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.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1126-1126
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Paulette Bryant ◽  
Jenny McDaniel ◽  
Kelly Tickle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Bleeding ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Acute Bleeding ◽  
Fviii Activity ◽  
Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

scholarly journals Prospective Data Collection on Patients with Fibrinogen and Factor XIII Deficiencies: Prelimary Results of the PRO-RBDD Project

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2838-2838 ◽  
Author(s):  
Flora Peyvandi ◽  
Marzia Menegatti ◽  
Roberta Palla ◽  
Simona Maria Siboni ◽  
Marco Boscarino ◽  
...  
Keyword(s):  
Linear Regression ◽  
Research Funding ◽  
Activity Level ◽  
On Demand ◽  
Treatment Type ◽  
Coagulant Activity ◽  
Bleeding Episodes ◽  
Fxiii Deficiency ◽  
Bleeding Severity

Abstract The PRO-RBDD is a prospective study of fibrinogen and FXIII deficiency designed to collect data on demographics, laboratory phenotype, genotype, clinical manifestations, obstetric data, surgery, treatment type and its efficacy and safety. Central laboratory testing is also available for diagnosis confirmation and genotyping. The aims of the study are to evaluate the prevalence of bleeding episodes, establish the minimum coagulant activity level to prevent bleeding (spontaneous or post-traumatic), and to monitor patients’ therapeutic regimens (efficacy and complications). The PRO-RBDD network involved 52 Hemophilia Treatment Centers (HTCs) worldwide for a predicted 380 and 573 patients with fibrinogen and FXIII deficiency, respectively. Data collection started in February 2013 and will continue for 3 years (baseline and 6 follow-up visits are planned). Clinical bleeding episodes were classified into four categories of severity relying on the location and potential clinical impact as well as spontaneity of bleeding. Statistical analysis was performed using chi-square. Linear regression analysis was used to explore the association between coagulation factor activity level and clinical bleeding severity, with the relationship between the two variables defined through the coefficient β. Currently, 26 HTCs have obtained local ethical committee approval and 15 have started data entry for 89 and 109 fibrinogen and FXIII deficient patients, respectively. Demographic data showed a similar distribution between males and females with a median age of 21 years (range: 1-84) and 19 years (range: 3-71) for fibrinogen and FXIII deficiency respectively; 38% and 22% of fibrinogen and FXIII deficient patients, respectively, were children (<12 years). The Table reports the association between residual coagulant level (laboratory severity) and clinical bleeding severity for both patient groups (p<0.01). Linear regression confirmed this association (fibrinogen: β=-0.29, p<0.01; FXIII: β=-12.94, p<0.01). Patient age at diagnosis and the type of treatments utilized are also reported (Table). In 33 women with fibrinogen deficiency and 21 with FXIII deficiency, 10 (30%) and 2 (10%), respectively, had menorrhagia; 5 out of 27 pregnancies (18%) in women with fibrinogen deficiency, and 16 out of 26 pregnancies (61%) in women with FXIII deficiency, resulted in spontaneous abortion; bleeding during pregnancy was observed in only 3/21 (14%) FXIII deficient women (only 1 of whom was on prophylaxis). Follow-up data are available for up to 500 days for 51 and 28 patients with fibrinogen and FXIII deficiencies, respectively. Three out of 6 patients with fibrinogen deficiency (50%) on prophylaxis (30-45 mg/kg/month fibrinogen concentrate), experienced bleeding, while no bleeding was observed for 39 of the 45 fibrinogen deficient patients treated on-demand. Of the 14 patients with FXIII deficiency not on prophylaxis, 2 (14%) had spontaneous bleeds. No bleeding was reported for patients with FXIII deficiency on prophylaxis. No thrombotic events were recorded for any patients. Preliminary data from the PRO-RBDD study of patients with fibrinogen and FXIII deficiency confirmed a strong association between coagulant activity levels and clinical severity in both deficiencies, and the efficacy of prophylaxis in patients with FXIII deficiency. For fibrinogen deficiency, the optimal prophylactic treatment regimen requires further study. Abstract 2838. Table Fibrinogen patients FXIII patients Laboratory severity Severe undetectable Moderate 0.1-1 g/L Mild >1 g/L Severe undetectable Moderate 5-30% Mild >30% Bleeding severity Asymptomatic (no documented bleeding episodes) 1 (1%) 16 (19%) 12 (14%) 0 0 9 (10%) Grade I (bleeding after trauma or drug ingestion) 1 (1%) 7 (8%) 4 (5%) 2 (2%) 3 (3%) 2 (2%) Grade II (spontaneous minor bleeding) 4 (5%) 4 (5%) 5 (6%) 1 (1%) 1 (1%) 1 (1%) Grade III (spontaneous major bleeding) 22 (26%) 9 (10%) 0 70 (74%) 6 (6%) 0 Age at diagnosis median (min,max) 1.5 (0,24) 9 (0,84) 29 (0,64) 5 (0,54) 7 (0,36) 30 (2,46) Treatment type On demand 17 (20%) 38 (43%) 21 (24%) 8 (8%) 8 (8%) 7 (7%) Prophylaxis 11 (13%) 0 0 67 (71%) 2 (2%) 4 (4%) Disclosures Peyvandi: Biotest: Research Funding; Baxter: speaker's fee Other; Bayer: speaker's fee Other; Grifols: speaker's fee, speaker's fee Other; LFB: speker's fee, speker's fee Other; CSL Behring: speaker's fee, speaker's fee Other; NovoNordisk: Research Funding, speaker's fee Other; Kedrion biopharma: Research Funding. Mumford:NovoNordisk: Consultancy, speaker fee Other.

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.

Cerebellotrigeminal Dermal Dysplasia (Gómez-López-Hernández Syndrome)

2018 ◽  
Vol 16 (05) ◽  
pp. 362-368 ◽  
Author(s):  
Federica Sullo ◽  
Agata Polizzi ◽  
Stefano Catanzaro ◽  
Selene Mantegna ◽  
Francesco Lacarrubba ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Number Of Patients ◽  
Wide Range ◽  
Visual Problems ◽  
Neurodevelopmental Abnormalities ◽  
Clinical Triad ◽  
High Degree ◽  
Motor Handicap

Cerebellotrigeminal dermal (CTD) dysplasia is a rare neurocutaneous disorder characterized by a triad of symptoms: bilateral parieto-occipital alopecia, facial anesthesia in the trigeminal area, and rhombencephalosynapsis (RES), confirmed by cranial magnetic resonance imaging. CTD dysplasia is also known as Gómez-López-Hernández syndrome. So far, only 35 cases have been described with varying symptomatology. The etiology remains unknown. Either spontaneous dominant mutations or de novo chromosomal rearrangements have been proposed as possible explanations. In addition to its clinical triad of RES, parietal alopecia, and trigeminal anesthesia, CTD dysplasia is associated with a wide range of phenotypic and neurodevelopmental abnormalities.Treatment is symptomatic and includes physical rehabilitation, special education, dental care, and ocular protection against self-induced corneal trauma that causes ulcers and, later, corneal opacification. The prognosis is correlated to the mental development, motor handicap, corneal–facial anesthesia, and visual problems. Follow-up on a large number of patients with CTD dysplasia has never been reported and experience is limited to few cases to date. High degree of suspicion in a child presenting with characteristic alopecia and RES has a great importance in diagnosis of this syndrome.

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.

scholarly journals Sequential Therapy of LMWH and Rivaroxaban in the Initial Treatment of Patients With Acute Pulmonary Embolism

2021 ◽  
Author(s):  
Wei Xiong ◽  
Yunfeng Zhao ◽  
He Du ◽  
Yanmin Wang ◽  
Xuejun Guo ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Initial Treatment ◽  
Acute Pulmonary Embolism ◽  
Sequential Therapy ◽  
Hemodynamic Instability ◽  
Efficacy And Safety ◽  
Bleeding Events ◽  
Once Daily ◽  
Number Of Patients

Abstract Background: Sequential low molecular weight heparin(LMWH) plus warfarin, LMWH plus edoxaban as well as LMWH plus dabigatran regimens have already showed efficacy and safety in the treatment of acute pulmonary embolism(PE). The efficacy and safety of sequential LMWH plus rivaroxaban regimen in the treatment of PE has been understudied. Methods: A retrospective study was performed to explore the efficacy and safety of sequential therapy regimens of subcutaneous LMWH( nadroparin 4100 IU every 12 hours for a week) followed by oral rivaroxaban(20mg once daily for 3 months) in the management of patients with established acute PE without hemodynamic instability, compared with those of LMWH plus dabigatran as well as LMWH plus warfarin.Results: The number of patients with total resolution of PE were 238(80.1%), 220(78.0%) and 166(62.6%), in the LMWH+rivaroxaban, LMWH+dabigatran, and LMWH+warfarin groups, respectively. (P=0.001) The prevalence of DVT at the 3-month follow-up visit were 18(6.1%), 14(5.0%) and 11(4.2%), in the aforementioned three groups, respectively.(P=0.559) The NT-proBNP level (pg/mL) at the 3-month follow-up visit were 122.5(97.4-158.9) , 131.7(102.2-166.3), and 357.8(275.4-433.2) in three groups, respectively.(P=0.001) The D-dimer level (ng/mL) at the 3-month follow-up visit were 387.3(310.9-465.2) , 432.5(382.4-489.6), and 854.0(721.5-993.7) in three groups, respectively.(P<0.001) The number of patients with major bleeding events were 3(0.9%), 6(1.8%), and 18(5.5%) in three groups, respectively. (P<0.001)Conclusions: The regimen of sequential subcutaneous LMWH for a week followed by oral rivaroxaban at a dose of 20mg once daily for three months is effective and safe in the initial treatment of patients with acute pulmonary embolism.

scholarly journals Cardiac Morbidity in Adolescents and Young Adult Survivors of Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Kristin C. Marr ◽  
Jonathan Simkin ◽  
Andrea C. Lo ◽  
Joseph M. Connors ◽  
Alina S. Gerrie ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Index Date ◽  
Population Based ◽  
Stage Disease ◽  
Increased Risk ◽  
Matched Case ◽  
Cv Disease ◽  
Relapsed Disease

INTRODUCTION Adolescents and young adult (AYA) survivors of Hodgkin lymphoma (HL) are potentially at increased risk of cardiovascular (CV) disease due to anthracycline exposure, in addition to use of mediastinal radiotherapy (RT). Although the risk has been well described in the pediatric age-group, the impact in the AYA population has been less well characterized. Capturing the incidence of these late effects is challenging given that events can occur more than a decade after therapy completion. Using population-based administrative data, we evaluated the incidence of CV disease (combined heart failure (HF) and ischemic heart disease (IHD)) in a cohort of AYA survivors treated for classical HL (cHL) using ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or equivalent chemotherapy. METHODS Patients with cHL aged 16-39 years (y), diagnosed between 1992-2013 and treated with an ABVD or equivalent therapy, were identified in the BC Cancer Lymphoid Cancer Database. Patients must have survived to an Index Date defined as 2 y from most recent HL event (primary diagnosis or if applicable, most recent relapse) and have had a minimum follow-up of 1 y beyond their Index Date. Patients were excluded if they had history of prior malignancy or HIV positivity. Limited stage disease was defined as stage IA, IB or IIA and absence of bulky disease (≥10cm); all others had advanced stage disease. Cases were linked with population-based databases of BC Cancer Registry; BC Radiation Oncology Database; and BC Ministry of Health (MOH) Chronic Disease Registry (CDR) that captures all BC residents registered with medical service plan coverage during the study period. The outcome variables, including HF and IHD, were defined by the BC MOH CDR using Standardized Case Definitions. To focus on late onset CV complications, only events that occurred after the Index Date were included in the analysis. A 10:1 individually-matched control population was identified from the CDR based on age, sex, and health authority region on the Index Date of the matched case. Controls were excluded if they had a pre-existing malignancy, HF, or IHD prior to the study window. Individual outcomes were collected from the Index Date of the matched case until December 31, 2015 or until an individual was censored due to loss to follow-up or death. Kaplan Meier (K-M) methodology and log-rank test was used to estimate cumulative incidence. A competing risk regression analysis was used to evaluate relative risk (RR) and p-values less than 0.05 were considered significant. RESULTS With a median follow-up time of 11 y (range 3-24 y) from most recent HL event, 764 AYA 2-y survivors were identified, aged 20 to 61 y (median 38 y) at the end of study period. The proportion of limited and advanced stage disease was 34.2% and 65.6%, respectively; and 49.9% were male. Eighty-eight patients (11.5%) had relapsed disease; eighty-six (11.3%) underwent high dose chemotherapy and autologous stem cell transplantation as part of their salvage therapy. In total, 268 patients (36.4%) were treated with mediastinal RT for primary therapy or for relapsed disease. Fifty-three percent received cumulative anthracycline dose ≥300 mg/m2. Survivors had a 3-fold increased risk of CV disease relative to controls (p&lt;0.0001). The onset of CV disease in survivors occurred at median of 11.7 y after most recent treatment (range 2.2-19.2 y), and at a median age of 44.3 y (range 21 - 58 y). At 15 y, the estimated cumulative incidence of CV disease was 6.3% in survivors compared to 2.3% in controls (Figure A). In the 496 survivors that received chemotherapy only, the incidence of CV disease at 15 y was 4.6% vs 2.3% in controls, and those that received anthracyclines and mediastinal RT had significantly higher incidence at 8.6% (Figure B). The increase in risk was greatest for a diagnosis of HF (RR 6.92, p&lt;0.0001): at 15 y, the cumulative incidence of HF was 2.2% vs 0.6% in controls. The RR of IHD was 2.63 (p&lt;0.0001) with incidence of 5.1% in cases compared to 1.8% in controls. CONCLUSION Similar to the pediatric population, AYA cHL survivors are at increased risk of both HF and IHD after completion of treatment. The majority of patients had received ABVD alone and had a lower incidence of CV disease at 15 y when compared to those that received treatment that included mediastinal RT. These results will inform counseling regarding risk factor modification and aid in the development of surveillance guidelines for AYA survivors. Disclosures Gerrie: Sandoz: Consultancy; Roche: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding. Villa:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AZ: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria. Scott:NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding. Sehn:AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Chugai: Consultancy, Honoraria. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria.

scholarly journals The photoplethysmography dictionary: practical guidance on signal interpretation and clinical scenarios from TeleCheck-AF

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
R M J Van Der Velden ◽  
D V M Verhaert ◽  
A N L Hermans ◽  
M Gawalko ◽  
D Duncker ◽  
...  
Keyword(s):  
Heart Rate ◽  
Clinical Scenario ◽  
On Demand ◽  
Practical Guide ◽  
Funding Sources ◽  
Internal Review ◽  
Clinical Scenarios ◽  
Number Of Patients

Abstract Introduction During the coronavirus disease 2019 (COVID-19) pandemic, numerous centres in Europe used on-demand photoplethysmography (PPG) technology to remotely assess heart rate and rhythm in conjunction with teleconsultations within the TeleCheck-AF project. Purpose To develop an educational structured stepwise practical guide on how to interpret PPG signals and to study typical clinical scenarios how on-demand PPG was used in the TeleCheck-AF project. Methods During an online conference, the structured stepwise practical guide on how to interpret PPG signals was discussed and further refined during an internal review process. We provide the number of respective PPG recordings and number of patients managed within a clinical scenario during the TeleCheck-AF project. Results To interpret PPG recordings, we introduce a structured stepwise practical guide and provide representative PPG recordings. In the TeleCheck-AF project, 2522 subjects collected 90.616 recordings. The majority of these recordings was classified by the PPG algorithm as sinus rhythm (57.6%), followed by atrial fibrillation (AF) (23.6%). In 9.7% of recordings the quality was too low to interpret. Other observed rhythms were tachycardia (1.4%), extra systoles (4.7%), bigeminy episodes (1.8%), trigeminy episodes (0.6%) and atrial flutter (0.2%). The most frequent clinical scenario where PPG technology was used in the TeleCheck-AF project was follow-up after AF ablation (1110 patients) followed by heart rate and rhythm assessment around (tele)consultation (966 patients), sometimes including remote PPG-guided adaption of rate or rhythm control. 275 patients were followed around cardioversion, either (semi-)acute or elective. Other possible scenarios are assessment of palpitations, assessment of symptom-rhythm correlation and monitoring during up-titration of heart failure medication. Conclusion We introduce a newly developed structured stepwise practical guide on PPG signal interpretation developed based on presented experiences from TeleCheck-AF. The present clinical scenarios for the use of on-demand PPG technology derived from the TeleCheck-AF project will help to implement PPG technology in the management of arrhythmia patients. FUNDunding Acknowledgement Type of funding sources: None. TeleCheck-AF clinical scenarios Classification of PPG recordings

scholarly journals Efficacy and Safety of a FLAG-Sequential Regimen Followed By Hematopoietic Stem Cell Transplantation for Myelodysplasia or Acute Leukemia in Fanconi Anemia: A Franco-Brazilian Report

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2498-2498
Author(s):  
Pierre-Edouard Debureaux ◽  
Flore Sicre de Fontbrune ◽  
Carmem M. S. Bonfim ◽  
Jean-Hugues Dalle ◽  
Nimrod Buchbinder ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Infectious Complications ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
History Of ◽  
Syncytial Virus

Background: Fanconi anemia (FA) is the most frequent genetic cause of bone marrow failure (BMF) due to a DNA repair mechanism defect. The natural history of FA is marked by progressive BMF during early childhood. Throughout life, the hematopoietic situation may change by clonal evolution toward myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure in FA patients. The role of HSCT for FA patients with AML or advanced MDS is less defined. Currently, HSCT first line result offers 50% Overall Survival (OS) for patients with cytogenetic abnormalities only and 30% OS for patients with advanced MDS or AML in FA (Ayas et al., JCO 2013; Mitchell et al., BJH 2014). We previously reported a FLAG-sequential approach in 6 patients with FA (5 AML and 1 advanced MDS), all alive at a median follow-up of 28 months (Talbot et al., Hematologica 2014). We update here those patients and report 12 more patients treated by FLAG-sequential since then. Materials & Methods: This retrospective study (2006-2019) was conducted in 7 centers in France and Brazil on behalf of the French Reference Center for Aplastic Anemia to evaluate FLAG-sequential in FA patients with morphological clonal evolution (no patients with cytogenetic abnormalities only). The study was conducted in accordance with the Declaration of Helsinki. Anonymous data collection was declared to the appropriate authorities. The FLAG-sequential treatment consisted of FLAG, Fludarabine 30 mg/m²/d for five days and Cytarabine 1 g/m²x2/d with G-CSF for five days, which was followed three weeks later by Cyclophosphamide 10 mg/kg/d for four days, Fludarabine 30 mg/m²/d for four days and TBI 2 Gy (Fig 1A). In a haploidentical setting, Cyclophosphamide at 30 mg/kg/d was performed only in post-transplantation, at Days +4 and +5 (Fig 1B). Results: Eighteen patients were included with 14 AML, 1 acute lymphoblastic leukemia (ALL), and 3 RAEB-2 (Table 1). The median age at the time of HSCT was 22 years (4-37 years). Fifteen patients (83%) were older than 10 years at the time of HSCT. The median follow-up was 31 months (3- 153 months). Eight patients (44%) had complex karyotype. None of the included patients had a history of solid malignancies before HSCT. All patients engrafted. The cumulative incidence of neutrophil engraftment at Day 60 was 94% (95% CI 63-100%) with a median of 18 days (12-343 days). The cumulative incidence of platelet engraftment at Day 60 was 83% (95% CI 50%-96%) with a median of 25 days (17-245 days). The donor chimerism was complete at Day +100 for 15 patients. The three patients without full donor chimerism at Day +100 either had a relapse (n=1) and 2 early deaths before Day+100 from steroid-refractory aGVHD (n=1) or septic shock (n=1). None of the patients received a second HSCT. Non-relapse mortality (NRM) at 3 years was 32% (95% CI 6-58%) (Fig 2). Cumulative incidence of grades II to IV aGVHD was 56% (35% grades III to IV). Cumulative incidence of extensive cGVHD was 16%. Infectious complications during HSCT include the following: CMV (n=8), EBV (n=2), adenovirus (n=4), BK virus (n=7), respiratory syncytial virus (n=1), candidaemias (n=2) and invasive aspergillosis (n=3). Progression free survival (PFS) and OS at 3 years were 53% (95%CI 32-89%) and 53% (95%CI 32-89%), respectively (Fig 2). Cumulative incidence of relapse at 3 years was 13% (95%CI 0-31%) (Fig 2). Seven patients died during the study. Causes of death were relapse (n=2), aGVHD (n=2), cGVHD (n=1), septic shock (n=1), and respiratory syncytial virus associated with invasive aspergillosis (n=1). GVHD-relapse free survival (GRFS) at 3 years was 48% (95%CI 29-78%). One patient had anal epidermoid carcinoma at 4 years after HSCT, which required multiple surgical ablations. Conclusion: With almost 3 years follow-up, which is long enough for our results to be considered robust, we report an OS and PFS of 53%, which compares favorably to historical controls since all of our 18 patients were treated with florid disease at time of HSCT (and not with cytogenetic abnormality only, known to be associated with a better prognosis). Toxicity is still a concern in this particular population of FA patients with notably a high rate of infectious complications. Future well designed prospective clinical trials will refine this sequential strategy, which appears promising in this particular difficult clinical situation. Disclosures Socie: Alexion: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

scholarly journals Assessing the Safety of Various VWF Regimens in Patients with Clinically Severe VWD: A Natural History Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1132-1132
Author(s):  
Robert F. Sidonio ◽  
Angela C. Weyand ◽  
Dunlei Cheng ◽  
Crystal Watson
Keyword(s):  
Board Of Directors ◽  
Study Design ◽  
Real World ◽  
Research Funding ◽  
Laboratory Data ◽  
Severe Bleeding ◽  
Advisory Committees ◽  
On Demand ◽  
Type 3 ◽  
Von Willebrand

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans affecting up to 1% of the population, while symptomatic prevalence is likely closer to 0.1%. A deficiency of von Willebrand factor (VWF) can be quantitative (type 1 or type 3) or qualitative (type 2) and lead to a bleeding diathesis of variable intensity roughly correlating with functional activity. Diagnosis can be challenging due to variable penetrance and large influence of multiple pre-analytic variables and a wide testing coefficient of variation. Treatment for VWD is focused on replacement of defective or deficient VWF with a plasma-derived or recombinant VWF-containing product, release and elevation of endogenous stores of VWF with Desmopressin (DDAVP), or prevention of premature fibrinolysis with an antifibrinolytic, such as aminocaproic acid. Although there is relative consensus on the management of mild VWD, there is scarce literature about the optimal treatment of patients with severe disease, especially in regard to factor replacement. Real World evidence for the use of primary (prior to significant bleeding) or secondary (following development of significant bleeding) prophylaxis is lacking with the majority of studies relying heavily on retrospective data. Additionally, ongoing VWD prophylaxis studies typically only allow participants to enroll if they previously have not been on prophylaxis, limiting our ability to learn about this growing population of patients. Study Design and Methods: Approximately 1,900 VWD patients were identified in the ATHNdataset with a VWF:Ag or VWF:RCo of ≤ 30%, with ~170 of these on prophylaxis. This group, in addition to those VWD patients with clinically significant bleeding and ≤ 40% of normal VWF:Ag or VWF:RCo, provide a potential unmet opportunity to examine prophylaxis and treatment patterns. Furthermore, a standardized laboratory assessment (including a standardized diagnostic battery, genetic evaluation of VWF gene, and inhibitor testing) will provide significant enrichment of the ATHNdataset by fully characterizing patients that are highly likely to utilize factor concentrates. Inclusion criteria are patients with severe VWD defined as type 3 VWD, or VWF:RCo, VWF:GP1bM or VWF:Ag≤ 30%, patients with clinically severe VWD as defined by VWF:Rco, VWF:GP1bM or VWF:Ag ≤ 40% with severe bleeding phenotype requiring recurrent use of factor concentrates, and co-enrollment in the ATHNdataset. Patients with platelet-type or acquired VWD are excluded. The primary objective is to assess the safety of various VWF regimens for different indications (on-demand, surgery, and prophylaxis) in adult and pediatric patients with clinically severe VWD. Safety is measured by the number of reported events as defined by the European Haemophilia Safety Surveillance (EUHASS) program. Secondary objectives are to enrich and analyze data from clinically severe congenital VWD patients by collecting laboratory data; to establish sub-studies for patients who are treated with VWF products on demand or who have started on or switched to a particular VWF containing product; to evaluate the use of factor replacement as prophylaxis in a cohort of severe VWD participants over 6 month time periods; to describe bleeding events, changes in overall bleeding, and annualized bleed rate as measured by the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) and if applicable the Pictorial Bleed Assessment Chart (PBAC); and to describe real-world effectiveness of VWD treatment as measured by health care utilization and quality of life measures (PROMIS® and V-WIQ questionnaires). Descriptive statistics will be calculated to analyze the primary and secondary outcomes. For each categorical variable, its frequency and percentage will be reported. In terms of a continuous measurement, its mean, median, standard deviation, interquartile range, minimum, and maximum values will be disclosed. The study will attempt to enroll a target number of at least 50 participants who are receiving VONVENDI but will not mandate the use of VONVENDI. More study design details are outlined in Table 1. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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