Association of inherited dysfibrinogenaemia and protein C deficiency in two unrelated families

Abstract

An inherited association of dysfibrinogenaemia and protein C deficiency was found in three members of the same family. The propositus was a 48-year-old man who suffered from severe and rapidly complicated atherosclerosis of the aorta and lower limbs arteries, which perhaps suggests that the association of these two molecular abnormalities may have enhanced the thrombotic process. The abnormal fibrinogen had a reduced ability to bind thrombin which may be thrombogenic. We found the same inherited association of dysfibrinogenaemia and protein C deficiency in a patient with venous thrombosis. The functional abnormality of the fibrinogen, which could have been responsible for thrombosis, was delayed proteolysis by plasmin. Not only fibrinogen, but also fibrin clots were resistant to plasmic degradation. These observations raise two questions: (1) Is the association of a protein C deficiency with a dysfibrinogenaemia fortuitous or the result of a common mechanism? (2) Is there a link between an increased thrombotic tendency and either both of the defects of haemostasis that we have found, or only one of them?

An Unknown Genetic Defect Increases Venous Thrombosis Risk, through Interaction with Protein C Deficiency

“…Table 4 Penetrance of Verified Thrombosis, by Genotype, Sex, and Age at First Thrombotic Episode There are many candidates for the inferred interacting gene. Factor V Leiden (Koeleman et al 1994;Gandrille et al 1995;Brenner et al 1996) and dysfibrinogenemia (Gandrille et al 1988) reportedly increase venous thrombotic risk, through interaction with protein C deficiency. However, we ruled out factor V Leiden , through mutation screening, and failed to find dysfunctional fibrinogen during functional analysis.…”

“…Since its identification, factor V Leiden has been found to be common among individuals whose venous thromboembolic disease previously had been attributed solely to deficiencies of protein C (Koeleman et al 1994;Gandrille et al 1995;Brenner et al 1996), protein S (Koeleman et al 1995;Zö ller et al 1995a), or antithrombin (van Boven et al 1996). Other pairs of genetic defects also have been reported for thrombosis patients (Gandrille et al 1988;Berruyer et al 1994;Zö ller et al 1995b;Beauchamp et al 1996;Zü ger et al 1996). In this study, we used two-locus segregation analysis to test for evidence of a genetic defect that interacts with protein C deficiency to increase the risk of venous thromboembolic disease in a single large pedigree with 283 studied members.…”

Fibrinogen Caracas V, an Abnormal Fibrinogen with an Aα 532 Ser→Cys Substitution Associated with Thrombosis

“…Several cases of dysfibrinogenemia with altered thrombin binding to abnormal fibrin have been reported: fibrinogen New York I (B␤ 9-72 deletion) (6,7), fibrinogen Naples (B␤ 68 AlaǞThr) (8), fibrinogen Malmö (9), fibrinogen Poitiers (10) and fibrinogen Pamplona II (11). A decreased capacity of fibrin to stimulate plasminogen activation by t-PA has been reported in fibrinogen Paris V (Dusart) (A␣ 554 ArgǞCys) (12,13), fibrinogen New York I (6,7), fibrinogen Nijmegen (B␤ 44 ArgǞCys) (14), fibrinogen Date (15), fibrinogen Argenteuil (10), and fibrinogen Pamplona II (11) (substitutions unknown). In fibrinogen Nijmegen the t-PA binding to fibrin is decreased while in Paris V there is a decreased plasminogen binding to fibrin (16).…”

Dysfibrinogenemia: A case with thrombosis (fibrinogen richfield) and an overview of the clinical and laboratory spectrum

“…One patient with both bleeding and thrombosis had abnormal FPA release, abnormal polymerization, and resistance to fibrinolysis [12]. Six thrombotic patients included: two with dysfibrinogen and Protein C deficiency [13]; one with both abnormal polymerization and FPA release [14]; one with a shortened clotting time [15]; one with delayed FPA and absent FPB release and shortened Reptilase time [16]; and one with liver disease, increased FDP, altered electrophoretic mobility, and slightly reduced FPA release [17].…”