with moderate hemophilia A and factor VIII Inhibitors

Cardiac tamponade is a rare, life-threatening complication of hemophilia. The management of pericardial bleeding in hemophilia A patients with inhibitors is particularly challenging because antibodies to factor (F) VIII render the use of high-dose FVIII ineffective. Fortunately, the management of uncontrollable bleeding in patients with hemophilia and inhibitors has improved since the introduction of treatments that bypass the need for FVIII and FIX. A case of hemopericardium complicated by cardiac tamponade occurring one month following an upper respiratory tract infection in a patient with hemophilia and FVIII inhibitors is presented. Management of the present case was based on current guidelines on the use of recombinant FVIIa for acute bleeding in patients with hemophilia and inhibitors. The subsequent development of hemothorax in the present case indicates that a more protracted course of recombinant FVIIa is justified following pericardiocentesis for pericardial bleeding in hemophilia with inhibitors. Alternative approaches to the management of this complication are also reviewed.