Therapeutic approaches for haemophilia

The life-long episodic bleeding associated with inherited deficiencies of blood coagulation Factor VIII (FVIII) or Factor IX (FIX) can be well controlled with periodic iv. injections of FVIII or FIX concentrates. Either concentrate can be isolated from large human pools (i.e., plasma-derived FVIII or FIX concentrate) or from culture supernatants of recombinant cells engineered to secrete FVIII or FIX. The validated viral inactivation strategies used by manufacturers of FVIII and FIX concentrates have essentially eliminated the transmission of hepatitis B, hepatitis C and HIV viruses. The low yields and inherent instability of FVIII (and FVIIIa in particular) and the additional costs of viral inactivation methods make the annual cost/patient for prophylaxis and treatment of haemophilia very expensive. Several strategies have been adopted and proposed to improve yields of FVIII. These include: deletion of portions of FVIII which are not associated with function; mutations to prevent inactivation of FVIII by protease degradation; and synthesis of FVIII fragments to replace portions deleted in some FVIII deficient patients. An approach to improve FIX replacement involves the production of more coagulatively active FIX mutants. Another promising approach in both FVIII and FIX replacement is gene therapy. Two major issues that will have to be critically addressed before gene therapy for haemophilia can become widespread are whether the procedures will be well-tolerated in patients with significant liver impairment (due to previous exposure to hepatitis viruses) and whether consistent long-term delivery of the transgenes can be achieved.     

The use of antibodies to coagulation factors for anticoagulant therapy

Current treatments for preventing thrombotic diseases are associated with a significant risk of bleeding. Improved anticoagulant agents are therefore still required. The specificity and pharmacokinetics properties of monoclonal antibodies to coagulation factors allow novel anticoagulation approaches. Treatment with human antibodies or humanized mouse monoclonal antibodies should avoid unacceptable side effects due to immune response to the drug. Such antibodies were developed against three coagulation factor: Tissue factor (TF), Factor IX (FIX) and Factor VIII (FVIII). A fully humanized antibody was successfully derived from a mouse monoclonal antibodies to TF. In vivo studies with monoclonal antibodies to TF demonstrated efficient antithrombotic activity. Anti-TF antibodies may also prove useful in cardiovascular disorders and cancer, given the role of TF in these diseases. Mouse and human monoclonal antibodies to FIX were also efficient to prevent thrombosis in animal models of venous and arterial thrombosis and in stroke. A humanized anti-FIX antibody was tested in phase I study in healthy volunteers. The pharmacokinetics of the antibody were determined by the rapid formation of stable complexes with newly synthesised FIX. Human anti-FVIII antibodies inhibiting only partially FVIII activity were recently described. Investigations in mice have established that treatment with such anti-FVIII antibodies is efficient to prevent deep vein thrombosis. Given the low concentration of FVIII in plasma and the long half-life of antibody, treatment with anti-FVIII antibody could be very convenient, allowing one administration every month. Altogether, monoclonal antibodies to coagulation factor appear as promising novel antithrombotic drugs.     

Pharmacokinetics of factor VIII in humans. Obtaining clinically relevant data from comparative studies.

The pharmacokinetics of Factor VIII procoagulant activity (FVIII:C) were investigated in 10 patients receiving 2 different high purity concentrates of FVIII. The in vivo recovery of FVIII:C depended on the method of blood volume estimation and on the in vitro assay used to define the potency of the concentrate; more generally, it also depends on the study design. The use of in vivo recovery to compare FVIII preparations should therefore be discouraged and the achieved area under the FVIII activity-time curve (AUC) should be used instead. The volume of distribution at steady-state (Vss) of FVIII:C was significantly greater than the estimated plasma volume of the patients. The mean terminal half-life of FVIII:C was slightly assay-dependent, being 14h by a 1-stage clotting assay and 12h by a chromogenic assay. The calculated apparent clearance (CL) of FVIII:C, as well as the Vss and the in vivo recovery, depended on the measured in vitro potency of the FVIII concentrate. These methodological aspects of pharmacokinetic studies are of direct interest to the clinician, since the routine administration of FVIII is based on the pharmacokinetic properties of the specific preparation.     

The safety of pharmacologic options for the treatment of persons with hemophilia

ABSTRACT

Introduction: The mainstay of treatment of hemophilia A and B is the replacement of the congenitally deficient coagulation factor through the intravenous infusion of specific concentrates (factor VIII, FVIII, in hemophilia A; factor IX, FIX, in hemophilia B). Several commercial brands of FVIII or FIX products extracted from human plasma or engineered using recombinant DNA technology are available.

Areas covered: We analyze the safety aspects of plasma-derived and recombinant FVIII and FIX products licensed in Europe, focusing on their pathogen safety and inhibitor and thrombosis risks. The safety aspects of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII) used for treatment of bleeding episodes in inhibitor patients will be also briefly discussed.

Expert opinion: The analysis of the published literature documents the high degree of safety from pathogen risk for both plasma-derived and recombinant products available for hemophilia treatment. The main threat to factor concentrate safety is represented by the development of neutralizing alloantibodies against the infused coagulation factor, which in hemophilia A seem to occur more frequently following the administration of recombinant than plasma-derived FVIII products. Great expectations are placed on newer products, particularly on those based upon mechanisms of action other than FVIII replacement.     

Stereoselective pharmacokinetics of cetirizine in the guinea pig: role of protein binding

PURPOSE: To characterize the pharmacokinetics of cetirizine enantiomers in the guinea pig including protein binding in both the guinea pig and human plasma. METHODS: Plasma concentrations of cetirizine enantiomers in the guinea pig were determined using a LC-MS/MS method after a short i.v. infusion (1, 2 and 4 mg/kg) of racemic cetirizine. Protein binding was determined using an in vitro equilibrium dialysis technique. A pharmacokinetic model was developed using NONMEM and the differences in pharmacokinetic parameters of levocetirizine and dextrocetirizine were estimated. RESULTS: The plasma concentration time data of both the enantiomers were best described by a three-compartment pharmacokinetics model. The clearance (CL) of levocetirizine and dextrocetirizine was 1.2 and 2.7 ml/min, respectively, and the volume of distribution at steady state (Vss) was 457 ml and 996 ml, respectively. The fraction unbound (fu) in guinea pig plasma for levocetirizine and dextrocetirizine was 7-10% and 16-21% while in human plasma, it was 8% and 12%, respectively. The factor describing the difference in the pharmacokinetic parameters of the cetirizine enantiomers was estimated to be 2.26. CONCLUSIONS: Cetirizine pharmacokinetics is stereoselective in the guinea pig. For levocetirizine, fu, CL and Vss were half those of dextrocetirizine, indicating that protein binding is an important factor affecting the pharmacokinetics of cetirizine. The effect of protein binding on the pharmacokinetics of the cetirizine enantiomers could be extrapolated to humans.     

Sucrose-formulated octocog alfa: a review of its use in patients with haemophilia A

Sucrose-formulated octocog alfa (Kogenate Bayer, Kogenate FS, Helixate FS, Helixate nexgen) is a full-length recombinant human coagulation factor VIII (FVIII) product that is purified and formulated without the addition of human serum albumin and is stabilized with sucrose. The purification process of this formulation includes a solvent/detergent viral inactivation step. Sucrose-formulated octocog alfa is approved in the EU and US for the treatment of bleeding in patients with haemophilia A (congenital FVIII deficiency). Additionally, it is approved in the EU for the prophylaxis of bleeding in patients with haemophilia A and as a continuous infusion treatment in patients undergoing major surgery. Sucrose-formulated octocog alfa is effective and well tolerated as a FVIII replacement therapy in patients with haemophilia A, including those with severe disease undergoing major surgery. The therapeutic profile of this sucrose-formulated product cannot be compared with that of other octocog alfa or moroctocog alfa products because of a lack of head-to-head comparative studies. Pathogen transmission has not been reported with use of sucrose-formulated octocog alfa. Available data indicate that sucrose-formulated octocog alfa is an appropriate alternative to other recombinant FVIII products for the treatment and prophylaxis of bleeding episodes in adults and children with haemophilia A.     

Modulators of the coagulation cascade: focus and recent advances in inhibitors of tissue factor, factor VIIa and their complex

Recent developments in the field of haemostasis and thrombosis highlighted the crucial role of the tissue factor/factor VIIa complex (TF/FVIIa) in the initiation of coagulation processes. Nowadays, anticoagulant therapies involving heparin or coumarin derivatives, thrombin or factor Xa inhibitors are generally associated with side effects such as bleeding and thrombocytopenia. In this context, the inhibition of TF, FVIIa and their complex by efficient antithrombotic drugs represents a new strategy to reduce this bleeding and to prevent thrombosis events. Moreover, TF/FVIIa inhibition is shown to be useful in the treatment of biological processes independent of the clotting cascade such as angiogenesis and cancer. Among the natural and genetically engineered TF/FVIIa inhibitors, injections of the recombinant protein rNAPc2 show clinical improvements, such as reduced bleeding and thromboembolism, over classical drugs used in the therapy of coronary angioplasty and hip or knee replacement surgery. The knowledge of the 3D-structure of TF/FVIIa complex and examination of co-crystal data of some drugs bound to this complex led to the design and synthesis of numerous TF/FVIIa inhibitors. Among them, the p-amidinophenylurea 18 (Ki = 0.027 microM), the pyrimidinones PHA-927 (30, IC50 = 0.016 microM) and PHA-798 (31, IC50 = 0.014 microM) and the pyridinone 37 (IC50 = 0.052 microM) are highly potent inhibitors of the TF/FVIIa complex, deprived of activity towards thrombin (IC50 > 30-100 microM) and factor Xa (IC50 > 10-100 microM), other proteases involved in the coagulation cascade. Both pyrimidinones prevent arterial thrombosis in non-human primate models of thrombosis and represent a safe approach to anti-thrombotic therapy in patients with cardiovascular risk factors.     

Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compounds

The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the C(vss)-MRT method. The first step was to demonstrate superposition of intravenous (i.v.) pharmacokinetic profiles of preclinical species following mathematical transformation of their respective concentration-time curves using the corresponding C(vss) (where C(vss)=dose/Vss; Vss is the volume of distribution at steady state) and mean residence time (MRT) values. The resultant profiles were then back-transformed to estimate human i.v. plasma concentration-time profiles using human C(vss) and MRT values. Human C(vss) and MRT values were estimated from projected human Vss and CL values. Projection of CL was based on scaled (in vitro) metabolic clearance, simple allometry with and without various correction factors and the unbound fraction corrected intercept method. Vss values were estimated by allometric scaling with and without correction for interspecies differences in plasma protein binding. The predicted human i.v. profiles, in combination with the estimated mean absorption rate constants and bioavailability, were then used to simulate the oral pharmacokinetics in human using one- or multi-compartment kinetic models. Overall, with this approach, key oral pharmacokinetic parameters such as AUC, C(max), C(min) and oral plasma T((1/2)) were projected to be within two-fold of the actual values in humans.     

Development of a Transgenic Mouse Model with Immune Tolerance for Human Coagulation Factor VIIa

Purpose

Human factor VIIa (FVIIa) is commonly used as bypassing therapy to treat bleeding episodes in hemophilia patients with neutralizing antibodies to factors VIII (FVIII) or IX (FIX). There is a need for a suitable animal model to assess the immunogenicity of new FVIIa products during preclinical development. The aim of this study was the design of a novel transgenic mouse model with immune tolerance to human FVIIa.

Methods

The model was generated by transgenic expression of human F7 cDNA. FVIIa-specific immune responses after treatment with human FVIIa were assessed by analyzing circulating antibodies, antibody producing plasma cells and CD4⁺ T cells.

Results

In contrast to wild-type mice, human FVII transgenic mice did not develop antibodies when treated with human FVIIa. The immune tolerance was specific and could be broken by application of human FVIIa together with a strong stimulus of the innate immune system. Break of tolerance was associated with increased numbers of pro-inflammatory FVIIa-specific CD4⁺ T cells.

Conclusions

The new mouse model is suitable to study the influence of the innate immune system on maintenance and break of immune tolerance against FVIIa and could be used to assess the immunogenicity of new FVIIa products during pre-clinical development.     

New insights into the coagulation system and implications for new therapeutic options with recombinant factor VIIa

The classical model of the coagulation cascade is to be replaced by a new, cell based model of coagulation emphasizing the interaction of coagulation proteins with cell surfaces of platelets subendothelial cells and the endothelium. According to current knowledge hemostasis is initiated by the formation of a complex between tissue factor (TF) exposed as a result of a vessel wall injury, and already activated factor (F) VII (FVIIa) normally present in the circulating blood. The TF-FVIIa complexes convert FX into FXa on the TF bearing cell. FXa then activates prothrombin (FII) into thrombin (FIIa). This limited amount of thrombin activates FVIII, FV, FXI and platelets. Thrombin-activated platelets change shape and as a result will expose negatively charged phospholipids, which form the perfect template for full thrombin generation involving FVIIIa and FIXa. Thrombin also converts fibrinogen into fibrin, it activates the fibrin stabilizing FXIII, as well as the thrombin activatable fibrinolysis inhibitor (TAFI). The fibrin structure has been found to be dependent on the amount of thrombin formed and the rate of thrombin generation. Full thrombin generation is necessary for the formation of a tight, stable fibrin hemostatic plug resistant to premature fibrinolysis which is required for full and sustained hemostasis. Since thrombin has such a crucial role in providing hemostasis, any agent that enhances thrombin generation in situations with impaired thrombin formation may be characterized as a 'general hemostatic agent' - a term that has been applied to recombinant activated FVII. Recombinant coagulation factor VIIa (rFVIIa; NovoSeven(R)) was originally developed and approved for the treatment of bleeding episodes and the prevention of bleeding during surgery in hemophilia patients with inhibitors and in patients with auto-antibodies against FVIII or FIX (acquired hemophilia). As rFVIIa in pharmacological doses enhances thrombin generation on activated platelets, it has been suggested that rFVIIa may also help to improve hemostasis in other situations involving impaired thrombin generation. This is substantiated by the accumulation of published data indicating that rFVIIa is able to control bleeding in patients with thrombocytopenia or platelet function deficiencies as well as in patients without pre-existing coagulopathies.     

Recent advances in the development of coagulation factors and procoagulants for the treatment of hemophilia

Hemophilia is a family of rare bleeding disorders. The two primary types, hemophilia A and hemophilia B, are caused by recessive X-chromosome linked mutations that result in deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Clinically, hemophilia is manifested by spontaneous bleeding, particularly into the joints (haemarthrosis) and soft tissue, and excessive bleeding following trauma or surgery. The total overall number of hemophilia patients worldwide is approximately 400,000, however only about 100,000 of these individuals are treated. The first treatment of hemophilia was initiated when it was determined that the clotting deficiency could be corrected by a plasma fraction taken from normal blood. The discovery of factor VIII enrichment by cryoprecipitation of plasma opened a new era of therapy which eventually led to the production of factor concentrates and the subsequent development of highly purified forms of plasma factors. The most significant improvements have been the availability of recombinant forms of factors VIII and IX. Unfortunately, recombinant factors still retain some of the limitations of plasma concentrates. These limitations include development of antibody responses in patients and the relatively short half-life of the molecules requiring frequent injection to maintain effective concentration. Treatment beyond replacement of native factors has been tried. They include the development of modified factor VIII and IX molecules with improved potency, stability and circulating half-life and enhancement of a prothrombotic responses and/or stabilization of coagulation factors via inhibition of key negative regulatory pathways. These approaches will be reviewed in this commentary.     

Prediction of pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in humans using animal data

The pharmacokinetics of CS-023 (RO4908463, formerly R-115685), a novel parenteral carbapenem antibiotic, in humans was successfully predicted using the data collected from mice, rats, rabbits, and dogs; while inclusion of the monkey data led to a significant underestimation of the total plasma clearance (CL). Double logarithmic plots of CL and distribution volume at the steady-state (Vss) vs. body weight in four animal species were linear with high correlation coefficients; and the predicted CL and Vss values in humans agreed well with the observed values after administration of CS-023 by an intravenous drip infusion for 30 min. The plasma concentration-time profile in humans, which was predicted using a bi-exponential equation fitted to a complex Dedrick plot of the animal data, approximated the observed profile. An underestimation of CL caused by including the monkey data in a prediction is quite likely due to the net tubular reabsorption in monkeys, but not at least in rabbits, dogs, and humans.     

Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor

The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested). Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%. Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution. Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers. Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L). Corresponding human "effective" t(1/2) values were also compared. The predicted human t(1/2) based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr). The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting "effective" t(1/2).     

Effects of age and dose on the pharmacokinetics of ibuprofen in the rat.

The pharmacokinetics of ibuprofen after 2.5 and 25 mg/kg doses were examined in young adult (5 months) and senescent (24 months) male Fischer 344 rats. Plasma concentrations of ibuprofen were determined by HPLC and protein binding was measured by equilibrium dialysis. The cytochrome P-450-mediated metabolism of ibuprofen was investigated in vitro using microsomal protein from rat liver as the source of drug-metabolizing enzymes. Dose had a marked effect on the disposition of ibuprofen, with free plasma clearance (CLfree) decreasing 40% and apparent free steady-state volume of distribution (Vssfree) decreasing 58% as dose increased from 2.5 to 25 mg/kg. These changes reflected saturation of elimination pathways and tissue-binding sites. The binding of ibuprofen to plasma proteins was dependent on drug concentration. Unlike the parameters based on free ibuprofen concentrations, there were no significant changes in total plasma clearance (CL) or steady-state volume of distribution (Vss) due to the nonlinear protein binding. Aging also had a significant effect on ibuprofen pharmacokinetics. Decreases in CLfree and Vssfree of 42 and 51%, respectively, suggested a reduction in metabolic activity and binding of ibuprofen to tissue components in the aged rats. A decrease in plasma protein binding in the old rats was related to decreases in albumin concentration and the number of albumin binding sites. Thus, due to the greater free fraction of ibuprofen in the plasma of aged rats, CL increased significantly, whereas Vss remained unaffected by age when total plasma concentrations were examined. The metabolic capacity exhibited an age-related decline of 42%, whereas the affinity of the metabolic enzymes for ibuprofen was unaffected by age.     

Pharmacokinetics and fate of [3H]trospectomycin sulfate, a novel aminocyclitol antibiotic, in male and female dogs and rabbits. Allometric scaling with human.

The pharmacokinetics and fate of [3H]trospectomycin sulfate, a novel aminocyclitol antibiotic, were examined in male and female dogs and rabbits. Total radioactivity levels in plasma were associated with unchanged trospectomycin in both dog and rabbit. No unchanged drug was found in rabbit urine. Two radioactive components were found in dog urine; one was indistinguishable from trospectomycin and the other was probably a degradation product. The disappearance of drug from plasma followed a biphasic pattern and was well described by a bi-exponential function with half-lives of 0.4-0.8 and 30-70 hr in the dog and 0.4 and 90-120 hr in the rabbit. There was a large distribution volume (Vss), which indicated some retention of drug by tissues. The clearance (CL) for both animals was within the normal range for glomerular filtration rate. CL and Vss were not different between the sexes in the dog or rabbit. Excretion in both animals was initially rapid (greater than 40% by 4 hr) and mainly by the urinary route (fecal excretion less than 10%). Urinary excretion was not significantly different between the sexes. Over the dose range of 25-100 mg/kg, the plasma pharmacokinetics in the dog were linear. However, the recovery of radioactivity in the urine was significantly reduced at the highest dose. Trospectomycin CL in rat, human (obtained from previous studies), dog, and rabbit was described by the allometric equation, CL (ml/hr) = 132 x M0.91 where M is the body mass in kg.     

vWF促进intein剪接的BDD-FVⅢ的分泌和活性

vWF是由巨核细胞和血管内皮细胞合成的糖蛋白,其主要功能之一为凝血VIII因子(FVIII)的载体,防止后者被血浆酶降解。作者最近的工作证明intein可应用于双载体转移B结构域缺失型FVIII(BDD-FVIII)基因,通过翻译后的蛋白质反式剪接形成完整的功能性BDD-FVIII蛋白。为了研究vWF对于intein连接的BDD-FVIII分泌和活性的影响,通过intein融合的BDD-FVIII重、轻链基因和vWF基因共转染培养的293细胞,采用ELISA观察了分泌至培养上清液中的由intein剪接的全长BDD-FVIII抗原量,并用Coatest检测了由其产生的活性。结果显示,vWF基因共转染细胞上清液中,全长BDD-FVIII抗原量为(235±21)ng·mL-1,活性为(1.98±0.2)u·mL-1,明显高于未转染vWF的细胞[(110±18)ng·mL-1和(1.10±0.15)u·mL-1],也明显高于单独转染BDD-FVIII基因的对照细胞[(131±25)ng·mL-1和(1.22±0.18)u·mL-1],表明vWF基因共转染可显著改善双载体转BDD-FVIII基因后intein剪接的BD...     

The role of tissue factor/factor VIIa in the pathophysiology of acute thrombotic formation.

Tissue factor (TF) is the essential cofactor for the coagulation protease factor VIIa (FVIIa), initiating the coagulation cascade. The role of TF in thrombotic diseases is becoming increasingly evident. Recent findings suggest that inhibition of TF/FVIIa activity could be important in the prevention of clinical sequelae associated with plaque rupture or vessel damage that exposes TF to blood. Furthermore, selective inhibitors of TF/FVIIa may be associated with less bleeding risk than other antithrombotic agents. Several TF/FVIIa inhibitors are in development, including the protein-based inhibitors (such as NAPc2, Corsevin M, FFR-FVIIa, and Tifacogin). Research into the development of small molecule inhibitors is on-going, but is at a less advanced stage.     

Treatment strategies in children with hemophilia

Hemophilia is an inherited bleeding disorder caused by quantitative or qualitative defects in the synthesis of factor VIII (FVIII) or factor IX (FIX). Clinically, it is divided into severe, moderate and mild disease depending on the levels of FVIII or FIX in the blood. The bleeding tendency is most pronounced and can start at a very young age in severe hemophilia, which is characterized by repeated hemorrhage into the joints and muscles. Without treatment, these episodes lead to severe arthropathy, and there is also a high risk of lethal cerebral hemorrhage. The treatment of bleeding symptoms requires the correction of the coagulation defect. Factor concentrates have been available for 30 years, initially with the development of cryoprecipitate, subsequently with increasingly purified plasma-derived forms, and ultimately with recombinant clotting factor concentrates. The advantage of this highly effective therapy has been subdued by the outbreak of HIV and Hepatitis C infections in patients with hemophilia treated with factor concentrates which did not have adequate viral inactivation steps in the purification process. Plasma-derived and recombinant factor concentrates are today considered to have a good safety profile, but are only available for a small group of hemophilia patients worldwide. A multidisciplinary team approach is important for early diagnosis, communication with the patient and parents, and to tailor the best treatment possible with the amount of clotting factor concentrates available. The main goal of hemophilia treatment is to prevent bleeding symptoms and allow normal integration in social life. In patients with severe hemophilia, this can best be achieved by early home treatment and primary prophylaxis. Future developments in gene therapy may transform severe hemophilia to a mild form, with no need for regular injections of clotting factor concentrates.     

Recombinant factor VIIa, its clinical properties, and the tissue factor pathway of coagulation

Recombinant factor VIIa (rFVIIa) is a synthetic coagulation protease that is structurally similar to human-derived plasma FVIIa. Pharmacologic doses of rFVIIa have been shown to enhance thrombin generation and assist in forming stable fibrin plugs at the site of injury. Recombinant factor VIIa appears to emerge as a valuable treatment alter-native for the treatment of bleeding episodes and for achieving hemostasis post surgery in those with bleeding disorders.     

Cost-of-illness study of severe haemophilia A and B in five French haemophilia treatment centres

Objective The aim of this study was to assess the consumption of anti-haemophilic drugs by adults and children with severe haemophilia A or B (residual activity of FVIII or FIX ≤2%) and to quantify the average direct medical costs. Method A retrospective multicentre cost-of-illness study from the perspective of French national health insurance system. The costs include only the use of clotting factors. Main outcome measure Consumption was expressed in UI/kg/year and costs in euros/kg/year. Results From January 1, 2001 to December 31, 2002, data from 81 adults and 30 children with severe haemophilia A (n = 92) or B (n = 19) and included in the “SNH” were collected and analysed. A coagulation factor inhibitor was present in 10 patients (9%). Four of them were high responders. Mean age and body weight were respectively 28 ± 17 years and 58 ± 24 kg. Except for one adult patient, all (99%) had outpatient treatment, 44 patients (40%) were hospitalized and treated by recombinant or/and plasma-derived FVIII or FIX or/and rFVIIa. Overall median annual consumption of anti-haemophilic drugs per patient was estimated at 1,333 UI/kg, with a median cost-of-illness of 1,156 euros/kg. Patients with severe haemophilia B consumed more than patients with severe haemophilia A, though not significantly (P = 0.096), with a median of 2,167 vs. 1,100 UI/kg/year and a median cost of 1,760 vs. 917 euros/kg/year (P = 0.13). Children consumed respectively more than adults (P = 0.008), with a median of 3,204 vs. 1,106 UI/kg/year and a median cost of 2,614 vs. 913 euros/kg/year (P = 0.012). The median cost for patients with an inhibitor was 3,291 euros/kg/year, approximately threefold higher than that of patients without an inhibitor (926 euros/kg/year) (P = 0.022). Conclusion It suggests a higher consumption and cost of anti-haemophilic drugs among children when compared to adults. Haemophilia B patients did not consume significantly more than haemophilia A patients, whereas the consumption and cost for patients with or without inhibitors differed significantly.