Abstract Number: OC 76.5
Meeting: ISTH 2022 Congress
Background: The fibrinogen αC-region is comprised of an αC-domain and connector, and contains binding sites for FXIIIa, α2-antiplasmin and plasminogen. Heterozygous dysfibrinogenaemia due to mutation within the αC-region may increase bleeding risk. The effects of mixtures between WT and truncation variants in a plasma environment are unknown.
Aims: To investigate the impact of αC-region truncations on fibrinolysis of clots made with mixed WT and truncated αC-region fibrinogens.
Methods: Fibrinolysis of recombinant WT, α390 and α220 fibrinogens produced in CHO-cells was studied by turbidimetric assay with and without α2-antiplasmin, and analysis of D-dimer elution from plasma-fibrinogen deficient clots. Clot structure of WT fibrinogen spiked with increasing percentages of truncated fibrinogens was analysed by laser-scanning-confocal-microscopy.
Results: In the presence of FXIIIa and α2-antiplasmin, resistance to fibrinolysis was increased for WT and α390, but not for α220 clots, which lack the α2-antiplasmin binding site. Clot porosity was reduced for α390 (2.75×10-8±2.97-9Ks) compared to WT clots (3.65×10-8±2.54-9Ks; p=0.0167). Permeation experiments in the presence of plasminogen and tPA showed reduced time to clot collapse in α390 compared to WT (89±6 and 106±4mins; p=0.0204). Due to the weak nature of α220 no data could be determined by permeation. WT clots with increasing percentages of α390 and α220 showed increasingly abnormal clot structure. Clots spiked with α390 fibrin became denser with shorter fibres and α220 spiked clots became more porous with short, stunted fibres.
Conclusion(s): Increased resistance to fibrinolysis was observed with the addition of α2-antiplasmin for both WT and α390 but not α220 fibrin. Reduced porosity did not provide resistance to fibrinolysis for fibrinogen lacking the αC-region. Inclusion of truncated fibrinogen altered clot structure in a dose-dependent manner and could result in clot destabilisation in vivo. These data show important mechanisms by which the risk of bleeding may be increased in patients with heterozygous dysfibrinogenaemia.
To cite this abstract in AMA style:mcPherson H, Duval C, Feller T, Ajjan R, Ariëns R. Clot Destabilisation by the Inclusion of Fibrin with Truncations in the αC-region [abstract]. https://abstracts.isth.org/abstract/clot-destabilisation-by-the-inclusion-of-fibrin-with-truncations-in-the-%ce%b1c-region/. Accessed September 26, 2022.
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