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.

OBJECTIVES:

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: V J Marder, A J Comerota, R D Shlansky-Goldberg, J P Davis, C Deng, K Hanna, D Fineberg
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 10 Issue 6 Pg. 985-91 (Jun 2012) ISSN: 1538-7836 [Electronic] England
• PMID: 22487025 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 International Society on Thrombosis and Haemostasis.

Chemical References

• Biomarkers
• Fibrinolytic Agents
• alpha-2-Antiplasmin
• alpha-Macroglobulins
• Fibrinogen
• Fibrinolysin

Topics

• Acute Disease
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Arterial Occlusive Diseases (blood, diagnostic imaging, drug therapy)
• Biomarkers (blood)
• Brazil
• Catheterization, Peripheral (adverse effects)
• Dose-Response Relationship, Drug
• Europe
• Female
• Fibrinogen (metabolism)
• Fibrinolysin (administration & dosage, adverse effects)
• Fibrinolytic Agents (administration & dosage, adverse effects)
• Graft Occlusion, Vascular (blood, diagnostic imaging, drug therapy)
• Hemorrhage (chemically induced)
• Humans
• Infusions, Intra-Arterial
• Lower Extremity (blood supply)
• Male
• Middle Aged
• Radiography
• South Africa
• Thrombolytic Therapy (adverse effects, methods)
• Time Factors
• Treatment Outcome
• United States
• Young Adult
• alpha-2-Antiplasmin (metabolism)
• alpha-Macroglobulins (metabolism)