Novel Aα chain truncation (fibrinogen Perth) resulting in low expression and impaired fibrinogen polymerization

Summary.  A young woman with a history of menorrhagia and easy bruising presented with a functional fibrinogen concentration of 1.8 mg mL⁻¹, a gravimetric concentration of 3.3 mg mL⁻¹ and a prolonged thrombin clotting time of 32 s. Both reverse phase analysis and reducing SDS–PAGE revealed a normal profile of Aα, Bβ, and γ chains. However, non-reducing gels revealed a broadened 340-kDa band, while the 305-kDa band was normal, suggesting a C-terminal truncation of the Aα chain. DNA sequencing of all exons and intron boundaries revealed a single heterozygous cytosine deletion at nucleotide 4841 of the Aα gene predicting a frameshift and the incorporation of 23 new residues (LMKLPSSTLPQLEKHSQVSSHLC) before termination after residue 517. In agreement with a predicted mass decrease of 9953 Da, the measured mass of the Aα^Perth chain was 56 242 Da, while that of the normal Aα^A chain was 66 189 Da. Tryptic mapping of isolated Aα chains revealed a new [M + 2H] ion at 607 m z⁻¹, corresponding to the predicted penultimate peptide LPSSTLPQLEK. The variant chain was poorly incorporated into plasma fibrinogen at a ratio of Aα^Perth/Aα^A of 0.15 : 1, suggesting the Aα^Perth chain might be out-competed by normal chains during molecular assembly in the hepatocyte. Despite the low expression, polymerization curves showed a decreased V_max and final turbidity, suggesting the fibrinogen Perth clots are composed of thinner fibers. However, the fibrinolytic rate was very similar to that of the control.