title: Fibrin derived from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis.
abstract: BACKGROUND
  Although acute pulmonary embolism is epidemiologically associated with chronic thromboembolic pulmonary hypertension, the factors responsible for resistance to thrombolysis and a shift toward vascular remodeling within the pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension are unknown.
  
  
  OBJECTIVE
  Determine whether fibrin from patients is more resistant to plasmin-mediated lysis than fibrin from healthy control subjects.
  
  
  METHODS
  Fibrinogen purified from patients and control subjects was used to prepare fibrin clots, which were subsequently digested with plasmin for various periods of time. The degradation of the alpha-, beta-, and gamma-chains of fibrin and the appearance of peptide fragments over time were assessed by polyacrylamide gel electrophoresis and Western blotting.
  
  
  RESULTS
  Densitometry of Coomassie-stained gels revealed significantly slower cleavage of all three polypeptide chains of fibrin from patients compared with control subjects (p < 0.05). In particular, release of N-terminal fragments from the beta-chain of fibrin, which promote cell signaling, cell migration, and angiogenesis, was retarded in patients compared with control subjects (p < 0.01).
  
  
  CONCLUSIONS
  The relative resistance of patient fibrin to plasmin-mediated lysis may be due to alterations in fibrin(ogen) structure affecting accessibility to plasmin cleavage sites. The persistence of structural motifs of fibrin, such as the beta-chain N-terminus, within the pulmonary vasculature could promote the transition from acute thromboemboli into chronic obstructive vascular scars.
authors.affiliation: Division of Pulmonary/Critical Care Medicine, Department of Medicine, University of California, San Diego, CA 92103-8378, USA. t1morris@ucsd.edu
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Morris
authors.forename: James J
authors.initials: JJ
authors.lastname: Marsh
authors.forename: Peter G
authors.initials: PG
authors.lastname: Chiles
authors.forename: William R
authors.initials: WR
authors.lastname: Auger
authors.forename: Peter F
authors.initials: PF
authors.lastname: Fedullo
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Woods
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005337:Fibrin / Q000187:drug effects* / Q000502:physiology; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000737:chemistry; D005341:Fibrinolysin / Q000494:pharmacology* / Q000627:therapeutic use; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010958:Plasminogen / Q000032:analysis; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000473:pathology; D015912:Thrombolytic Therapy; D000979:alpha-2-Antiplasmin / Q000032:analysis
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D000979:alpha-2-Antiplasmin; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D005341:Fibrinolysin