Dose-Finding Study: Rational Proceeding in Patients with VWD,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3326-3326
Author(s):  
Susan Halimeh ◽  
Hannelore Rott ◽  
Ulrike Nowak-Gottl
Keyword(s):  
Replacement Therapy ◽  
Conflicts Of Interest ◽  
Dose Finding ◽  
Recurrent Bleeding ◽  
Bleeding Events ◽  
Prophylactic Regimen ◽  
On Demand ◽  
Bleeding Episodes ◽  
Bleeding Score ◽  
Type 3

Abstract Abstract 3326 In patients with von Willebrand's disease (VWD) replacement therapy with factor VIII/VWF concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes were diagnosed with VWD. In all patients, decision for initiating prophylaxis was based on a bleeding score >2 prior to diagnosis, concomitant with recurrent bleedings associated with anemia in patients with on-demand therapy. We report results on secondary prophylactic VWF replacemment therapy applied 13 children, 7 adolescents and 4 adults (n=24) with VWD type 1 (n=4), 2 (n=12) and the severe type 3 (n=8). Based on individual 24h VWF:RCo recoveries [aim: 0.01 to 0.02 IU/ml > baseline] median dose was 40 [min. 20- max. 47] IU/kg, 15 patients were give substitution therapy semiweekly, 7 patients thrice weekly and 2 children four times per week. Within a 12-months-period hemoglobin conentrations returned to normal values. Median duration of prophylaxis was 3 years. Recurrent bleeding episodes stopped in 23/24 patients. One female type 3 patient additionally needed locally applied tranexamic acid [tooth bruising]. Following a 12-months observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the pre-prophylaxis/ pre-diagnostic values. Conclusion: The use of secondary prophylactic VWF replacement therapy with FVIII/VWF concentrate is an effective tolerated treatment modality, highly benefical for patients with VWD, who present recurrent bleeding events during an on-demand therapy. Disclosures: No relevant conflicts of interest to declare.

Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease

2011 ◽  
Vol 105 (04) ◽  
pp. 597-604 ◽  
Author(s):  
Susan Halimeh ◽  
Anne Krümpel ◽  
Hannelore Rott ◽  
Nadja Bogdanova ◽  
Ulrich Budde ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Von Willebrand Disease ◽  
Recurrent Bleeding ◽  
On Demand ◽  
Bleeding Episodes ◽  
Bleeding Score ◽  
Type 3 ◽  
Von Willebrand

SummaryIn patients with von Willebrand disease (VWD) replacement therapy with factor VIII/von Willebrand (VWF) concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes (spontaneous, peri- or postoperative) were diagnosed with VWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. In all patients, decision for initiating prophylaxis was based on a bleeding score > 2 prior to diagnosis, concomitant with recurrent bleeds associated with anaemia in patients with on-demand VWD therapy. We report results on secondary prophylactic VWF replacement therapy applied in 32 patients [children n=13; adolescents n=7; adults n=12] with VWD [type 1: 4; type 2: 15; type 3: 13], 15 of which were females, and nine of these at the reproductive period. Eight patients were treated with Humate P→ or Wilate→ (n=24). Median [min-max] dose [vWF:RCo] was 40 [20–47] IU/kg, 23 patients were given substitution therapy twice weekly, seven patients three times a week, and two children four times per week. Within a 12-month-period haemoglobin concentrations returned to normal values. Median duration of prophylaxis was three years. Recurrent bleeding episodes stopped in 31 of 32 patients, whereas inhibitors developed in one. Following a 12-month observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the preprophylaxis/pre-diagnostic values. The use of secondary prophylactic VWF replacement therapy is an effective tolerated treatment modality, highly beneficial for patients with VWD, who present with recurrent bleeding events during on-demand therapy.

Long-Term Prophylaxis In Children, Adolescents and Young Adults with Von Willebrand Disease – First Results of a Cohort Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 714-714
Author(s):  
Susan Halimeh ◽  
Anne Kruempel ◽  
Hannelore Rott ◽  
Nadja Bogdanova ◽  
Ulrich Budde ◽  
...  
Keyword(s):  
Young Adults ◽  
Replacement Therapy ◽  
Von Willebrand Disease ◽  
Recurrent Bleeding ◽  
On Demand ◽  
Bleeding Episodes ◽  
Children And Young Adults ◽  
Bleeding Score ◽  
Von Willebrand

Abstract Abstract 714 In children and young adults with von Willebrand disease [vWD] replacement therapy with von Willebrand factor (vWF)/factor VIII concentrates is increasingly performed as “prophylactic” therapy. Between 2000 and 2008, 82 consecutively enrolled children, adolescents and young adults with clinically meaningful bleeding episodes [spontaneous, peri- or postoperative] were diagnosed with vWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. Here we report results of prophylaxic VWF replacement therapy in 32 patients [female: n=15; >Tanner 2: 9/15] with VWD type 1 [n=4], 2 [n=15] and 3 [n=13] in which a prophylactic treatment regimen was performed. Decision on prophylaxis was based on i) a pre-diagnostic bleeding score, and ii) on recurrent bleeds associated with microcytic anemia after diagnosis in patients with on-demand VWD therapy. Patients were treated with Humate P® (n=8; once switched to Wilfact®) or Wilate® (n=24). Median [min-max] dose was 40 (20-47) IU/kg, 23 patients were substituted twice weekly, 7 were treated three times, and two children 4 times per week. Within a six-months-period hemoglobin concentrations returned to normal values. Median [min-max] duration of prophylaxis was 3 years [1.0-9.0]. Recurrent bleeding episodes stopped in 31/32 patients, inhibitor development occurred in one. Following a 12-months observation period the bleeding frequency/bleeding score was significantly reduced, compared to pre-prophylaxis/pre-diagnostic values. The use of prophylactic VWF replacement therapy is an effective and well tolerated treatment modality, highly beneficial for children and young adults with vWD with recurrent bleeding events on on-demand therapy. Disclosures: No relevant conflicts of interest to declare.

Lack of Seasonal Variation in Bleeding and Patient-Assessed Pain Patterns in Patients with Hemophilia B Receiving On-Demand Therapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1136-1136
Author(s):  
Frank E. Shafer ◽  
Lynne Smith ◽  
Nicholas Vendetti ◽  
Pablo Rendo ◽  
Marcus E. Carr
Keyword(s):  
Seasonal Variation ◽  
Pain Score ◽  
Temporal Pattern ◽  
Hemophilia B ◽  
Bleeding Events ◽  
Prophylactic Regimen ◽  
On Demand ◽  
Significant Pain ◽  
Patient Reported ◽  
Bleeding Episodes

Abstract Abstract 1136 Background: Bleeding events associated with hemophilia are characterized by spontaneous or trauma-related hemorrhage into soft tissue, muscles, and joints. Spontaneous hemorrhage in patients with hemophilia is generally considered to occur randomly and without a predictable temporal or seasonal pattern. While there are a few reports that have examined the effects that weather, temperature, and atmosphere might have on spontaneous bleeding, there is a lack of evidence in the medical literature for consistent seasonal variation in bleeding risk in patients with hemophilia (Linde P & Syrbe G, Gesamte Inn Med 1990;45:657–9; Linde P & Syrbe G, Folia Haematol Int Mag Klin Morphol Blutforsch 1990;117:519–25; Rainsford SG & Hall A, Br J Haematol 1973;24:539–51; Benbassat J, Br Med J 1971;3:771; van Dijk K et al, Blood 2004). Objective: This post hoc analysis of a randomized controlled trial examined the influence of seasonality on bleeding frequency and patient-assessed pain in patients with hemophilia B. Methods: In a multicenter, open-label crossover study, 50 patients with moderately severe and severe (FIX C ≤ 2%) hemophilia B were enrolled and treated on demand for 16 weeks, and 47 were subsequently randomized to 1 of 2 prophylactic regimens (100 IU/kg once weekly or 50 IU/kg biweekly) for 16 weeks. Following the initial prophylactic regimen, and before crossing over to the other prophylactic regimen, patients underwent an 8-week washout period of on-demand (OD) therapy. The primary end point was the annualized number of bleeding episodes, expressed as the annualized bleeding rate (ABR). The results of this study were previously reported (Valentino LA, et al, 2011 ISTH poster 1293). This post hoc analysis presents, as a scatterplot, the ABR during the calendar months when the patients were receiving OD therapy. Also presented as scatterplots are results of a patient-reported measure of pain completed during every joint bleeding event (spontaneous or traumatic) during the OD periods (Brief Pain Inventory; 0 [“no pain”] to 10 [“pain as bad as you can imagine”]). The OD periods were selected for this analysis in order to evaluate bleeding events without the influence of the prophylactic regimens. Results: Figure 1 shows the ABR for each patient for each OD period with data. Because most patients had relatively similar ABR values for both OD periods, the data were combined. Data for OD1 and OD2 are included in Figure 1, up to 2 values per patient. The time point shown for each patient's ABR is the midpoint of that patient's participation in that period. The observed ABRs during the OD periods showed no distinguishable trend over time. The proportion of joint bleeding episodes during which a patient reported pain is shown in Figure 2. Each point represents the proportion of joint bleeding events for which the patient answered “Yes” to question 1 on the Brief Pain Inventory (“Have you experienced significant pain today?”) plotted at the midpoint of the patient's participation in that period. For patients reporting significant pain as a result of a joint bleeding episode, no distinguishable temporal pattern was observed in the raw pain score (plotted on the day the episode occurred; Figure 3A) reported for each episode. A pain score of 0 was then imputed for any joint bleeding episode for which a patient reported no significant pain. The median pain score (plotted at the midpoint of the patient's participation in that period; Figure 3B) recorded by each patient for all joint bleeding episodes during the OD periods likewise showed no distinguishable temporal pattern. Conclusions: In this analysis, no discernible seasonal or temporal pattern was observed with respect to the frequency of bleeding episodes, as assessed by the ABR during the calendar months when patients were receiving OD treatment. Likewise, no pattern was observed in patient-reported occurrence or intensity of pain during joint bleeding episodes. These results support the observation that there is no apparent seasonal variation in bleeding pattern or patient-reported pain in patients with hemophilia B. Disclosures: Shafer: Pfizer: Employment. Smith:Pfizer, Inc: Employment. Vendetti:Pfizer, Inc: Employment. Rendo:Pfizer, Inc: Employment. Carr:Pfizer, Inc: Employment.

scholarly journals Long-Term Prophylaxis in Patients with Von Willebrand Disease and Recurrent Bleeding in Italy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5056-5056 ◽  
Author(s):  
Piercarla Schinco ◽  
Cultrera Dorina ◽  
Federica Valeri ◽  
Alessandra Borchiellini ◽  
Cristina Teruzzi ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Von Willebrand Disease ◽  
Recurrent Bleeding ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Transfusion Requirements ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand

Abstract INTRODUCTION: Von Willebrand disease (VWD) is a congenital bleeding disorder caused by Von Willebrand factor (VWF) deficiency or abnormalities. Apart from administration of desmopressin in mild-moderate cases, replacement therapy with VWF/Factor VIII (FVIII) concentrates is the therapy of choice for short-term prophylaxis (STP) during surgery or clinical interventions and it is the conventional approach for Long-Term Prophylaxis (LTP) in patients with severe bleeding tendency. However, LTP with FVIII/VWF concentrates is not always effective and in some cases. Repeated infusions of FVIII/VWF concentrates may increase the risk of thromboembolic events due to FVIII:C overload. The aim of this analysis was to evaluate the effectiveness of LTP with a VWF concentrate almost devoid of FVIII:C ( vWF conc.) vs VWF/FVIII concentrate in VWD patients with a heavy bleeding phenotype. METHODS: A retrospective analysis on four VWD patients [type 3 (n= 1), type 2M (n= 1) and type 1 (n= 2)] was carried out in two Italian Hemophilia Centers. These Centers have clinical experience with VWD patients with severe bleeding tendency, on LTP, who switched from VWF/FVIII concentrates to vWF conc. in order to obtain a better control of the bleedings. The patients were included in the analysis if they fulfilled the following criteria: periodical bleeding episodes and previous prophylaxis with VWF/FVIII concentrates. The patients had been previously treated with VWF/FVIII concentrates (prophylaxis: 35-50 IU/Kg/3 times per week; bleeding episodes: 30-50 IU/Kg/day as long as needed), before starting prophylaxis with vWF conc. (prophylaxis: 30-50 IU/Kg/2 times per week and in one case 30 IU/Kg/3 times per week; bleeding episodes: 30-50 IU/Kg/day as long as needed). Data on number of bleeding episodes and hospital admittances, hemoglobin, FVIII:C levels, and number of transfusions were collected. Data after 1 year’s prophylaxis with vWF conc. were compared with those after 1 year’s prophylaxis with VWF/FVIII concentrates. RESULTS: The number of all bleeding episodes decreased by 96% (mean 14 to 0,5 episodes) and all patients showed a consistent reduction of their own bleeding frequency. Hemoglobin and FVIII:C levels respectively increased by a mean of 2,8 gr/dl (from 8,05 gr/dl to 10,85 gr/dl) and 40% (from 17% to 57%) after LTP with vWF conc. The patient transfusion requirements (number of packed red blood cell concentrate-PRBC) dropped from a mean of 3.5 to zero, and the number of ordinary hospitalizations and day hospital admittances decreased by 100% after LTP with vWF conc. (mean of 15 to 0). CONCLUSIONS: Our analysis suggests that LTP with a VWF concentrate almost devoid of FVIII is effective and well tolerated highly beneficial for patients both in terms of reduction of bleeding episodes and reduction of number of days spent in hospital with an obvious improvement of the quality of life. A collection of clinical data from a larger population of patients is required to confirm and support these results. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Unique Case of Type 3 Von Willebrand Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5031-5031
Author(s):  
Mamatha Mandava ◽  
John Lazarchick ◽  
Emily Curl ◽  
Shayla Bergmann
Keyword(s):  
Replacement Therapy ◽  
Von Willebrand Factor ◽  
Conflicts Of Interest ◽  
Von Willebrand Disease ◽  
Compound Heterozygosity ◽  
Increased Risk ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder worldwide. Genetic mutations in the von Willebrand gene may result in either quantitative (Types 1 and 3 vWD) or qualitative defects (Type 2 vWD) of von Willebrand Factor (vWF). Type 3 is the rarest and most severe form of vWD, resulting in a virtual absence of vWF. Type 3 vWD follows autosomal recessive inheritance and is most often reported in patients who are homozygous for the same gene mutation. We report a patient with type 3 vWD who inherited two different mutations, one from each parent, resulting in compound heterozygosity. Case: Our patient, now a 2 year old female, initially presented with prolonged bleeding lasting approximately 5 hours at the injection site of her 2 month immunizations. Labs on initial presentation showed a normal WBC count, hemoglobin, hematocrit, and platelet count, with normal levels of Factor IX, XI, and XII activity. PTT was prolonged at 59 (reference range 23.3-35.7) with a normal INR. Von Willebrand panel showed markedly decreased Factor VIII (2%), vWF antigen (6%), and vWF activity (8%). VWF multimers were absent, consistent with a diagnosis of type 3 vWD. VWF gene sequence analysis showed two pathologic variants, one on each allele: c2345delC in exon 18 and a deletion within exon 6. Her parents, both 27 years old and with no history of abnormal bleeding, are non-consanguineous. Analysis of parents for vWD revealed that mother is heterozygous for the c2345delC variant and the patient's father is heterozygous for the deletion within exon 6 of the VWF gene. The patient's older sibling who is now 4 years old developed unusual petechiae and bruising after an altercation at school, his testing was positive for only the maternal mutation, resulting in a diagnosis of Type 1 vWD, and a younger brother was negative for both mutations. Our patient has subsequently suffered recurrent episodes of bruising, gingival bleeding, and poor tissue healing and currently requires replacement therapy (prophylaxis) with Humate-P three times each week and additionally as needed. Discussion: Type 3 vWD is quite rare, with a prevalence ranging from 0.1-5.3 per million. Our case is especially interesting due to the unique inheritance pattern resulting in our patient's type 3 vWD phenotype. Type 3 vWD cases are often described in patients homozygous for a mutation in the VWF gene, frequently as a result of consanguinity. Our patient inherited a unique variant from each parent, resulting in heterozygous expression of two defective VWF alleles (compound heterozygosity). Our patient's maternally inherited defect c2435delC in exon 18 is the variant found in the original vWD family described by Dr. Erik von Willebrand in 1926. Less is understood about the paternally inherited defect of a deletion in exon 6 of VWF. In our patient's family, because each parent is heterozygous for a mutation in the VWF gene, future children have a 75% chance of inheriting at least one mutation, and a 25% chance of inheriting both mutations, leading to Type 3 vWD. Type 3 vWD patients have impaired endogenous synthesis of functional vWF, thus therapies such as desmopressin, used in other types of vWD to stimulate secretion of endogenous vWF, are ineffective. Instead, first-line treatment in Type 3 is replacement therapy with Humate-P as needed during bleeding episodes and/or as prophylaxis. Humate P is VWF/FVIII concentrate obtained from pooled human plasma from many carefully screened plasma donors and contains the clotting proteins VWF and FVIII. Humate-P has a VWF:FVIII ratio of approximately 2.4:1. Complications of therapy include the rare development of anti-vWF alloantibodies, which most often occurs in patients with partial or complete VWF gene deletions. Our patient has received aminocaproic acid for minimal bleeding episodes and due to her severe intensity of disease and age of increased risk of injuries had received plasma derived vWF/FVIII concentrates for multiple episodes of moderate bleeding. She has not developed antibodies yet, but is at high risk. The rWVF (recombinant von Willebrand factor) offers new perspective in treatment of vWD more so with type 3 disease. It is a homogenous protein synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line, retains its intact multimer pattern because it is never exposed to proteases(ADAMTS13) which can degrade it. The rVWF is currently in phase 3 clinical trials Disclosures No relevant conflicts of interest to declare.

scholarly journals Prospective Evaluation of Bleeding Incidence in Fibrinogen Deficiency (PRO-RBDD Study)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 207-207
Author(s):  
Roberta Palla ◽  
Marzia Menegatti ◽  
Marco Boscarino ◽  
Jan Blatny ◽  
Ondrej Zapletal ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Severe Bleeding ◽  
Bleeding Events ◽  
On Demand ◽  
Number Of Patients ◽  
Wide Range ◽  
Bleeding Episodes

Abstract BACKGROUND: Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenaemia) or both (hypodysfibrinogenaemia) of fibrinogen. Afibrinogenemia is associated with mild-to-severe bleeding, whereas hypofibrinogenemia is most often asymptomatic. Previously, our group (Peyvandi et al, JTH 2006) showed that in a group of 100 patients with afibrinogenemia and hypofibrinogenemia, the mean annual incidence of bleeding episodes was 0.7 on on-demand therapy (range 0-16.5) and 0.5 on prophylactic replacement therapy (range 0-2.6). Dys- and hypodysfibrinogenemia are commonly associated with bleeding, thrombosis, or both; however, most individuals are asymptomatic. Treatment of fibrinogen deficiency is challenging because the minimum amount of fibrinogen to prevent bleeding is unknown and because thromboembolism may occur in association with fibrinogen substitution therapy. Therefore a guideline for optimal treatment is not available yet. AIMS: The 3-year observational prospective study on rare bleeding disorders (PRO-RBDD) aimed at evaluating the incidence of bleeding episodes in patients with fibrinogen deficiency and the benefits and complication of current treatment regimens. METHODS: 17 Hemophilia Treatment Centers worldwide collected data in a web-based database at baseline (patient history) and at pre-specified time-points (every 6 months, follow up study); 146 patients (86 females/60 males) were recorded. Analysis was carried out on patients with available data on both antigen and activity levels. Bleeding incidence was calculated to evaluate number of bleeding episodes in patients on on-demand therapy. A survival analysis was also made to evaluate the cumulative incidence of the first bleeding requiring replacement therapy. Analysis was done using R v.3.3.1 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Data on activity and antigen level were available on 96 patients (54 females/42 males), of whom 81 are currently on follow up. Twenty-one (26%) patients were afibrinogenemic, 17 (21%) hypofibrinogenemic, 36 (44%) dysfibrinogenemic and 7 hypodysfibrinogenemic (9%), according to standard classification. Patients were followed up for a median of 810 days (IQR: 728-916, min-max: 221-1215). In on-demand therapy, the bleeding incidence was 0.86 patient-year-1 (95%CI 0.57-1.15) in afibrinogenemia, 0.30 (95%CI 0.15-0.52) in hypofibrinogenemia, 0.14 (95%CI 0.06-0.25) in dysfibrinogenemia and 0.06 (95%CI 0.-0.27) in hypodysfibrinogenemia. At 1200 days of follow up, the bleeding cumulative incidence of the first bleeding treated with replacement therapy was 0.43 (95%CI 0.11-0.64) in afibrinogenemia, 0.30 (95%CI 0.05-0.49) in hypofibrinogenemia, 0.06 (95%CI 0.0-0.14) in dysfibrinogenemia and 0.14 (95%CI 0.0-0.37) in hypodysfibrinogenemia. Prophylaxis regimen (dosage range 50 - 666 mg/Kg/month) with fibrinogen concentrate was used only in one third of patients (6/21) with afibrinogenemia and it seems to reduce the median number of bleeding events per year [from 1 (min-max: 1-3/year) to 0.4 (min-max: 0-1.25)]. Only one allergic reaction and no thrombotic events were reported. CONCLUSION: The results of this prospective observational study on patients with fibrinogen deficiency showed that the bleeding incidence decreased accordingly to plasmatic fibrinogen levels. Preliminary data on a limited number of patients with afibrinogenemia showed a reduction of bleeding episodes even if a wide range of prophylaxis dosage has been used. A larger group of patients and a longer follow up period are required to evaluate the efficacy of prophylaxis and to find the optimal target level to prevent spontaneous major bleeding in afibrinogenemic patients. Disclosures Palla: Pfizer: Other: travel support . Menegatti:Pfizer: Other: travel support . Blatny:CSL Behring: Speakers Bureau. Halimeh:Bayer Healthcare GmbH: Research Funding, Speakers Bureau; Baxalta Innovations GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; CSL Behring GmbH: Research Funding, Speakers Bureau; Novartis Pharma GmbH: Speakers Bureau; Novo Nordisk Pharma GmbH: Research Funding, Speakers Bureau; Octapharma GmbH: Research Funding, Speakers Bureau; LFB GmbH: Speakers Bureau; Pfizer Pharma GmbH: Research Funding, Speakers Bureau. Siboni:LFB: Speakers Bureau; Bayer: Speakers Bureau. Laros-Van Gorkom:Baxter: Research Funding; CSL Behring: Research Funding; Sanquin: Speakers Bureau. Schutgens:CSL Behring: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta: Research Funding; Novonordisk: Research Funding. De Moerloose:Bayer: Consultancy, Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding, Speakers Bureau; LFB: Speakers Bureau; Stago: Speakers Bureau; Novonordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Research Funding. Casini:CSL Berhing: Speakers Bureau; Bayer: Other: Travel support. Makris:CSL Behring: Consultancy; Novo Nordisk: Consultancy; Freeline Therapeutics: Consultancy; Bayer: Speakers Bureau; Biogen: Speakers Bureau; Grifols: Speakers Bureau. Chapin:Baxalta: Consultancy; CSL Behring: Consultancy; Novo Nordirsk: Consultancy; Alexion Pharmaceuticals: Consultancy; Apopharma: Consultancy; Bayer: Consultancy. Peyvandi:CSL Behring: Speakers Bureau; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; Grifols: Speakers Bureau; SOBI: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Bayer: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau.

scholarly journals Peak Thrombin and D-Dimer Levels in Subjects with Severe Hemophilia Receiving Acute Treatment for Bleeding Episodes Experienced during Prophylactic Marstacimab Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Satyaprakash Nayak ◽  
Sangeeta Raje ◽  
John Teeter ◽  
Lutz Harnisch ◽  
Steven Arkin
Keyword(s):  
Bleeding Episode ◽  
Phase 2 ◽  
Bleeding Events ◽  
Post Hoc Analysis ◽  
On Demand ◽  
Increased Risk ◽  
Phase 2 Study ◽  
Bleeding Episodes ◽  
Post Hoc ◽  
D Dimer

Introduction: Marstacimab is a fully humanized monoclonal immunoglobulin G1 that targets the shared K2 domains of tissue factor pathway inhibitor (TFPI)α and (TFPI)β and is currently in phase 3 development. The intended indication is routine prophylaxis treatment to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B (with or without inhibitors). Factor replacement or bypass treatment for bleeding events may lead to increased levels of peak thrombin and D-dimer associated with an increased risk of thrombosis . In this post hoc analysis of data from a phase 2 study in patients with hemophilia with and without bleeding episodes, receiving prophylactic marstacimab treatment, peak thrombin and D-dimer levels were investigated to assess the changes in these biomarker levels observed after bleeding episodes. Methods: Individual subject data from the phase 2 study (clinicaltrials.gov identifier: NCT02974855)were used for this analysis. Biomarker data for healthy volunteers who received single doses of marstacimab in a phase 1 dose escalation study (clinicaltrials.gov identifier: NCT02531815) were used as control data, as these subjects represent an intact and uncompromised coagulation system. Study subjects in the phase 2 study received subcutaneous (SC) marstacimab at doses of (1) 150 mg once weekly (QW), with a loading dose of 300 mg, (2) 300 mg QW, and (3) 450 mg QW. All subjects with bleeding episodes were identified, along with on-demand treatment administered for each bleeding episode. Treatments permitted for bleeding episodes included activated coagulation factor VIIa, factor VIII, or factor IX; use of activated prothrombin complex concentrate was prohibited. D-dimer and peak thrombin data collected within 3 days after each bleeding episode were used for this analysis. Time profiles of peak thrombin and D-dimer levels were analyzed to assess the effect of bleed treatment. Biomarker profiles were compared between subjects with and without bleeding episodes, as well as with the data from healthy volunteers (n=41). Results: A total of 15 bleeding episodes were reported in 8 of 26 subjects during the study (excluding screening and follow-up). No subject participating in the study showed any relevant increases in D-dimer levels after receiving on-demand treatment for a bleeding episode while receiving regular prophylaxis with marstacimab, compared with levels seen in subjects who did not experience a bleeding episode. Based on the peak thrombin data (see Figure), 150 nM was observed as the upper limit for 18 of 26 subjects who did not experience any bleeding episodes, which was approximately 50% of the 300 nM observed in healthy volunteer controls treated with 450 mg intravenous marstacimab. Transient increases in peak thrombin of &gt;150 nM were observed at several time points in 3 of 8 subjects who experienced bleeding episodes. The highest peak thrombin level reported was approximately 211 nM in one subject receiving marstacimab 300 mg SC QW and factor VIII concentrate on demand during the study. Conclusions: No transient increases in D-dimer could be attributed to the administration of bleeding episode treatment. The transient increases in peak thrombin levels following on-demand treatment for bleeding episodes did not exceed peak thrombin levels seen in subjects without bleeding events or the levels seen in healthy volunteer controls receiving single doses of marstacimab. Based on peak thrombin and D-dimer levels observed in this post hoc analysis, there does not appear to be any indication of an increased risk of thrombosis post administration of acute on-demand bleeding episode treatment while on prophylactic marstacimab therapy at the doses studied. Disclosures Nayak: Pfizer Inc.: Current Employment, Other. Raje:Pfizer Inc.: Current Employment, Other. Teeter:Pfizer Inc.: Current Employment. Harnisch:Pfizer Inc.: Current Employment, Other. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company.

Cost-effectiveness of prophylaxis against on-demand treatment in boys with severe hemophilia A in Iran

2009 ◽  
Vol 25 (4) ◽  
pp. 584-587 ◽  
Author(s):  
Aliasghar Ahmad Kia Daliri ◽  
Hassan Haghparast ◽  
Jahanara Mamikhani
Keyword(s):  
Cost Effectiveness ◽  
Chart Review ◽  
Prophylactic Treatment ◽  
Bleeding Event ◽  
Retrospective Chart Review ◽  
Third Party ◽  
Bleeding Events ◽  
On Demand ◽  
Bleeding Episodes ◽  
Hemophilia Treatment Centers

Objective: The aim of this study was to assess the incremental cost-effectiveness of on-demand versus prophylactic hemophilia therapy in Iran from a third-party payers’ perspective.Methods: A retrospective chart review of twenty-five type A hemophiliacs who were treated in three hemophilia treatment centers was conducted. The patients were boys 0–9 years old receiving one of two treatments: (i) prophylaxis with concentrate at clinic; (ii) concentrate at clinic as on-demand. Fourteen boys received on-demand infusions for bleeding events, and eleven boys received infusions prophylaxis. Data were extracted from documents in the hemophilia treatment centers during a period of approximately 6 months.Results: The patients receiving prophylactic treatment had fewer bleeding events each month (mean, 0.26 versus 2.74) but used more concentrate (225.31 versus 87.20 units/kg per month). Average monthly cost per patient in the prophylaxis group was approximately 1.9 times higher than in the on-demand group. Compared with on-demand infusion, prophylaxis costs 3,201,656 Rials (€213.45) per bleeding event prevented.Conclusion: Prophylactic care markedly reduces the number of bleeding episodes, but at considerable cost.

scholarly journals The Efficacy of Ultrasound Joint Examination for the Management in Patients with Hemophilia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5027-5027
Author(s):  
Shiho Nishimura ◽  
Keita Tomioka ◽  
Maiko Shimomura ◽  
Yoko Mizoguchi ◽  
Shinobu Sasaki ◽  
...  
Keyword(s):  
Early Detection ◽  
Replacement Therapy ◽  
Conflicts Of Interest ◽  
Bone Erosion ◽  
Joint Damage ◽  
Factor Ix ◽  
Joint Effusion ◽  
Clotting Factors ◽  
Prophylactic Regimen ◽  
Joint Examination

Abstract The regular prophylactic replacement therapy with clotting factors has significantly reduced the arthropathy in patients with hemophilia. Early detection of the signs of joint damage is important to prevent the progressive joint damage. For the early detection, we have introduced the regular ultrasound (US) joint examination in patients with hemophilia from 2014 based on the hemophilia early arthropathy detection with ultrasound (Head-US) scanning protocol. US examination has been performed at the time of annual comprehensive clinic in Hiroshima University Hemophilia Center. Forty-five patients aged 1 to 33 years were enrolled and more than 280 joints were evaluated in this study. US joint examination was performed within 30 minutes without the sedation in all aged children. Abnormal findings, such as cartilage changes, subchondral bone erosion, synovial hypertrophy and/or joint effusion were observed in 8 out of 45 patients. The replacement therapy with clotting factors of all 8 patients aged 13 to 33 years was an insufficient prophylaxis during early childhood. The residual 37 patients aged less than 15 years have relatively followed the prophylactic treatment. The prophylactic regimen has been individually determined based on the trough levels of factor IX concentration in plasma for hemophilia B and pharmacokinetics of factor VIII using MyPKFitR for hemophilia A patients, respectively. The result suggests the importance of the careful prophylactic replacement therapy considering the factor concentration in plasma. Four patients aged 4, 5, 18, and 19 years, respectively, suffered from painful and/or swollen joint episodes from 2014 to 2018. Urgent US examination without the use of any sedatives revealed ankle, knee, or hip joint bleeding in each case. According to the replacement therapy for breakthrough bleeding, hemoarthropathy was accessed by consecutive examination of US. These results suggest that US joint examination could be necessary for the early detection of joint damage and for appropriate treatment of hemoarthropathy. Collectively, utilization of US examination would be essential for the management through the life in patients with hemophilia. Disclosures No relevant conflicts of interest to declare.

Efficacy, Safety and Tolerability of a Novel High-Purity, Double Virus-Inactivated VWF/FVIII-Concentrate in the Treatment of Von Willebrand Disease (VWD) - Clinical Experience in the Treatment of Bleeding and Surgery.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2144-2144
Author(s):  
B.A. Schwartz ◽  
J. Windyga ◽  
M. von Depka ◽  
O. Walter ◽  
M. Jansen ◽  
...  
Keyword(s):  
Clinical Efficacy ◽  
Surgical Procedures ◽  
Von Willebrand Disease ◽  
Efficacy And Safety ◽  
Open Label ◽  
Prophylactic Regimen ◽  
Acute Bleeding ◽  
Good Efficacy ◽  
Bleeding Episodes ◽  
Type 3

Abstract Introduction: Wilate is a highly purified, double viral inactivated, VWF/FVIII-concentrate developed for the treatment of VWD. A program of prospective studies was conducted in VWD patients to investigate the clinical efficacy and safety of Wilate® in acute bleeding episodes, prophylaxis and surgical procedures. Methods: In these prospective open label studies 70 VWD patients (37 VWD of type 3) were treated with the VWF/FVIII concentrate Wilate and followed to assess clinical efficacy and tolerability. Dosing and monitoring were performed using FVIII assays. This is standard practice in most of the study sites and was feasible because of the product’s physiological 1:1 ratio and parallel PK profiles of FVIII and VWF. Dosing decisions were based on established guidelines and the investigators’ clinical judgment. The efficacy of the product was rated on a four-point scale by the investigator. Results: Bleeding- 43 patients (25 of type 3) were treated for a total number of 1088 bleeding episodes (BE). The median dose per exposure day (ED) was calculated to be 31 IU VWF/FVIII:C/kg and were treated for a median of 1.2 days, with excellent or good efficacy achieved in 96% of treatments. Surgery- Efficacy and safety was also studied in 31 VWD patients who underwent 54 elective or urgent surgical procedures of which 27 were classified as major; the overall efficacy was rated as excellent or good in most cases (94%), with a mean dose per infusion being 34 IU VWF/FVIII:C/kg. Pediatric Use- A total of 8 children below 12 years of age with 310 BE s were treated, with an excellent/good efficacy in 98% of bleedings. Prophylaxis- 19 patients were on a prophylactic regimen for more than 10 consecutive weeks (total of 2,338 ED), with an overall reduction of bleeding frequency. Tolerability - Out of 5,662 rated infusions in all studies, the tolerability was assessed as “very good” or “good” in 99% of the cases. Conclusions: The results of the prospective clinical trial program demonstrate the safety, efficacy and tolerability of this VWF/FVIII concentrate for the treatment of acute bleeding episodes, prophylaxis and surgical procedures in patients with VWD.

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