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Abstract |
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We evaluated the effects of hydroxyethyl starch with a molecular weight of 200 kD (HES 200 kD) on platelets to gain insight into the potential mechanisms involved in the anticoagulant effects of HES 200 kD. Blood was obtained before and after an IV infusion (10 mL/kg) of either saline (n = 15) or HES 200 kD (n = 15) in otherwise healthy patients scheduled for minor elective surgery. Flow cytometry was used to assess the expression of glycoprotein (GP) IIb-IIIa, GP Ib, and P-selectin on agonist-activated platelets. Overall platelet function was evaluated by assessing thromboelastographic maximum amplitude (MA) in celite-activated blood and platelet function analyzer-closure times by using collagen/adenosine diphosphate cartridges. Saline infusion had no effects on platelet variables, whereas HES 200 kD reduced GP IIb-IIIa expression and MA and prolonged platelet function analyzer-closure times, without affecting the expression of P-selectin and GP Ib. In vitro experiments extended these observations by a concentration-related inhibiting effect of HES 200 kD on GP IIb-IIIa expression. This study demonstrates that cellular abnormalities with decreased availability of platelet GP IIb-IIIa are involved in the anticoagulant effects of HES 200 kD.
Implications: The present data indicate that an antiplatelet effect of hydroxyethyl starch 200 kD should be considered during plasma volume expansion with this synthetic colloid.
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Introduction |
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Synthetic colloids are widely used for plasma volume expansion and have been implicated in the impairment of the coagulation system in vitro (1–4). However, extrapolating experimental in vitro findings to clinical practice is difficult. Although hydroxyethyl starch (HES) may cause platelet dysfunctions in vivo when administered in large quantities (5,6), in vivo effects of clinically relevant volumes (less than 20 mL · kg-1 · d-1) or the relation between the in vitro and in vivo effects of HES on platelets remain poorly understood. The mechanism of the observed antiplatelet action of HES has not been fully delineated, but plasmatic abnormalities, such as decreases in Von-Willebrand factor (7,8), fibrinogen levels (9), and thrombin generation (4), may contribute to a decreased platelet responsiveness. However, pharmacological normalization of Von-Willebrand factor levels by desmopressin did not reverse prolonged bleeding times after HES administration (7), and the addition of thrombin did not restore platelet function in aggregation studies (4).
Together, these results indicate that abnormalities, other than plasma levels of coagulation factors, may be involved in the antiplatelet effects of HES. We hypothesized that cellular abnormalities play a role in HES-induced platelet dysfunctions. Accordingly, we assessed platelet aggregability and adhesive capacity on individual cells by evaluating platelet surface receptor expression using whole blood flow cytometry. This method of flow cytometry is increasingly used for characterization of cellular abnormalities of platelets because this technique permits assessment of platelet reactivity in a physiological manner (10,11). Maximal amplitude (MA) in the thrombelastographic tracing and platelet function analyzer (PFA)-closure times were also evaluated in the present study as indices of overall platelet function (12,13). The molecular weight of HES solutions and the degree of substitution are important characteristics in determining their effects on blood coagulation (14–16). We investigated the effects of the HES solution most commonly used in European countries with a mean molecular weight of 200 kD and a degree of substitution of 0.6–0.66. We performed platelet analyses of whole blood in patients before and after an IV infusion of clinically relevant volumes of HES 200 kD or saline, as well as in whole blood after hemodilution with HES 200 kD or saline in vitro.
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Methods |
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Blood samples were obtained from 30 otherwise healthy patients scheduled for minor elective surgery, such as inguinal hernia repair and knee arthroscopy. All participants denied taking any medication within the previous 14 days. Exclusion criteria were preexisting bleeding disorders, renal dysfunction, and liver disease. Patients fasted for 10 h and received no premedication before the study. The study was approved by the institutional review board, and written, informed consent was obtained from all participants.
Patients received a test infusion of 10 mL/kg of either 0.9% saline (n = 15) or HES (Elohäst® 6%; Fresenius Pharma Austria GmbH., Graz, Austria) 200 kD (n = 15) administered IV for 30 min. Blood samples were obtained before, as well as immediately after, the IV test infusion. Blood was withdrawn by venipuncture without stasis from the antecubital vein contralateral of the infusion site into Vacutainer®TM tubes (Becton Dickinson, Rutherford, NJ) containing 3.8% trisodium citrate (9:1 vol/vol) after discarding the first 3 mL. Samples were processed within 3 min. All blood samples were taken before the induction of anesthesia for elective surgery. Demographic data and preinfusion coagulation variables of the study population were documented.
The following measurements were performed on duplicate samples. For assessment of platelet function using flow cytometry, blood was diluted (1:5) in phosphate-buffered saline (100 mM sodium phosphate, pH 7.3, and 0.145 M NaCl). Each phosphate-buffered saline-diluted sample was further divided into six aliquots for fluorescent staining. To evaluate the extent of platelet reactivity, three aliquots were incubated with the strong platelet agonist thrombin receptor activator peptide 6 (TRAP, 60 µM; SFLLRN, Bachem AG, Bubendorf, Switzerland), and three aliquots were incubated with the weak platelet agonist adenosine diphosphate (ADP, 10 µM; Sigma Chemical Co., St. Louis, MO) before flow cytometric analysis. Pilot studies confirmed that these concentrations of platelet agonists induced maximum responses in monoclonal antibody binding. Flow cytometric analysis was performed as described previously (17). Platelet activation transforms platelet membrane glycoprotein (GP) IIb-IIIa complexes to a conformational state that is competent for binding fibrinogen (18). To determine the expression of activated GP IIb-IIIa complex, one aliquot of each agonist-activated sample was incubated with a fluorescein isothiocyanate (FITC)-conjugated activation-dependent antihuman platelet GP IIb-IIIa monoclonal antibody, PAC-1TM (Becton Dickinson Immunocytometry Systems, San Jose, CA). Platelet membrane GP Ib, the receptor for Von-Willebrand factor, mediates platelet adhesion and binding of platelets to subendothelium (19). To determine the expression of Von-Willebrand receptor GP Ib, one aliquot of each agonist-activated sample was incubated with a FITC-conjugated monoclonal antibody (anti-CD42bTM; Becton Dickinson Immunocytometry Systems). P-selectin, which is expressed on the surface of activated platelets as the internal alpha-granule membrane becomes integrated into the cytoplasmatic membrane (20), serves as a marker for platelet secretion and activation. To determine the percentage of platelets expressing P-selectin, the remaining aliquot of each agonist-activated sample was incubated with a FITC-conjugated activation-independent antihuman platelet GP IIIa monoclonal antibody (anti-CD61TM; Becton Dickinson Immunocytometry Systems), which binds to all platelets, and a phycoerythrin-conjugated monoclonal antibody against human platelet P-selectin (anti-CD62PTM; Pharmingen, San Diego, CA). After 30 min of incubation with saturating concentrations of monoclonal antibodies at room temperature in the dark, samples were fixed in 1% paraformaldehyde (pH 7.3) at 4°C. In each experiment, one tube was used to evaluate cellular autofluorescence, and another for isotype control. Fluorescence was measured with a FACSCaliburTM flow cytometer and analyzed with CellQuest 3.1TM software (Becton Dickinson Immunocytometry Systems). Quantum fluorescence microbeads (Calibrite BeadsTM; Becton Dickinson Immunocytometry Systems) were used each day for the standardization of instrument settings. A Thrombelastograph® (TEG®; Haemoscope, Morton Grove, IL) records the dynamics of whole blood coagulation, including the interaction of cellular elements and coagulation factors (12). For thromboelastographic testing, 360 µL of 1% celite-activated blood was recalcified with 40 µL 0.2M CaCl2 and analyzed at 37°C. The basic functional principle of the TEG® has been described previously (12). Thromboelastographic MA was documented as a variable of platelet function (normal range: 45–53 mm). For assessment of PFA-closure times, 800 µL of blood was analyzed by using the PFA-100® (Dade, Miami, FL) with collagen/ADP as agonists. The principle of the PFA-100® is very similar to that described by Kratzer and Born (21). The blood is aspirated through a capillary with a coated membrane and passes through an aperture. In response to the stimulation by collagen and ADP present in the coating and the shear stresses at the aperture, platelets adhere and aggregate on the collagen surface. The platelet plug ultimately occludes the aperture. The time required to obtain full occlusion of the aperture is defined as the PFA-closure time (normal range: 71–118 s).
To evaluate concentration-related effects of HES 200 kD and saline on the expression of activated GP IIb-IIIa, citrated whole blood was obtained from 10 patients before the administration of their test infusion. Blood was pipetted into five polypropylene tubes: 800 µL of blood was incubated with 200 µL (20% hemodilutions) of either HES 200 kD or saline, 600 µL of blood was incubated with 400 µL (40% hemodilutions) of either HES 200 kD or saline, and 1000 µL of blood was not further diluted (undiluted control). Incubations were performed at room temperature for 5 min. Flow cytometric analysis was performed as described above by using TRAP for platelet activation and monoclonal antibody PAC-1 for fluorescent staining. The pH level of all samples was documented.
Data were tested for normal distribution by using the Kolmogorov-Smirnov-test. The effect of the IV test infusion on platelet function was analyzed by using a paired t-test. Differences between the two groups were analyzed by using unpaired Student’s t-test. The effect of in vitro hemodilution was assessed by using analysis of variance for repeated measures. Post hoc comparisons between undiluted control and hemodilutions were made with a paired t-test. The level of significance was adjusted according to Bonferroni’s correction. Data were expressed as mean ± SD.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Demographic data and preinfusion coagulation variables were comparable between the two groups (Table 1).
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Evaluation of platelet surface GP IIb-IIIa is shown in Figure 1A. The monoclonal antibody PAC-1 was used to identify activated GP IIb-IIIa complex on agonist-activated platelets in citrated whole blood. Saline infusion had no effect on GP IIb-IIIa expression on both TRAP and ADP agonist-activated platelets. The IV infusion of HES 200 kD decreased GP IIb-IIIa expression on TRAP-activated platelets by 22% ± 9% and on ADP-activated platelets by 18% ± 10% when compared with preinfusion values (P < 0.05).
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Evaluation of platelet surface GP Ib is shown in Figure 1B. The monoclonal antibody anti-CD42b was used to identify GP Ib receptors on agonist-activated platelets in citrated whole blood. Both HES 200 kD and saline had no effect on GP Ib expression on both TRAP and ADP agonist-activated platelets.
Evaluation of the expression of platelet P-selectin is shown in Figure 1C. Platelets were identified as positive for GP IIIa (CD61), and the presence of the monoclonal antibody against P-selectin (anti-CD62P) was used to determine the percentage of platelets expressing P-selectin. Both HES 200 kD and saline had no effect on the binding of anti-CD62P to P-selectin on both TRAP- and ADP-activated platelets.
To further evaluate the observed effect of decreased expression of the GP IIb-IIIa on activated platelets in the presence of HES 200 kD (Fig. 1A), we studied thromboelastographic MA in recalcified celite-activated blood and PFA-closure times using collagen/ADP cartridges (Table 2). Preinfusion values of MA exceeded the normal range in both groups, indicating a mild hypercoagulable preoperative state. The saline infusion had no significant effect on MA and PFA-closure times. The IV infusion of HES 200 kD decreased MA by 17% ± 6% (P < 0.05), and prolonged PFA-closure times by 27% ± 22% (P < 0.05) when compared with preinfusion values.
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The effect of in vitro hemodilution of blood samples with HES 200 kD and saline on the expression of GP IIb-IIIa on TRAP-activated platelets is shown in Figure 2. Dilution with saline had no significant effect on GP IIb-IIIa expression. Exposure of platelets to HES 200 kD decreased GP IIb-IIIa expression in a concentration-related manner when compared with undiluted controls. The pH values were similar between undiluted controls and in vitro hemodilutions and were below physiologic limits (7.15 ± 0.03).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Platelet activation transforms platelet GP IIb-IIIa complex to a conformational state that is competent for binding fibrinogen (18). This reaction is a prerequisite for platelet aggregation. In the current study, the expression of GP IIb-IIIa was determined by the binding of an activation-dependent antihuman platelet GP IIb-IIIa monoclonal antibody (PAC-1) to agonist-activated platelets (17). Results presented in Figure 1A demonstrate that HES 200 kD inhibits agonist-induced expression of GP IIb-IIIa after IV infusion at a clinically relevant volume of 10 mL/kg infused for 30 min in otherwise healthy patients scheduled for elective minor surgery. In vitro experiments extend the observation of HES 200 kD-induced platelet dysfunction: hemodilution of blood samples with HES 200 kD decreased GP IIb-IIIa expression in a concentration-related manner (Fig. 2). In contrast, IV infusion of saline in vivo, and in vitro hemodilution with saline, had no effect on GP IIb-IIIa expression (Figs. 1A and 2).
Together, these results indicate that cellular abnormalities with decreased availability of GP IIb-IIIa complex on activated platelets are involved in the antiplatelet effect of HES 200 kD, which has been observed previously (4,5,9,22,23). Decreased expression of activated GP IIb-IIIa complexes could be caused by a direct platelet-inhibiting effect of HES 200 kD. If so, downstream platelet responses such as release reaction should be decreased similarly. However, alpha-granule membrane protein expression on the platelet plasma membrane was unaffected by HES 200 kD, as determined by unchanged binding of a monoclonal antibody to P-selectin. Another possible explanation for the reduced availability of GP IIb-IIIa complex on activated platelets could be a modification of the platelet cytoplasmatic membrane structure by HES 200 kD, which inhibits conformational activation of the GP IIb-IIIa complex after subsequent stimulation. Such an unspecific coating effect of HES 200 kD does not appear to involve platelet adhesive capacity because platelet membrane expression of GP Ib was unaltered in our experiments. These possible pathophysiological mechanisms warrant further evaluation at the molecular level.
Thromboelastographic MA and PFA-closure times were evaluated as on-site platelet assays. The MA and PFA-closure times depend on the interaction of platelet membrane receptors GP IIb-IIIa and GP Ib with their ligands such as fibrinogen and Von-Willebrand factor (12,13). Confirming previous reports (1–3,24), we observed a decrease in MA after the IV infusion of HES 200 kD, as well as a prolongation in PFA-closure times (Table 2). Together, our study indicates that HES 200 kD impairs MA and PFA-closure times by attenuating the availability of activated GP IIb-IIIa complexes. The molecular weight of HES solutions and the degree of substitution are important characteristics determining their effects on blood coagulation (14–16). Additional studies are needed to compare potential antiplatelet effects of HES 200 kD with HES 450 kD available in the United States and with the recently developed HES 40 kD.
One limitation of our study is that the degree of hemodilution after the IV infusion of 10 mL/kg of either HES 200 kD or saline was not controlled. However, there are no homeostatic mechanisms in vitro. Thus, controlled degrees of hemodilution achieved in the in vitro experiments demonstrate a genuine concentration-related antiplatelet effect of HES 200 kD. Another limitation of our study is that sodium citrate was used as an anticoagulant for platelet analysis. The anticoagulant per se as well as unphysiological calcium and pH levels may have influenced monoclonal antibody binding. However, electrolyte and pH values were comparable among all citrated blood samples. Therefore, the observed changes in antibody binding are suggested to represent genuine changes in platelet receptor availability.
The degree of platelet dysfunction which induces clinically important microvascular bleeding remains unknown. Nevertheless, the present data indicate that the observed inhibiting effect of HES 200 kD on platelet function should be considered during plasma volume expansion with this synthetic colloid. Reduced platelet reactivity may aggravate blood loss especially in patients with preexisting platelet dysfunction after long cardiac operations with cardiopulmonary bypass or in patients after massive fluid resuscitation.
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Acknowledgments |
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This work was supported by the Department of Anesthesiology and General Intensive Care, University of Vienna, Vienna, Austria.
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References |
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