Fibrinogen ‘Haifa’ – A New Fibrinogen Variant

Brook, J.G.; Tabori, S; Tatarsky, Ilana; Hashmonai, M; Schramek, A

doi:10.1159/000214763

Cited by 4 publications

(3 citation statements)

References 4 publications

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“…Similarly, FPB release evidently exposes a central ,.B" polymenzation site (23,24), efficient utllization of which by the complementary ..b') site may depend on proper alignment of two outer D domains in an o, Pfibrin polyme r (26). Our present studies confirm previous observations (1,2,4) indicating that the TztsAtg--+His substitution results in marked impairment of fibrin polymenzation, although FPA and FPB release, per se, is unimpaired.…”

Section: Discussionsupporting

confidence: 85%

The Polymerization of Fibrin Prepared from Fibrinogen Haifa (γ275Arg→His)

et al. 1989

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SummaryFibrinogen Haifa is a congenital heterozygous fibinogen variant (γ275 Arg→His) characterized by prolonged thrombin and reptilase times and normal fibrinopeptide (FPA, FPB) release. We compared the polymerization rate (by turbidity measurements at 350 nm) and the ultrastructure of Haifa α-, β-, and α, β-fibrin with that of normal. Haifa α, β-fibrin polymerized less rapidly than did normal and formed a highly branched matrix with a smaller mean fiber diameter; this network closely resembled that of normal α, β-fibrin with EDTA added. In the presence of CaCl2 (1 to 10 mM), Haifa α, β-fibrin polymerized more rapidly than in buffer alone and possessed a matrix structure closely resembling that of normal fibrin. From these observations it appears that the functional defect in Haifa fibrin can be related to the inability of the abnormal molecule to effectively utilize available calcium. The polymerization profile of Haifa α-fibrin differed only modestly from that of normal α-fibrin, whereas that of Haifa β-fibrin was markedly impaired. This finding plus similarities in the ultrastructure of Haifa and normal α-fibrin specimens suggests that the defective γ chain structure of Haifa fibrinogen results in greater impairment of the carboxy terminal “b” polymerization domain reacting with the site exposed by cleavage of FPB (“B” site) than it does that of the carboxy terminal “a” domain reacting with the site exposed by cleavage of FPA (“A” site). Whether this effect is due to absolute differences in the degree of impairment of these two types of polymerization sites, or whether proper utilization of the “B” to “b” site is dependent upon participation of the “A” to “a” site remains to be determined.

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Section: Discussionsupporting

confidence: 85%

The Polymerization of Fibrin Prepared from Fibrinogen Haifa (γ275Arg→His)

et al. 1989

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“…Of the numerous dysfibrinogenemic families that are characterized by an amino acid substitution at posi tion 275R of the normal γ chain, either R to C, R to H, or R to S, 1,59,[82][83][84][85][86][87][88][89][90] all but five are asymptomatic. Of the fam ilies reporting thrombophilia, there are two with 7R275C, Bologna I 2 and Cedar Rapids, 84 and three with γR275H substitutions.…”

Section: Fibrinogen Cedar Rapidsmentioning

confidence: 99%

“…Of the fam ilies reporting thrombophilia, there are two with 7R275C, Bologna I 2 and Cedar Rapids, 84 and three with γR275H substitutions. The 7R275H Haifa I patient 85 presented at the age of 30 with arterial occlusions, Barcelona III with venous thrombosis, 82 and Bergamo II with pulmonary embolism associated with pregnancy. 86 Clearly, there is no simple direct linkage between this type of structural abnormality and thromboembolism, and other associated conditions must be sought.…”

Section: Fibrinogen Cedar Rapidsmentioning

confidence: 99%

Dysfibrinogenemia and Thrombosis

Mosesson¹

1999

Semin Thromb Hemost

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Congenital abnormal fibrinogen molecules (dysfibrinogenemias) are due to structural defects in the molecule. The molecular structure of the fibrinogen molecule is to a great extent known and this has allowed identification of the abnormalities at a molecular level. While most patients with dysfibrinogenemia are clinically asymptomatic, some present with a bleeding diathesis, others with thrombophilia, and occasionally with both, bleeding and thromboembolism. In principle, the dysfibrinogenemias are due to either impaired release of the fibrinopeptides, defective fibrin polymerization, or abnormal cross-linking by factor XIIIa. Dysfibrinogenemias associated with thrombophilia have been reported in those related to abnormal fibrinopeptide release or defective polymerization. In addition, abnormal interactions with platelets, defective fibrinolysis, defective assembly of the fibrinolytic system, and abnormal calcium binding have been described. The presently identified dysfibrinogenemias associated with thrombosis and their molecular defects are described in this review. It must also be recognized that some patients with abnormal fibrinogen molecules have additional hemostasis defects, such as abnormalities of antithrombin, protein C, protein S, factor V Leiden, and others. On rare occasions, dysfibrinogenemias can be associated with hypofibrinogenemia.

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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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Fibrinogen ‘Haifa’ – A New Fibrinogen Variant

Cited by 4 publications

References 4 publications

The Polymerization of Fibrin Prepared from Fibrinogen Haifa (γ275Arg→His)

The Polymerization of Fibrin Prepared from Fibrinogen Haifa (γ275Arg→His)

Dysfibrinogenemia and Thrombosis

Familial Dysfibrinogenemia and Thrombophilia

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