Potentiation of Thrombin Generation in Hemophilia A Plasma by Coagulation Factor VIII and Characterization of Antibody-Specific Inhibition
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{"title"=>"Potentiation of Thrombin Generation in Hemophilia A Plasma by Coagulation Factor VIII and Characterization of Antibody-Specific Inhibition", "type"=>"journal", "authors"=>[{"first_name"=>"Bhavya S.", "last_name"=>"Doshi", "scopus_author_id"=>"55364897200"}, {"first_name"=>"Bagirath", "last_name"=>"Gangadharan", "scopus_author_id"=>"8291717600"}, {"first_name"=>"Christopher B.", "last_name"=>"Doering", "scopus_author_id"=>"7006815580"}, {"first_name"=>"Shannon L.", "last_name"=>"Meeks", "scopus_author_id"=>"15030283600"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "pui"=>"365953226", "issn"=>"19326203", "pmid"=>"23144741", "doi"=>"10.1371/journal.pone.0048172", "sgr"=>"84868113526", "scopus"=>"2-s2.0-84868113526"}, "id"=>"f592f717-d6d8-391f-89f4-0dbb7f982ae0", "abstract"=>"Development of inhibitory antibodies to coagulation factor VIII (fVIII) is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20-30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa). However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs) with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as \"type I\") kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as \"type II\") inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined fVIII/rfVIIa therapy may provide better hemostatic control than current therapy in some patients with anti-fVIII inhibitors.", "link"=>"http://www.mendeley.com/research/potentiation-thrombin-generation-hemophilia-plasma-coagulation-factor-viii-characterization-antibody", "reader_count"=>16, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>1, "Researcher"=>5, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>1, "Researcher"=>5, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>6, "Agricultural and Biological Sciences"=>7, "Social Sciences"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Social Sciences"=>{"Social Sciences"=>1}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/551905"], "description"=>"<p>Thrombin generation curves are shown for fVIII deficient plasma (negative control), fVIII deficient plasma with 1 U/ml of fVIII (positive control) and 1 U/ml of fVIII in the presence of 5 µg/ml of specified group 2 MAb at both the immediate and 1 hr time points (A) Thrombin generation curves comparing fVIII alone, rfVIIa alone, and fVIII and rfVIIa in the presence of MAb at the 1 hr time points (B). Graphs shown are representative of 3 independent experiments.</p>", "links"=>[], "tags"=>["inhibition", "thrombin", "anti-fviii"], "article_id"=>222403, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.g004", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Time_dependent_inhibition_of_thrombin_generation_by_group_2_anti_fVIII_MAbs_/222403", "title"=>"Time dependent inhibition of thrombin generation by group 2 anti-fVIII MAbs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-29 00:40:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/552129"], "description"=>"<p>ETP, peak thrombin and index velocity are presented as ratios compared to fVIII deficient plasma supplemented with 1 U/ml fVIII in the absence of any anti-fVIII MAb.</p><p>ETP – endogenous thrombin potential.</p>", "links"=>[], "tags"=>["parameters", "anti-fviii"], "article_id"=>222628, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.t002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TGA_parameters_for_anti_fVIII_MAbs_/222628", "title"=>"TGA parameters for anti-fVIII MAbs.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-10-29 00:43:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/552161"], "description"=>"<p>Characteristics of anti-fVIII MAbs.</p>", "links"=>[], "tags"=>["anti-fviii"], "article_id"=>222661, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.t001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characteristics_of_anti_fVIII_MAbs_/222661", "title"=>"Characteristics of anti-fVIII MAbs.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-10-29 00:44:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/551690"], "description"=>"<p>The relative epitopes of anti-fVIII MAbs are shown. MAbs 4A4, 2–54, 1D4 and 2–93 target non-overlapping epitopes in the A2 domain. MAbs G38 and 2–113 target non-overlapping epitopes in the A3 domain at residues 1690–1817 and 1818–1916, respectively. MAbs I109 and 2–77 target non-overlapping epitopes in the C2 domain. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048172#pone.0048172-Meeks1\" target=\"_blank\">[13]</a>.</p>", "links"=>[], "tags"=>["non-overlapping"], "article_id"=>222184, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.g001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Epitope_map_of_non_overlapping_MAbs_/222184", "title"=>"Epitope map of non-overlapping MAbs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-29 00:36:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/551758"], "description"=>"<p>Varying concentrations of fVIII were mixed 1∶1 with rfVIIa at a final concentration of 2.25 µg/ml to determine the level of fVIII activity necessary for restoration of thrombin generation of rfVIIa to fVIII at 1 U/ml. The resulting data was transformed using manufacturer’s software to yield thrombin generation curves (A), peak thrombin concentration (B) and index velocity (C). Error bars represent sample standard deviation.</p>", "links"=>[], "tags"=>["fviii", "thrombin"], "article_id"=>222253, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Amount_of_fVIII_needed_to_restore_thrombin_generation_of_rfVIIa_/222253", "title"=>"Amount of fVIII needed to restore thrombin generation of rfVIIa.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-29 00:37:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/551982"], "description"=>"<p>Thrombin generation curves are shown comparing fVIII alone, rfVIIa alone, and fVIII and rfVIIa in the presence of MAb at the 1 hr time points. Graphs shown are representative of 3 independent experiments.</p>", "links"=>[], "tags"=>["anti-fviii"], "article_id"=>222481, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.g005", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Thrombin_generation_in_the_presence_of_group_2_anti_fVIII_MAbs_/222481", "title"=>"Thrombin generation in the presence of group 2 anti-fVIII MAbs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-29 00:41:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/295467", "https://ndownloader.figshare.com/files/295534"], "description"=>"<div><p>Development of inhibitory antibodies to coagulation factor VIII (fVIII) is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20–30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa). However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs) with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as “type I”) kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as “type II”) inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined fVIII/rfVIIa therapy may provide better hemostatic control than current therapy in some patients with anti-fVIII inhibitors.</p> </div>", "links"=>[], "tags"=>["potentiation", "thrombin", "hemophilia", "plasma", "coagulation", "viii", "characterization", "antibody-specific", "inhibition"], "article_id"=>118194, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0048172.s001", "https://dx.doi.org/10.1371/journal.pone.0048172.s002"], "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Potentiation_of_Thrombin_Generation_in_Hemophilia_A_Plasma_by_Coagulation_Factor_VIII_and_Characterization_of_Antibody_Specific_Inhibition__/118194", "title"=>"Potentiation of Thrombin Generation in Hemophilia A Plasma by Coagulation Factor VIII and Characterization of Antibody-Specific Inhibition", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-10-29 02:16:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/552057"], "description"=>"<p>The inhibitor titer for each MAb was compared with the peak thrombin generation of fVIII alone or fVIII + rfVIIa at the immediate (solid circles, r<sup>2</sup> = 0.36) or 1 hr (open circles, r<sup>2</sup> = 0.09) time points (A.) and with residual fVIII activity at the immediate (solid circles, r<sup>2</sup> = 0.004) or 1 hr (r<sup>2</sup> = 0.07) time points (B.).</p>", "links"=>[], "tags"=>["inhibitory", "titer", "residual", "fviii", "thrombin"], "article_id"=>222548, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.g006", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Influence_of_inhibitory_titer_on_residual_fVIII_activity_and_peak_thrombin_generation_/222548", "title"=>"Influence of inhibitory titer on residual fVIII activity and peak thrombin generation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-29 00:42:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/551834"], "description"=>"<p>Thrombin generation curves are shown for fVIII deficient plasma (negative control), fVIII deficient plasma with 1 U/ml of fVIII (positive control) and 1 U/ml of fVIII in the presence of 5 µg/ml of specified group 1 MAb. Data represent mean ± sample standard deviation for 3 experiments where duplicates of each measurement were taken and averaged.</p>", "links"=>[], "tags"=>["thrombin", "anti-fviii"], "article_id"=>222327, "categories"=>["Pharmacology", "Biotechnology", "Biochemistry", "Hematology", "Immunology"], "users"=>["Bhavya S. Doshi", "Bagirath Gangadharan", "Christopher B. Doering", "Shannon L. Meeks"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0048172.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_thrombin_generation_by_group_1_anti_fVIII_MAbs_/222327", "title"=>"Inhibition of thrombin generation by group 1 anti-fVIII MAbs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-29 00:38:47"}

PMC Usage Stats | Further Information

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Relative Metric

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