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 L. David; David H. Farrell

doi:10.1160/TH07-06-0427

Thrombosis and Haemostasis, Inhaltsverzeichnis

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 α_IIbβ₃ binding site

Veronica H. Flood

¹Division 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

²Division of Hematology/Oncology, College of Medicine, Pennsylvania State University, The Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA

,

Chantelle M. Rein

³Department of Pathology and

,

Kristine S. Alexander

³Department of Pathology and

,

Rehana S. Lovely

³Department of Pathology and

,

Kelley M. Shackleton

³Department of Pathology and

,

Larry L. David

⁴Department of Molecular Biology and Biochemistry, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA

,

David H. Farrell

³Department of Pathology and

› Institutsangaben

Abstract

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 α_IIbβ₃. 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 α_IIbβ₃ 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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Referenzen

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