Summary
Accurate and precise potency determination by manufacturers of different types of factor VIII product (plasma‐derived and recombinant FVIII rFVIII) is vital to clinicians and patients using ...FVIII concentrates. A separate, but related, requirement is ascertaining the FVIII activity levels in clinical samples for diagnosing and treating hemophilia A. The one‐stage clotting assay (OSA) and the chromogenic substrate assay (CSA) are the main assays used for these measurements, with both assays being used for potency assignments, and the OSA also being widely used for clinical monitoring. Although the assays can produce concordant results, discrepancies often occur, e.g. when measuring FVIII levels in patients with mild or moderate hemophilia A, or when assaying high‐purity FVIII products. Modifications to rFVIII proteins, such as B‐domain deletion (BDD), and technologies for improving the pharmacokinetic profile of rFVIII may exacerbate assay discrepancies. The CSA appears to be essentially unaffected by these modifications. However, the OSA underestimates the FVIII activity levels and therapeutic potential of some further modified BDD rFVIII products, especially those conjugated to poly(ethylene glycol); the extent of the effects is dependent on the specific OSA reagents used. Although the OSA remains the preferred choice for clinical monitoring in Europe and the USA, an awareness of the limitations of that assay has prompted more laboratories to adopt the CSA.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Advances in the treatment of bleeding disorders Peyvandi, F.; Garagiola, I.; Biguzzi, E.
Journal of thrombosis and haemostasis,
November 2016, 2016-11-00, 20161101, Volume:
14, Issue:
11
Journal Article
Peer reviewed
Open access
Summary
Historically, the bleeding episodes in subjects with coagulation disorders were treated with substitution therapy, initially with whole blood and fresh frozen plasma, and more recently with ...specific factor concentrate. Currently, patients with hemophilia have the possibility of choosing different effective and safe treatments, including novel extended half‐life and alternative hemostatic drugs. The availability of novel extended half‐life products could probably overcome current prophylaxis limitations, particularly in hemophilia B patients, by reducing the frequency of injections, achieving a higher trough level, and improving the quality of life of the patients. In addition, subcutaneous administration of alternative therapeutics would simplify prophylaxis in patients with hemophilia A and B with and without inhibitors. Regarding von Willebrand disease, a recombinant von Willebrand factor was recently developed to control bleeding episodes in patients with this disease, in addition to available von Willebrand factor/factor VIII concentrates. The management of patients affected by rare bleeding disorders (RBDs) is still a challenge, owing to the limited number of specific products, which are mainly available only in countries with high resources. Some improvements have recently been achieved by the production of new recombinant factor (F) XIII A subunit‐derived and FX plasma‐derived products for the treatment of patients affected by FXIII and FX deficiency. In addition, the development of novel alternative therapeutics, such as anti‐tissue factor pathway inhibitor, ALN‐AT3, and ACE910, for patients with hemophilia might also have a role in the treatment of patients affected by RBDs.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: The European Network of Rare Bleeding Disorders (EN‐RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs.
Objectives: To explore the ...relationship between coagulation factor activity level and bleeding severity in patients with RBDs.
Patients/Methods: Cross‐sectional study using data from 489 patients registered in the EN‐RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity.
Results: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL−1; FV, 12 U dL−1; combined FV + VIII, 43 U dL−1; FVII, 25 U dL−1; FX, 56 U dL−1; FXI, 26 U dL−1; FXIII, 31 U dL−1. Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL−1 for combined FV + VIII; < 8 U dL−1 for FVI; < 10 U dL−1 for FX; and < 25 U dL−1 for FXI.
Conclusions: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Factor XIII deficiency (FXIIID) is a rare hereditary bleeding disorder arising from heterogeneous mutations, which can lead to life‐threatening hemorrhage. The diagnosis of FXIIID is challenging due ...to normal standard coagulation assays requiring specific FXIII assays for diagnosis, which is especially difficult in developing countries. This report presents an overview of FXIIID diagnosis and laboratory methods and suggests an algorithm to improve diagnostic efficiency and prevent missed or delayed FXIIID diagnosis. Assays measuring FXIII activity: The currently available assays utilized to diagnose FXIIID, including an overview of their complexity, reliability, sensitivity, and specificity, as well as mutational analysis are reviewed. The use of a FXIII inhibitor assay is described. Diagnostic tools in FXIIID: Many laboratories are not equipped with quantitative FXIII activity assays, and if available, limitations in lower activity ranges are important to consider. Clot solubility tests are not standardized, have a low sensitivity, and are therefore not recommended as routine screening test; however, they are the first screening test in almost all coagulation laboratories in developing countries. To minimize the number of patients with undiagnosed FXIIID, test quality should be improved in less well‐equipped laboratories. Common country‐specific mutations may facilitate diagnosis through targeted genetic analysis in reference laboratories in suspected cases. However, genetic analysis may not be feasible in every country and may miss spontaneous mutations. Centralized FXIII activity measurements should also be considered. An algorithm for diagnosis of FXIIID including different approaches dependent upon laboratory capability is proposed.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Essentials
An international collaboration provides a consensus for clinical definitions.
This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP).
The consensus ...defines diagnosis, disease monitoring and response to treatment.
Requirements for ADAMTS‐13 are given.
Summary
Background
Thrombotic thrombocytopenic purpura (TTP) and hemolytic–uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small‐vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre‐eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways.
Objectives
To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs).
Methods
The International Working Group has proposed definitions and terminology based on published information and consensus‐based recommendations.
Conclusion
The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune‐mediated TTP.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Future of coagulation factor replacement therapy Peyvandi, F.; Garagiola, I.; Seregni, S.
Journal of thrombosis and haemostasis,
June 2013, 2013-Jun, 2013-06-00, 20130601, Volume:
11
Journal Article
Peer reviewed
Open access
Summary
Over a million patients worldwide currently suffer from hemophilia and other congenital clotting factor deficiencies. Patients affected with hemophilia A and B are treated by intravenous ...replacement therapy of factor VIII and factor IX, respectively. Current hemophilia treatments have favorably supported their efficacy, tolerability, and safety profiles. The onset of alloantibodies inactivating the infused coagulation factor is the main problem in hemophilia patients rendering replacement therapies ineffective; another disadvantage is the short half‐life of the infused clotting factors with the need for multiple and frequent infusions to manage a bleeding episode. Now, the challenge in the management of hemophilia treatment is the prolongation of the half‐life and reduction in the immunogenicity of recombinant clotting factors. The bioengineering strategies, previously applied successfully to other therapeutic proteins, encourage the current efforts to produce novel coagulation factors with more prolonged bioavailability, with increased potency and resistance to inactivation and potentially reduced immunogenicity.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Rare bleeding disorders (RBDs) are inherited deficiencies of coagulation factors such as fibrinogen, factor (F) II, FV, FVII, combined FV+FVIII, FX, FXI and FXIII. These disorders usually ...have a low prevalence in the general population and constitute approximately 3–5% of all coagulation disorders. However, in some countries they may have the same prevalence as haemophilia B due to the practice of consanguineous marriage. The clinical picture of RBDs is highly variable and can vary markedly from mild to severe, making both diagnosis and optimal treatment quite challenging. This review focuses on: (i) the efforts to establish a bleeding assessment tool adequate to RBDs, (ii) the optimal management of patients affected with FXI deficiency and (iii) the correlation between clinical severity and laboratory diagnosis when determining the minimum coagulant activity required to prevent bleeding in each RBD.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Essentials
Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality.
Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was ...studied.
Fewer caplacizumab‐treated patients had a major TE event, an exacerbation, or died versus placebo.
Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP.
Summary
Background
Acquired thrombotic thrombocytopenic purpura (aTTP) is a life‐threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti‐von Willebrand factor Nanobody® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment.
Objective
The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura‐related death during the study.
Methods
The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for ‘embolic and thrombotic events’ was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo.
Results
Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo‐treated patients died from aTTP during the study.
Conclusion
In total, 11.4% of caplacizumab‐treated patients and 43.2% of placebo‐treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The European principles of care in haemophilia marked their first decade in 2018. These guiding principles were the beginning of the European Haemophilia Consortium (EHC) review of countries' ...adherence to these principles in 2009, 2012, 2015 and 2018. The aim of this paper was to examine the implementation of the principles and how they have impacted the evolution of care in the last decade, as well as to identify remaining gaps and proposes future directions. In 2018, the EHC distributed a survey to EHC national member organisations in English and Russian and encouraged them to discuss responses with local clinicians for accuracy. Data was also cross-referenced and validated for countries in earlier surveys using additional available resources. The 10-year-old European principles had a significant impact on the development of care for haemophilia and related bleeding disorders in Europe. They set objectives around which multi-stakeholder groups have established recommendations and specific steps for the progressive improvement of care for bleeding disorders. However, some have been promoted and implemented more than others. Monitoring adherence to, and impact of, the European Principles of Care significantly assists in tracking developments and highlighting gaps. Countries' inability to report consistent and coherent data remains a challenge and hinders both provision of treatment and care for patients as well as optimal national and European healthcare systems.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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