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 Blood, 27 August 2009, Vol. 114, No. 9, pp. 1929-1936.
Prepublished online as a Blood First Edition Paper on July 7, 2009; DOI 10.1182/blood-2009-03-208264.

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THROMBOSIS AND HEMOSTASIS

High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension

Timothy A. Morris1, James J. Marsh1, Peter G. Chiles1, Marisa M. Magaña1, Ni-Cheng Liang1, Xavier Soler1,2, Daniel J. DeSantis1, Debby Ngo1, and Virgil L. Woods, Jr3

1 Division of Pulmonary and Critical Care Medicine, University of California, San Diego; 2 Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain; and 3 Department of Medicine and Biomedical Sciences Graduate Program, University of California, San Diego

The mechanism by which chronic thromboembolic pulmonary hypertension (CTEPH) develops after acute pulmonary thromboembolism is unknown. We previously reported that fibrin from CTEPH patients is relatively resistant to fibrinolysis in vitro. In the present study, we performed proteomic, genomic, and functional studies on fibrin(ogen) to investigate whether abnormal fibrin(ogen) might contribute to the pathogenesis of CTEPH. Reduced and denatured fibrinogen from 33 CTEPH patients was subjected to liquid chromatography–mass spectrometry analysis. Fibrinogen from 21 healthy controls was used to distinguish atypical from commonly occurring mass peaks. Atypical peaks were further investigated by targeted genomic DNA sequencing. Five fibrinogen variants with corresponding heterozygous gene mutations (dysfibrinogenemias) were observed in 5 of 33 CTEPH patients: Bβ P235L/{gamma} R375W, Bβ P235L/{gamma} Y114H, Bβ P235L, A{alpha} L69H, and A{alpha} R554H (fibrinogensSan Diego I-V). Bβ P235L was found in 3 unrelated CTEPH patients. Functional analysis disclosed abnormalities in fibrin polymer structure and/or lysis with all CTEPH-associated mutations. These results suggest that, in some patients, differences in the molecular structure of fibrin may be implicated in the development of CTEPH after acute thromboembolism.


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