Homophenotypic aα R16H Fibrinogen (Kingsport): Uniquely Altered Polymerization Associated With Slower Fibrinopeptide A Than Fibrinopeptide B Release
Document Type
Article
Publication Date
12-1-2007
Description
We detail for the first time the uniquely altered fibrin polymerization of homophenotypic Aα R16H dysfibrinogen. By polymerase chain reaction amplification and DNA sequencing, our new proposita's genotype consisted of a G>A transition encoding for Aα R16H, and an 11 kb Aα 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 μmol/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 (μ = 0.30) or of monoclonal antiβ(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.
Citation Information
Galanakis, Dennis K.; Neerman-Arbez, Marguerite; Scheiner, Tomas; Henschen, Agnes; Hubbs, Doris; Nagaswami, Chandrasekaran; and Weisel, John W.. 2007. Homophenotypic aα R16H Fibrinogen (Kingsport): Uniquely Altered Polymerization Associated With Slower Fibrinopeptide A Than Fibrinopeptide B Release. Blood Coagulation and Fibrinolysis. Vol.18(8). 731-737. https://doi.org/10.1097/MBC.0b013e3282f10157 PMID: 17982313 ISSN: 0957-5235