Prothrombin Habana: a new dysfunctional molecule of human prothrombin associated with a true prothrombin deficiency

Rubio, Rodolfo Rubio; D, Almagro; Cruz, Achilles Machado; Corral, J.

doi:10.1111/j.1365-2141.1983.tb02133.x

Cited by 16 publications

(2 citation statements)

References 15 publications

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“…The effects of an experiment with the proteasome inhibitor MG-132 suggest that this protein is subjected to intracellular degradation by the proteasome, as indicated by its poor stability. Therefore, a homozygous F2 c.1787G>C mutation resulting in the 596Pro variant would likely cause a bleeding tendency similar to those observed in patients with prothrombin deficiencies (18)(19)(20).…”

Section: Discussionmentioning

confidence: 90%

Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance

Takagi¹,

Murata²,

Kozuka³

et al. 2016

Thromb Haemost

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Antithrombin (AT) and thrombomodulin (TM) play important roles in the process of natural anticoagulation in vivo. Recently, we reported that the prothrombin Yukuhashi mutation (p.Arg596Leu) was associated with AT and TM resistance-related thrombophilia. To assess the AT and TM resistances associated with other missense mutations by single base substitution in the Arg596 codon, we generated recombinant variants (596Gln, 596Trp, 596Gly, and 596Pro) and investigated the effects on AT and TM anticoagulant functions. All variants except 596Pro were secreted in amounts comparable to that of the wild-type but exhibited variable procoagulant activities. After a 30-minute inactivation by AT, the relative residual activity of wild-type thrombin decreased to 15 ± 4.0 %, in contrast to values of all variants were maintained at above 80 %. The thrombin-AT complex formation, as determined by enzyme-linked immunosorbent assay, was reduced with all tested variants in the presence and absence of heparin. In the presence of soluble TM (sTM), the relative fibrinogen clotting activity of wild-type thrombin decreased to 16 ± 0.12 %, whereas that of tested variants was 37 %-56 %. In a surface plasmon resonance assay, missense Arg596 mutations reduced thrombin-TM affinity to an extent similar to the reduction of fibrinogen clotting inhibition. In the presence of sTM or cultured endothelial-like cells, APC generation was enhanced differently by variant thrombins in a thrombin-TM affinity-dependent manner. These data indicate that prothrombin Arg596 missense mutations lead to AT and TM resistance in the variant thrombins and suggest that prothrombin Arg596 is important for AT- and TM-mediated anticoagulation.

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Section: Discussionmentioning

confidence: 90%

Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance

Takagi¹,

Murata²,

Kozuka³

et al. 2016

Thromb Haemost

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show abstract

“…It does not correspond to prothrombin Padua [ 11, Metz [2], Gainesville [3], Houston [4], Denver [5], Madrid [6], La Habana [7], Cardeza [8], Barcelona [9], San Juan [lo], and Quick [ll], for they all lead to coagulation dysfunction, to some degree, as well as other physicochemical differences.…”

Section: Discussionmentioning

confidence: 99%

Prothrombin “Mexico city,” an asymptomatic autosomal dominant prothrombin variant

Valls-de-Ruiz

Ruı́z-Argüelles

et al. 1987

American J Hematol

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A functionally normal but structurally abnormal prothrombin variant was found in a Mexican family. Immunoisoelectricfocusing studies revealed that this variant has a more acidic isoelectric point (4.01) than normal prothrombin (4.29), but it proved to have a normal molecular weight as assessed by sodium-dodecyl-sulphate polyacrylamide gel electrophoresis. Two-dimensional immunoelectrophoresis studies showed an abnormal cleavage of the prothrombin molecule by factor Xa and Echis carinatus venom as well, despite the fact that both yield functionally normal thrombin molecules. Finally, the ability of the molecule to bind calcium ions as well as its overall antigenic structure were investigated and found to be normal. These results taken together suggest a simple (substitution or translocation) mutation at the fragment 2 level. Since this prothrombin variant is different from others described previously, the name "Mexico City" is proposed to identify it.

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Andere angeborene Koagulopathien

Mammen¹

1985

Blut Und Blutkrankheiten

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Prothrombin Habana: a new dysfunctional molecule of human prothrombin associated with a true prothrombin deficiency

Cited by 16 publications

References 15 publications

Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance

Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance

Prothrombin “Mexico city,” an asymptomatic autosomal dominant prothrombin variant

Andere angeborene Koagulopathien

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