Alessandro Gringeri - Academia.edu (original) (raw)

Papers by Alessandro Gringeri

Blood, 2005

The occurrence of inhibitors in severe hemophilia A can make replacement with factor VIII concent... more The occurrence of inhibitors in severe hemophilia A can make replacement with factor VIII concentrates insufficient for treatment of acute hemorrhages. An alternative is use of bypassing agents. The FEIBA® NovoSeven® Comparative Study (FENOC) is a randomized multicenter equivalence trial conducted in Europe and North America to study the efficacy of two bypassing agents. The usual framework of testing for differences between effectiveness of two treatments is not the focus in an equivalency trial. Instead, one tests that there is no clinically significant difference between treatments. In FENOC, the goal was to show that FEIBA® and NovoSeven® differed by less than 15% in efficacy. Subjects age 2+ with factor VIII deficiency, a history of inhibitor and need for bypassing agents were eligible. An episode of ankle, elbow, or knee bleeding was treated with one dose of FEIBA® and two doses of NovoSeven® with crossover between the options for the following episode. Subjects reported evalu...

Blood, 2014

Introduction: Prevention of bleeding represents the standard of care for patients with hemophilia... more Introduction: Prevention of bleeding represents the standard of care for patients with hemophilia without inhibitors. However, standard prophylactic dosing regimens with FVIII are currently based on body weight alone and do not take into account considerable inter-individual variability in FVIII PK profiles. In order to facilitate personalization of prophylaxis to individual needs and individual PK response we have developed a device that allows PK guided dosing in routine clinical care. In fact, the major barrier of PK-guided dosing in clinical practice is the necessity of multiple blood samples (6 to 11 over 48 hours) associated with a single infusion and the lack of easy-to-use statistical software to generate classical PK profiles. Leveraging the vast rAHF-PFM clinical database with more than 150 classical PK assessments, a Population PK model for children and adults was combined with a Bayesian algorithm to create a user friendly medical device. This methodology allows the use ...

Thrombosis and Haemostasis, 1991

SummaryIn the last 10 years 63 courses (283 infusions) of porcine FVIII were given to 25 hemophil... more SummaryIn the last 10 years 63 courses (283 infusions) of porcine FVIII were given to 25 hemophiliacs with high titer alloantibodies and to 5 patients with autoantibodies to factor VIII. Although the product was in general clinically efficacious, adverse effects of treatment were more frequent and severe than previously reported. After 63 courses there was a median percentage fall in baseline platelet count of 54% (range 8-86%); for 10 courses (16%), thrombocytopenia was severe or moderately severe (<100 × 109/1), with nadirs of platelet count ranging from 10 to 99 × 109/1 (median 67). Allergic reactions were seen in 15 of 30 patients (50%), in 20 of 63 courses (32%), more frequently but not exclusively after the first infusion. Relatively mild symptoms (fever, Hushing, urticaria, shivering) occurred in 15 courses; 5 courses, however, were accompanied by more severe anaphylactoid reactions, 2 of which required resuscitation therapy. Allergic reactions were observed both in patien...

Seminars in Thrombosis and Hemostasis, 2006

Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especi... more Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especially in those requiring surgery or with refractory bleeding events. Equally challenging are those patients who develop autoantibodies against factor VIII (FVIII) in the absence of a prior history of FVIII deficiency (acquired hemophilia). Physicians seeking both short- and long-term treatment strategies for bleeding events must often rely on FVIII-bypassing agents such as activated prothrombin complex concentrate (e.g., factor eight bypassing activity [FEIBA VH, Baxter BioScience, Westlake Village, CA]) or recombinant factor VIIa (rFVIIa [NovoSeven, NovoNordisk, Bagsvaerd, Denmark]). Surgical procedures in patients with inhibitors present a considerable challenge, from both a risk-benefit and a cost-benefit aspect. Hemostasis is difficult to achieve in these patients and new treatment options are being explored. Similarly challenging are refractory bleeds, the management of which is likely to benefit from a systematic treatment approach.

Journal of Thrombosis and Haemostasis, 2003

12±48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay w... more 12±48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay was steeper. In conclusion, the more homogeneous results of in vivo recovery and pharmacokinetic analysis, due to the decrease of discrepancy between the two methods when RLS was used, make the cheaper and more widely used one-stage assay preferable to the more expensive chromogenic assay, on condition that the ReFacto speci®c standard has used.

Haemophilia, 2012

Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement t... more Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement therapy in haemophilia. Recently, concerns have been raised regarding association of CI with the development of inhibitors. The aim of this study was to gain information on the current practices in Europe regarding CI and the true inhibitor incidence after this mode of therapy. In a cross sectional study performed in 22 Comprehensive Care Centres (CCCs), we evaluated CI techniques, treatment protocols, efficacy, safety and complications of CI including inhibitors. Thirteen (59%) CCCs reported a total of 1079 CI treatments, given peri-operatively or for major bleeds, in 742 patients. Most centres used &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;adjusted dose&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; CI aimed at median target FVIII level of 0.8 IU mL(-1). CI was haemostatically very effective with a low incidence of complications: median incidence of postoperative bleeding was 1.8%, six centres observed phlebitis in 2-11% of CI treatments. Only nine (1.2%) patients developed inhibitors (0.45% of 659 severe and 7.2% of 83 mild haemophilia patients). Additional analysis of inhibitor patients revealed several confounding factors (low number of prior FVIII exposure days, high steady-state factor levels during CI, high-risk genotype). In this unprecedentedly large cohort, CI treatment appears to be an effective and safe treatment that does not increase the risk of inhibitor development in patients with severe haemophilia. Thus, previous small case series reports suggesting that CI may increase inhibitors cannot be confirmed. Inhibitor risk in mild haemophilia could not be evaluated as the influence of other, potentially confounding, risk factors could not be excluded.

Haemophilia, 2011

Highly active antiretroviral therapy (HA-ART) of HIV+ patients with haemophilia poses specific qu... more Highly active antiretroviral therapy (HA-ART) of HIV+ patients with haemophilia poses specific questions on safety and effectiveness because of longlasting HIV infection, multidrug resistance, concomitant chronic liver disease and bleeding risk. Raltegravir belongs to a new class of drugs that inhibits HIV integrase and is known to have a good effectiveness and safety profile. The aim of this study was to evaluate safety and effectiveness of HAART with raltegravir in patients with haemophilia. HIV+ patients with haemophilia treated with raltegravir for ‡6 months were included in this retrospective study. Safety criteria were: occurrence of any adverse event, unexpected blood test abnormalities and increased consumption of coagulation factors. Effectiveness criteria were: no disease progression, viral load <40 HIV-RNA copies mL)1 and increased or stable CD3+ CD4+ cell count above 200 cells cmm)1. Seven patients with HCV co-infection underwent treatment with raltegravir for a median of 20 months (min-max: 7-30). Before starting treatment with raltegravir, three patients had CD3+ CD4+ cell counts <200 cells cmm)1. The median viral load was 7547 copies mL)1 (min-max: <40-37 807). During treatment, no new sign of disease progression was observed. All patients showed suppression of viral replication (<40 HIV-RNA copies mL)1). CD3+ CD4+ cell counts showed a median increase of 152 cells cmm)1 (min-max: 40-525). Two patients suffered from peripheral neuropathy, which was deemed as possibly associated with raltegravir. There was no evidence of increased bleeding frequency, modification of bleeding sites and lack of response to replacement therapy. Raltegravirbased HAART appeared to be effective and generally well-tolerated in patients with haemophilia, and it might represent a useful option in these patients.

British Journal of Haematology, 1992

To assess the efficacy of home treatment with intramuscular anti-D immunoglobulins (anti-D IgG) i... more To assess the efficacy of home treatment with intramuscular anti-D immunoglobulins (anti-D IgG) in patients with idiopathic or HIV-related chronic immune thrombocytopenic pnrpnra (I'TP). we conducted an open label. non-controlled, prospective study with a follow-up of h months in 5 1 consecutive patients with HTV-related (n = 24) or idiopathic ITP (ti = 2 7). Anti-l) IgG (I 3 &kg) were infused

Haemophilia, 2011

Some 10-20% of bleeding events in haemophilia patients with high-responding inhibitors cannot be ... more Some 10-20% of bleeding events in haemophilia patients with high-responding inhibitors cannot be controlled with bypassing agents. However, sequential combined bypassing therapy (SCBT) has been reported to be successful in five children. To extend this observation, a survey was undertaken by the European Haemophilia Treatment Standardisation Board (EHTSB) in children and adults. Data were collected from all centres belonging to the EHTSB network by a retrospective medical record review. SCBT courses were defined as the administration of both recombinant activated factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within 12 h. A web-based database was prepared to collect data on SCBT courses in a standardized and anonymous manner from patients' files. Eleven inhibitor patients underwent SCBT (nine haemophilia A; two haemophilia B). Two children had refractory knee haemarthrosis and one, an unresponsive calf haema-toma. Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post-traumatic upper limb haematoma and haemarthrosis. SCBT administration alternated one APCC dose to 1-3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20-80 U kg)1) was given every 8-12 h; rFVIIa (90-270 lg kg)1) was given every 3-12 h. Bleeding control was achieved in 12-24 h in all patients. SCBT was discontinued after 1-15 days. No clinical adverse events were observed, but a significant increase in D-dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A prospective clinical trial is needed to provide further evidence.

Haemophilia, 2006

The management of patients with inhibitors is an important challenge in haemophilia care. The lac... more The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasersÕ attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Welldesigned trials are warranted to guide decisionmaking, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

La Ricerca in Clinica e in Laboratorio

La Ricerca in Clinica e in Laboratorio

Treatment of haemophilia has vastly improved over the last years, but many needs are still unmet.... more Treatment of haemophilia has vastly improved over the last years, but many needs are still unmet. Baxter is continuously pursuing the aim to provide new therapeutic options to patients with haemophilia and to their treating physicians. In fact, there are several opportunities to improve existing therapies, e.g., by new indications for existing products, the introduction of new products, and by novel therapeutic approaches other than factor replacement. Among these, Baxter is working on a number of innovations, such as pharmacokinetics-tailored factor VIII prophylaxis, bypassing agent prophylaxis with FEIBA in inhibitor patients, development of a longer acting pegylated recombinant FVIII, a new recombinant factor IX, a new recombinant factor FVIIa, the first recombinant von Willebrand factor, recombinant ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) as well as gene therapy to cure haemophilia B. Conclusion: Baxter is truly committed to t...

Blood

3374 Patients with hemophilia A and factor VIII inhibitors are at increased risk for repetitive, ... more 3374 Patients with hemophilia A and factor VIII inhibitors are at increased risk for repetitive, poorly controlled joint bleeding and progression to end-stage joint disease. The investigator-initiated, prospective, randomized, crossover Prophylaxis with Factor Eight Inhibitor Bypassing Activity (Pro-FEIBA) study showed that prophylaxis with activated prothrombin complex concentrates (aPCC) infused at a target dose of 85 U/kg (±15%) on 3 nonconsecutive days per week safely reduced the frequency of hemarthroses and target joint bleeding by 61% and 72%, respectively (P<0.001), as compared with aPCC on-demand therapy (target dose 85 U/kg [±15%]). A majority of patients (62%) had ≥50% reduction in bleeding during the prophylaxis period. Deemed “good responders,” these patients missed significantly fewer days from school or work and experienced improved health-related quality of life while receiving prophylactic infusions of aPCC. Methods: To determine whether aPCC prophylaxis in good ...

Blood

4187 Introduction: Prophylaxis with anti-inhibitor complex concentrate (AICC; FEIBA NF, Baxter He... more 4187 Introduction: Prophylaxis with anti-inhibitor complex concentrate (AICC; FEIBA NF, Baxter Healthcare Corporation, Westlake Village, CA) has been shown to safely and significantly decrease the frequency of joint and other bleeding events in patients with severe hemophilia A and inhibitors. Nonetheless, AICC prophylaxis is an expensive therapeutic intervention, and evidence of its cost-effectiveness is needed to guide healthcare decision-making in this era of global economic downturn. Methods: Hemophilia A patients >2 years of age with inhibitors and using bypassing therapy to treat bleeding were enrolled in a prospective, randomized, crossover study comparing 6 months of AICC infused prophylactically at a dose of 85U/kg ± 15% on 3 nonconsecutive days per week with 6 months of AICC used on-demand for bleeding episodes at a dose of 85 U/kg ± 15%. The 2 treatment periods were separated by a 3-month washout during which patients used on-demand therapy for bleeding. Clotting facto...

Blood

720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding... more 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients…

Blood

Background: Haemophilia and its treatment influence the every-day-life of patients and impact on ... more Background: Haemophilia and its treatment influence the every-day-life of patients and impact on their quality of life. For the adequate assessment of quality of life validated instruments are necessary. While haemophilia-specific questionnaires for children are existing (v. Mackensen et al., 2004; Young et al., 2004), up to now no validated instrument for adults is available. Currently some developmental works are on-going in order to develop such an instrument as well for adults. In a multi-centre validation study a health-related quality of life questionnaire for adults with haemophilia was developed and pilot tested in Italy. Aim: This study was designed to develop and validate a haemophilia-specific quality of life measurement for adults (Haem-A-QoL) in Italy. Methods: The study consisted of three phases: a) a qualitative study including focus groups (with patients and physicians), item formulation and expert ratings of a catalogue of items by patients and physicians, b) a psyc...

Blood

Introduction and Objectives: The use of bypassing agents have contributed to a better management ... more Introduction and Objectives: The use of bypassing agents have contributed to a better management of bleeding (prevention and treatment) of persons with haemophilia (PWH) and inhibitors. One of these, an activated prothrombin complex concentrate (APCC - FEIBA - FVIII inhibitor bypassing activity, Shire) became commercially available 40 years ago in 1975. While bypassing therapy has been proven effective, it introduced a potentially increased risk of treatment-associated thrombo-embolic events (TEEs). The small size of clinical trials and post-authorization surveillance studies in PWH with inhibitors limits the capability to ascertain risk factors for APCC-associated TEEs. The present review provides an overview of clinical details of all spontaneous and literature cases TEEs reported with the use of APCC in congenital haemophilia, documented in the Company's global safety database. Materials and Methods: The global safety database was reviewed for all spontaneous and literature a...

Blood, 2005

The occurrence of inhibitors in severe hemophilia A can make replacement with factor VIII concent... more The occurrence of inhibitors in severe hemophilia A can make replacement with factor VIII concentrates insufficient for treatment of acute hemorrhages. An alternative is use of bypassing agents. The FEIBA® NovoSeven® Comparative Study (FENOC) is a randomized multicenter equivalence trial conducted in Europe and North America to study the efficacy of two bypassing agents. The usual framework of testing for differences between effectiveness of two treatments is not the focus in an equivalency trial. Instead, one tests that there is no clinically significant difference between treatments. In FENOC, the goal was to show that FEIBA® and NovoSeven® differed by less than 15% in efficacy. Subjects age 2+ with factor VIII deficiency, a history of inhibitor and need for bypassing agents were eligible. An episode of ankle, elbow, or knee bleeding was treated with one dose of FEIBA® and two doses of NovoSeven® with crossover between the options for the following episode. Subjects reported evalu...

Blood, 2014

Introduction: Prevention of bleeding represents the standard of care for patients with hemophilia... more Introduction: Prevention of bleeding represents the standard of care for patients with hemophilia without inhibitors. However, standard prophylactic dosing regimens with FVIII are currently based on body weight alone and do not take into account considerable inter-individual variability in FVIII PK profiles. In order to facilitate personalization of prophylaxis to individual needs and individual PK response we have developed a device that allows PK guided dosing in routine clinical care. In fact, the major barrier of PK-guided dosing in clinical practice is the necessity of multiple blood samples (6 to 11 over 48 hours) associated with a single infusion and the lack of easy-to-use statistical software to generate classical PK profiles. Leveraging the vast rAHF-PFM clinical database with more than 150 classical PK assessments, a Population PK model for children and adults was combined with a Bayesian algorithm to create a user friendly medical device. This methodology allows the use ...

Thrombosis and Haemostasis, 1991

SummaryIn the last 10 years 63 courses (283 infusions) of porcine FVIII were given to 25 hemophil... more SummaryIn the last 10 years 63 courses (283 infusions) of porcine FVIII were given to 25 hemophiliacs with high titer alloantibodies and to 5 patients with autoantibodies to factor VIII. Although the product was in general clinically efficacious, adverse effects of treatment were more frequent and severe than previously reported. After 63 courses there was a median percentage fall in baseline platelet count of 54% (range 8-86%); for 10 courses (16%), thrombocytopenia was severe or moderately severe (<100 × 109/1), with nadirs of platelet count ranging from 10 to 99 × 109/1 (median 67). Allergic reactions were seen in 15 of 30 patients (50%), in 20 of 63 courses (32%), more frequently but not exclusively after the first infusion. Relatively mild symptoms (fever, Hushing, urticaria, shivering) occurred in 15 courses; 5 courses, however, were accompanied by more severe anaphylactoid reactions, 2 of which required resuscitation therapy. Allergic reactions were observed both in patien...

Seminars in Thrombosis and Hemostasis, 2006

Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especi... more Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especially in those requiring surgery or with refractory bleeding events. Equally challenging are those patients who develop autoantibodies against factor VIII (FVIII) in the absence of a prior history of FVIII deficiency (acquired hemophilia). Physicians seeking both short- and long-term treatment strategies for bleeding events must often rely on FVIII-bypassing agents such as activated prothrombin complex concentrate (e.g., factor eight bypassing activity [FEIBA VH, Baxter BioScience, Westlake Village, CA]) or recombinant factor VIIa (rFVIIa [NovoSeven, NovoNordisk, Bagsvaerd, Denmark]). Surgical procedures in patients with inhibitors present a considerable challenge, from both a risk-benefit and a cost-benefit aspect. Hemostasis is difficult to achieve in these patients and new treatment options are being explored. Similarly challenging are refractory bleeds, the management of which is likely to benefit from a systematic treatment approach.

Journal of Thrombosis and Haemostasis, 2003

12±48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay w... more 12±48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay was steeper. In conclusion, the more homogeneous results of in vivo recovery and pharmacokinetic analysis, due to the decrease of discrepancy between the two methods when RLS was used, make the cheaper and more widely used one-stage assay preferable to the more expensive chromogenic assay, on condition that the ReFacto speci®c standard has used.

Haemophilia, 2012

Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement t... more Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement therapy in haemophilia. Recently, concerns have been raised regarding association of CI with the development of inhibitors. The aim of this study was to gain information on the current practices in Europe regarding CI and the true inhibitor incidence after this mode of therapy. In a cross sectional study performed in 22 Comprehensive Care Centres (CCCs), we evaluated CI techniques, treatment protocols, efficacy, safety and complications of CI including inhibitors. Thirteen (59%) CCCs reported a total of 1079 CI treatments, given peri-operatively or for major bleeds, in 742 patients. Most centres used &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;adjusted dose&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; CI aimed at median target FVIII level of 0.8 IU mL(-1). CI was haemostatically very effective with a low incidence of complications: median incidence of postoperative bleeding was 1.8%, six centres observed phlebitis in 2-11% of CI treatments. Only nine (1.2%) patients developed inhibitors (0.45% of 659 severe and 7.2% of 83 mild haemophilia patients). Additional analysis of inhibitor patients revealed several confounding factors (low number of prior FVIII exposure days, high steady-state factor levels during CI, high-risk genotype). In this unprecedentedly large cohort, CI treatment appears to be an effective and safe treatment that does not increase the risk of inhibitor development in patients with severe haemophilia. Thus, previous small case series reports suggesting that CI may increase inhibitors cannot be confirmed. Inhibitor risk in mild haemophilia could not be evaluated as the influence of other, potentially confounding, risk factors could not be excluded.

Haemophilia, 2011

Highly active antiretroviral therapy (HA-ART) of HIV+ patients with haemophilia poses specific qu... more Highly active antiretroviral therapy (HA-ART) of HIV+ patients with haemophilia poses specific questions on safety and effectiveness because of longlasting HIV infection, multidrug resistance, concomitant chronic liver disease and bleeding risk. Raltegravir belongs to a new class of drugs that inhibits HIV integrase and is known to have a good effectiveness and safety profile. The aim of this study was to evaluate safety and effectiveness of HAART with raltegravir in patients with haemophilia. HIV+ patients with haemophilia treated with raltegravir for ‡6 months were included in this retrospective study. Safety criteria were: occurrence of any adverse event, unexpected blood test abnormalities and increased consumption of coagulation factors. Effectiveness criteria were: no disease progression, viral load <40 HIV-RNA copies mL)1 and increased or stable CD3+ CD4+ cell count above 200 cells cmm)1. Seven patients with HCV co-infection underwent treatment with raltegravir for a median of 20 months (min-max: 7-30). Before starting treatment with raltegravir, three patients had CD3+ CD4+ cell counts <200 cells cmm)1. The median viral load was 7547 copies mL)1 (min-max: <40-37 807). During treatment, no new sign of disease progression was observed. All patients showed suppression of viral replication (<40 HIV-RNA copies mL)1). CD3+ CD4+ cell counts showed a median increase of 152 cells cmm)1 (min-max: 40-525). Two patients suffered from peripheral neuropathy, which was deemed as possibly associated with raltegravir. There was no evidence of increased bleeding frequency, modification of bleeding sites and lack of response to replacement therapy. Raltegravirbased HAART appeared to be effective and generally well-tolerated in patients with haemophilia, and it might represent a useful option in these patients.

British Journal of Haematology, 1992

To assess the efficacy of home treatment with intramuscular anti-D immunoglobulins (anti-D IgG) i... more To assess the efficacy of home treatment with intramuscular anti-D immunoglobulins (anti-D IgG) in patients with idiopathic or HIV-related chronic immune thrombocytopenic pnrpnra (I'TP). we conducted an open label. non-controlled, prospective study with a follow-up of h months in 5 1 consecutive patients with HTV-related (n = 24) or idiopathic ITP (ti = 2 7). Anti-l) IgG (I 3 &kg) were infused

Haemophilia, 2011

Some 10-20% of bleeding events in haemophilia patients with high-responding inhibitors cannot be ... more Some 10-20% of bleeding events in haemophilia patients with high-responding inhibitors cannot be controlled with bypassing agents. However, sequential combined bypassing therapy (SCBT) has been reported to be successful in five children. To extend this observation, a survey was undertaken by the European Haemophilia Treatment Standardisation Board (EHTSB) in children and adults. Data were collected from all centres belonging to the EHTSB network by a retrospective medical record review. SCBT courses were defined as the administration of both recombinant activated factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within 12 h. A web-based database was prepared to collect data on SCBT courses in a standardized and anonymous manner from patients' files. Eleven inhibitor patients underwent SCBT (nine haemophilia A; two haemophilia B). Two children had refractory knee haemarthrosis and one, an unresponsive calf haema-toma. Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post-traumatic upper limb haematoma and haemarthrosis. SCBT administration alternated one APCC dose to 1-3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20-80 U kg)1) was given every 8-12 h; rFVIIa (90-270 lg kg)1) was given every 3-12 h. Bleeding control was achieved in 12-24 h in all patients. SCBT was discontinued after 1-15 days. No clinical adverse events were observed, but a significant increase in D-dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A prospective clinical trial is needed to provide further evidence.

Haemophilia, 2006

The management of patients with inhibitors is an important challenge in haemophilia care. The lac... more The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasersÕ attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Welldesigned trials are warranted to guide decisionmaking, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

La Ricerca in Clinica e in Laboratorio

La Ricerca in Clinica e in Laboratorio

Treatment of haemophilia has vastly improved over the last years, but many needs are still unmet.... more Treatment of haemophilia has vastly improved over the last years, but many needs are still unmet. Baxter is continuously pursuing the aim to provide new therapeutic options to patients with haemophilia and to their treating physicians. In fact, there are several opportunities to improve existing therapies, e.g., by new indications for existing products, the introduction of new products, and by novel therapeutic approaches other than factor replacement. Among these, Baxter is working on a number of innovations, such as pharmacokinetics-tailored factor VIII prophylaxis, bypassing agent prophylaxis with FEIBA in inhibitor patients, development of a longer acting pegylated recombinant FVIII, a new recombinant factor IX, a new recombinant factor FVIIa, the first recombinant von Willebrand factor, recombinant ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) as well as gene therapy to cure haemophilia B. Conclusion: Baxter is truly committed to t...

Blood

3374 Patients with hemophilia A and factor VIII inhibitors are at increased risk for repetitive, ... more 3374 Patients with hemophilia A and factor VIII inhibitors are at increased risk for repetitive, poorly controlled joint bleeding and progression to end-stage joint disease. The investigator-initiated, prospective, randomized, crossover Prophylaxis with Factor Eight Inhibitor Bypassing Activity (Pro-FEIBA) study showed that prophylaxis with activated prothrombin complex concentrates (aPCC) infused at a target dose of 85 U/kg (±15%) on 3 nonconsecutive days per week safely reduced the frequency of hemarthroses and target joint bleeding by 61% and 72%, respectively (P<0.001), as compared with aPCC on-demand therapy (target dose 85 U/kg [±15%]). A majority of patients (62%) had ≥50% reduction in bleeding during the prophylaxis period. Deemed “good responders,” these patients missed significantly fewer days from school or work and experienced improved health-related quality of life while receiving prophylactic infusions of aPCC. Methods: To determine whether aPCC prophylaxis in good ...

Blood

4187 Introduction: Prophylaxis with anti-inhibitor complex concentrate (AICC; FEIBA NF, Baxter He... more 4187 Introduction: Prophylaxis with anti-inhibitor complex concentrate (AICC; FEIBA NF, Baxter Healthcare Corporation, Westlake Village, CA) has been shown to safely and significantly decrease the frequency of joint and other bleeding events in patients with severe hemophilia A and inhibitors. Nonetheless, AICC prophylaxis is an expensive therapeutic intervention, and evidence of its cost-effectiveness is needed to guide healthcare decision-making in this era of global economic downturn. Methods: Hemophilia A patients >2 years of age with inhibitors and using bypassing therapy to treat bleeding were enrolled in a prospective, randomized, crossover study comparing 6 months of AICC infused prophylactically at a dose of 85U/kg ± 15% on 3 nonconsecutive days per week with 6 months of AICC used on-demand for bleeding episodes at a dose of 85 U/kg ± 15%. The 2 treatment periods were separated by a 3-month washout during which patients used on-demand therapy for bleeding. Clotting facto...

Blood

720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding... more 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients…

Blood

Background: Haemophilia and its treatment influence the every-day-life of patients and impact on ... more Background: Haemophilia and its treatment influence the every-day-life of patients and impact on their quality of life. For the adequate assessment of quality of life validated instruments are necessary. While haemophilia-specific questionnaires for children are existing (v. Mackensen et al., 2004; Young et al., 2004), up to now no validated instrument for adults is available. Currently some developmental works are on-going in order to develop such an instrument as well for adults. In a multi-centre validation study a health-related quality of life questionnaire for adults with haemophilia was developed and pilot tested in Italy. Aim: This study was designed to develop and validate a haemophilia-specific quality of life measurement for adults (Haem-A-QoL) in Italy. Methods: The study consisted of three phases: a) a qualitative study including focus groups (with patients and physicians), item formulation and expert ratings of a catalogue of items by patients and physicians, b) a psyc...

Blood

Introduction and Objectives: The use of bypassing agents have contributed to a better management ... more Introduction and Objectives: The use of bypassing agents have contributed to a better management of bleeding (prevention and treatment) of persons with haemophilia (PWH) and inhibitors. One of these, an activated prothrombin complex concentrate (APCC - FEIBA - FVIII inhibitor bypassing activity, Shire) became commercially available 40 years ago in 1975. While bypassing therapy has been proven effective, it introduced a potentially increased risk of treatment-associated thrombo-embolic events (TEEs). The small size of clinical trials and post-authorization surveillance studies in PWH with inhibitors limits the capability to ascertain risk factors for APCC-associated TEEs. The present review provides an overview of clinical details of all spontaneous and literature cases TEEs reported with the use of APCC in congenital haemophilia, documented in the Company's global safety database. Materials and Methods: The global safety database was reviewed for all spontaneous and literature a...