Structural locations of fibrinogen variants in patients with CTEPH. The positions of the alterations expected from the various mutations are illustrated on a ribbon model of chicken fibrinogen.²¹  In fibrinogen_{San Diego I}, the oligosaccharides attached to Bβ Asn-364 and γ Asn-52 are excessively disialylated, which imparts negative charges to the regions, thereby promoting the formation of “thin” fibrin fibers.^22,23  A similar situation exists for fibrinogen_{San Diego V} (Aα R554H), in which the arginine→histidine substitution would also reduce the net charge in that region (not shown because it occurs in a region too flexible for crystallographic resolution). In fibrinogen_{San Diego II} (γ Y114H) and fibrinogen_{San Diego IV} (Aα L69H) the substitutions result in the insertion of a polar imidazole side chain within the “helix-permissive” hydrophobic center of the coiled coil,²⁴  which could disrupt the molecular structure. In fibrinogens_{San Diego I-III}, the Bβ P235L substitution occurs at an articulation site in the βC region that ordinarily allows exposure of a t-PA binding site within the coiled coil. Substitution of leucine for the conformationally rigid proline in this area could affect the flexibility between the βC region and the coiled coil,¹⁴  which normally allows exposure of a region (circa Aα-157) that has been implicated in the activation of t-PA by fibrin.²⁵