Letters to the Editor: Letters & Announcements
Thank you for the opportunity to respond to the comments of Dr. Nielsen to our article (1).
Enhanced hemostasis may result from an increase in procoagulants such as activated platelets or increased levels of ionized calcium, a decrease in anticoagulants such as heparin-dependent serpins, or a combination of both. The novel hetastarch diluted in a balanced electrolyte formulation containing calcium, lactate buffer, and a physiologic level of glucose (Hextend®) has been reported to enhance hemostasis: lower thromboelastographic R values were found in patients receiving Hextend® compared with hetastarch in saline (2). Similarly, lower R times were observed by Nielsen et al. after 75% in vitro dilution of blood with Hextend® (3) and after about 40% isovolemic hemodilution in rabbits (4) when compared with albumin. The underlying mechanisms for enhanced dynamic clot formation after Hextend® still remain unclear. Among other factors, ionized calcium levels affect R time. In vitro 75% hemodilution using albumin significantly deceased calcium concentrations and prolonged R time, which was reversible by calcium supplementation (3). In contrast to albumin, isovolemic hemodilution using Hextend® containing calcium in the commercially available solution resulted in no decrease in calcium levels (3–5). Similarly, Hextend-treated patients required less intraoperative calcium and were less likely to receive calcium supplementation than patients treated with hetastarch in saline (2). In his letter, Dr. Nielsen stated that we misinterpreted his studies in our discussion section (1). However, the discussion on the importance of calcium in facilitating hemostasis was clearly related to our study results performed in citrated whole blood.
R time is also dependent on platelet procoagulant activity. Our in vitro experiments demonstrated an increase in platelet activation after incubation of citrated whole blood with Hextend® and indicate that this effect is, at least in part, due to the solvent of Hextend® containing calcium (1). Maintenance of calcium concentration within physiological ranges and acid-base balance may attenuate fluid-specific pharmacodynamic effects of Hextend® on platelets. Nielsen questions in his letter this potential mechanism by demonstrating some data on low calcium levels achieved after in vitro Hextend® dilution that were below the threshold for plasma clotting kinetics. To the best of our knowledge a calcium level threshold for calcium-mediated platelet activation has not been determined. Calcium is the key second messenger in platelets and although not determined in detail so far, a high sensitivity of platelets to the extracellular electrolyte milieu can be anticipated.
R time is further dependent on anticoagulants. Since in vitro experiments exclude many compensatory changes such as anticoagulant production, secretion, and removal, as well as modifying mechanisms of the endothelium, our findings are not likely to be related to anticoagulant activities. In vivo, however, the decrease in heparin-dependent serpin activities in the presence of Hextend® as reported by Nielsen et al. (4,5) has to be considered as a cause of enhanced hemostasis.
E. Deusch, MD
S. Kozek-Langenecker, MD
Medical University of Vienna; Vienna, Austria; firstname.lastname@example.org
1. Deusch E, Thaler U, Kozek-Langenecker S. The effects of high molecular weight hydroxyethyl starch solutions on platelets. Anesth Analg 2004;99:665–8.
2. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. Hextend, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Anesth Analg 1999;88:992–8.
3. Nielsen VG, Baird MS. Extreme hemodilution in rabbits: an in vitro and in vivo thrombelastographic analysis. Anesth Analg 2000;90:541–5.
4. Nielsen VG. Resuscitation with Hextend® decreases endogenous circulating heparin activity and accelerates clot initiation after hemorrhage in the rabbit. Anesth Analg 2001;93:1106–10.
5. McCammon AT, Wright JP, Figueroa M, Nielsen VG. Hemodilution with albumin, but not Hextend®, results in hypercoagulability as assessed by thrombelastography in rabbits: role of heparin-dependent serpins and factor VIII complex. Anesth Analg 2002:95:844–50.