Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of gammaAla327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism.
Thrombophilic dysfibrinogen Tokyo V was identified in a 43-year-old man with recurrent thromboembolism. Based on analyses of the patient fibrinogen genes, the amino acid sequence of the aberrant fibrinogen peptide, and deglycosylation experiments, fibrinogen Tokyo V was shown to have an amino acid substitution of gamma Ala327Thr and possibly extra glycosylation at gamma Asn325 because the mutation confers the N-linked glycosylation consensus sequence Asn-X-Thr. The mutation resulted in impaired function and hypofibrinogenemia (hypodysfibrinogen). Polymerization of fibrin monomers derived from patient fibrinogen was severely impaired with a partial correction in the presence of calcium, resulting in very low clottability. Additionally, a large amount of soluble cross-linked fibrin was formed upon thrombin treatment in the presence of factor XIII and calcium. However, Tokyo V-derived fibrin was resistant to degradation by tissue plasminogen activator (tPA)-catalyzed plasmin digestion. The structure of Tokyo V fibrin appeared severely perturbed, since there are large pores inside the tangled fibrin networks and fiber ends at the boundaries. Taken together, these data suggest that Tokyo V fibrin clots are fragile, so that fibrinolysis-resistant insoluble fibrin and soluble fibrin polymers may be released to the circulation, partly accounting for the recurrent embolic episodes in the patient.
Hamano
Akiei
A
Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical School, Tochigi-ken, Japan.
Mimuro
Jun
J
Aoshima
Motonori
M
Itoh
Takeyoshi
T
Kitamura
Noboru
N
Nishinarita
Susumu
S
Takano
Katsuhiro
K
Ishiwata
Akira
A
Kashiwakura
Yuji
Y
Niwa
Kazuki
K
Ono
Tomoko
T
Madoiwa
Seiji
S
Sugo
Teruko
T
Matsuda
Michio
M
Sakata
Yoichi
Y
D000328:Adult; D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism; D015241:Fibrinogens, Abnormal / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008855:Microscopy, Electron, Scanning; D012008:Recurrence; D012995:Solubility; D013923:Thromboembolism / Q000097:blood* / Q000235:genetics*; D019851:Thrombophilia / Q000097:blood* / Q000235:genetics*; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D015241:Fibrinogens, Abnormal; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D002118:Calcium