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CARDIOVASCULAR ANESTHESIA

Hemostatic Changes in Patients Receiving Hydroxyethyl Starch: The Influence of ABO Blood Group

Catherine Huraux, MD^*, Annick Ankri A, MD, Daniel Eyraud, MD^*, Odile Sevin, Fabrice Ménégaux, MD, Pierre Coriat, MD^*, and Charles-Marc Samama, MD, PhD^*

*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 d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 47, Boulevard de l’Hôpital, 75651 Paris, Cedex 13, France. Address e-mail to catherine.huraux{at}psl.ap-hop-paris.fr

	Abstract

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Hydroxyethyl starches (HES) interfere with coagulation because of their molecular structure and the amount infused during surgery. Coagulation defects include platelet dysfunction and a decrease of the VIII/von Willebrand factor complex (VIII/vWF). We examined the effects of 6% HES 200/0.6 on hemostasis by using an in vitro platelet function analyzer, the usual coagulation tests, the VIII/vWF complex assessment, and TEG® analysis in patients undergoing abdominal surgery. The influence of the blood group was investigated. HES infusion induced primary hemostasis alterations, assessed by a prolonged platelet function analyzer closure time in the presence of epinephrine and adenosine diphosphate, which was not correlated with the platelet count. The decrease in VIII/vWF complex was proportional to the volume of infused HES (20 and 30 mL/kg) and was more pronounced in patients of the O blood group. The preoperative hypercoagulability status assessed by TEG® analysis was reversed 24 h after HES infusion. In conclusion, 6% HES 200/0.6 induced immediate hemostasis alterations. Patients of the O blood group were likely to develop a von Willebrand-like syndrome after HES infusion. We conclude that intraoperative use of 6% HES 200/0.6 should be restricted in patients of the O blood group undergoing surgical procedures with high risk for bleeding.

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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In surgical patients, colloids are used as plasma substitutes because of their ability to increase intravascular volume compared with crystalloids: the volume expansion is larger with colloids (0.8 to 1.4 times) compared with crystalloids (0.2 times). However, bleeding complications can occur with the use of hetastarch, a high-molecular-weight colloid solution (1,2). These effects have been related to the types of solutions available in the market and to the amount and duration of hydroxyethyl starch (HES) infusion (3). Other studies have produced controversial data regarding the effects of HES on hemostasis during the perioperative period: Vogt et al. (4) compared HES 6% 200/0.5 with 5% albumin infusion and showed no influence of HES on bleeding and blood transfusion requirements in patients undergoing total hip arthroplasty. HES infusion-induced adverse effects are well described, although their mechanisms are not fully understood. HES infusion decreases the VIII-von Willebrand factor (vWF) complex, resulting in a vWF-like syndrome (5). The effects on platelet function are more controversial. In an in vitro model, Blaicher et al. (6) observed no significant impairment in platelet aggregability, whereas the assessment of platelet function in vivo remains unknown. Moreover, patients of the O blood group have a lower level in VIII/vWF complex (7). However, no report has measured the vWF plasma level in patients of the O blood group and in patients of the non-O blood groups or compared the bleeding risk in both populations. The question of whether HES infusion-induced VIII/vWF complex decrease was more pronounced in patients of the O blood group was raised.

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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Forty patients scheduled for abdominal surgery were involved in the study after ethical committee approval. Exclusion criteria included hemoglobin levels <12 g/dL, platelet count <1.50 x 10¹¹/L, hemostasis disorders, cardiovascular diseases, increased serum creatinine levels (>120 µmol/L), history of liver dysfunction, previous sensitization to HES, and use of antiplatelet agents. The following characteristics were recorded: sex, age, body weight, and preoperative treatments. All patients received premedication with hydroxyzine or midazolam. Intraoperative monitoring included three leads of electrocardiogram, cuff blood pressure, oxygen saturation, expired CO₂, and esophageal temperature. The trachea was intubated after infusion of sufentanil (0.5 µg/kg), propofol (1 to 3 mg/kg), and atracurium (0.5 mg/kg). Anesthesia was maintained with inhaled isoflurane (0.5 to 1 minimum alveolar anesthetic concentration) in a mixture of oxygen and NO₂ (50%:50%). Prophylactic IV antibiotic therapy was administered according to the surgical procedure. Patients received 20 mL/kg HES (6% Elohes^® 200/0.6; Fresenius^TM, Sèvres, France), or 30 mL/kg HES infusion. The volume requirements were assessed by the clinical estimation of blood loss, the hemodynamic variables, and the duration of surgery. The mean rate of infusion was 10 mL · kg^-1 · h^-1. Bleeding was measured during and after surgery (aspiration volume, surgical fields, pad weights, and suction bottles). An hemoglobin level <8 g/dL triggered red blood cell transfusions. Patients were then transferred to the postanesthesia care unit, where they were extubated. Deep vein thrombosis was prevented by a daily subcutaneous injection of low molecular weight heparin (dalteparin sodium, 5000 IU anti-Xa) started 6 h after the end of surgery.

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-100^TM (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-l’Etoile, 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 Student’s 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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Patient characteristics and details of surgical procedures are presented in Table 1. Group 1 included patients who received 20 mL/kg HES (n = 26), and Group 2 included those who received 30 mL/kg HES (n = 14). There was no significant difference regarding age and sex ratios between groups. The O blood group was found in 18 (45%) of 40 patients.

View larger version (14K): [in this window] [in a new window]   Figure 1. Effects of hydroxyethyl starch (HES; 6% Elohes®, 200/0.6; FreseniusTM) on the closure time (CT) assessed by the PFA-100TM analyzer with a collagen-epinephrine and collagen-adenosine diphosphate (ADP) test cartridge in Group 1 (n = 26) and Group 2 (n = 14). Group 1 received 20 mL/kg HES and Group 2 received 30 mL/kg HES. HES infusion prolonged the CT in the presence of epinephrine, whereas the prolonged CT in the presence of ADP was not as pronounced. The volume of infused HES did not clearly influence the CT. *P < 0.05.

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-100^TM system between groups. The TEG^® data were identical before and after HES infusion in the two groups.

View larger version (27K): [in this window] [in a new window]   Figure 2. Influence of the blood group on the VIII/von Willebrand factor (VIII/vWF) complex of the patient. In the preoperative period (Panel A), the factor VIII activity (VIII:C), the von Willebrand antigen (vWF), and the von Willebrand ristocetin cofactor activity (vWFRCo) were significantly less in patients of the O group compared with patients of the non-O group, indicated with *. 20 mL/kg HES infusion decreased the VIII/vWF complex, and the difference between the two groups remained significant (Panel B).

	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-100^TM 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 (10–12). 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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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (20) Citing Articles via Google Scholar Google Scholar Articles by Huraux, C. Articles by Samama, C.-M. Search for Related Content PubMed PubMed Citation Articles by Huraux, C. Articles by Samama, C.-M. Related Collections Cardiovascular Blood

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999