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*Department of Anesthesiology;
Laboratory of Hematology; and
Department of General Surgery, Hôpital Pitié-Salpêtrière, Paris, France; and
Department of Anesthesiology, Hôpital Avicennes, Bobigny, France
Address correspondence and reprint requests to Catherine Huraux, Département dAnesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 47, Boulevard de lHôpital, 75651 Paris, Cedex 13, France. Address e-mail to catherine.huraux{at}psl.ap-hop-paris.fr
| Abstract |
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Implications: A von Willebrand-like syndrome occurred immediately after 6% HES 200/0.6 infusion in patients undergoing abdominal surgery. These hemostasis alterations were more pronounced in patients of the O blood group and may suggest a restricted intraoperative use of HES in this patients population undergoing surgical procedures with a high risk for bleeding.
| Introduction |
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Therefore, we examined the effects of 6% HES 200/0.6 on the coagulation status in O blood group patients and non-O blood group patients undergoing abdominal surgery.
| Methods |
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Blood samples were drawn by clean venipuncture and collected into Vacutainer tubes (Vacutainer; Becton Dickinson, Franklin Lakes, NJ) containing 0.129 mol/L trisodium citrate (1 volume) for the hemostatic tests and the measurement of thromboelastogram tracings (TEG®). Vacutainer tubes containing EDTA were used for the determination of hematocrit and platelet count. Blood was sampled before the induction of anesthesia, 5 min after HES infusion (20 and 30 mL/kg), and 24 h after the end of HES infusion. The samples were immediately transferred to the laboratory. At the time of each sample withdrawal, we recorded the volume and type of administered fluids other than HES, blood loss, urine output, body temperature, and adverse events.
Hematocrit and platelet counts were performed with an H1 analyzer (Bayer Technicon, Puteaux, France), and ABO blood groups were determined by standard agglutination assays.
The closure time was measured on the whole blood on a PFA-100TM (platelet function analyzer) system. This system (Dade-Behring, Paris-La Défense, France) simulates primary hemostasis in vitro. The system consists of a microprocessor-controlled instrument and a disposable test cartridge that contains a reservoir for whole blood and a capillary surmounted by a cup containing a collagen-coated membrane with a central aperture. The analyzer provides a constant negative pressure that aspirates whole blood (800 µL) through the capillary into the cup, where it comes into contact with the membrane and then passes through the aperture. In response to stimulation by collagen, in addition to either epinephrine or adenosine diphosphate (ADP), as well as by high shear rates, platelets adhere and aggregate on the membrane surface at the area surrounding the aperture. The platelet plug occludes the aperture. The time required to obtain occlusion of the aperture is defined as the closure time and is expressed in seconds. The upper limits of the normal range are 120 and 160 s for ADP and epinephrine, respectively, according to the manufacturer.
Enzyme-linked immunosorbent assays from Diagnostica Stago (Asnières, France) were used for measurement of plasmatic vWF (ASSERACHROM® vWF R). The vWF ristocetin cofactor activity (vWRCo) was assessed by a platelet agglutination method on a Behring coagulation timer analyzer by using a commercial kit, BC vWF reagent® (Dade Behring, Marburg, Germany). The normal values ranged from 50% to 110%.
Platelet-poor plasma was obtained by centrifugation at 3500g for 20 min at 15°C. Activated partial thromboplastin time (aPTT) was performed with Automated APTT (Organon Teknika Corporation, Durham, NC). Factor VIII coagulant (VIII:C) activity was evaluated by using a one-stage clotting assay with aPTT reagent and specific factor-deficient plasma with factor VIII-deficient plasma, HEMOLAB cofac VIII (BioMerieux, Marcy-lEtoile, France). All these tests were performed on the automated coagulometer STA (Diagnostica Stago).
The normal values for VIII:C were determined by manufacturers and ranged from 60% to 150%.
A TEG® tracing was obtained from the whole blood on a two-channel 3000T Thrombelastograph® (Haemoscope, Morton Grove, IL). A sample of 330 µL of whole blood was placed in a disposable cup inserted in a rotating metal cuvette heated to the corresponding body temperature. A piston with a rotation motion was dropped into the blood sample. The addition of 30 µL of CaCl2 (0.1M) triggered the coagulation cascade, and fibrin strands formed between the wall of the cuvette and the piston. An electronic amplification system allowed the characteristic tracing to be recorded. The TEG® tracings were measured for the standard variables r (time for initial fibrin formation; normal, 7.5 to 15 min); K (coagulation time; normal, 3 to 6 min);
angle (normal, 29 to 43 degrees) (
and K variables represent measures of the speed of clot strengthening); and MA (maximum amplitude clot strength; normal, 50 to 60 min). Hypercoagulability was defined by an increase of MA more than 60 and
angle more than 43 degrees.
Data were expressed as mean ± SD. The comparison of the values at different times were assessed using repeated-measures analysis of variance followed by a Scheffé test. A Students t-test for unpaired values was used for the comparison between male and female data and for studying the influence of the blood group on the hemostatic variables. A nonparametric Mann-Whitney U-test was performed for the comparison between the closure time (CT) values and the bleeding loss. Correlation between two variables was assessed with the least-squares method. All P values are two-tailed, and a P value <0.05 was considered significant.
| Results |
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Interestingly, there was no correlation between the CT values and both hematocrit and platelet count, either for the collagen-epinephrine test cartridges or for the collagen-ADP test cartridges after a 20-mL/kg HES infusion.
In Group 1, a 20-mL/kg HES infusion significantly decreased the coagulation index (3.2 ± 1.3 vs 1.5 ± 1.6), whereas the decrease in MA and
angle was not significant. TEG® data were in the normal range in the postoperative period (Table 2).
We further examined whether the hemostasis of the patients was influenced by the ABO group in the preoperative period and after a 20-mL/kg infusion. Before infusion of HES, platelet count and hematocrit showed no significant difference between O group and non-O group patients (Table 3). Interestingly, the aPTT and VIII/vWF complex were significantly different in patients in the O group compared with those in the non-O group (Fig. 2). The decrease of the VIII/vWF complex induced by the 20-mL HES infusion was slightly more pronounced in patients in the O group, and this difference was significant regarding vWRCo. There was no difference in the CT values obtained from the PFA-100TM system between groups. The TEG® data were identical before and after HES infusion in the two groups.
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| Discussion |
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The effects of HES infusion on primary hemostasis explored with the PFA analyzer were a prolonged CT in the presence of both epinephrine and ADP. These results might be partly related to the effects of hemodilution. However, the absence of correlation between hematocrit, platelet counts, and CT values suggests that there is likely another mechanism supporting an alteration in platelet functions. The PFA-100TM is relevant for detecting von Willebrand disease with both test cartridges (8,9). In our study, HES infusion-induced prolonged CT was more pronounced in the presence of epinephrine than ADP. Interestingly, the prolonged CT was detected immediately after HES infusion and returned to normal values 24 hours after the end of HES infusion.
The effects of HES on hemostasis include a type-I von Willebrand-like syndrome likely caused by an accelerated elimination of the VIII/vWF complex after complexing with HES (1012). Our study confirmed these data, showing that the decrease in factor VIII/vWF complex was dependent on the amount of infused HES. HES infusion led to an immediate decrease in VIII:C, vWF antigen, and vWRCo, which reversed with the elimination of HES.
Because individuals in the O group have lower levels of vWF than those of other groups, we sought to determine whether the coagulation status was different considering the blood group of the population (13). As expected, the VIII/vWF complex was significantly less before and after HES infusion in the O blood group patients, although the percentage differences after HES infusion were of the same magnitude in O group patients and other patients. Of note, the VIII/vWF complex values were dramatically decreased after 20 milliliters of HES infusion in patients of the O blood group. The question whether decreased VIII/vWF complex is correlated with increased bleeding risk remains to be clarified in this surgical population. Koster et al. (14) showed an increased risk of thrombosis with increasing vWF or factor VIII concentration. This risk was increased in patients of the non-O blood group compared with patients of the O blood group. One hypothesis is the potential differences in the release or catabolism of vWF for the several blood groups. In cardiac surgery, small levels of vWF represent one mechanism underlying bleeding complications (15). No data are available with regard to the role of the blood group on the risk for bleeding during and after surgery. In our study, seven patients who received 30 milliliters of HES had blood loss more than 1000 milliliters during the first postoperative day. Six of those were of the O blood group. However, most of these patients underwent procedures at high risk for bleeding, including esophagectomy, gastrectomy, pancreatectomy, and perineal amputation.
Low hematocrit has been thought to interfere with the primary hemostasis (16). The authors found that patients with severe anemia presented with a bleeding time prolongation, although platelet count and vWF activity were normal in this population. Two mechanisms may lead to decreased platelet adhesion to subendothelium surfaces: a small red cell count and a diminished release of ADP by lysed red blood cells. In our study, hematocrits were not significantly different between patients from Group 2 who experienced hemorrhage and those who did not.
The CT values for both epinephrine and ADP were slightly prolonged in the O group before and after HES infusion compared with the non-O group. It is noteworthy that CT values obtained after the 20 mL/kg HES infusion remained close to the upper limits of the normal range in the non-O group patients (CT epinephrine <160 seconds and CT ADP <130 seconds). In comparison, the CT values increased up to the normal range in patients of the O blood group, although the difference was not significant. In summary, our results indicate that HES infusions are likely to alter the primary hemostasis, particularly in patients of the O blood group.
The limitations of our study included the lack of comparison between HES and another solutions, such as crystalloids or albumin, and the variability of the surgical procedures. Other authors found that crystalloids and albumin compromised blood coagulation (17,18). Crystalloids lead to hypercoagulability, which might worsen surgery-induced hypercoagulability (19). In our study, the coagulation variables were in the normal range 24 hours after the end of HES infusion.
In conclusion, we confirmed that HES infusion impairs primary hemostasis in a volume-dependent manner. HES infusion may decrease the VIII/vWF complex more severely in patients of the O blood group. Therefore, the risk for bleeding during surgery might be higher in this patients population. HES infusion-induced hemodilution may enhance the risk for bleeding. Intraoperative use of 6% HES 200/0.6 should be restricted in patients of the O blood group undergoing surgical procedures with a high risk for bleeding.
| References |
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