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Anesth Analg 2007;104:425-430
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000253484.19070.87

GENERAL ARTICLES

A New Plasma-Adapted Hydroxyethylstarch Preparation: In Vitro Coagulation Studies Using Thrombelastography and Whole Blood Aggregometry

Joachim Boldt, MD, PhD, Michael Wolf, MD, and Andinet Mengistu, MD

From the Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany.

Address correspondence and reprint requests to Joachim Boldt, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Address e-mail to boldtj{at}gmx.net.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: The lack of acceptance of hydroxyethylstarch (HES) for intravascular volume replacement is most likely due to reports of abnormal coagulation. In a blinded in vitro study, we compared the effects on hemostasis of a new HES, prepared in a balanced solution, with a conventional HES preparation and Ringer’s lactate solution.

METHODS: Blood was taken from 10 healthy young male volunteers. Blood was diluted by 10%, 30%, and 50% using either 6% HES 130/0.42 prepared in a balanced solution, a conventional nonbalanced 6% HES 130/0.4 or Ringer’s lactate solution. Rotation thrombelastography, was performed after adding two activators (thromboplastin-phospholipid to monitor the intrinsic system; tissue factor to monitor the extrinsic system). Whole blood aggregometry adding adenosine diphosphate, collagen, and thrombin receptor-activating protein was used to assess changes of platelet function.

RESULTS: Dilution of blood (30% and 50%) resulted in clot formation time that was significantly more prolonged in the nonbalanced than in the balanced HES group. In the 50% diluted sample using the unbalanced HES, maximum clot firmness was significantly more reduced than by 50% dilution using the balanced HES. In the 50% diluent using the nonbalanced HES, adenosine diphosphate-, collagen-, and thrombin receptor activating protein-induced aggregometry was more reduced than in the balanced HES group.

CONCLUSIONS: A balanced HES preparation showed fewer negative effects on thrombelastographic data and platelet aggregation than a nonbalanced HES preparation, especially when using higher degrees of dilution. Future clinical studies may show a decreased influence of balanced HES solutions on coagulation.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Intravascular volume therapy with hydroxyethylstarch (HES) has become an established approach to correct hypovolemia under a variety of conditions. HES is thought to significantly alter coagulation and platelet function, leading to increased bleeding tendency (1–5). HES with a high mean molecular weight (Mw) and a high molar substitution (e.g., Hetastarch®: Mw 450 kD, molar substitution 0.7) diminished factor VIII related antigen and factor VIII ristocetin cofactor more than HES with lower Mw and lower molar substitution (6,7). Platelet function abnormalities are more commonly associated with infusion of high-Mw HES (8,9). Subsequently, more rapidly degradable HES preparations showing a lower Mw (medium Mw HES), a lower molar substitution, and a lower C2/C6 ratio have been developed to improve safety and reduce the negative impact on coagulation (5,10–13). HES with a lower Mw (130 kD) and a lower molar substitution (0.4; 0.42) showed more favorable physicochemical properties than other HES preparations, but similar hemodynamic efficacy (14,15). Using SONOCLOT-analysis and in vitro hemodilution, HES 130/0.4 affected the maturation process significantly less than other HES preparations. HES 130/0.4 seems to be preferable with regard to some aspects of clot formation and retraction (10). Unfortunately, all HES solutions are prepared in an unbalanced solution containing unphysiological high concentrations of sodium (154 mmol/L) and chloride (154 mmol/L) that may result in acid–base derangements, e.g., hyperchloremic acidosis.

Another way to improve the safety of HES as an intravascular volume replacement strategy has been developed by modifying the solvent of HES. Hextend® is a high-Mw HES (weight average Mw approximately 670 kD) with a high molar substitution (0.75) that is dissolved in a physiologically "balanced" solution (16). By this modification, Hextend® is reported to have beneficial impact on patients’ comfort and cause fewer coagulation problems than conventional, nonbalanced high-Mw HES preparations (16–19). Based on these considerations, a medium-Mw HES prepared in a plasma-adapted (balanced) solution has been developed to avoid unwanted derangements in acid–base status. The present study was designed to assess the effects of in vitro hemodilution using this new, unapproved, balanced HES preparation on coagulation and platelet function in comparison with a conventional, nonbalanced HES preparation and Ringer’s lactate solution (RL).


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After approval by the IRB and informed consent was obtained, blood was obtained from 10 healthy male volunteers, 25–30 yr old. The volunteers had not been taking any medication, in particular, no cyclooxygenase inhibitors or aspirin, within the 4 wk before blood withdrawal.

Fifteen milliliter of citrated blood was taken for thrombelastography. Another 15 mL of blood was mixed with thrombin inhibitor (TI; melagatran 14 µg/mL) for whole blood aggregometry. After harvesting an undiluted sample, the blood was diluted by 10%, 30%, and 50% using either a new, unapproved 6% HES solution (Mw 130 kD, MS 0.42, C2/C6 ratio 6:1) prepared in a plasma adapted solution (containing Na+ 140 mmol/L, Cl– 118 mmol/L, K+ 4 mmol/L, Ca2+ 2.5 mmol/L, Mg2+ 1 mmol/L, acetate 24 mmol/L, malate 5 mmol/l; B. Braun, Melsungen Germany; "balanced HES" group), a conventional nonbalanced 6% HES solution (Mw 130 kD, MS 0.4, C2/C6 ratio 9:1; prepared in saline solution containing 154 mmol/L of soldium and 154 mmol/L of chloride; Fresenius Kabi, Bad Homburg, Germany, "nonbalanced HES" group) or RL (Fresenius Kabi, Bad Homburg, Germany). Precise hemodilution was performed using a semiautomatic micropipetting system. The person who diluted the blood was blinded to the diluent.

Thrombelastography
Activated thrombelastography was done with a four-channel analyzer (RoTEM®, Pentapharm, Munich, Germany). Thrombelastography was performed using a semiautomatic pipetting system. The RoTEM system uses a different power transduction system than conventional thrombelastography machines, which makes it less susceptible to mechanical stress, movement, and vibration. RoTEM analysis relies on continuous measurement of clot firmness, allowing the determination of the onset of coagulation (coagulation time [CT], standard thrombelastography: reaction time), kinetics of clot formation (clot formation time [CFT], standard thrombelastography: coagulation time), and maximum clot firmness [MCF] (standard thrombelastography: maximal amplitude). Thrombelastography was performed after addition of two activators. Clot formation was measured after recalcification (20 µL of CaCl2 0.2 M) of 300 µL of whole blood and adding thromboplastin-phospholipid (20 µL) to monitor the intrinsic system (intrinsic thrombelastography). Intrinsic thrombelastography resembles an activated partial thromboplastin time in whole blood. The contact activator is ellagic acid, an organic contact activator which, unlike kaolin or celite, has a much smaller tendency to sediment. Thromboplastin is coagulation-activating tissue extract, e.g., made of rabbit brain. Thromboplastin contains both phospholipids and tissue factor. Clot formation was also monitored after addition of CaCl2 to 300 µL of whole blood and addition of liquid stable thromboplastin reagent derived from rabbit brain (i.e., tissue factor + phospholipids) (20 µL] for monitoring the extrinsic system (extrinsic thrombelastography). All reagents were taken from the manufacturer of the RoTEM system and measurements were performed at 37°C within 30 min after blood withdrawal according to the guidelines of the manufacturer by the same person who was blinded with regard to the diluent.

Whole Blood Aggregometry
For assessing platelet function, we used a platelet function analyzer (PFA) (Multiplate®, Dynabyte Medical, Munich, Germany) based on whole blood impedance aggregometry (20). Blood is stirred using an electromagnetic stirrer by 800 rpm. The attachment of platelet aggregates on the electrodes increases the impedance between them. The change of the impedance is transformed to arbitrary aggregation units (AU) and plotted against time. Unlike optical aggregometry, centrifugation is not needed and whole blood aggregometry tests platelet function under more physiological conditions. The system allows assessment of platelet function in whole blood samples after activation by adenosine diphosphate (ADP), thrombin-receptor-activating protein (TRAP), and collagen (COL). For measurement of platelet aggregometry, 300 µL of TI-blood were mixed with 300 µL prewarmed isotonic saline solution. After incubation for 3 min, 20 µL of activating substrate were added to the probe. Activated platelet function was recorded for 6 min. The Multiplate analyzer allows duplicate measurement of each probe. The computer analyzed the area under the curve of the clotting procedure of each measurement and calculated the mean values. We performed three tests using ADP (ADPTest® 2 mM/mL, Instrumentation Laboratory, Munich, Germany), TRAP (TRAPTest 1 mM/mL, Instrumentation Laboratory, IL, Munich, Germany), and COL (COLTest® 100 µg/mL, Instrumentation Laboratory, IL, Munich, Germany) for every sample. Measurements were performed within 30 min after blood withdrawal always by the same person that was blinded to the grouping.

Statistics
Statistical analysis was performed with SPSS/PC+ (V 4.0. SPSS, Chicago). Data are presented as Box-and-Whisker plots showing mean, medium as well as 5%, 25%, 75, and 95% percentile. Normal distribution was tested by Kolmogorov–Smirnov test. Effects of in vitro hemodilution were analyzed using nonparametric analysis of variance for repeated measures (ANOVA). Post hoc comparisons between undiluted control and hemodilutions were made with a paired t-test. The level of significance was adjusted according to Bonferroni correction. A P <0.05 was considered significant.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
At baseline, hemoglobin ranged between 13.2 and 14.2 mg/dL and there were no significant differences in hemoglobin among the groups in the three dilution levels. The platelet count was also similar in all groups at baseline ranging from 320 to 400 (109/L) and also did not differ among the groups in the three dilution levels.

Intrinsic Thrombelastography
CT moderately increased by dilution with both HES preparations without significant differences between the two HES preparations through all degrees of dilution. CFT was significantly more prolonged in the nonbalanced than in the balanced HES group in the 30% and the 50% diluted sample. MCF was significantly reduced by 30% and 50% dilution with both HES preparations. In the 50% diluted sample MCF was significantly more reduced with the unbalanced (from 54 ± 5 to 37 ± 4 mm) than with the balanced HES (from 52 ± 3 to 42 ± 5 mm). Diluting blood with RL was associated with a significant shortening of CT of (50% dilution: from 227 ± 35 to 155 ± 18 s), a significant prolongation of CFT, whereas MCF remained unchanged (Fig. 1).


Figure 134
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  		Figure 1. Changes of coagulation time (onset of coagulation; normal values: 39–70 s; conventional thrombelastography: r-value), clot formation time (kinetics of clot formation; normal values: 34–159 s; conventional thrombelastography: k-value), and maximum clot firmness (normal value: 50–72 mm; conventional thrombelastography: MA) using extrinsic activation (extrinsic thrombelastography). Data are presented as Box-and-Whisker plots (25% and 75% percentile; 5% and 95% percentile; –median; {square} mean). *P < 0.05 different to baseline data, +P < 0.05 different to the other groups. HES = hydroxyethylstarch; RL = Ringer’s lactate solution.

 

Extrinsic Thrombelastography
CT was significantly prolonged in all HES-diluted samples, with significantly more prolongation with the nonbalanced HES in the 30% and 50% dilution than the balanced HES (nonbalanced HES: 50% diluent from 55 ± 7 to 99 ± 9 s; balanced HES: 50% diluted sample from 60 ± 12 to 83 ± 16 s). CFT was also significantly more prolonged in the nonbalanced than in the balanced HES preparation in the 30% and 50% diluted sample. MCF was significantly reduced by both HES preparations in the 50% diluted sample with the significantly higher reduction of MCF in the nonbalanced (from 53 ± 4 to 39 ± 4 mm) than in balanced HES group (from 54 ± 6 to 45 ± 4) (Fig. 2). Dilution by RL resulted in almost unchanged CT, an increase in CFT, and an unchanged MCF.


Figure 234
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  		Figure 2. Changes of coagulation time (onset of coagulation; normal value: 100–240 s; conventional thrombelastography: r-value), clot formation time (kinetics of clot formation; normal value: 30–110 s; conventional thrombelastography: k-value), and maximum clot firmness (normal value: 50–72 mm; conventional thrombelastography: MA-value) using activation of the inctrinsic system (IntrinsicThrombelastography). Data are presented as Box-and-Whisker plots (25% and 75% percentile; 5% and 95% percentile; –median; {square} mean). *P < 0.05 different to baseline data, +P < 0.05 different to the other groups. HES = hydroxyethylstarch; RL = Ringer’s lactate solution.

 

Whole Blood Aggregometry
Using ADP as an inductor, there were no significant differences between the groups in the 10% and 30% dilution sample (Fig. 3). In the 50% diluted sample using the nonbalanced HES, ADP-induced aggregometry was significantly more reduced (from 565 ± 123 to 356 ± 117 AU) than in the balanced HES group (from AU 572 ± 97 to 356 ± 117 AU). COL-induced aggregometry showed a similar reduction by all three diluents with the significantly largest reduction in the 50% diluted sample using the unbalanced HES. Induction of platelet aggregation by TRAP showed almost no influence in the 10% and 30% diluted sample, whereas 50% dilution by the nonbalanced HES preparation resulted in the significantly highest reduction in whole blood aggregation (from 807 ± 241 to 605 ± 156 AU).


Figure 334
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  		Figure 3. Changes of whole blood aggregometry using adenosin diphosphate (ADP), collagen, and thrombin-activating protein as stimulators. AU: arbitrary aggregation units. Data are presented as Box-and-Whisker plots (25% and 75% percentile; 5% and 95% percentile; –median; {square} mean). *P < 0.05 different to baseline data, +P < 0.05 different to the other groups. HES = hydroxyethylstarch; RL = Ringer’s lactate solution; TRAP = thrombin-receptor-activating protein; COL = collagen.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We noted that more extensive hemodilution (30% and 50%) with both HES preparations resulted in prolonged CT and CFT, suggesting altered in vitro coagulation. Intravascular volume replacement may alter hemostasis either by dilution of clotting proteins or by substance-specific adverse effects of the plasma substitute. Also, the importance of the solvent’s effects on coagulation is currently an issue of interest (15–19). Our results agree with other studies, reporting that hemodilution with large amounts of colloids causes dilutional coagulopathy, regardless of the colloid used (21,22). This is most likely due to clotting proteins or platelet dilution. The direct effects on coagulation, however, cannot only be attributed to simple hemodilution; the effects on coagulation may also depend on the HES. The different physicochemical characteristics, especially the molar substitution, play an important role: in an in vivo study using thrombelastography, it has been shown that at low substitution, high-Mw HES did not compromise coagulation to a greater extent than low-Mw HES (23).

Another finding from our study demonstrates the importance of the solvent of the colloid. Changes in thrombelastography were more pronounced in the nonbalanced than in the balanced HES group: CFT and MCF were significantly more reduced by 30% and 50% hemodilution using the unbalanced HES. Other reports confirm the importance of the HES solution solvent. Roche et al. (19) found little difference between a balanced high-Mw HES (Hextend®) and RL, but noted coagulation disturbances with a high-Mw HES in unbalanced solution, suggesting the differences were due to the electrolyte composition of the plasma substitutes.

We also found that hemodilution with RL resulted in a mild hypercoagulable state. Early clot formation (CT) was reduced by 30% and 50% dilution with RL. Other in vitro and in vivo studies also showed hypercoagulability by crystalloid hemodilution (24–26). An imbalance between naturally occurring anticoagulants and activated procoagulants with a decrease in antithrombin was suggested as an explanation for this phenomenon (26).

Platelet dysfunction may occur secondary for several reasons in the trauma, surgical and intensive care patient. For platelet aggregation, (receptor-dependent) fibrinogen-binding and glycoprotein (GP) are necessary. When platelet activation progresses, granule secretion occurs, membrane receptors of the platelets are altered, and aggregation is facilitated.

Our study evaluated whole blood aggregometry with different platelet agonists to assess the effects of hemodilution from different plasma substitutes. Previous reports used a PFA-100 that measures global platelet function, and is dependent on the interaction of GP IIb-IIIa and GP Ib with their ligands (e.g., fibrinogen and von Willebrand factor) (5). Certain HES preparations have been reported to be associated with compromised platelet function, decreasing aggregation and increased bleeding tendency (4,5). Decreases in von Willebrand factor, fibrinogen level, and thrombin generation in vivo are assumed to contribute to platelet dysfunction after intravascular volume replacement with high-Mw HES preparations (27). In vitro experiments using flow cytometry reported platelet inhibition by HES (27): HES with a Mw of 200 kD and a high molar substitution (0.62) inhibited GP IIb-IIIa expression on agonist-activated platelets (27). HES preparations with higher Mw and/or higher molar substitution have been reported to prolong PFA-closure time, indicating adverse effects on platelets (5). In an in vitro study using HES 200/0.62, platelet-rich platelet aggregation revealed reduced platelet activity after induction with collagen and epinephrine especially at high degrees of hemodilution (28). Not only the physicochemical characteristics of the HES preparation may affect platelet function, the electrolyte composition of the solvent of the HES preparation may influence it as well (29). By preparing a slow degradable high-Mw HES (Mw > 500 kD) with a high molar substitution (7.5) (Hextend®) that is predisposed to exert negative effects on platelet function in a balanced solution, the platelets’ GP IIb-IIIa availability increased significantly after hemodilution with this solution. This unexpected platelet stimulating effect is unique among the currently available starches and is most likely induced by its solvent containing calcium chloride dihydrate (2.5 mmol/L), the same concentration as in our new HES preparation. In vitro studies and studies in patients undergoing surgery showed that more rapidly degradable HES preparations with a lower Mw and a lower molar substitution dissolved in saline had fewer negative effects on platelets (9,30). After extensively diluting blood (50%) with the balanced HES preparation, we found only moderately altered platelet function (similar to dilution with RL) and the most compromised platelet function with the unbalanced HES preparation.

Our in vitro findings need to be cautiously considered when compared with the clinical setting (31,32). Even after minor surgery, a hypercoagulable state is seen, whereas after complex, lengthy surgery, hypocoagulability may also be present (33). In in vitro studies, these surgery-related effects are absent. The endothelium, absent in our assays, plays an important role in the coagulation process (e.g., via von Willebrand factor). Moreover, in the clinical setting, HES is not given exclusively, but large amounts of crystalloids (e.g., RL) are given in combination with the colloid, and additional surgical injury occurs.

We conclude that in vitro hemodilution with a new balanced HES resulted in less overall alteration in thrombelastography data than hemodilution with a conventional nonbalanced HES solution. Whole blood aggregometry showed more negative effects on platelet function by extensive hemodilution (50% dilution) with the nonbalanced HES than with the balanced HES preparation. It is assumed that the balanced HES preparation may be of benefit, especially for patients in whom large amounts of intravascular volume are necessary or for those in whom hemostasis is already disturbed before intravascular volume therapy. In vivo studies, however, are necessary to confirm this assumption in the clinical setting.


   Footnotes
 
Accepted for publication November 2, 2006.

Supported by Klinikum der Stadt Ludwigshafen.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Lippincott, Williams & Wilkins 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 HighWire Press