Real-Life Population Pharmacokinetics of Recombinant Factor XIII and Dosing Considerations for Preventing the Risk of Bleeding in Patients with FXIII Congenital Deficiency.

BACKGROUND AND OBJECTIVE: Recombinant factor XIII (rFXIII) at the recommended dosage of 35 IU/kg every 4 weeks is currently used for prophylaxis of bleeding in patients affected by FXIII deficiency. The aim of this study was to describe the population pharmacokinetics of rFXIII in patients with FXIII deficiency being treated with rFXIII in real-life and to assess, using Monte Carlo simulations, the attainment of defined FXIII concentration thresholds associated with prevention of the risk of bleeding over time. METHODS: A nonlinear mixed-effects model approach was used for population analysis. Monte Carlo simulations were used to generate 10,000 FXIII concentration-time profiles associated with incremental doses of 25, 30, 35, 40, 45 and 50 IU/kg of rFXIII. The probability of target attainment (PTA) of FXIII concentrations at thresholds of > 0.05, > 0.10 and > 0.15 IU/mL were calculated weekly, from days 7 to 49. RESULTS: A total of 18 patients provided 99 FXIII concentrations; most patients (77.8%, 14/18) had severe FXIII deficiency. A two-compartment pharmacokinetic model with linear elimination from the central compartment best described rFXIII data. No covariates were associated with rFXIII disposition. Pharmacokinetic parameter estimates were 0.16 mL/h/kg for clearance, 57.35 mL/kg for volume of distribution at steady-state, and 11.72 days for elimination half-life. The standard 35 IU/kg dose resulted in PTAs of the pharmacodynamic thresholds of FXIII concentrations of > 0.05, > 0.10 and > 0.15 IU/mL at day 28 that were equal to 89.9%, 68.9% and 47.8%, respectively. CONCLUSIONS: Intensive FXIII monitoring from day 14, and/or shortening the dosing interval between rFXIII administrations, should be considered to minimise the risk of bleeding.

The impact of antenatal factor XIII levels on postpartum haemorrhage: a prospective observational study.

PURPOSE: Postpartum haemorrhage (PPH) is a leading cause of maternal mortality and morbidity. Our aim was to investigate the relationships between antenatal factor XIII (FXIII), fibrinogen levels, and blood loss at childbirth. METHODS: This prospective observational study evaluated an unselected cohort of pregnant women admitted for intended vaginal deliveries of singletons at term. To determine clotting factor levels, we obtained blood samples at a maximum of three days prior to vaginal delivery. A calibrated collecting drape was used to quantify blood loss in the third stage of labour. Moderate and severe PPH were diagnosed as blood losses ≥ 500 mL and ≥ 1000 mL, respectively. In a multiple logistic regression analysis, we determined whether coagulation factors and their interactions could independently predict (severe) PPH. RESULTS: We analysed 548 vaginal deliveries that occurred during the study period. Of those, 78 (14.2%) lost ≥ 500 mL and 18 (3.3%) lost ≥ 1000 mL of blood. The mean pre-delivery FXIII activity in women with PPH (79.33% ± 15.5) was significantly (p < 0.001) lower than in women without PPH (86.45% ± 14.6). A receiver operating characteristic curve analysis detected antenatal FXIII cutoff levels of 83.5% and 75.5% for PPH and severe PPH, respectively. The multiple logistic regression analysis showed that FXIII alone (p < 0.001) and its interaction with fibrinogen (p = 0.03) significantly predicted PPH. FXIII was not significantly correlated with blood loss among patients with severe PPH. CONCLUSION: Our results suggested that antenatal FXIII levels may have a significant influence on PPH. The interaction between FXIII and fibrinogen might also provide slight advantages in forecasting PPH.

High-dose Factor XIII administration induces effective hemostasis for trauma-associated coagulopathy (TAC) both in vitro and in rat hemorrhagic shock in vivo models.

BACKGROUND: Trauma-associated coagulopathy (TAC) is an early and primary complication in severe trauma patients. Factor XIII (FXIII) is reported to stabilize a clot in the late phase of the coagulation cascade. The goal of this study was to investigate whether the administration of FXIII improves the condition of TAC both in vitro and in vivo. METHODS: We evaluated the effects of different doses, including a very high dose of FXIII (3.6-32.4 IU/mL) on tissue-plasminogen activator-induced hyperfibrinolysis and the combined condition of dilutional coagulopathy and tissue-plasminogen activator-induced hyperfibrinolysis in vitro. The coagulation status was analyzed by rotational thromboelastometry (ROTEM) and Sonoclot. Then, we evaluated the effect of high-dose FXIII (300 IU/kg) for severe coagulopathy in vivo using a rat liver trauma model in which coagulopathy similar to TAC was observed. Survival time and the amount of intra-abdominal bleeding of rats were measured, and a coagulation test was also performed. Histologic evaluations of rats' lung and kidney after FXIII administration were completed. RESULTS: High-dose FXIII significantly improved clot strength as well as increased resistance to hyperfibrinolysis in vitro which was confirmed by ROTEM. Platelet function on Sonoclot was significantly increased by FXIII in a dose-dependent manner. Factor XIII significantly decreased the total amount of bleeding and prolonged the survival time compared to control (control vs FXIII: 108.9 ± 11.4 vs 32.6 ± 5.5 mL/kg; p < 0.001; 26.0 ± 8.8 vs 120 minutes, p < 0.001) in a rat model. Rotational thromboelastometry parameters and platelet function on Sonoclot were significantly improved in the FXIII (+) group compared to control. No adverse effects of FXIII were detected histologically. CONCLUSION: Factor XIII not only generated stable clot resistance to hyperfibrinolysis but also enhanced platelet function by facilitating clot retraction. High-dose FXIII administration therapy has significant clinical impact for severe trauma accompanied with TAC. STUDY TYPE: Human in vitro and rat in vivo experimental study.

Factor XIII cotreatment with hemostatic agents in hemophilia A increases fibrin α-chain crosslinking.

Essentials Factor XIII (FXIII)-mediated fibrin crosslinking is delayed in hemophilia. We determined effects of FXIII cotreatment with hemostatic agents on clot parameters. FXIII cotreatment accelerated FXIII activation and crosslinking of fibrin and α2 -antiplasmin. These data provide biochemical rationale for FXIII cotreatment in hemophilia. SUMMARY: Background Hemophilia A results from the absence, deficiency or inhibition of factor VIII. Bleeding is treated with hemostatic agents (FVIII, recombinant activated FVII [rFVIIa], anti-inhibitor coagulation complex [FEIBA], or recombinant porcine FVIII [rpFVIII]). Despite treatment, some patients have prolonged bleeding. FXIII-A2 B2 (FXIII) is a protransglutaminase. During clot contraction, thrombin-activated FXIII (FXIIIa) crosslinks fibrin and α2 -antiplasmin, which promotes red blood cell retention and increases clot stability and weight. We hypothesized that FXIII cotreatment in hemophilia would accelerate FXIII activation, leading to increased fibrin crosslinking. Methods FVIII-deficient plasma and whole blood were clotted with or without hemostatic agents (FVIII, rFVIIa, FEIBA, or recombinant B-domain-deleted porcine FVIII [rpFVIII]) and/or FXIII. The effects on FXIII activation, thrombin generation, fibrin and α2 -antiplasmin crosslinking, clot formation and clot weight were measured by western blotting, calibrated automated thrombography, thromboelastography, and clot contraction assays. Results As compared with FVIII-treated hemophilic plasma, FVIII + FXIII cotreatment accelerated FXIIIa formation without increasing thrombin generation. As compared with buffer-treated or FXIII-treated hemophilic plasma, FVIII treatment and FVIII + FXIII cotreatment increased the generation and amount of crosslinked fibrin, including α-chain-rich high molecular weight species and crosslinked α2 -antiplasmin. In the presence of FVIII inhibitors, as compared with hemostatic treatments (rFVIIa, FEIBA, or rpFVIII) alone, FXIII cotreatment increased whole blood clot weight. Conclusion In hemophilia A plasma and whole blood, FXIII cotreatment with hemostatic agents accelerated FXIIIa formation, increased the generation and amount of fibrin α-chain crosslinked species, accelerated α2 -antiplasmin crosslinking, and increased clot weight. FXIII cotreatment with hemostatic therapy may augment hemostasis through increased crosslinking of fibrin and α2 -antiplasmin.

Recombinant factor XIII prophylaxis is safe and effective in young children with congenital factor XIII-A deficiency: international phase 3b trial results.

Essentials Prophylaxis is the standard of care for congenital factor XIII-A (FXIII-A) deficiency. Six children with FXIII-A deficiency received once-monthly prophylaxis with recombinant FXIII-A. Prophylaxis was well tolerated and no anti-FXIII antibodies were detected. Prophylaxis was effective with an annualized bleeding rate of zero. SUMMARY: Background Factor XIII deficiency is a rare, severe congenital bleeding disorder. Monthly prophylaxis with recombinant FXIII A-Subunit (rFXIII) has demonstrated favorable safety and efficacy in patients aged ≥ 6 years, and may similarly benefit younger children. Objective To evaluate the long-term safety and efficacy of rFXIII in children aged < 6 years with congenital FXIII A-subunit deficiency. Patients/methods Six children, who had previously completed a single-dose pharmacokinetic trial of rFXIII, received 35 IU kg-1 rFXIII every 28 days (± 2 days) for a minimum of 52 weeks, and were evaluated for bleeding and adverse events. The Berichrom FXIII activity assay was used to monitor FXIII activity. Results The children, three girls and three boys, had an average age of 3.0 years (range: 1-4 years) at enrollment. The total treatment duration was 1.8-3.5 years, giving a total of 16.6 patient-years. No antibody development, thromboembolic events or allergic reactions occurred. There were 93 mild and seven moderate adverse events. Two adverse events (lymphopenia and gastroenteritis) were reported as probably or possibly related to rFXIII in two children. Two serious adverse events, unrelated to rFXIII, were reported in a single child, each related to head injury, and neither resulting in intracranial hemorrhage. The geometric mean FXIII activity trough was 0.19 IU mL-1 . No bleeding episodes requiring treatment with an FXIII-containing hemostatic agent occurred during the trial; thus, the annualized bleeding rate was 0. Conclusions Consistent with data from older age groups, prophylaxis with rFXIII appears to be safe and effective in young children with congenital FXIII A-subunit deficiency.

Long-term prophylaxis in patients with severe congenital factor XIII deficiency is not complicated by inhibitor formation.

: Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder accompanied by a variety of bleeding events. Severely deficient patients require regular replacement therapy. With development of FXIII concentrate, the risk of viral infections transmitted by fresh frozen plasma and cryoprecipitate is diminished, but the possibility of inhibitor development remains a challenging issue in the management of these patients. The aim of this study was to assess FXIII inhibitor development in Iranian patients with FXIII deficiency (FXIIID). This study enrolled 50 (30 women and 20 men) patients with severe congenital FXIIID from southeast Iran who underwent long-term (more than 4 years or more than 50 injections) prophylaxis with FXIII concentrate (Fibrogammin P, Dade Behring, Marburg, Germany). We evaluated plasma FXIII activity and FXIII inhibitor on day 28 after the last prophylaxis administration. The method for investigation of FXIII inhibitor was based on Bethesda assay. The mean age of the study population was 13.8 ±â€Š8.3 years. The minimum and maximum FXIII activity levels were less than 1-4.5% (mean ±â€ŠSD, 2.6 ±â€Š0.7%). Our investigations showed that all patients with severe form of FXIIID were treated without inciting inhibitor development. Despite long-term prophylaxis in the studied patients, none was found to have developed FXIII inhibitors.

[Factor XIII : Pharmacodynamic and pharmacokinetic characteristics]. / Gerinnungsfaktor XIII : Pharmakodynamische und pharmakokinetische Eigenschaften.

Factor XIII (FXIII) plays an important role in the field of blood coagulation. In the last decade, both congenital and acquired deficiencies have been investigated in clinical studies. FXIII is a versatile enzyme that leads to a covalent cross-linking of fibrin fibrils at the end of the clotting cascade and supports platelet adhesion to the damaged sub-endothelium with the result of a mechanically stable clot.Symptoms of FXIII deficiencies vary within a broad spectrum from superficial skin bleeding episodes to severe, sometimes life threatening hemorrhage, requiring prophylactic or therapeutic replacement therapy.Since 1993 purified plasma-derived FXIII concentrate has been available in Germany, large parts of Europe and in the USA and Canada. The administration is conducted intravenously, and FXIII is immediately available in the plasma. The dosage should be determined by measuring actual plasma FXIII-activity. Repetitive application is possible, especially with regard to the mean half-time of 7.9 days.Administration is considered to be safe and effective, but there are some case reports, as with other coagulation factors, describing the appearance of inhibitory antibodies.This summary seeks to provide an insight into the principle pharmacokinetic and pharmacodynamic characteristics of plasma-derived FXIII concentrate, reviewing the current literature. For detailed use in clinical settings, the application of FXIII concentrate or substitution therapy with fresh frozen plasma, we therefore refer to current guidelines and significant studies that have been recently published.

Pharmacokinetics of recombinant factor XIII in young children with congenital FXIII deficiency and comparison with older patients.

Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe form is associated with a significant bleeding phenotype, requiring regular prophylactic therapy. A recently developed recombinant FXIII (rFXIII) has demonstrated safety and efficacy in children aged ≥6 years and adults (mentor1 trial). This article describes the mentor4 trial, which has assessed the pharmacokinetics (PK) and safety of rFXIII in younger children (1 to <6 years) with congenital FXIII deficiency, and compares extrapolated PK parameters with the mentor1 trial. Six children with congenital FXIII A-subunit deficiency received a single, 35 IU kg(-1) rFXIII dose. PK properties were similar in all the children, with a mean area under the concentration vs. 30-day time curve of 248.6 IU h(-1) mL(-1) , maximal FXIII activity (30 min) of 0.67 IU mL(-1) , and mean 30-day trough of 0.21 IU mL(-1) . All patients maintained FXIII activity above the lower target level (0.1 IU mL(-1) ). rFXIII half-life was 15.1 days (range, 10-25). No safety findings of clinical concern were observed. PK properties of rFXIII were similar in patients from both trials. The study demonstrated that a single dose of 35 IU kg(-1) rFXIII maintained plasma FXIII levels above 0.1 IU mL(-1) over a 30-day period in young children with congenital FXIII deficiency, and is, therefore, likely to provide adequate prophylaxis in this age group. The study extends the previous findings of the mentor1 trial and confirms that no dose adjustment is required for different age groups with congenital FXIII deficiency.

Efficacy and safety of recombinant factor XIII on reducing blood transfusions in cardiac surgery: a randomized, placebo-controlled, multicenter clinical trial.

OBJECTIVES: Cardiac surgery with cardiopulmonary bypass frequently leads to excessive bleeding, obligating blood product transfusions. Because low factor XIII (FXIII) levels have been associated with bleeding after cardiac surgery, we investigated whether administering recombinant FXIII after cardiopulmonary bypass would reduce transfusions. METHODS: In this double-blinded, placebo-controlled, multicenter trial, 409 cardiac surgical patients at moderate risk for transfusion were randomized to receive an intravenous dose of recombinant FXIII, 17.5 IU/kg (n = 143), 35 IU/kg (n = 138), or placebo (n = 128) after cardiopulmonary bypass. Transfusion guidelines were standardized. The primary efficacy outcome was avoidance of allogeneic blood products for 7 days postsurgery. Secondary outcomes included amount of blood products transfused and reoperation rate. Serious adverse events were measured for 7 weeks. RESULTS: Study groups had comparable baseline characteristics and an approximately 40% decrease in FXIII levels after cardiopulmonary bypass. Thirty minutes postdose, FXIII levels were restored to higher than the lower 2.5th percentile of preoperative activity in 49% of the placebo group, and 85% and 95% of the 17.5- and 35-IU/kg recombinant FXIII groups, respectively (P < .05 for both treatments vs placebo). Transfusion avoidance rates were 64.8%, 64.3%, and 65.9% with placebo, 17.5 IU/kg, and 35 IU/kg recombinant FXIII (respective odds ratios against placebo, 1.05 [95% confidence interval, 0.61-1.80] and 0.99 [95% confidence interval, 0.57-1.72]). Groups had comparable adverse event rates. CONCLUSIONS: Replenishment of FXIII levels after cardiopulmonary bypass had no effect on transfusion avoidance, transfusion requirements, or reoperation in moderate-risk cardiac surgery patients (ClinicalTrials.gov identifier: NCT00914589).

Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer. A preliminary report.

Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A(2)) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A(2) (11.9, 25, 35 or 50 IU/kg) or placebo in a 4:1 ratio. Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5-7. The primary end-point was incidence and severity of adverse events. Thirty-five patients were randomised to rFXIII-A(2) and eight to placebo. Eighteen serious adverse events were reported. These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/kg rFXIII-A(2) was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25-50 IU/kg rFXIII-A(2) restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A(2), in doses from 11.9 IU/kg up to 50 IU/kg, was well tolerated. For post-operative FXIII replenishment, 35 IU/kg of rFXIII-A(2) may be the most appropriate dose.

Unrelated donor bone marrow transplantation using a chemotherapy-only preparative regimen for adults with high-risk acute myelogenous leukemia.

Limited data are available for adults undergoing unrelated donor (URD) BMT for AML using chemotherapy-only preparative regimens. Previous studies incorporated irradiation, included adults and children, and excluded secondary leukemia. Herein we report long-term outcomes for adults with poor-prognostic AML receiving a novel regimen of busulfan (16 mg/kg), cytarabine (8,000 mg/m(2)), and cyclophosphamide (120 mg/kg) (BAC), followed by URD BMT. From June 1995 through October 2001, 45 adults were enrolled. Adverse features included unfavorable cytogenetics (49%), secondary AML (47%), leukemia at transplant (42%), and extramedullary disease (16%). At time of BMT, 23 were in remission (12 CR1) while 22 had leukemia. Four (9%) died early. Acute and chronic GVHD rates were 44 and 67%, respectively. Seventeen (38%) were disease-free 52 months post-BMT; 13 were leukemia-free (eight CR1) at transplant. Eleven relapsed. Three-year DFS and OS were 42 and 46%, respectively. DFS and OS were longer, and relapses less, for those in CR at time of BMT. Secondary leukemia, cytogenetics, cell dose, and GVHD did not influence outcome. In poor-risk AML, BAC provided cytoreduction comparable to reported TBI-containing regimens, when administered for URD BMT. With decreasing treatment-related mortality, it is justified to proceed early to URD BMT for patients with poor prognostic features.

Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study.

Factor XIII (FXIII) is a plasma transglutaminase that covalently cross-links fibrin proteins to one another and to other proteins, increasing the mechanical strength of blood clots. Endogenous FXIII is the final enzyme in the clotting cascade and circulates as a heterotetramer comprising 2 FXIII-A subunits and 2 FXIII-B subunits. Recombinant human FXIII A2 (rFXIII) homodimer is produced in Saccharomyces cerevisiae. Upon injection, rFXIII combines with the free FXIIIB subunit that circulates in excess to form the rA2B2 tetramer. In this placebo-controlled, double-blind, multi-dose study, the safety, pharmacokinetics, and pharmacodynamics of rFXIII were studied in 24 healthy volunteers, who were randomized in 2 cohorts of 12 subjects each. In each cohort, 8 subjects received 5 daily intravenous doses of rFXIII (10 or 25 U/kg), and 4 subjects received placebo. Recombinant FXIII was well tolerated. No deaths or serious adverse events occurred. The type and frequency of adverse events showed no pattern or dose response. No clinically significant changes in haematology, serum chemistry, or urinalysis laboratory values were observed. No clinical coagulopathy or thrombosis was observed. Recombinant FXIII did not produce any anti-yeast or anti-FXIII antibodies. After 5 daily doses of rFXIII, accumulation indices indicated a 3 to 4fold accumulation of rFXIII in plasma. The elimination half-life, estimated for rFXIII as the heterotetramer, ranged from 228-346 hours for the 10U/kg dose group and 167-197 hours for the 25U/kg dose group. The safety, pharmacokinetic, and immunogenic profile of rFXIII suggests it may have potential use in patients with congenital or acquired FXIII deficiency.

Pharmacokinetics and tolerability of factor XIII concentrates prepared from human placenta or plasma: a crossover randomised study.

The pharmacokinetics and tolerability of factor XIII (FXIII) from plasma were compared with those of FXIII from placenta in a randomised, double-blind, crossover study involving 13 patients with congenital FXIII deficiency. Both FXIII activity and FXIII antigen were monitored. No difference was seen in the mean half-lives of the two preparations (9.3 days and 9.1 days for plasma and placenta FXIII activity, respectively). Response was similar for both preparations, but was slightly greater for FXIII from plasma (1.6 ormula: see text] vs 1.5 [formula: see text]). Similar results were found for recovery (65% vs 60%). The area under the data completed by extrapolation was significantly higher for FXIII from plasma. No differences between preparations in terms of efficacy or tolerability were observed. It can be concluded that treatment with FXIII concentrate from plasma is as efficient as with FXIII concentrate from placenta in terms of recovery and half-life. Both preparations were equivalent in terms of safety during the observation period. With the administration of monthly injections of approximately 30 U/kg serious bleeding events were prevented and no other serious adverse events occurred.

Hepatitis C antibody and chronic liver disease in haemophilia.

A radioimmunoassay was used to detect antibodies to hepatitis C virus (anti-HCV) in 154 patients with haemophilia. Prevalence of anti-HCV was associated with exposure to clotting factor concentrates. 76 of 129 (59%) who had received factor VIII or IX had anti-HCV: 42 of 55 (76%) who required over 10,000 units of concentrate annually had anti-HCV, compared with 34 of 74 (46%) who required less, and 0 of 25 patients who had never received concentrates. Anti-HCV were significantly more common in patients seropositive for antibodies against human immunodeficiency virus (anti-HIV) or with markers of previous hepatitis B infection than in those without anti-HIV or hepatitis B markers (88% vs 39% and 75% vs 46%, respectively). 5 of 23 (22%) haemophiliacs treated only with heated concentrates had anti-HCV compared with 71 of 106 (67%) patients who received unmodified products. 35 patients with chronic liver disease underwent liver biopsy: histological examination showed features associated with post-transfusion hepatitis in 24, all of whom were anti-HCV-positive; of the other 11 patients with no histological features of non-A, non-B hepatitis, 5 were anti-HCV-positive. HCV appears to be the major predisposing factor for most non-A, non-B hepatitis and chronic liver disease in haemophilia.

Successful use of fibrin glue during 2 years of surgery at a university medical center.

A method for producing concentrated fibrinogen, an essential component of fibrin glue, from individually stored, single-donor units of human plasma is reported. The plasma is screened for hepatitis B antigen and HIV-1 virus to reduce the risk of transmission of hepatitis and acquired immunodeficiency syndrome (AIDS). This material is routinely stocked in some operating rooms. It is thus readily available when requested by a surgeon for use in combination with topical bovine thrombin to produce fibrin glue. From April 1985 to March 1987 this material was used by surgeons from eight different surgical specialties on 413 patients with a 91 per cent success rate (376/413). Uses have included sealing vascular suture lines, reinforcing pulmonary and esophageal staple lines, closing dural cerebrospinal fluid leaks, fixing split-thickness skin grafts, reducing lymphatic leakage, and controlling bone bleeding. Additional uses include closure of bronchopleural fistulas by means of the flexible bronchoscope, reduction of perioperative hemorrhage by spraying fibrin glue on the anterior mediastinum during cardiac surgery, and reduction of bleeding during debridement of burn eschars. Careful monitoring and patient follow-up detected no cases of transmission of blood-borne diseases. Only one complication, a local wound infection, has been documented. This material has been an important adjunct for the surgical services and may be safely used at hospitals with local blood bank facilities.

Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study.

A multicenter study was conducted to test the efficacy and safety of fibrin sealant as a topical hemostatic agent in patients undergoing either reoperative cardiac surgery (redo) or emergency resternotomy. A total of 333 patients from 11 centers in the United States were included in the study. Patients were randomly assigned to initially receive the fibrin sealant or a conventional topical hemostatic agent when such was required during an operation. The end point used to evaluate the agent's efficacy was local hemostasis, the number of bleeding episodes controlled within 5 minutes. The fibrin sealant group from the prospective study was compared with historical matched control subjects for postoperative blood loss, need for resternotomy, blood products received, and hospital stay. It was also compared with historical nonmatched control subjects for the incidence of resternotomy and mortality. The results showed a 92.6% success rate for fibrin sealant in controlling bleeding within 5 minutes of application, compared with only a 12.4% success rate with conventional topical agents (p less than 0.001). Fibrin sealant also rapidly controlled 82.0% of those bleeding episodes not initially controlled by conventional agents. High-volume postoperative blood loss was significantly less (p less than 0.05) in the fibrin sealant group than in the matched controls. Additionally, resternotomy rates after redo operations were significantly lower in the fibrin sealant group (5.6%) than in the nonmatched historical control group (10%) (p less than 0.0089). There were no significant differences in hospital stay or blood products received between the fibrin sealant group and matched historical controls and no difference in mortality between the fibrin sealant group and nonmatched historical controls. There were no documented instances of adverse reactions, transmission of viral infection (hepatitis B, non-A/non-B hepatitis), or human immunodeficiency virus seroconversion. This study shows that fibrin sealant is safe and highly effective in controlling localized bleeding in cardiac operations. Fibrin sealant reduces postoperative blood loss and decreases the incidence of emergency resternotomy. These findings make fibrin sealant a valuable hemostatic agent in cardiac surgery.