title: Homophenotypic Aalpha R16H fibrinogen (Kingsport): uniquely altered polymerization associated with slower fibrinopeptide A than fibrinopeptide B release.
abstract: We detail for the first time the uniquely altered fibrin polymerization of homophenotypic Aalpha R16H dysfibrinogen. By polymerase chain reaction amplification and DNA sequencing, our new proposita's genotype consisted of a G>A transition encoding for Aalpha R16H, and an 11 kb Aalpha gene deletion. High-performance liquid chromatography disclosed fibrinopeptide A release approximately six times slower than its fibrinopeptide B. Turbidimetric analyses revealed unimpaired fibrin repolymerization, and abnormal thrombin-induced polymerization (1-7 mumol/l fibrinogen, > 96% coagulable), consisting of a prolonged lag time, slow rate, and abnormal clot turbidity maxima, all varying with thrombin concentration. For example, at 0.2-3 U/ml, the resulting turbidity maxima ranged from lower to higher than normal control values. By scanning electron microscopy, clots formed by 0.3 and 3 thrombin U/ml displayed mean fibril diameters 42 and 254% of the respective control values (n = 400). Virtually no such differences from control values were demonstrable, however, when clots formed in the presence of high ionic strength (micro = 0.30) or of monoclonal antibeta(15-42)IgG. The latter also prolonged the thrombin clotting time approximately three-fold. Additionally, thrombin-induced clots displayed decreased elastic moduli, with G' values of clots induced by 0.3, 0.7 and 3 thrombin U/ml corresponding to 11, 34, and 45% of control values. The results are consistent with increased des-BB fibrin monomer generation preceding and during polymerization. This limited the inherent gelation delay, decreased the clot stiffness, and enabled a progressively coarser, rather than finer, network induced by increasing thrombin concentrations. We hypothesize that during normal polymerization these constitutive des-BB fibrin monomer properties attenuate their des-AA fibrin counterparts.
authors.affiliation: Blood Bank, L5, University Hospital, HSC, SUNY, Stony Brook, New York 11794-7530, USA. dennis.galanakis@stonybrook.edu
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Galanakis
authors.forename: Marguerite
authors.initials: M
authors.lastname: Neerman-Arbez
authors.forename: Tomas
authors.initials: T
authors.lastname: Scheiner
authors.forename: Agnes
authors.initials: A
authors.lastname: Henschen
authors.forename: Doris
authors.initials: D
authors.lastname: Hubbs
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Nagaswami
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
mesh_terms: D000328:Adult; D005260:Female; D005337:Fibrin / Q000502:physiology; D005340:Fibrinogen / Q000235:genetics* / Q000502:physiology; D015241:Fibrinogens, Abnormal / Q000235:genetics / Q000502:physiology; D005344:Fibrinopeptide A / Q000737:chemistry / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010641:Phenotype; D011108:Polymers; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D015241:Fibrinogens, Abnormal; D011108:Polymers; C464794:fibrinogen Aalpha; D005344:Fibrinopeptide A; D005337:Fibrin; D005340:Fibrinogen