High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension.
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: Bbeta P235L/gamma R375W, Bbeta P235L/gamma Y114H, Bbeta P235L, Aalpha L69H, and Aalpha R554H (fibrinogens(San Diego I-V)). Bbeta 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.
Morris
Timothy A
TA
Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA 92103-8378, USA. t1morris@ucsd.edu
Marsh
James J
JJ
Chiles
Peter G
PG
Magaña
Marisa M
MM
Liang
Ni-Cheng
NC
Soler
Xavier
X
Desantis
Daniel J
DJ
Ngo
Debby
D
Woods
Virgil L
VL
D000328:Adult; D000368:Aged; D025861:Blood Coagulation Disorders, Inherited / Q000150:complications* / Q000453:epidemiology*; D004252:DNA Mutational Analysis; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics*; D015241:Fibrinogens, Abnormal / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000453:epidemiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D015995:Prevalence; D011655:Pulmonary Embolism / Q000150:complications* / Q000453:epidemiology* / Q000235:genetics
D015241:Fibrinogens, Abnormal; D005337:Fibrin; D005340:Fibrinogen