SummaryCalibrated automated thrombography (CAT) enables continuous measurement of thrombin generation (TG). Initial clinical studies using the CAT method showed large variability of normal values, indicating the necessity for a standardized CAT protocol. This international study assessed the intra-and inter-assay imprecision of CAT as well as the inter-centre variability of results in five European centres using locally available reagents and conditions (study 1) and a standardized protocol in which results were normalized (study 2). Samples with and without corn trypsin inhibitor from six healthy volunteers, two haemophilia patients and one protein C deficient patient were assayed. Study 1 confirmed that the use of different sources and concentrations of tissue factor (TF) and different phospholipid (PL) mixtures produced large variability in results. The second study demonstrated that, using the same source and concentration of TF, PL and the same test procedure, this variability could be significantly reduced. Normalization of results improved the inter-centre variability. The benefit of contact factor inhibition prior to TG measurement was confirmed. These results demonstrated that standardization of CAT reduces the variability of results to acceptable limits. Standardization and normalization should be considered in future clinical studies which apply TG testing to clinical decision making.

Background and Purpose-The functional integrity of the hemostatic system is a prerequisite for the safe performance of neurosurgical procedures. To monitor the individual coagulation capacity of each patient, standard tests are effective to detect deficiencies involving the generation of fibrin. However, fibrin clot strength depends primarily on coagulation factor XIII, which cross-links fibrin monomers and enhances clot resistance against fibrinolysis. Therefore, factor XIII is functionally involved in both the hemostatic and fibrinolytic systems. The objective of this prospective study was to determine the incidence and clinical relevance of perioperative decreased factor XIII with respect to standard coagulation parameters and the occurrence of postoperative hematoma. Methods-In 876 patients, 910 neurosurgical procedures were performed. Prothrombin time (PT), partial thromboplastin time (PTT), platelet count, fibrinogen, and factor XIII were tested in each patient preoperatively and postoperatively. Results-Postoperative intracranial hematoma (defined as requiring surgical evacuation) occurred after 39 (4.3%) of 910 surgical procedures. Patients with postoperative hematoma had significantly lower factor XIII and fibrinogen levels preoperatively and postoperatively than patients without hematoma. In patients with postoperative hematoma, PT and platelets differed significantly only postoperatively, whereas PTT was different neither preoperatively nor postoperatively. Of the 39 patients with a postoperative hematoma, 13 (33.3%) had a postoperative factor XIII Ͻ60% compared with 61 (7%) of 867 patients without hematoma (PϽ0.01, Fisher's exact test). The relative risk of developing a postoperative hematoma is therefore increased 6.4-fold in patients with postoperative factor XIII Ͻ60%. The risk is increased 12-fold in patients who additionally have postoperative decreased fibrinogen levels (Ͻ1.5 g/L) and 9-fold in patients with platelet count Ͻ150ϫ10 9 /L and factor XIII Ͻ60%. Conclusions-This is the first prospective study that demonstrates the association of decreased perioperative factor XIII with an increased risk of postoperative hematoma in neurosurgical patients. The risk is further increased in those patients with low factor XIII and additional abnormalities of fibrinogen, PT, platelets, and PTT. Factor XIII testing and specific replacement, as accepted for other clotting factors, may reduce the risk of postoperative hematoma.

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Thrombin generation was investigated in platelet-rich plasma (PRP) from 11 healthy controls, 17 patients with severe haemophilia A and 7 patients with severe haemophilia B. Mean endogenous thrombin potential (ETP) in arbitrary fluorescence units (FU) was 226.9 +/- 44.6, 186.4 +/- 22.5, 154.2 +/- 41.3 in controls, haemophilia A and B, respectively, all at a platelet count of 200 x 10(9)/l (p = 0.004 for controls vs. haemophilia A, p = 0.003 for controls vs. haemophilia B, no significant difference between haemophilia A and B). The contribution of FVIII to thrombin generation in haemophilia A was 1.31 +/- 0.16 FU/% of FVIII:C activity, while for FIX in haemophilia B this was 0.80 +/- 0.21 FU/% of FIX activity. There was an almost linear relationship between increasing platelet count and thrombin generation up to a mean platelet count of 100 x 10(9)/l. Further increase in platelet count has only a marginal influence on thrombin generation. Platelets increase ETP in haemophilia A by 0.184 +/- 0.022 FU/10(9) platelets/l and in haemophilia B by 0.319 +/- 0.085 FU/10(9) platelets/l, and this was significantly different between the two groups (p = 0.0002). This influence of plate-lets diminishes with increasing concentration of either FVIII or FIX. In conclusion, there is a difference in thrombin generation between haemophilia A and B, and this may be attributed to the role of platelets in the assembly of the tenase complex on their surface.