title: Safety of catheter-delivered plasmin in patients with acute lower extremity arterial or bypass graft occlusion: phase I results.
abstract: BACKGROUND
  Current treatment of acute peripheral artery or bypass graft occlusion utilizes catheter-directed thrombolysis of a plasminogen activator (PA). Plasmin is a direct-acting thrombolytic with a striking safety advantage over PA in preclinical models.
  
  
  OBJECTIVE
  To report the first use of purified plasmin for acute lower extremity arterial or bypass graft thrombosis in a phase I dose-escalation study of a catheter-delivered agent.
  
  
  METHODS
  Eighty-three patients with non-embolic occlusion of infrainguinal native arteries or bypass grafts were enrolled (safety population) into seven sequential dose cohorts to receive 25-175 mg of plasmin by intrathrombus infusion over 5 h. Arteriograms were performed at baseline, 2 h, and 5 h, and subjects were monitored for 30 days for clinical outcomes and laboratory parameters of systemic fibrinolysis.
  
  
  RESULTS
  Major bleeding occurred in four patients (4.8%), and minor bleeding alone in 13 (15.7%), with no trend towards more bleeding at higher dosages of plasmin. There was a trend towards lower plasma concentrations of fibrinogen, α(2) -antiplasmin and α(2) -macroglobulin with increasing doses of plasmin, but the nadir fibrinogen concentration was > 350 mg dL(-1) at the highest plasmin dose. Individual nadir values were above 200 mg dL(-1) in 82 of 83 subjects, and were not different in patients with or without bleeding. Thrombolysis (≥ 50%) occurred in 79% of subjects receiving 125-175 mg of plasmin, as compared with 50% who received 25-100 mg.
  
  
  CONCLUSIONS
  Catheter-delivered plasmin can be safely administered to patients with acute lower extremity arterial occlusion at dosages of 25-175 mg.
authors.affiliation: Division of Hematology/Medical Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. vmarder@mednet.ucla.edu
authors.forename: V J
authors.initials: VJ
authors.lastname: Marder
authors.forename: A J
authors.initials: AJ
authors.lastname: Comerota
authors.forename: R D
authors.initials: RD
authors.lastname: Shlansky-Goldberg
authors.forename: J P
authors.initials: JP
authors.lastname: Davis
authors.forename: C
authors.initials: C
authors.lastname: Deng
authors.forename: K
authors.initials: K
authors.lastname: Hanna
authors.forename: D
authors.initials: D
authors.lastname: Fineberg
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D001938:Brazil; D002406:Catheterization, Peripheral / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005341:Fibrinolysin / Q000008:administration & dosage* / Q000009:adverse effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006083:Graft Occlusion, Vascular / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007261:Infusions, Intra-Arterial; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D011859:Radiography; D013019:South Africa; D015912:Thrombolytic Therapy / Q000009:adverse effects / Q000379:methods*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult; D000979:alpha-2-Antiplasmin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005343:Fibrinolytic Agents; D000979:alpha-2-Antiplasmin; D000511:alpha-Macroglobulins; D005340:Fibrinogen; D005341:Fibrinolysin