Safety and efficacy of thrombin-JMI: a multidisciplinary expert group consensus.

BACKGROUND: The use of bovine thrombin has been an effective approach to aiding hemostasis during surgery for over 60 years. Its use has a reported association with the development of antibodies to coagulation factors with limited evidence to the clinical significance. METHODS: The Collaborative Delphi survey methodology was used to develop a consensus on specified topic areas from a panel of 12 surgeons/scientists who have had experience with topical thrombins; it consisted of 2 rounds of a Web-based survey and a final live discussion. RESULTS: Some key issues that reached consensus included: bovine, human plasma-derived and recombinant human thrombin are equally effective hemostatic agents with similar adverse event rates, and immunogenicity to a topical protein rarely translate into adverse events. CONCLUSIONS: Although a risk of immunogenicity is associated with all topical thrombins, no conclusive clinical evidence is available that these antibodies have any significant effect on short- and long-term clinical consequences.

Topical bovine thrombin: a 21-year review of topical bovine thrombin spontaneous case safety reports submitted to FDA's Adverse Event Reporting System.

PURPOSE: To review topical bovine thrombin spontaneous adverse event (AE) reports that were forwarded to the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) between January 1986 and December 2006. METHODS: Forty-one spontaneous AE reports were summarized for reported AE profile and chronological reporting patterns. Each AE report was adjudicated by a hematologist for the topical bovine thrombin product that was given and the AE(s) that were reported. AEs were grouped as allergic, coagulopathy/bleeding, and all other AEs combined. Grouped AE serial analyses were carried out using successive 3-year time increments between 1986 (the year an AE report was first noted for a bovine thrombin product) and 2006 (the first full year that was available at the time of initiation of the data summary). MAIN OUTCOME MEASURES: The primary outcome measures were every 3-year trend lines for all-AE reports, all reporters, and topical bovine thrombin brand mentions for 2 AE groups of interest (allergic events and coagulopathy/bleeding events). RESULTS: The all-AE spontaneous reporter trend showed a downward appearance for AE reporting activity that started in 1995-1998 and continued through 2004-2006. The all-AE reports trend showed two potential safety signals that could be identified serially: (1) a prominent 1989-1991 peak that was attributable to allergic events (in particular, anaphylaxis), and (2) a small 1995-2000 broad peak that was attributable in part to coagulopathy/bleeding events. Allergic events were predominantly reported with products approved prior to 1995, were not temporally associated with prior medical literature case reports, and continued to be forwarded to the FDA at low levels up to the end of this study in 2006. Coagulopathy/bleeding events were reported only with products approved prior to 1995, were temporally associated with medical literature case reports, and were not forwarded to the FDA after 2000. CONCLUSIONS: Overall, spontaneous AE reporting for topical bovine thrombin occurs at very low levels, and appears to have been decreasing since 1995. The serial reporting patterns for topical bovine thrombin are best explained as a strong safety signal for allergic events with ongoing, low level reporting, and a weak safety signal for coagulopathy/bleeding events that ceased on or before 2000. Although this descriptive trend analysis cannot measure associations or causation, the coagulopathy/bleeding signal may have been prompted by multiple, antecedent published case reports. The subsequent diminishment of signal attributed to thrombin likewise may coincide with lack of such reporting in larger follow-up clinical trials or, alternatively, in the introduction and growing market share of thrombin brands of greater purity. Currently marketed topical bovine thrombin formulations are rarely volunteered as possible causes of adverse events.

Locally applied recombinant plasmin results in effective thrombolysis in a porcine model of arteriovenous graft thrombosis.

PURPOSE: Arteriovenous (AV) graft thrombosis is a frequent complication in patients undergoing hemodialysis. Thrombolytic therapy with tissue plasminogen activator (TPA) is hampered by the risk of bleeding complications. Locally delivered plasmin may have similar thrombolytic efficacy with a superior safety profile, so herein it was compared with TPA in a porcine model of AV graft thrombosis. MATERIALS AND METHODS: AV grafts were created bilaterally between the carotid artery and jugular vein. Graft thrombosis was induced by clamping the grafts for 1 hour. On day 3, one graft was treated with a 2-mL local recombinant plasmin injection (10 mg; n = 10) with the contralateral graft being infused with TPA (10 mg, n = 8) or saline solution (n = 2). Thrombolytic efficacy was assessed by weighing the residual clot and released clot fragments. RESULTS: After saline solution injection, the mean residual clot weight in the graft was 618 mg. Local administration of TPA showed the least residual clot in the graft (69 mg +/- 26), with large clot particles reaching the venous outflow (241 mg +/- 23). Plasmin treatment significantly reduced the released clot mass versus TPA (52 mg +/- 23; P < .05), whereas residual clot weight was greater compared with TPA treatment (140 mg +/- 22; P < .05). Overall thrombolytic activity of plasmin (ie, residual clot plus released clot) was significantly better than that of TPA (193 mg +/- 25 vs 310 mg +/- 35; P < .05). CONCLUSIONS: The thrombolytic efficacy of recombinant plasmin was shown to be superior to that of TPA in this study.

Novel controlled-release Lemna-derived IFN-alpha2b (Locteron): pharmacokinetics, pharmacodynamics, and tolerability in a phase I clinical trial.

Locteron, a newly developed controlled-release formulation of Lemna-derived free (unpegylated) recombinant interferon-alpha2b (IFN-alpha2b, Biolex Therapeutics, Pittsboro, NC) in poly(ether-ester) microspheres (PolyActive, OctoPlus N.V., Leiden, the Netherlands), was evaluated in 27 volunteers injected with either 20, 80, or 320 microg Locteron (equivalent to 6.25, 25, or 100 x 10(6) IU, respectively), 80 microg pegylated IFN-alpha2b (PEG-IFN-alpha2b), microspheres not containing IFN-alpha2b, or placebo. Serum free or PEG-IFN-alpha2b and two biomarkers of IFN activity, neopterin and 2',5'-oligoadenylate synthetase (2',5'-OAS), were measured. After injection of 320 microg Locteron, serum IFN-alpha2b remained elevated through 14 days. The elimination half-life of Locteron was more than 2-fold that of PEG-IFN-alpha2b. The effects of 80 microg Locteron and 80 microg PEG-IFN-alpha2b on both neopterin and 2',5'-OAS were in a comparable range. Serum persistence of both these biomarkers was similar at 14 days after 320 microg Locteron compared with 7 days after 80 microg PEG-IFN-alpha2b. Mild, moderate, or severe influenza-like symptoms developed in all 6 subjects receiving 80 microg PEG-IFN-alpha2b. No such symptoms occurred after 20 or 80 microg Locteron doses. Among the 4 recipients of 320 microg Locteron, 1 experienced mild and 2 experienced moderate influenza-like symptoms. Locteron merits further clinical investigation as a hepatitis C therapy suitable for dosing once per 2 weeks.

Cross-linked fibrin in the nasal fluid of patients with the common cold.

To determine whether adherent material found on the walls of the paranasal sinuses during common colds might be fibrin clot, we examined the nasal fluid (a surrogate for sinus secretion) of 11 young adults with experimentally induced rhinovirus colds and that of 4 control subjects for the presence of fibrin. The mean concentration (+/- the standard error) of insoluble fibrin (measured as D-dimer) in subjects with rhinovirus colds increased from a baseline level of 0.8+/-0.4 microgram/mL to a peak of 2.4+/-0.7 microgram/mL (P=.0008) on day 4 after inoculation of the virus, but the fibrin concentration remained at baseline levels in the 4 uninfected control subjects.