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Anesth Analg 2002;95:844-850
© 2002 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Hemodilution with Albumin, but Not Hextend®, Results in Hypercoagulability as Assessed by Thrombelastography® in Rabbits: Role of Heparin-Dependent Serpins and Factor VIII Complex

Andrew T. McCammon, MD, Jonathan P. Wright, MD, Mario Figueroa, MD, and Vance G. Nielsen, MD

Department of Anesthesiology, The University of Alabama at Birmingham

Address correspondence and reprint requests to Vance G. Nielsen, MD, Department of Anesthesiology, The University of Alabama at Birmingham, 619 S. 19th St., Birmingham, AL 35249. Address e-mail to vance.nielsen{at}ccc.uab.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Isovolemic hemodilution (IVHD) has been advocated as an effective method of reducing the need for transfusion but has been associated with hypercoagulability. We tested the hypothesis that IVHD enhances hemostatic function by decreasing circulating antithrombin activity in rabbits. Furthermore, it was determined whether different replacement solutions would affect hemostasis. Sedated rabbits were randomly assigned to groups that underwent IVHD (40% blood volume removed) with 5% human albumin (n = 10) or a 6% hetastarch solution (Hextend®). Antithrombin and Factor VIII complex (VIII:C) activities were determined, and thrombelastography® was performed with or without platelet inhibition. IVHD resulted in a significant (P < 0.05) decrease in antithrombin (32%–39%) without fluid-specific differences observed. VIII:C did not change in the albumin group, whereas the hetastarch group had a significant (P < 0.05) decrease (43%) in VIII:C that was also significantly (P < 0.05) less than the albumin group. The time to clot initiation was decreased, and the rate of clot formation increased significantly via thrombelastography® in albumin animals. No significant change in clot kinetics was observed in hetastarch animals. In rabbits, the primary determinant of hemostasis after IVHD was the interaction of changes in antithrombin activity and VIII:C. These data serve as a rational basis to determine whether IVHD-mediated hypercoagulability encountered clinically may be attenuated or exacerbated by the choice of colloid administered.

IMPLICATIONS: Isovolemic hemodilution (IVHD) is associated with hypercoagulability. Rabbits hemodiluted with albumin, but not Hextend®, became hypercoagulable secondary to a loss of antithrombin activity with simultaneous maintenance of Factor VIII complex activity (VIII:C). Hextend®-treated animals had proportionate decreases in both antithrombin activity and VIII:C. IVHD-mediated hypercoagulability encountered clinically may be attenuated or exacerbated by the choice of colloid administered.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Isovolemic hemodilution (IVHD) has been advocated as an effective method of reducing the need for allogeneic blood administration in the perioperative period. Investigations have demonstrated that IVHD to a hemoglobin concentration as small as 5 g/dL can be tolerated for short periods of time (1), whereas others note that 7 g/dL is better tolerated with regard to electrocardiographic changes (2). Similarly, IVHD (75% of estimated blood volume) with various colloids in rabbits demonstrated neither hepatic ischemia nor histologic injury (3). Further study with rabbits demonstrated that 75% hemodilution was associated with a decrease in time to clot initiation, maintenance of the speed of clot formation, and a decrease in total clot strength, as determined by thrombelastography® (4). These data obtained from rabbits are consistent with the increase in hemostatic function observed during elective surgery, during which 5% to 80% of the blood volume was replaced (5). Although IVHD is associated with the maintenance or enhancement of hemostatic function, the underlying mechanisms are still poorly defined.

Decreases in endogenous anticoagulants and the maintenance or enhancement of procoagulants could significantly contribute to the hypercoagulability associated with IVHD (5). In support of this concept, a reduction of the heparin-dependent serine protease inhibitor (serpin) antithrombin (AT, formerly antithrombin III) in the circulation has been associated with hypercoagulability after major abdominal surgery (6), and a decrease in both circulating AT and endogenous heparin activity resulted in accelerated clotting in a rabbit model of hemorrhagic shock (7). Also of interest, the administration of albumin is associated with more circulating Factor VIII complex activity (VIII:C) than after the administration of similar quantities of a hydroxyethyl starch solution (8,9). On the basis of these data, changes in hemostasis associated with IVHD may be mediated in part by changes in circulating heparin-dependent serpins, endogenous heparin, and coagulation proteins.

Thus, one goal of this study was to determine whether IVHD enhances hemostatic function by decreasing circulating heparin-dependent serpin and endogenous heparin activity in rabbits. Another goal was to determine whether the colloidal solution administered would decrease circulating procoagulant activity and hemostatic function. We used thrombelastography® and simultaneous measurement of AT and VIII:C activities and other procoagulants and anticoagulants to achieve these goals by using a rabbit model of IVHD.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by the Animal Review Committee of the University of Alabama at Birmingham. All animals received humane care in compliance with the Principles of Laboratory Care formulated by the National Society for Medical Research and with the Guide for the Care and Use of Laboratory Animals prepared by the National Research Council and the National Academy Press (Revised October 1996, Washington, DC).

Male New Zealand White rabbits (Myrtle’s Rabbits, Thompson Station, TN) weighing 1.8–2.8 kg were briefly restrained (<2 min) and had 22-gauge catheters placed in the central ear artery of the right ear and the marginal ear vein of the left ear and were left unrestrained on a padded surgical table. The ambient temperature was 25°C during all experimentation. One of the authors continuously attended the animals throughout experimentation. After a 5-min resting period, baseline mean arterial blood pressure (MAP) and heart rate (HR) were recorded. MAP and HR were subsequently continuously recorded for the duration of the experiment. Rabbits (n = 10 per group) were randomly assigned to a group hemodiluted with 5% human albumin (Baxter Healthcare Corp., Glendale, CA) or a group hemodiluted with a 6% hetastarch solution (Hextend®; Abbott Laboratories, Chicago, IL; average molecular weight of 450 kd). After baseline blood samples described subsequently were obtained, all rabbits were administered ketamine 5 mg/kg IV. Animals then underwent IVHD by removal of 28 mL/kg (40% of estimated blood volume) of blood (less the volume of blood obtained at baseline) while simultaneously an equivalent volume of either albumin or hetastarch solution (prewarmed to 39°C) was administered IV. The process of hemodilution was performed over 4–6 min. Sixty minutes later, additional hemodynamic measurements and arterial blood samples were obtained, and the animals were subsequently killed with an overdose of pentobarbital 100 mg/kg IV.

Arterial blood samples (8 mL) were obtained at baseline and at the conclusion of the experiments for arterial blood gas (ABG), hematological assays, and thrombelastographic analysis. The arterial pH, PaCO2, PaO2, Ca2+, and K+ concentrations and the hematocrit of arterial blood samples were determined at 37°C by using a blood gas analyzer. Platelet concentrations were concurrently determined with a Sysmex K-800. A portion of the whole blood (4.5 mL) was placed in tubes containing sodium citrate (129 mM final concentration), and then centrifuged at 2500g for 15 min at room temperature, with the plasma then removed and centrifuged a second time at 2500g for 15 min to obtain platelet-poor plasma. Plasma samples were immediately stored at -85°C before determination of anti-Xa and AT activities via chromogenic kits (Biopool International, Ventura, CA). Because heparin-deficient plasma was not available, the standard curve for determination of anti-Xa activity was generated by addition of heparin to 5% human albumin (Baxter Healthcare Corp.). Heparin cofactor II (HCII) activities were determined with a commercially available chromogenic kit (American Diagnostica, Inc., Greenwich, CT). VIII:C activities were determined with a chromogenic kit (diaPharma, West Chester, OH). Fibrinogen concentrations were determined with a coagulation analyzer (ACL 100/200; Instrumentation Laboratory). Except for anti-Xa activity determinations, all values derived from the aforementioned assays were compared with commercially available plasma standards or pooled plasma obtained from the baseline samples (n = 20) of all rabbits in this study.

Thrombelastographic analyses were performed with two computer-controlled Thrombelastograph® coagulation analyzers (Model 5000; Haemoscope Corp., Skokie, IL), each with two channels wherein disposable plastic cups were placed. The three thrombelastographic conditions were as follows: 1) 350 µL of blood with 10 µL of 0.9% NaCl; 2) 350 µL of blood with 10 µL of cytochalasin D (final concentration 10 µM); and 3) 350 µL of blood with 10 µL of 0.9% NaCl in the presence of heparinase I (from Flavobacterium heparinum, 2.0 IU per cup). Cytochalasin D inhibits microtubule formation (and glycoprotein IIb/IIIa subunit assembly) in platelets, resulting in a thrombelastographic signature due only to coagulation proteins in whole blood (10,11). Cups containing 2 IU of heparinase will digest up to 6 IU/mL of heparin activity, an activity far greater than that observed endogenously in the rabbit (7). The proper functioning of the thrombelastograph® was confirmed daily with quality control standards purchased from Haemoscope. The following thrombelastographic variables were measured for each sample over 1 h at 39°C (the normal temperature of the rabbit): reaction time (R; min), angle ({alpha}; degrees), maximum amplitude (MA; mm) and shear elastic modulus (G; dynes/cm2). A detailed description of the methodology of thrombelastography® has been presented in great detail elsewhere (11,12). In brief, R is defined as the time from when the blood sample is placed into the thrombelastograph® cup until initial fibrin formation occurs, as noted by a signal of 2-mm amplitude, and {alpha} is the angle formed from R to the inflection point of the thrombelastographic signal as clot strength stabilizes; it is a measure of the kinetics of clot formation. MA is the largest amplitude of the thrombelastographic signal and is a measure of clot strength. Furthermore, G is a measure of clot strength calculated from MA as follows: G = (5000 x MA)/(100 - MA) (12). The relationship between MA and G is curvilinear; as MA varies from 0 to 100, G concordantly varies from 0 to infinity. Consequently, whereas MA was determined, G was reported. The contribution of platelets to G (GP) was defined by the total G of whole blood not exposed to cytochalasin D (GT) minus the G of blood exposed to cytochalasin D, which is attributable to the soluble components of the coagulation pathway (GSC) (10). A representative series of thrombelastograms® of the three conditions previously described is displayed in Figure 1.



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  		Figure 1. Representative thrombelastographic conditions. The three conditions that samples were submitted to at each time point were as follows: 1) unmodified, 2) platelet inhibition with cytochalasin D, or 3) exposure to heparinase I.

 
All variables are expressed as mean ± SD. Analyses of the effects of IVHD and of the replacement fluid on hemodynamic, ABG, electrolyte, hematological, and thrombelastographic variables were conducted by analysis of variance with repeated measures. Post hoc analyses were performed with Student-Newman-Keuls tests. The number of subjects chosen per group was based on that required to obtain a ß > 0.8 with an {alpha} < 0.05, as demonstrated in previous studies (4,7,10). A P value of <0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
With the exception of brief sedation after ketamine administration, the rabbits showed no significant behavioral changes during experimentation. Hemodynamic, ABG, and electrolyte data are displayed in Table 1. IVHD resulted in a significant decrease in MAP and a significant increase in HR, without any replacement fluid-specific differences noted. Furthermore, arterial pH, PaCO2, PaO2, and Ca2+ concentrations did not change after IVHD. Hematocrit significantly decreased by 43%–45% compared with baseline, and K+ concentrations were also significantly decreased after IVHD.


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  		Table 1. Hemodynamics and Arterial Blood Gas Data
 
With regard to endogenous anticoagulants, IVHD resulted in a significant decrease in anti-Xa (31%–33%), AT (32%–39%), and HCII (27%–32%) activities, without any replacement fluid-specific differences observed (Table 2). In the case of circulating procoagulants, VIII:C activity did not significantly change after IVHD in the group administered albumin, whereas the group administered hetastarch solution had a significant decrease (43%) in VIII:C activity that was significantly different from the group administered albumin. Of interest, IVHD resulted in a significant decrease in fibrinogen (39%–45%) and platelet (38–40%) concentrations, without any replacement fluid-specific differences observed.


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  		Table 2. Anticoagulant and Procoagulant Variables
 
Animals hemodiluted with albumin had a significant decrease in R and an increase in {alpha} without a significant change in GT noted in unmodified thrombelastographic samples (Table 3). In contrast, rabbits administered hetastarch solution had no significant change in R and {alpha} but had a significant decrease in GT in unmodified thrombelastographic samples. With regard to GP, IVHD did not significantly change the contribution of platelets to clot strength. There were no significant intergroup differences in unmodified thrombelastographic samples. Platelet-inhibited thrombelastography® revealed a significant decrease in R and nearly doubling of {alpha} without a change in GSC in animals hemodiluted with albumin. Unlike albumin-treated animals, rabbits administered hetastarch solution had no significant change in R or {alpha}, but instead had a significant decrease in GSC in platelet-inhibited samples. Furthermore, in platelet-inhibited-samples, both {alpha} and GSC values were significantly less in the hetastarch solution-treated animals than in those administered albumin. In rabbits hemodiluted with albumin, samples modified with heparinase exhibited a significant decrease in R, an increase in {alpha}, and a decrease in GT values. Rabbits administered hetastarch solution did not have a significant change in R or {alpha} but did have a significant decrease in GT values in samples modified with heparinase. Finally, {alpha} values were significantly greater in albumin-treated animals compared with rabbits administered hetastarch solution in heparinase-modified samples.


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  		Table 3. Thrombelastograph (TEG®) Variables R (min), {alpha} (degrees), and G (dynes/cm2)
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrated that a decrease in heparin-dependent serpin activity with a concurrent maintenance of normal VIII:C is the mechanism for enhanced hemostasis in the rabbit after IVHD with albumin. Animals administered albumin displayed hypercoagulability in platelet-inhibited samples, without any significant GP or change in circulating VIII:C observed—implicating a coagulation protein-mediated event as the source of hypercoagulability. This is further supported by data derived from heparinase-modified thrombelastography®, because animals administered albumin displayed similar decreases in R and increases in {alpha} values compared with unmodified samples. These heparinase-modified data consequently diminished the importance of changes in endogenous heparin activity as a major contributor to IVHD-mediated hypercoagulability. Furthermore, animals administered hetastarch solution had a similar decrease in both anticoagulant and procoagulant components, without a concurrent enhancement of hemostatic function. In summary, these data support the hypothesis that, in the rabbit, the primary determinant of the prothrombotic state after hemodilution is the interaction of heparin-dependent serpin and VIII:C activities.

The serpins AT and HCII are the two heparin-enhanced enzymes in greatest abundance in plasma, with activities more than 1000-fold increased in the presence of heparin or heparan (13,14). Whereas AT inactivates several enzymes in the coagulation pathway (e.g., Factors IXa, Xa, XI, a, and thrombin), HCII inactivates only thrombin (14). Congenital AT deficiency is associated with venous thrombotic disease, and acquired deficiency occurs in the settings of sepsis, trauma, malignancy, and cardiopulmonary bypass (15). AT activity <60%–70% of normal is associated with a marked increase in venous thrombosis (15), whereas the role played by HCII in normal hemostasis is less certain than AT. In summary, a deficiency of heparin-dependent serpin activity plays an important role in enhanced hemostasis and perhaps subsequent thrombosis in both humans and rabbits.

The fluid-specific changes in VIII:C observed in this study are likely secondary to differential secretion of VIII:C and von Willebrand factor (vWF) activity from the vascular endothelium. VIII:C decreases to the same extent in vitro after dilution with hetastarch solution compared with saline dilution in human plasma (16). Of interest, cultured human umbilical vein endothelial cells demonstrated a significant decrease in thrombin-stimulated vWF secretion in the presence of hetastarch compared with albumin exposure—albumin actually increased vWF secretion compared with standard cell culture media (17). In cell culture, the synthesis and secretion from the endothelium of VIII:C is energy dependent and slow (18,19), with several tissues such as the liver, spleen, lung, and kidney significantly contributing to circulating VIII:C activity (18). The data derived from albumin-hemodiluted animals in this study suggest that VIII:C secretion is remarkably swift, with near restoration of baseline values within 60 minutes. Two analogous human studies (8,9), wherein significantly lesser volumes were administered, demonstrated dilutional changes in VIII:C similar to this study. Healthy volunteers were administered a 500-mL bolus of either 5% human albumin or 6% hydroxyethyl starch solution (average molecular weight 200 kd) over 45 minutes, and it was observed 20–400 minutes postinfusion that subjects administered albumin had no significant change in VIII:C (8). However, volunteers administered hydroxyethyl starch solution had a significant decrease in VIII:C during the same time period (8). In another study, patients undergoing prostatectomy because of benign hypertrophy were administered 15 mL/kg of either 5% human albumin or 6% hydroxyethyl starch solution (average molecular weight, 200 kd) over 90–120 minutes (9). Patients administered hydroxyethyl starch solution had a significant decrease in VIII:C after infusion compared with baseline values, but those administered albumin did not demonstrate a change in VIII:C (9). Two other studies, wherein 20–30 mL/kg of hydroxyethyl starches was administered during elective abdominal surgery, demonstrated a decrease in both VIII:C and vWF (20,21), with a concurrent decrease in AT noted in one study (21). Of interest, the decrease in VIII:C and vWF activity was proportionate with the volume of hydroxyethyl starch administered (20). Compared with these studies (8,9,20,21), our work involved a far more rapid hemodilution of a significantly larger portion of the circulating volume—yet VIII:C did not change in albumin-treated rabbits. Thus, in both rabbits and humans, the ability of the endothelium to replace VIII:C loss in vivo is rapid, and replacement fluid-specific changes in secretion of VIII:C are similar between the two species.

An important task that remains is the identification of the mechanisms responsible for the regulation of VIII:C secretion during IVHD with albumin or crystalloid solutions. IVHD in anesthetized dogs resulted in a significant increase in circulating norepinephrine (22), and an increase in catecholamines increases VIII:C in humans (23). Also of interest, exercise-induced increases in VIII:C in humans were attenuated by the administration of the nitric oxide inhibitor N-monomethyl-L-arginine (24), supportive of a possible role for nitric oxide in the release of VIII:C. IVHD reduces hematocrit and red cell scavenging of nitric oxide at the endothelial-blood interface, potentially resulting in an increase in nitric oxide—and perhaps a nitric oxide-mediated increase in VIII:C. In summary, future experimentation is required to determine the role of circulating catecholamines or nitric oxide in the release of VIII:C activity observed after IVHD.

The mechanisms responsible for hetastarch-mediated attenuation of VIII:C secretion cannot be discerned from this study. Hetastarch solutions have not been determined to either scavenge nitric oxide or block adrenergic receptors. Of interest, the administration of desmopressin (a V2 agonist) or vasopressin increases VIII:C activity (25,26). Unfortunately, the mechanism and site of desmopressin-mediated VIII:C activity release are still controversial. The administration to conscious dogs of antagonists to the vasopressor response (V1 receptors) or antidiuretic response (V2 receptors) of vasopressin had no effect on desmopressin-stimulated increases in VIII:C, suggesting that desmopressin elicits VIII:C activity release via an unknown class of receptors (27). What this study demonstrated was that hetastarch solution administration appears to reduce the rate of release/restoration of VIII:C activity to a rate similar to that of the other procoagulant and anticoagulant variables measured. Furthermore, hetastarch solution did not selectively decrease VIII:C activity beyond that expected with hemodilution in this study. It must be noted that hemostasis was assessed after only 60 minutes of IVHD in this study, and the duration of these hemostatic phenomena cannot be extrapolated from our results. The elucidation of the mechanisms responsible for hetastarch-mediated modulation of VIII:C release is important, because this information could serve as the rational basis for new anticoagulant strategies that could decrease perioperative thrombotic complications.

In conclusion, this study demonstrated the novel finding that a decrease in heparin-dependent serpin activity coupled with unchanged VIII:C activity results in hypercoagulability detected by thrombelastography® in the rabbit after IVHD with albumin. The administration of hetastarch solution attenuated hemodilution-mediated hypercoagulability by decreasing VIII:C activity to the same extent as other important hemostatic modulators. The strategies of enhancing heparin-dependent serpin activity or decreasing VIII:C activity may hold promise as therapeutic interventions to decrease perioperative hypercoagulability and thrombosis.


   Acknowledgments
 
This study was supported in part by a grant from BioTime, Inc. (Berkeley, CA) and the Department of Anesthesiology, The University of Alabama at Birmingham.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication June 20, 2002.




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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