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Thromb Haemost 2008; 99(06): 1008-1012
DOI: 10.1160/TH07-06-0427
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Veronica H. Flood
1   Division of Pediatric Hematology/Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA; present address: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
,
Hamid A. Al-Mondhiry
2   Division of Hematology/Oncology, College of Medicine, Pennsylvania State University, The Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
,
Chantelle M. Rein
3   Department of Pathology and
,
Kristine S. Alexander
3   Department of Pathology and
,
Rehana S. Lovely
3   Department of Pathology and
,
Kelley M. Shackleton
3   Department of Pathology and
,
Larry L. David
4   Department of Molecular Biology and Biochemistry, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA
,
David H. Farrell
3   Department of Pathology and
› Author Affiliations
Further Information

Publication History

Received 26 June 2007

Accepted after major revision 20 April 2008

Publication Date:
27 November 2017 (online)

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Summary

The carboxyl terminal segment of the fibrinogen γ chain from γ408–4ll 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.

Keywords

Fibrinogen/fibrin - GP IIb/IIIa - inherited coagulation disorders - integrins - platelet glycoproteins
 

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