Fibrin Derived from Patients with Chronic Thromboembolic Pulmonary Hypertension Is Resistant to Lysis

• Published in: American journal of respiratory and critical care medicine Vol. 173; no. 11; pp. 1270 - 1275
• Main Authors: Morris, Timothy A, Marsh, James J, Chiles, Peter G, Auger, William R, Fedullo, Peter F, Woods, Virgil L., Jr
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01.06.2006; American Lung Association; American Thoracic Society
• Subjects: Adult; Aged; alpha-2-Antiplasmin - analysis; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Case-Control Studies; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; F. Pulmonary Vascular Disease; 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; Intensive care medicine; Male; Medical sciences; Middle Aged; Monoclonal antibodies; Peptides; Plasminogen - analysis; Pneumology; Proteins; Pulmonary arteries; Pulmonary Embolism - drug therapy; Pulmonary Embolism - pathology; Pulmonary embolisms; Pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Thromboembolism; Thrombolytic Therapy; Veins & arteries; United States > US; California; Human; blood coagulation factors; Intensive care; Hemostatic; Respiratory disease; Cardiovascular disease; Thrombosis; Embolism; Pulmonary hypertension; Vascular disease; fibrinolysis; Fibrin; Chronic; Lysis; vascular diseases; Thromboembolism; pulmonary embolism; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200506-916OC

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. Determine whether fibrin from patients is more resistant to plasmin-mediated lysis than fibrin from healthy control subjects. 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. 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). 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.