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Fibrinogen naples I (B beta A68T) nonsubstrate thrombin-binding capacities
D A Meh1, M W Mosesson, K R Siebenlist
1Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI 53201-2178, USA.
Thrombosis Research
|July 4, 2001
Summary
Fibrinogen Naples I mutation impairs thrombin binding and fibrin assembly. Homozygotes show absent low-affinity binding and reduced high-affinity binding, unlike heterozygotes, impacting clot formation.
Area of Science:
- Hematology
- Molecular Biology
- Biochemistry
Background:
- Fibrinogen Naples I (Bbeta A68T) is a genetic variant associated with thrombophilia.
- This mutation affects thrombin binding and fibrinopeptide cleavage in the fibrinogen E domain.
Purpose of the Study:
- To investigate the impact of Fibrinogen Naples I on thrombin binding affinities.
- To evaluate the fibrin network assembly in individuals with Fibrinogen Naples I.
Main Methods:
- Scatchard analysis of 125I-thrombin binding to fibrin from affected and unaffected individuals.
- Electron microscopy to assess fibrin network structure.
- Genomic sequencing, ELISA, and mass spectrometry to analyze gamma' chain structure.
Main Results:
- Homozygotes for Fibrinogen Naples I exhibited virtually absent low-affinity thrombin binding and impaired high-affinity binding.
- Heterozygotes showed moderately reduced low-affinity binding and near-normal high-affinity binding.
- Fibrin networks in homozygotes displayed wider fiber bundles, suggesting slowed fibrin assembly.
Conclusions:
- The Bbeta A68T mutation significantly disrupts thrombin binding to fibrin.
- Impaired thrombin binding, particularly the absence of low-affinity sites, may contribute to thrombophilic phenotypes in Fibrinogen Naples I homozygotes.
- Gamma' chain structure remains normal in Fibrinogen Naples I, indicating the defect is primarily in thrombin interaction.