Familial Dysfibrinogenemia and Thrombophilia

Abstract

SummaryApproximately 250 cases of dysfibrinogenemia have been reported; 55% were asymptomatic (detected by chance), 25% had a tendency to bleeding, and 20% were reported to have a tendency to thrombosis.To establish a possible association between familial dysfibrinogenemia and thrombophilia, data on cases with both affections were collected in a study within the framework of the SSC Subcommittee on Fibrinogen of the International Society on Thrombosis and Haemostasis. Registry forms of 51 cases were received. Twenty-six cases fulfilled the (arbitrarily chosen) criteria of familial dysfibrinogenemia and of thrombosis not due to other causes. Protein C and protein S deficiency and APC resistance as a cause of thrombosis could not be excluded in probands on anticoagulants or investigated before the discovery of the assays.The prevalence of dysfibrinogenemia in patients with a history of venous thrombosis is low, i.e. 0.8%, as deduced from 9 studies in 7 countries on 2376 patients. The 26 cases fulfilling the criteria are characterized by predominantly venous thrombosis at a young age. Severe bleeding was rare and limited to bleeding post partum. Homozygosity was established in 2 cases (Marburg and Naples), hypodysfibrinogenemia (less than 1.5 mg antigen per ml) in 5 cases. A high incidence of problems related to pregnancy, in particular thrombosis post partum and spontaneous abortions was noted amongst the 15 women with thrombophilic dysfibrinogenAn association between dysfibrinogenemia and thrombophilia is indicated by studies on relatives of the 26 probands. Analysis of 187 investigated family members showed that thrombophilia affected 20 persons exclusively in the group of 99 relatives with dysfibrinogenemia, no thrombosis was reported in the group of 88 relatives without the defect. Convincing evidence for such an association became apparent for only 5 individual propositi of whom 2 or more family members had both the defect and thrombotic episodes at a young age (Caracas V, Frankfurt IV/Vlissingen, Melun, Naples and Paris V, also named Dusart).Mainly two mechanisms to explain thrombosis as a consequence of malfunctioning fibrinogen have been suggested: a) A defective binding of thrombin to abnormal fibrin which leads to increased thrombin levels (Malmö, Naples, New York I, Pamplona II, Poitiers), b) A defective stimulatory function of abnormal fibrin in the t-PA mediated fibrinolysis (Argenteuil, Chapel Hill III, Date, New York I, Nijmegen, Pamplona II, Paris V).Defects at the molecular level, elucidated in 15 out of the 26 cases fulfilling the criteria, were localised in the C-terminal part of the γ-chain (3 cases), in the N-terminal part of the Bβ-chain (3 cases) and in the Aα-chain (4 cases) of fibrinogen. Why a particular molecular defect leads to malfunction of fibrin(ogen) is still unknown.

Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γ Ala327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism

“…Thrombophilic dysfibrinogen is a rare molecular abnormality and mechanisms for thrombophilia may be assigned to defective binding of thrombin to abnormal fibrin, which leads to increased thrombin levels, or to defective stimulatory function of abnormal fibrin in tPA-mediated fibrinolysis. 5 Data from SDS-PAGE analyses of purified fibrinogen followed by Western blotting using ␥ chain-specific monoclonal antibody JIF 25, peptide mapping analysis of patient fibrinogen ␥ chain, and plasmin degradation of the fibrinogen D1 fragment in the presence of calcium suggested that the molecular abnormality of fibrinogen Tokyo V was impaired function and hypofibrinogenemia, even though the patient was heterozygous for the mutation. Although the molecular mechanism for decreased plasma levels of the Tokyo V fibrinogen molecule is not studied yet, a decreased assembly, an intracellular transport defect, or hypercatabolism in the circulation of the abnormal molecules may be responsible for hypodysfibrinogenemia.…”

“…Thrombophilic dysfibrinogen is a rare molecular abnormality. 5 Here we report a new thrombophilic dysfibrinogen with an amino acid substitution of ␥ Ala327Thr, inserting a possible extra N-glycosylation site at ␥ Asn325. The defective fibrinogen results in formation of fragile but fibrinolysis-resistant clots caused by conformation defects in the vicinity of the "a" polymerization pocket, the high-affinity calcium ion binding site, and the tissue plasminogen activator (tPA) binding site of the ␥ chain.…”

“…During synthesis in the liver, these chains are translated, processed, and assembled to the mature molecules. 3 Many reports have shown that a variety of genetic mutations result in molecular defects in fibrinogen molecules (dysfibrinogen) 4,5 or decreased levels of fibrinogen in blood (afibrinogenemia and hypofibrinogenemia). 6 Analyses of molecular and functional abnormalities of dysfibrinogens participate in elucidation of structure-function relationships and fibrin polymerization mechanisms.…”

On the Identification of Beneficial and Detrimental Molecular Forms of Fibrinogen

“…the one of arginine to histidine and to cysteine at the thrombin cleavage site of the A· chain (position A· 16), are present in 26 and 18 families, respectively. Dysfibrinogenemia is in many cases correlated with a tendency to hemorrhagic or thrombotic disorders, as exemplified in table 5 [19,20].…”

Fibrin clot structure in patients with congenital dysfibrinogenaemia

“…During the natural course of the disease, even asymptomatic patients at the time of the diagnosis are at risk of developing adverse outcomes [5]. However, neither standard haemostasis assays nor specific genotypes, with exception of some thrombotic-related mutations [6], are able to predict the clinical phenotype. Recently, abnormal fibrin structure has been correlated with several thrombotic and cardiovascular diseases [7,8].…”