Which Hemostatic Changes Determine Clinical Outcome?

Abstract

In Response: Kozek-Langenecker and Scharbert's1 question regarding hemostatic changes that determine clinical outcome, e.g., blood loss and transfusion requirement is important.2 However, to answer it would have required a completely different study design, including a larger patient population, restriction to a single operative procedure and, lastly, a control group which, because of ethical reasons, was not considered. It was not our intention to await profound hemostasis derangement, which, independent of surgical blood loss, determines final blood loss. Furthermore, it should be remembered that transfusion of red cells is only a surrogate indicator of coagulation-dependent blood loss. For example, about 20% of patients undergoing hip or knee replacement need transfusion of red cells, although they show a rather hypercoagulopathic profile. In response to the comments by Kozek-Langenecker, we were surprised by the assumption that transfusion requirement, blood loss, fibrinogen administration should have been greatest in patients receiving gelatin solution. In actual fact, and as stated in the Results, transfusion requirements and fibrinogen administration were greatest in both colloid groups. Blood loss (especially also calculated loss, which should be more accurate), although not an independent variable in the study design, did not significantly differ for patients receiving lactated Ringer's solution, gelatin, or hydroxyethyl starch solution. Second, we did not claim that the change in ROTEM® parameters, especially that describing fibrinogen/ fibrin polymerization, predicts bleeding tendency, although several recent clinical studies have clearly shown that fibrinogen concentrations are related to bleeding volume2–5 and the ROTEM FIBTEM® assay enables this important coagulation factor to be monitored. Third, measurements of prothrombin time and von Willebrand Ristocetin Cofactor activity decreased significantly more with gelatin, whereas those of von Willebrand factor antigen were comparable among groups, and the activity of FVII and fibrinogen concentration was least with gelatin only at the late measurement points (AUC-BL A–F); these findings should be interpreted with caution in light of the small numbers of patients and the imbalance in groups, as shown in Table 2. Interestingly, despite the lower fibrinogen concentration at this late time, fibrinogen/fibrin polymerization was better maintained, although not statistically significant for gelatin when compared with hydroxyethyl starch. Last, Kozek-Langenecker asks whether the combined decreased activity of factors VII, VIII, IX, and von Willebrand factor might explain the differences in blood loss and fibrinogen requirement. All these factors, although they specifically and differently interact with primary platelet adhesion and thrombin generation and thus fibrinogen/ fibrin polymerization, were well within levels thought to guarantee adequate hemostasis. Indeed, the results of our study showed coagulation time to not significantly change in either infusion group, and, moreover, markers of thrombin generation (thrombin-antithrombin complex, d-dimer, prothrombin fragment F1 + 2) were similar in all groups, even at the late measurement times. Nevertheless, as stated in the Discussion, gelatin and hydroxyethyl starch might alter the kinetic profile of thrombin generation, which can be evaluated only with specific methods for measuring thrombin generation, which were not available at our institution at the time the study was conducted. However, even if this assumption is true, it is not known whether combined coagulation factor administration, as suggested by Kozek- Langenecker, can overcome this colloid-associated effect on thrombin kinetics and it is also not known whether this mechanism primarily affects fibrinogen/ fibrin polymerization. Nevertheless, it should be investigated in further studies. Markus Mittermayr, MD Corinna Velik-Salchner, MD Petra Innerhofer, MD Department of Anesthesiology and Critical Care Medicine Innsbruck Medical University Innsbruck, Austria [email protected]