Congenital dysfibrinogenemia: fibrinogen detroit

Abstract

A B S T R A C T A 17 yr old female with a congenital bleeding disorder was found to suffer from dysfibrinogenemia. Whole blood and plasma coagulation times were delayed and thrombelastograms were grossly abnormal. Clottability of plasma fibrinogen by addition of thrombin was not demonstrated during the 30 min test period. Fibrinogen was revealed by turbidometric and immunologic techniques. Other coagulation factors were present in normal amounts and prothrombin activation was normal. Patient's plasma inhibited thrombin clotting times of normal plasma and purified normal fibrinogen. Fibrinolysis was not detected.The plasma fibrinogen migrated normally on paper and cellulose acetate electrophoresis, but on immunoelectrophoresis it displayed a faster mobility than normal fibrinogen. On immunodiffusion the antigenic determinants were similar to those of normal fibrinogen. The patient's fibrinogen-antifibrinogen precipitins required longer to appear and the resultant precipitin was broader and hazier than those elicited with normal fibrinogen. These findings suggest the presence of two discrete populations of fibrinogen molecules.Investigation of the family of the patient suggested that the defect has an autosomal dominant pattern of heredity. Immunologic comparisons of our patient's plasma and of her relatives with plasma of patients with "Fibrinogen Baltimore" and "Fibrinogen Cleveland" revealed certain differences in immunoelectrophoretic mobility as well as in immunodiffusion. In keeping with the nomenclatures of abnormal fibrinogens in the literature, we propose the term "Fibrinogen Detroit" for this fibrinogen.Physicochemical properties of "Fibrinogen Detroit" were investigated also and compared with those of nor- In an investigation with Doctors Blomback a specific molecular defect was revealed in the N-terminal disulfide knot of the alpha (A) chain in which the arginine at the 19th position was replaced by serine. It is believed that the substitution of a strongly basic amino acid with a neutral hydroxy acid may result in considerable conformational changes in the N-terminal disulfide knot of fibrinogen which might affect the "active site" for polymerization. The lower carbohydrate content observed in "Fibrinogen Detroit" may have been the result of a change in primary and tertiary structure of the protein.

Fibrinogen Philadelphia. A hereditary hypodysfibrinogenemia characterized by fibrinogen hypercatabolism.

“…Clinical expression of the defect is variable, ranging from no clinical manifestations (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), to bleeding (9,(12)(13)(14)(15)(16)(17)(18)(19)(20) and even thrombotic episodes (14,20,21). Wound dehiscence also has been reported (1,3).…”

Functional evaluation of an inherited abnormal fibrinogen: fibrinogen “Baltimore”

“…Abnormal fibrinogens occurring in successive generations have been recognized in at least seven families (2)(3)(4)(5)(6)(7)(8). Abnormal fibrinogens inherited as dominants have been demonstrated (9,10) in two additional families originally reported as having congenital hypofibrinogenemia (11) and factor XIII deficiency (12).…”

“…Abnormal fibrinogens inherited as dominants have been demonstrated (9,10) in two additional families originally reported as having congenital hypofibrinogenemia (11) and factor XIII deficiency (12). The precise molecular defects of these abnormal fibrinogens remain unknown, although an amino acid substitution (arginine to serine) in the N-terminal portion of the a-(A)-chain (13) and a decreased content of carbohydrate (7) have been reported in one. A comparative study (9) of six of the abnormal fibrinogens (2-4, 6, 7, 11) suggested that at least five (2-4, 6, 7) are distinct.…”

Fibrinogen St. Louis: A New Inherited Fibrinogen Variant, Coincidentally Associated with Hemophilia A

“…Since then, other inherited fibrinogen variants have been described (2)(3)(4)(5)(6)(7)(8)(9), and several previous reports (10,11) of hypofibrinogenemia are now believed to be qualita-tive rather than quantitative abnormalities. The clinical concomitants of these abnormal fibrinogens have varied greatly, ranging from no clinical symptoms to bleeding tendencies.…”