Fibrinogen date: Congenital hypodysfibrinogenemia associated with decreased binding of tissue‐plasminogen activator

Ieko, Masahiro; Sawada, Kenichi; Sakurama, Shoki; Yamagishi, Ikuko; Isogawa, Shin; Nakagawa, Shoichi; Satoh, Masahiro; Yasukouchi, T; Matsuda, Michio

doi:10.1002/ajh.2830370403

Cited by 12 publications

(4 citation statements)

References 15 publications

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“…Resistance against lysis of fibrin by plasmin was reported for Argenteuil (16), Chapel Hill III (36), and Pamplona II (56). A defective role of fibrin in stimulating the activation of plasminogen by tissue plasminogen activator (t-PA) was more specifi cally explained by a defective binding of t-PA to fibrin Date (19), New York I (55) and Nijmegen (23), or by a defective binding of plasminogen [Paris V (58)]. Molecular defects elucidated so far reveal that abnormal t-PA binding is associated with defects at the N-terminal site of the fibrin P-chain, i.e.…”

Section: Discussionmentioning

confidence: 99%

Familial Dysfibrinogenemia and Thrombophilia

Haverkate¹,

Samama

1995

Thromb Haemost

305

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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.

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Section: Discussionmentioning

confidence: 99%

Familial Dysfibrinogenemia and Thrombophilia

Haverkate¹,

Samama

1995

Thromb Haemost

305

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Marchi¹,

Lundberg²,

Grimbergen³

et al. 2000

Thromb Haemost

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SummaryA new dysfibrinogenemia associated with thrombophilia has been identified in a Venezuelan kindred. Thrombin and Reptilase times were prolonged and the accelerating capacity of the patient’s fibrin on the t-PA-induced plasminogen activation was decreased. In addition the affinity of fibrinogen for plasminogen was diminished. Permeability and electron microscopy studies revealed that the abnormal clot was made up of thin and densely packed fibres giving rise to a reduced fibrin gel porosity. This was confirmed by turbidity studies showing a decreased fibre mass/length ratio. Affected members were heterozygous for an Aα 532 Ser→ Cys mutation as demonstrated by genetic analyses. This abnormal fibrinogen has been designated as Fibrinogen Caracas V. The family study showed a convincing association between the mutation and thrombotic manifestations. The thrombotic tendency may be ascribed to lack of accelerating capacity of fibrin to induce fibrinolysis caused by an abnormal clot structure with thin fibres and reduced porosity.

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“…Independently of accuracy problems, these two tests are easy to perform in every laboratory and we think CFg/IFg ratio may give important informa tion for screening purposes in selected pa tients. To give a crude anticipation of a possi ble screening for dysfibrinogenemia based on CFg/IFg ratio, we examined some reports of dysfibrinogenemia in the literature in which data on Fibrinogen determined by the two methods employed in this paper were re ported [15][16][17][18][19][20][21] and we evaluated CFg/IFg ra-tio. Values of CFg/IFg ratio ranging from 0.33 to 0.59 were calculated.…”

Section: Discussionmentioning

confidence: 99%

Clottable to Immunological Fibrinogen Ratio in Plasma from Control Subjects and Hyperfibrinogenemic Patients

Prisco

Zarone²,

Liotta³

et al. 1995

Pathophysiol Haemos Thromb

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The measurement of fibrinogen (Fg) plasma levels is one of the more frequently performed tests in clinical practice, usually by clotting assay. However, for the diagnosis of dysfibrinogenemia the use of an immunological assay is necessary to compare total and clottable protein. Little information is available on the range of the ratio clottable (C) Fg/immunological (I) Fg levels in normal population. This study aimed at evaluating the CFg/IFg ratio in 70 control subjects (age range 17-74 years – group A), in 57 acute patients (age range 17-79 years – group B) and in 14 pregnant women (age range 27-41 years, pregnancy weeks 30-40 – group C), as a physiologic model of hyperfibrinogenemia. CFg was assayed on citrated plasma by the Clauss clotting method and IFg was assayed by radial immunodiffusion technique. In the three groups, CFg/IFg ratios were not significantly different (respectively group A 0.98 ± 0.17, group B 1.02 ± 0.18 and group C 1.01 ± 0.11), whereas both CFg (310 ± 45 mg/dl) and IFg (326 ± 70mg/dl) levels were lower (p < 0.001) in control subjects than in patients (CFg 556 ± 92 mg/dl; IFg 561 ± 121 mg/dl) and in pregnant women (CFg 530 ± 65 mg/dl; IFg 530 ± 77 mg/dl). The analysis of the relationship between CFg and IFg in the three groups (group A: y = 11.53 + 1.01x, r = 0.64, p < 0.001; group B: y = 68.72 + 0.88x, r = 0.67, p < 0.001; group C: y = 71.59 + 0.87x, r = 0.73, p < 0.01) indicates that a good correlation exists (p < 0.001) for values of fibrinogenemia ranging from 180 to over 700 mg/dl. A reference range of CFg/IFg (mean ± 2 SD in group A) was 0.64-1.32. These data could be of practical importance for a rapid screening of dysfibrinogenemias.

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Fibrinogen date: Congenital hypodysfibrinogenemia associated with decreased binding of tissue‐plasminogen activator

Cited by 12 publications

References 15 publications

Familial Dysfibrinogenemia and Thrombophilia

Familial Dysfibrinogenemia and Thrombophilia

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

Clottable to Immunological Fibrinogen Ratio in Plasma from Control Subjects and Hyperfibrinogenemic Patients

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