Fibrin derived from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis

Am J Respir Crit Care Med. 2006 Jun 1;173(11):1270-5. doi: 10.1164/rccm.200506-916OC. Epub 2006 Mar 2.


Rationale: 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.

Measurements and main 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Female
  • Fibrin / drug effects*
  • Fibrin / physiology
  • Fibrin Fibrinogen Degradation Products / analysis
  • Fibrinogen / chemistry
  • Fibrinolysin / pharmacology*
  • Fibrinolysin / therapeutic use
  • Fibrinolysis
  • Fibrinolytic Agents / pharmacology*
  • Fibrinolytic Agents / therapeutic use
  • Humans
  • Hypertension, Pulmonary / pathology*
  • Male
  • Middle Aged
  • Plasminogen / analysis
  • Pulmonary Embolism / drug therapy*
  • Pulmonary Embolism / pathology
  • Thrombolytic Therapy*
  • alpha-2-Antiplasmin / analysis


  • Fibrin Fibrinogen Degradation Products
  • Fibrinolytic Agents
  • alpha-2-Antiplasmin
  • Fibrin
  • Fibrinogen
  • Plasminogen
  • Fibrinolysin