Journal
BLOOD
Volume 114, Issue 9, Pages 1929-1936Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-03-208264
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Funding
- NCI NIH HHS [P30 CA023100, 2 P30CA023100-23, CA118595, CA099835, R21 CA118595, R21 CA099835, R33 CA099835] Funding Source: Medline
- NHLBI NIH HHS [R21 HL080302, HL-095089, HL-080302, R01 HL095089] Funding Source: Medline
- NIAID NIH HHS [AI076961, R21 AI076961] Funding Source: Medline
- NIGMS NIH HHS [K01 GM103817] Funding Source: Medline
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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: B beta P235L/gamma R375W, B beta P235L/gamma Y114H, B beta P235L, A alpha L69H, and A alpha R554H (fibrinogens(San Diego I-V)). B beta 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. (Blood. 2009; 114: 1929-1936)
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