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• W2896798548 abstract "At first sight the diagnosis of hemophilia A is obvious and is defined as a deficiency of factor VIII activity. The internationally accepted definition from the International Society of Thrombosis and Haemostasis (ISTH) has served us well, especially in separating severe from non‐severe hemophilia 1.White G.C. Rosendaal F.R. Aledort L.M. Lusher J.M. Rothchild C. Ingerslev J. Definitions in Hemophilia. Recommendation of the scientific and subcommittee of factor VIII and factor IX of the Scientific and Standardization Committee of the International society on Thrombosis and Haemostasis.Thromb Haemost. 2001; 85: 560Crossref PubMed Scopus (702) Google Scholar. This international definition considers mild hemophilia A to have FVIII:C > 5 IU dL−1 and <40 IU dL−1 without specifying the type of assay to be used 1.White G.C. Rosendaal F.R. Aledort L.M. Lusher J.M. Rothchild C. Ingerslev J. Definitions in Hemophilia. Recommendation of the scientific and subcommittee of factor VIII and factor IX of the Scientific and Standardization Committee of the International society on Thrombosis and Haemostasis.Thromb Haemost. 2001; 85: 560Crossref PubMed Scopus (702) Google Scholar. At the upper end, however, the situation is not so easy or clear because many mutations can result in a dysfunctional molecule and the different FVIII assays may yield different FVIII:C results 2.Peyvandi F. Oldenburg J. Friedman K.D. A critical appraisal of one‐stage and chromogenic assays of factor VIII activity.J Thromb Haemost. 2016; 14: 248-61Crossref PubMed Scopus (104) Google Scholar. Additional complexity arises from day to day variability in FVIII:C, from the increase in FVIII with age, inflammation and also the increase as a result of the acute phase response 3.Rumley A. Emberson J.R. Wannamethee S.G. Lennon L. Whincup P.H. Lowe G.D.O. Effects of older age on fibrin D‐dimer, C‐reactive protein and other hemostatic and inflammatory variables in men aged 60‐79 years.J Thromb Haemost. 2006; 4: 982-7Crossref PubMed Scopus (75) Google Scholar, resulting in different inter‐ and intra‐individual factor levels even among patients with the same F8 genotype 4.Loomans J.I. van Velzen A.S. Eckhardt C.L. Peters M. Makipernaa A. Holmstrom M. Brons P.P. Dors N. Haya S. Voorberg J. van der Bom J.G. Fijnvandraat K. Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations.J Thromb Haemost. 2017; 15: 246-54Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar. Some patients can bleed more than normal with FVIII:C levels that are higher than 40 IU dL−1 (i.e. 0.4 IU mL−1) 5.Plug I. Mauser‐Bunschoten E.P. Brocker‐Vriends A.H.J.T. Van Amstel H.K. van der Bom J.G. van Diemen‐Homan J.E. Willemse J. Rosendaal F.R. Bleeding in carriers of hemophilia.Blood. 2006; 108: 52-6Crossref PubMed Scopus (239) Google Scholar. Within families, blood group differences can partially account for some of the variation in FVIII:C level. Although we believe the initial ISTH definition should be maintained, it should be modified in accordance with the following proposals. 1.A patient can be defined as having mild hemophilia A if they have an isolated reduced FVIII:C level of <40 IU dL−1.2.Patients may be labelled as having mild hemophilia A if they have a FVIII:C of > 40 IU dL−1 provided that they also have a DNA change in the F8 gene and one of the following:a.a family member with the same DNA change and FVIII of < 40 IU dL−1, and the DNA change is found in < 1% of the population; andb.the international databases list the DNA change as being associated with hemophilia A and < 40 IU dL−1 FVIII:C3.All tests should be confirmed on a repeat sample. In the presence of an inflammatory condition the repeat sample should be taken at the time of resolution of inflammation.4.Female carriers with FVIII:C levels < 40 IU dL−1 should be considered as having hemophilia and be managed as such.5.In the absence of a family history of hemophilia or pathogenic FVIII mutation, von Willebrand disease (VWD), including type 2N VWD, should be excluded before diagnosing mild hemophilia. Combined FV and FVIII deficiency can be ruled out by the presence of a normal prothrombin time.6.The benefit of identification of hemophilic individuals with FVIII > 40 IU dL−1 is both the clinical management of that person in terms of treating or preventing bleeding and also identifying other affected family members. FVIII:C can be measured by one‐stage clotting or chromogenic assays 2.Peyvandi F. Oldenburg J. Friedman K.D. A critical appraisal of one‐stage and chromogenic assays of factor VIII activity.J Thromb Haemost. 2016; 14: 248-61Crossref PubMed Scopus (104) Google Scholar. In the past, a two‐stage clotting assay was available but this has largely been superseded by the chromogenic assay, which is based on the same principle 2.Peyvandi F. Oldenburg J. Friedman K.D. A critical appraisal of one‐stage and chromogenic assays of factor VIII activity.J Thromb Haemost. 2016; 14: 248-61Crossref PubMed Scopus (104) Google Scholar. Although in severe and moderate hemophilia the one‐stage and chromogenic assays give equivalent results, in mild hemophilia approximately 30% of patients yield discrepant results 6.Poulsen A.L. Pedersen L.H. Hvas A.M. Poulsen L.H. Thykjaer H. Ingerslev J. Assay discrepancy in mild haemophilia A: entire population study in a National Haemophilia Centre.Haemophilia. 2009; 15: 285-9Crossref PubMed Scopus (33) Google Scholar. This discrepancy has been described in many different populations, including Australia, Denmark, France, Germany, Spain and the UK 6.Poulsen A.L. Pedersen L.H. Hvas A.M. Poulsen L.H. Thykjaer H. Ingerslev J. Assay discrepancy in mild haemophilia A: entire population study in a National Haemophilia Centre.Haemophilia. 2009; 15: 285-9Crossref PubMed Scopus (33) Google Scholar, 7.Duncan E.M. Duncan B.M. Tunbridge L.J. Lloyd J.V. Familial discrepancy between one‐stage and two stage factor VIII methods in a subgroup of patients with haemophilia A.Br J Haematol. 1994; 87: 846-8Crossref PubMed Scopus (80) Google Scholar, 8.Trossaert M. Lienhart A. Nougier C. Fretigny M. Sigaud M. Meunier S. Fouassier M. Ternisien C. Negrier C. Dargaud Y. Diagnosis and management challenges in patients with mild haemophilia A and discrepant FVIII measurements.Haemophilia. 2014; 20: 550-8Crossref PubMed Scopus (34) Google Scholar, 9.Pavlova A. Delev D. Pezeshkpoor B. Muller J. Oldenburg J. Haemophilia A mutations in patients with non‐severe phenotype associated with a discrepancy between one‐stage and chromogenic FVIII assays.Thromb Haemost. 2014; 111: 851-61Crossref PubMed Scopus (54) Google Scholar, 10.Cid A.R. Calabuig M. Cortina V. Casana P. Haya S. Moret A. Cabrera N. Aznar J.A. One‐stage and chromogenic FVIII:C assay discrepancy in mild haemophilia A and the relationship with the mutation and bleeding phenotype.Haemophilia. 2008; 14: 1049-54Crossref PubMed Scopus (55) Google Scholar, 11.Bowyer A.E. van Veen J.J. Goodeve A.C. Kitchen S. Makris M. Specific and global assays in the diagnosis of discrepant hemophilia A.Haematologica. 2013; 98: 1980-7Crossref PubMed Scopus (46) Google Scholar, 12.Bowyer A.E. Goodeve A. Liesner R. Mumford A.D. Kitchen S. Makris M. p.Tyr365Cys change in FVIII: haemophilia A, but not as we know it.Br J Haematol. 2011; 154: 618-25Crossref PubMed Scopus (22) Google Scholar. Patients with the discrepancy have mutations in the FVIII molecule domain interfaces, reducing the stability of the molecule, and this is more obvious in the chromogenic assay because of the longer incubation time 9.Pavlova A. Delev D. Pezeshkpoor B. Muller J. Oldenburg J. Haemophilia A mutations in patients with non‐severe phenotype associated with a discrepancy between one‐stage and chromogenic FVIII assays.Thromb Haemost. 2014; 111: 851-61Crossref PubMed Scopus (54) Google Scholar, 13.Pipe S.W. Eickhorst A.N. Mckinley S.H. Saenko E.L. Kaufman R.J. Mild hemophilia A caused by increased rate of factor VIII A2 subunit dissociation: evidence for nonproteolytic inactivationof factor VIIIa in vivo.Blood. 1999; 93: 176-83Crossref PubMed Google Scholar. In most cases of a discrepancy, both the one‐stage and chromogenic results will be below 40 IU dL−1, but there are well‐described cases where the results of one of the assays are entirely normal and would thus fail to diagnose the hemophilia 11.Bowyer A.E. van Veen J.J. Goodeve A.C. Kitchen S. Makris M. Specific and global assays in the diagnosis of discrepant hemophilia A.Haematologica. 2013; 98: 1980-7Crossref PubMed Scopus (46) Google Scholar. Although in many with a discrepancy the one‐stage assay is the lower result, cases have been described where the chromogenic assay is the lowest 11.Bowyer A.E. van Veen J.J. Goodeve A.C. Kitchen S. Makris M. Specific and global assays in the diagnosis of discrepant hemophilia A.Haematologica. 2013; 98: 1980-7Crossref PubMed Scopus (46) Google Scholar, 14.Trossaert M. Boisseau P. Quemener A. Sigaud M. Fouassier M. Ternisien C. Lefrancois‐Bettembourg A. Tesson C. Thomas C. Bezieau S. Prevalence, biological phenotype and genotype in moderate/mild hemophilia with discrepancy between one‐stage and chromogenic factor VIII activity.J Thromb Haemost. 2011; 9: 524-30Crossref PubMed Scopus (38) Google Scholar. The bleeding phenotype is not consistently related to the chromogenic or one‐stage assay and if the mutation affects a thrombin cleavage site, the chromogenic assay might display normal values 9.Pavlova A. Delev D. Pezeshkpoor B. Muller J. Oldenburg J. Haemophilia A mutations in patients with non‐severe phenotype associated with a discrepancy between one‐stage and chromogenic FVIII assays.Thromb Haemost. 2014; 111: 851-61Crossref PubMed Scopus (54) Google Scholar, 12.Bowyer A.E. Goodeve A. Liesner R. Mumford A.D. Kitchen S. Makris M. p.Tyr365Cys change in FVIII: haemophilia A, but not as we know it.Br J Haematol. 2011; 154: 618-25Crossref PubMed Scopus (22) Google Scholar, 15.Trossaert M. Regnault V. Sigaud M. Boisseau P. Fressinaud E. Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay to assess the bleeding phenotype.J Thromb Haemost. 2008; 6: 486-93Crossref PubMed Scopus (72) Google Scholar. Chromogenic assays vary in their capacity to detect the discrepancy, with kits that have a longer initial incubation period performing best 16.Rodgers S.E. Duncan E.M. Barbulescu D.M. Quinn D.M. Lloyd J.V. In vitro kinetics of factor VIII activity in patients with mild haemophilia A and a discrepancy between one‐stage and two‐stage factor VIII assay results.Br J Haematol. 2007; 136: 138-45Crossref PubMed Scopus (34) Google Scholar, 17.Rodgers S.E. Duncan E.M. Sobieraj‐Teague M. Lloyd J.V. Evaluation of three automated chromogenic FVIII kits for the diagnosis of mild discrepant haemophilia A.Int J Lab Hematol. 2009; 31: 180-8Crossref PubMed Scopus (24) Google Scholar. Our recommendations for discrepant mild hemophilia are as follows. 1.All patients with mild hemophilia A should have their FVIII:C measured with both the one‐stage and chromogenic assays.2.When reporting a discrepancy, the results should be reported as the ratio of the one‐stage assay over the chromogenic assay.3.Ratios of > 2.0 and < 0.5 indicate a significant discrepancy.4.All tests should be confirmed on a repeat sample. In the presence of an inflammatory condition, the repeat sample should be at the time of resolution of inflammation.5.A normal FVIII:C level with a single assay does not exclude mild hemophilia and where a bleeding disorder is being investigated both the one‐stage and chromogenic FVIII:C assays should be performed during the work‐up.6.A number of chromogenic assays are available on the market and their ability to detect a discrepancy varies. An assay with a longer incubation period is preferable.7.Where the chromogenic assay is not routinely available outside normal working hours, it is often possible to manage discrepant patients with the one‐stage assay provided the relationship between the different assays is known in the individual patient. The treatment of mild hemophilia A should be with desmopressin (DDAVP), irrespective of whether a discrepancy is present 18.Srivastava A. Brewer A.K. Mauser‐Bunschoten E.P. Key N.S. Kitchen S. Llinas A. Ludlam C.A. Mahlangu J.N. Mulder K. Poon M.C. Street A. Guidelines for the management of hemophilia A.Haemophilia. 2013; 19: e1-47Crossref PubMed Scopus (1316) Google Scholar. It must be appreciated that the FVIII released from endothelial stores by desmopressin will be the abnormal molecule and will also show the discrepancy. These stores become depleted when DDAVP is used on consecutive days, leading to a reduced response (tachyphylaxis). Where the response to desmopressin is inadequate, FVIII concentrate should be used. Our recommendations for the treatment of mild hemophilia A are as follows. 1.Treatment should be based on the patient's bleeding history and the clinical situation requiring it.2.DDAVP is the treatment of choice for mild hemophilia A, unless the patient has been shown to be non‐responsive or DDAVP is contraindicated.3.All patients with mild hemophilia A should have a trial of DDAVP. FVIII:C should be measured 1 h and, if possible, 4 h after administration. The FVIII:C should be measured with both the one‐stage and chromogenic assay during this trial.4.Monitoring of response following DDAVP should be with the assay with the lowest FVIII:C baseline level.5.Patients in whom DDAVP is contraindicated are candidates for treatment with a FVIII concentrate. It is well established that severe hemophilia patients have a 20–40% risk of inhibitor development, with most occurring in the first 20 exposure days 19.Peyvandi F. Mannucci P.M. Garagiola I. El‐Beshlawy A. Elalfy M. Ramanan V. Eshghi P. Hanagavadi S. Varadarajan R. Karimi M. Manglani M.V. Ross C. Young G. Seth T. Apte S. Nayak D.M. Santagostino E. Mancuso M.E. Sandoval Gonzalez A.C. Mahlangu J.N. et al.A randomized trial of factor VIII and neutralizing antibodies in hemophilia A.N Engl J Med. 2016; 374: 2054-64Crossref PubMed Scopus (334) Google Scholar. The incidence of inhibitors in mild hemophilia is dependent on the mutation, with some defects leading to an inhibitor rate that exceeds that of severe hemophilia A 20.Eckhardt C.L. van Velzen A.S. Peters M. Astermark J. Brons P.P. Castaman G. Cbossen M.H. Dors N. Escuriola‐Ettinghausen C. Hamulyak K. Hart D.P. Hay C.R. Haya S. van Heerde W.L. Hermans C. Holmstrom M. Jimenez‐Yuste V. Keenan R.D. Klamroth R. Laros‐van Gorkom B.A. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.Blood. 2013; 122: 1954-62Crossref PubMed Scopus (167) Google Scholar. In contrast with severe hemophilia, the inhibitor rate in mild disease does not appear to plateau out after 50 exposure days and therefore patients are at lifelong risk of inhibitor development 20.Eckhardt C.L. van Velzen A.S. Peters M. Astermark J. Brons P.P. Castaman G. Cbossen M.H. Dors N. Escuriola‐Ettinghausen C. Hamulyak K. Hart D.P. Hay C.R. Haya S. van Heerde W.L. Hermans C. Holmstrom M. Jimenez‐Yuste V. Keenan R.D. Klamroth R. Laros‐van Gorkom B.A. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.Blood. 2013; 122: 1954-62Crossref PubMed Scopus (167) Google Scholar, 21.van Velzen A.S. Eckhardt C.L. Streefkerk N. Peters M. Hart D.P. Hamulyak K. Klamroth R. Meijer K. Nijziel M. Schinco P. Yee T.T. van der Bom J.G. Fijnvandraat K. INSIGHT study groupThe incidence and treatment of bleeding episodes in non‐severe haemophilia A patients with inhibitors.Thromb Haemost. 2016; 115: 543-50Crossref PubMed Google Scholar. The inhibitor rate in mild hemophilia may be mitigated by the fact that most mild hemophilic patients can be managed with desmopressin without the need for exogenous FVIII. The inhibitor appearing after FVIII concentrate use can be directed only towards the exogenous FVIII, but in some cases also against the endogenous FVIII, which can change the phenotype of a patient from mild to severe 21.van Velzen A.S. Eckhardt C.L. Streefkerk N. Peters M. Hart D.P. Hamulyak K. Klamroth R. Meijer K. Nijziel M. Schinco P. Yee T.T. van der Bom J.G. Fijnvandraat K. INSIGHT study groupThe incidence and treatment of bleeding episodes in non‐severe haemophilia A patients with inhibitors.Thromb Haemost. 2016; 115: 543-50Crossref PubMed Google Scholar. Inhibitors are extremely rare in female patients with mild hemophilia A in comparison to male patients with the same mutation. Our recommendations for inhibitor detection in mild hemophilia are as follows. 1.All patients with mild hemophilia should have their mutation identified.2.Patients with mutations known to be associated with an increased inhibitor risk should be carefully evaluated for their need for replacement therapy.3.All patients with mild hemophilia A exposed to FVIII concentrate should have an inhibitor test 4–6 weeks later, or earlier if bleeding symptoms occur. Testing of female patients with mild hemophilia is not required.4.A FVIII inhibitor should be excluded before surgery or invasive procedures in mild hemophilia A patients.5.The Nijmegen modified Bethesda assay should be used to detect inhibitors. A heat treatment stage is required in the presence of endogenous FVIII. All the authors developed the initial outline of the manuscript. M. Makris wrote the first draft. All authors critically revised all the drafts and gave their final approval for the published version of the article. E. P. Mauser‐Bunschoten received unrestricted research/educational support from CSL Behring, Bayer, Baxter, Grifols, Novo Nordisk, Pfizer, Biotest and Sanquin. J. Oldenburg reports grants and personal fees from Baxalta (now Shire), Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer and Baxter; and personal fees from Biogen Idec, Chugai, Roche and Swedish Orphan Biovitrium, outside the submitted work. G. Castaman participated in advisory boards or as speaker for CSL Behring, Baxalta/Shire, Bayer, Kedrion, Novo Nordisk, Roche, SOBI and UniQure. G. Castaman also reports unrestricted research grants from Pfizer, CSL Behring and SOBI. K. Fijnvandraat has received unrestricted research grants from CSL Behring and Novo Nordisk as well as consultancy fees from Shire, Novo Nordisk and Bayer. The other authors state that they have no conflict of interests. The members of the ISTH SSC Mild Haemophilia A Working Group were: Mike Makris, Johannes Oldenburg, Evelien Mauser‐Bunschoten, Karin Fijn van Draat, Giancarlo Castaman, Kathelijne Peerlinck, Thomas Sannie, Maria Elisa Mancuso, Simon McRae and Lisa Boggio." @default.
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• W2896798548 title "The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH" @default.
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