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.

Efficacy and tolerability of a pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiency.

The efficacy and tolerability of a pasteurised human fibrinogen concentrate were assessed in an open, multi-centre, non-controlled retrospective study in patients with congenital fibrinogen deficiency. Haemostatic efficacy was assessed by laboratory investigation and clinical observation. The study included 12 patients (afibrinogenaemia, n = 8; hypofibrinogenaemia, n = 3; dysfibrinogenaemia combined with hypofibrinogenaemia, n = 1). Fibrinogen substitution was indicated: to stop an ongoing bleed; as prophylaxis before surgery; or for routine prophylaxis to prevent spontaneous bleeding. In total, 151 fibrinogen infusions were recorded. The median single dosage was 63.5mg/kg body weight for bleeding events or surgery and 76.9 mg/kg for prophylaxis. The median total dose per event for bleeding events or surgery was 105.6 mg/kg. Fibrinogen was administered in 26 bleeding episodes; 11 surgical operations; and 89 prophylactic infusions, of which 86 were received by one patient. The median response (n = 8) was 1.5 mg/dl per substituted mg of fibrinogen per kg body weight (0.8-2.3). The median in vivo recovery (n = 8) was 59.8% (32.5-93.9). Clinical efficacy was very good in all events with the exception of one surgical procedure, where it was moderate. No intercurrent bleeding occurred during prophylaxis. All but one infusion was well tolerated; the patient, who was administered 86 prophylactic infusions, experienced an anaphylactic reaction after the 56th infusion. In addition, one patient developed deep vein thrombosis and non-fatal pulmonary embolism with treatment for osteosynthesis after collum femoris fracture. Fibrinogen substitution could not be excluded as a contributing factor in this high-risk patient. Substitution with pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiencies is efficient and generally well tolerated.

Pharmacokinetic properties of a pasteurised fibrinogen concentrate.

The main pharmacokinetic characteristics of a plasma-derived, pasteurised fibrinogen concentrate were assessed in an open, multicentre, non-controlled study in five patients with congenital afibrinogenaemia or severe congenital hypofibrinogenaemia. Plasma samples were assayed for fibrinogen content in laboratories of the participating clinical centres (CCs) and additionally in a central laboratory at Aventis Behring (ABL). The values of the pharmacokinetic variables, using the fibrinogen determination at ABL, yielded a somewhat shorter terminal half-life compared with that determined at the CCs, with median (range) values of 2.7 days (2.5-3.7 days) versus 3.6 days (3.0-5.3 days), respectively. Fibrinogen clearance rate was clearly lower at the ABL with values of 0.91 ml/h/kg (0.84-1.22 ml/h/kg) compared with 1.65 ml/h/kg (0.82-2.55 ml/h/kg) at the CCs. The distribution volume at steady state (V-ss) of 89 ml/kg (81-116 ml/kg) was also smaller at the ABL than at the CCs (101 ml/kg [84-139 ml/kg]). Response, in vivo recovery and area under the curve did not differ noticeably between the laboratories. The normalisation or near normalisation of pre-infusion pathological coagulation tests indicated a good haemostatic efficacy of the tested fibrinogen concentrate, which was also generally well tolerated and not associated with any serious adverse reactions.

C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction.

OBJECTIVE: To investigate the efficacy and the safety of the parenteral administration of C1-inhibitor to patients with severe sepsis or septic shock. DESIGN: Double blind, randomized, and placebo-controlled trial. SETTING: Surgical and medical intensive care units of a tertiary care university hospital. PATIENTS: Forty consecutive patients (20 C1-inhibitor/20 placebo) who entered the intensive care unit with severe sepsis or septic shock. INTERVENTION: C1-inhibitor intravenously in a 1-hr infusion, starting with 6000 IU, followed by 3000 IU, 2000 IU, and 1000 IU at 12-hr intervals, compared with placebo. MEASUREMENTS AND MAIN RESULTS: C1-inhibitor administration significantly increased plasma C1-inhibitor antigen and activity levels during days 1-4 (p <.007). Patients in the C1-inhibitor group had significantly lower serum creatinine concentrations on day 3 (p =.048) and 4 (p =.01) than placebo patients. Multiple organ dysfunction assessed by logistic organ dysfunction and sepsis-related organ failure assessment scores was less pronounced in patients treated with C1-inhibitor. Mortality rate was similar in both groups. There were no C1-inhibitor-related side effects. CONCLUSIONS: C1-inhibitor administration attenuated renal impairment in patients with severe sepsis or septic shock.