Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding.

BACKGROUND: Excessive intraoperative bleeding is associated with significant morbidity and mortality. The authors and others have shown that fibrin monomer allows preoperative risk stratification for intraoperative blood loss, likely due to an imbalance between available factor XIII and prothrombin conversion. The authors hypothesized that the use of factor XIII would delay the decrease of clot firmness in high-risk patients. METHODS: The concept was tested in a prospective, randomized, double-blind, placebo-controlled trial in elective gastrointestinal cancer surgery. Patients were randomized to receive factor XIII (30 U/kg) or placebo in addition to controlled standard therapy. RESULTS: Twenty-two patients were evaluable for a planned interim analysis. For the primary outcome parameter maximum clot firmness, patients receiving factor XIII showed a nonsignificant 8% decrease, and patients receiving placebo lost 38%, a highly significantly difference between the two groups (P = 0.004). A reduction in the nonprimary outcome parameters fibrinogen consumption (-28%, P = 0.01) and blood loss (-29%, P = 0.041) was also observed in the factor XIII group. Three patients experienced adverse events that seemed unrelated to factor XIII substitution. The trial was stopped early after a planned interim analysis with the primary endpoint reached. CONCLUSIONS: This proof of concept study confirms the hypothesis that patients at high risk for intraoperative blood loss show reduced loss of clot firmness when factor XIII is administered early during surgery. Further clinical trials are needed to assess relevant clinical endpoints such as blood loss, loss of other coagulation factors, and use of blood products.

Preoperative fibrin monomer measurement allows risk stratification for high intraoperative blood loss in elective surgery.

We recently demonstrated that patients with increased blood loss due to intraoperative coagulopathy show a persistent pre-, intra- and postoperative increase in fibrin monomer concentration. We thus tested the hypothesis that preoperative fibrin monomer concentrations can be used as a risk indicator for intraoperative blood loss in a study designed for diagnostic test evaluation in 168 patients admitted to the surgical service of our hospital. Intraoperative blood loss increased with preoperative fibrin monomer concentration (median blood loss of 50, 100, 200 and 400 ml in preoperative fibrin monomer quartile groups 1 to 4, p<0.001, ANOVA on ranks; interquartile comparisons p < 0.05 (4/6), Mann Whitney Rank Sum test). In contrast, intraoperative blood loss was unrelated to preoperative values of prothrombin time, activated partial thromboplastin time and platelet count. By multivariate (logistic regression) analysis, only fibrin monomer remained a significant predictor of intraoperative blood loss > 500 ml when age, gender, BMI, fibrin monomer and the different types of surgical procedures (tumor surgery, vascular surgery, cholecystectomy, gastric banding, varicous vein surgery and hernia repair) were included as independent variables. Most importantly, accuracy evaluation showed that preoperative fibrin monomer concentration < 3 microg/l excluded intraoperative blood loss > 500 ml with 92% sensitivity and 95% negative predictive value. These results support our hypothesis that preoperative fibrin monomer concentrations are related to intraoperative blood loss in elective surgery. Fibrin monomer should be further investigated for it's potential to serve as a routine tool for preoperative risk stratification of intraoperative bleeding.