A. Pashov | Bulgarian Academy of Sciences (original) (raw)

Papers by A. Pashov

Research paper thumbnail of Restricted BV gene usage by Factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A

Thrombosis and Haemostasis, 2003

Hemophilia A is an X-linked recessive bleeding disorder characterized by a deficiency in the acti... more Hemophilia A is an X-linked recessive bleeding disorder characterized by a deficiency in the activity of coagulation factor VIII (FVIII). Hemophilia is referred to as severe or mild depending on residual FVIII activity in circulation (1). 20% to 50% of patients with hemophilia A develop anti-FVIII alloantibodies upon FVIII replacement therapy (2). FVIII inhibitors are characterized by their ability to neutralize the pro-coagulant activity of FVIII and preclude the further therapeutic use of homologous FVIII. The occurrence of FVIII inhibitors is associated with large deletions in the FVIII gene, gene inversions and stop mutations (3). Several mechanisms have been proposed for the inactivation of FVIII by FVIII inhibitors, including the blockade of the interaction of FVIII with thrombin, factor IX, von Willebrand factor or phospholipids by steric hindrance and the hydrolysis of FVIII by proteolytic antibodies (4, 5).

Research paper thumbnail of Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome--Disease-Relevant or Benign?

Journal of the American Society of Nephrology, 2014

Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with ov... more Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association. J Am Soc Nephrol 25: ccc-ccc, 2014 ISSN : 1046-6673/2509-ccc RR, homozygous for arginine (R); RW, heterozygous for arginine and tryptophan; NA, not available; FI, Factor I; MCP, membrane cofactor protein; TM, thrombomodulin; RQ, heterozygous for arginine and glutamine.

Research paper thumbnail of Restricted BV gene usage by Factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A

Thrombosis and Haemostasis, 2003

Hemophilia A is an X-linked recessive bleeding disorder characterized by a deficiency in the acti... more Hemophilia A is an X-linked recessive bleeding disorder characterized by a deficiency in the activity of coagulation factor VIII (FVIII). Hemophilia is referred to as severe or mild depending on residual FVIII activity in circulation (1). 20% to 50% of patients with hemophilia A develop anti-FVIII alloantibodies upon FVIII replacement therapy (2). FVIII inhibitors are characterized by their ability to neutralize the pro-coagulant activity of FVIII and preclude the further therapeutic use of homologous FVIII. The occurrence of FVIII inhibitors is associated with large deletions in the FVIII gene, gene inversions and stop mutations (3). Several mechanisms have been proposed for the inactivation of FVIII by FVIII inhibitors, including the blockade of the interaction of FVIII with thrombin, factor IX, von Willebrand factor or phospholipids by steric hindrance and the hydrolysis of FVIII by proteolytic antibodies (4, 5).

Research paper thumbnail of Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome--Disease-Relevant or Benign?

Journal of the American Society of Nephrology, 2014

Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with ov... more Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association. J Am Soc Nephrol 25: ccc-ccc, 2014 ISSN : 1046-6673/2509-ccc RR, homozygous for arginine (R); RW, heterozygous for arginine and tryptophan; NA, not available; FI, Factor I; MCP, membrane cofactor protein; TM, thrombomodulin; RQ, heterozygous for arginine and glutamine.