Fibrinogen Hershey IV: A novel dysfibrinogen with a γV411I mutation in the integrin αIIbβ3 binding site

Veronica H. Flood, Hamid A. Al-Mondhiry, Chantelle M. Rein, Kristine S. Alexander, Rehana S. Lovely, Kelley M. Shackleton, Larry David, David Farrell

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The carboxyl terminal segment of the fibrinogen γ chain from γ408-411 plays a crucial role in platelet aggregation via interactions with the platelet receptor αIIbβ3. We describe here the first naturally-occurring fibrinogen point mutation affecting this region and demonstrate its effects on platelet interactions. DNA sequencing was used to sequence the proband DNA, and platelet aggregation and direct binding assays were used to quantitate the biological effects of fibrinogen Hershey IV. The Hershey IV proband was found to be heterozygous for two mutations, γV411I and γR275C. Little difference in aggregation was seen when fibrinogen Hershey IV was compared to normal fibrinogen. However, less aggregation inhibition was observed using a competing synthetic dodecapeptide containing the V411I mutation as compared to the wild-type dodecapeptide. Purified fibrinogen Hershey IV also bound to purified platelet αIIbβ3 with a lower affinity than wild-type fibrinogen. These findings show that the γV411I mutation results in a decreased ability to bind platelets. In the heterozygous state, however, the available wild-type fibrinogen appears to be sufficient to support normal platelet aggregation.

Original languageEnglish (US)
Pages (from-to)1008-1012
Number of pages5
JournalThrombosis and Haemostasis
Volume99
Issue number6
DOIs
StatePublished - Jun 2008

Fingerprint

Integrins
Fibrinogen
Binding Sites
Blood Platelets
Mutation
Platelet Aggregation
DNA Sequence Analysis
Point Mutation
fibrinogen Hershey IV

Keywords

  • Fibrinogen/fibrin
  • GP IIb/IIIa
  • Inherited coagulation disorders
  • Integrins
  • Platelet glycoproteins

ASJC Scopus subject areas

  • Hematology

Cite this

Flood, V. H., Al-Mondhiry, H. A., Rein, C. M., Alexander, K. S., Lovely, R. S., Shackleton, K. M., ... Farrell, D. (2008). Fibrinogen Hershey IV: A novel dysfibrinogen with a γV411I mutation in the integrin αIIbβ3 binding site. Thrombosis and Haemostasis, 99(6), 1008-1012. https://doi.org/10.1160/TH07-06-0427

Fibrinogen Hershey IV : A novel dysfibrinogen with a γV411I mutation in the integrin αIIbβ3 binding site. / Flood, Veronica H.; Al-Mondhiry, Hamid A.; Rein, Chantelle M.; Alexander, Kristine S.; Lovely, Rehana S.; Shackleton, Kelley M.; David, Larry; Farrell, David.

In: Thrombosis and Haemostasis, Vol. 99, No. 6, 06.2008, p. 1008-1012.

Research output: Contribution to journalArticle

Flood, Veronica H. ; Al-Mondhiry, Hamid A. ; Rein, Chantelle M. ; Alexander, Kristine S. ; Lovely, Rehana S. ; Shackleton, Kelley M. ; David, Larry ; Farrell, David. / Fibrinogen Hershey IV : A novel dysfibrinogen with a γV411I mutation in the integrin αIIbβ3 binding site. In: Thrombosis and Haemostasis. 2008 ; Vol. 99, No. 6. pp. 1008-1012.
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