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Ann Thorac Surg 2000;69:1827-1832
© 2000 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Heparin-induced platelet dysfunction and cardiopulmonary bypass

^a Department of Cardiac Surgery, University of Glasgow, Royal Infirmary, Glasgow, Scotland, United Kingdom

Address reprint requests to Dr Muriithi, Department of Cardiac Surgery, University of Glasgow, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, Scotland
e-mail: e.w.muriithi{at}clinmed.gla.ac.uk

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Cardiopulmonary bypass is associated with impaired platelet macroaggregation. Heparin contributes to platelet dysfunction before extracorporeal circulation. In vitro heparinization of whole blood does not impair macroaggregation. Heparin releases several endothelial proteins; thus heparin may inhibit macroaggregation indirectly.

Methods. Patients undergoing operations using cardiopulmonary bypass and ABO blood group compatible volunteers were studied. Whole blood impedance aggregometry assessed macroaggregation in response to collagen (0.6 µg ml^-1) in blood diluted either with normal saline or with platelet poor plasma, obtained from patients at different stages of cardiopulmonary bypass.

Results. Before heparinization, blood diluted with its own platelet poor plasma recorded an impedance change of 13.0 (4.7 to 15.6) Ohms. Platelet poor plasma obtained after heparinization or during extracorporeal circulation reduced this response to 3.7 (1.1 to 8.4) and 2.0 (1.1 to 3.3) Ohms, respectively (both p < 0.0001 versus pre-heparin; n = 13). Macroaggregation in blood from volunteers was similarly inhibited by patients’ platelet poor plasma (n = 30). The macroaggregatory response in blood sampled after heparinization for cardiopulmonary bypass, decreased gradually from 11.4 (8.2 to 15.9) Ohms immediately after sampling to 1.7 (1.4 to 4.1) Ohms 2 hours later (p < 0.0001; n = 11).

Conclusions. In vivo heparinization induces plasma changes that inhibit platelet macroaggregation. This is an indirect, delayed inhibition that is transferable in vitro to normal platelets.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Excessive bleeding results in increased transfusion requirements in 29% of patients undergoing operations using cardiopulmonary bypass [1]. A major factor contributing to the hemostatic defect after cardiopulmonary bypass is platelet dysfunction [2]. Heparin contributes to platelet dysfunction before the onset of extracorporeal circulation [3, 4].

Platelet aggregation is a three-phase response: shape change, microaggregation (primary aggregation), and macroaggregation (secondary aggregation) [5]. Previous investigators showed that while macroaggregation, the formation of large stable aggregates, is impaired by cardiopulmonary bypass, microaggregation, the formation of aggregates containing up to 100 platelets per aggregate, is well preserved [4, 6, 7].

In vivo heparinization impairs platelet macroaggregation, but in vitro heparinization of whole blood does not [4, 8]. This suggests that the endothelium, or another cell type not present in whole blood, in vitro, may play a role. Intravenous administration of heparin and other sulphated glycosaminoglycans releases numerous endothelial proteins into the plasma [9]. We postulated that if in vivo heparinization inhibited platelet macroaggregation through release of one or more endothelial proteins into the plasma, platelet poor plasma obtained from blood with dysfunctional platelets would impair the function of normal platelets.

We studied platelet macroaggregation in whole blood using impedance aggregometry. The first study investigated the effect of incremental in vivo heparin administration. The second study investigated the effect of dilution of blood with platelet poor plasma. Platelet poor plasma was obtained from patients before heparinization, after heparinization but before the start of extracorporeal circulation, and during extracorporeal circulation.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Patients
All studies were carried out with the approval of the Royal Infirmary of Glasgow Research Ethics Committee. Informed consent was obtained from all patients. Twenty-eight patients undergoing elective operations using cardiopulmonary bypass were recruited into these studies. Of these patients, 15 were enrolled into the first study (incremental heparin dosage) and the remaining 13 into the second study (plasma transfer) (see below). Time effects were studied in 11 of the patients in the plasma transfer study. Patients on non-steroidal antiinflammatory drugs (NSAIDS) including aspirin, other platelet suppressants, or warfarin, patients with diabetes, and those dependent upon intravenous nitrates or heparin were excluded.

Anesthetic premedication was with temazepam, and induction was with propofol. Opiate analgesia was used, and maintenance anesthesia was with propofol infusion. Preparation for, and conduct of, cardiopulmonary bypass was undertaken according to the individual surgeon’s normal practice, except for the incremental heparin dosage study (see below). The patients were anticoagulated with unfractionated porcine mucosal heparin (Leo Laboratories, Risborough, UK) given through a central venous cannula or directly into the right atrium just before cannulation. No antifibrinolytic drugs were administered. Anticoagulation was monitored by the activated clotting time in whole blood using a Hemacron (International Technodyne Corporation, Metuchen NJ) whole blood coagulation system model 401 regularly during cardiopulmonary bypass. If the activated clotting time was less than 400 seconds, more heparin was given. The cardiopulmonary bypass circuit consisted of an Avecor tubing set, an Affinity 40 µm arterial line filter (Avecor Ltd, Bellshill, Strathclyde, UK) and a membrane oxygenator (Duo-Cobe) driven by a Stöckert roller pump (Stöckert Instrumente, Munich, Germany). The pump prime was 2.0 l of Ringer lactate solution, 50 mM NaHCO₃, and 8,000 U sodium heparin. Flows were maintained at 2.4 l · min^-1m^-2. Ringer lactate solution was used to maintain pump reservoir volume. If the hematocrit fell below 25%, packed red cells were given. pH management was by -stat.

The heart was arrested using either antegrade crystalloid (St. Thomas’ Hospital No. 1 solution) or blood cardioplegia. Core temperature ranged between 28 and 33°C.

All blood samples from patients were taken from the indwelling radial artery line.

Volunteers
Venous blood was taken, using a 19 G needle, from the antecubital fossa of healthy volunteers without a tourniquet. These subjects had not taken aspirin or any other NSAID or any other antiplatelet therapy for 7 days. Seven milliliters of blood was placed in a hirudin containing siliconized glass tube, final concentration 200 U ml^-1.

Impedance aggregometry
An impedance aggregometer (Chronolog 500-VS, Chronolog Corporation, Haverton, PA) measured macroaggregation in whole blood. Five hundred microliters of whole blood was mixed with the same volume of saline (0.9%) or platelet poor plasma (see below) in plastic cuvettes and the sample equilibrated at 37°C before measurement. Each sample was then stirred at 1,000 rpm for 3 minutes at 37°C in the aggregometer to allow for spontaneous platelet aggregation. The macroaggregatory response to collagen (0.6 µg ml^-1) was read as the scale deflection in centimeters at 5 minutes. The aggregometer was calibrated so that a 20 Ohm change in electrical impedance would give a deflection of 14 cm, giving a conversion factor of 1.43 Ohms per centimeter.

Study 1: incremental heparin dosing study
Two heparin doses were studied: 30 U kg^-1 and 300 U kg^-1; these doses were selected as they represent the upper and lower limits of common clinically targeted levels of heparinization. A blood sample was taken and 30 µ kg^-1 heparin administered. A second blood sample was taken 5 minutes later and additional heparin 270 U kg^-1, to make up a total of 300 U kg^-1, administered. A third blood sample was taken 5 minutes after the second dose of heparin. Extracorporeal circulation was not started until all three blood samples had been obtained. The samples were anticoagulated with hirudin (final concentration 200 U ml^-1).

Study 2: plasma transfer study
1. Patients
Two blood samples were taken before the onset of extracorporeal circulation, one just before, and the other 5 minutes after, the administration of 300 U kg^-1 heparin as a single bolus. A third sample was taken 1 hour after the start of extracorporeal circulation. Fifty milliliters of blood was taken at each sampling and anticoagulated with hirudin (final concentration 200 U ml^-1). Seven milliliters of each sample was set aside for impedance aggregometry with saline dilution (see above).

The remainder of the blood was centrifuged at 3,000 rpm for 15 minutes and the supernatant platelet poor plasma pippetted off. Aggregometry was then repeated on the pre-heparin samples diluted 1:1 with platelet poor plasma from the same patient before heparin, and repeated with platelet poor plasma from each of the other two sampling times.

2. Volunteers
Macroaggregation was studied in whole blood, anticoagulated with hirudin 200 U ml^-1, from 30 healthy volunteers. This was first done with blood diluted 1:1 with normal saline. Next this was repeated with the blood diluted 1:1 with the volunteer’s own platelet poor plasma and then with platelet poor plasma obtained from an ABO blood group compatible patient described above, at each of the three sampling times (see Patients).

Time effects
In 11 patients and 3 volunteers, we studied changes in platelet macroaggregatory response occurring in heparinized blood after sampling. Blood was sampled from the patients exactly 5 minutes after heparinization, and the macroaggregatory response determined immediately and repeated 1 hour and 2 hours later. Heparin, 4 U ml^-1, was added to blood from volunteers in vitro and studied at the same time intervals. Similarly the macroaggregatory response in blood sampled before heparinization and during cardiopulmonary bypass was reassessed 1 and 2 hours later.

Stastical analysis
Summary statistics are presented as medians (interquartile range) unless otherwise stated. Serial impedance changes were compared by a Friedman two-way analysis of variance and confirmed by Wilcoxon-signed rank tests. All p values quoted in the results section are from Friedman ANOVA unless otherwise stated. Analyses were performed using Arcus Quickstat Biomedical software (Addison Wesley Longman trading as Research Solutions, Cambridge, UK).

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Study 1: incremental heparin doses in vivo
Administration of 30 U kg^-1 of heparin caused a significant reduction in the macroaggregatory response (p = 0.008). Additional heparin 270 U kg^-1 had no significant effect (p = 0.1 versus heparin 30 U kg^-1; p = 0.0001 versus pre-heparin; n = 15) (see Table 1).

View larger version (16K): [in this window] [in a new window]   Fig 1. Whole blood impedance aggregometry in response to collagen 0.6 µg ml-1; blood sampled from patients at different stages of cardiopulmonary bypass diluted 1:1 with normal saline. Box and whisker plot key: maximum, top whisker; 3rd quartile, top of box; median, bar with dotted line; 1st quartile, bottom of box; and minimum, bottom whisker (Friedman 2-way ANOVA).

Volunteers
Plasma from 7 of the patients reported above was used in this part of the study. Their platelet poor plasma was used to dilute the blood of ABO blood group compatible volunteers. As observed in the patients (see above), dilution of blood from a volunteer with platelet poor plasma obtained after heparinization or during extracorporeal circulation resulted in markedly reduced macroaggregatory responses when compared with the responses elicited when diluted with platelet poor plasma obtained before heparinization (both p < 0.0001; n = 30) (see Table 2). Again, there was no significant difference between the macroaggregatory response with blood diluted with platelet poor plasma obtained after heparinization and with platelet poor plasma obtained during extracorporeal circulation (p = 0.5; n = 30) (see Table 2).

We noted early during these studies that plasma obtained from blood sampled after heparinization almost totally inhibited platelet macroaggregation in both the patient’s own and in volunteers’ blood. Platelet macroaggregation however was only partially blunted in saline diluted blood sampled at the same time (see above). We therefore investigated time related changes in macroaggregation occurring ex vivo in blood sampled after heparinization but before the start of extracorporeal circulation, diluted with saline.

Time effects after in vivo heparinization
The macroaggregatory response in blood sampled exactly 5 minutes post-heparinization, when determined immediately after sampling, was significantly lower than the response obtained before heparinization, 11.4 (8.2 to 15.9) Ohms and 21.9 (15.9 to 23.0) Ohms, respectively (p = 0.0007, n = 11). When repeated after storage at room temperature, 1 hour later, the macroaggregatory response in the heparinized sample had fallen further to 6.6 (3.2 to 12.1) Ohms (p = 0.0055 versus immediate reading, n = 11). Two hours later, also stored at room temperature, it was even further reduced, 1.7 (1.4 to 4.1) Ohms (p > 0.0001 versus 1 hour, n = 11) (see Fig 2). The difference between the macroaggregatory responses in heparinized blood 2 hours after sampling and those in blood sampled 1 hour into extracorporeal circulation 2.1 (1.6 to 3.4) Ohms was not statistically significant (p = 0.3, n = 11).

View larger version (14K): [in this window] [in a new window]   Fig 2. Whole blood impedance aggregometry in response to collagen 0.6 µg ml-1; sequential measurements in blood sampled after in vivo heparinization. Box and whisker plot key: maximum, top whisker; 3rd quartile, top of box; median, bar with dotted line; 1st quartile, bottom of box; and minimum, bottom whisker (Friedman 2-way ANOVA).

In contrast to our findings in blood heparinized in vivo, the macroaggregatory responses in whole blood from 3 healthy volunteers, 14.0, 9.2, and 17.5 Ohms, were unaffected by heparinization in vitro and did not change over the next 3 hours even when the samples were incubated at 37°C. The final responses were 14.0, 9.5, and 17.0 Ohms.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
This study confirms that platelet dysfunction, which is manifest as the impaired ability to form macroaggregates, is induced by heparin before the onset of extracorporeal circulation. We further demonstrated that platelet dysfunction is secondary to a plasma change and is transferable in vitro to normal platelets. The inhibition of platelet macroaggregation is not dose related when heparin doses of 30 U kg^-1 or more are administered. This delayed action of heparin, when fully developed, almost completely abolishes platelet macroaggregation. Thus, any effects of extracorporeal circulation on platelet macroaggregation are obscured. The use of alternative anticoagulants for cardiopulmonary bypass would help to clarify this.

Previous workers suggested that the platelet defect associated with cardiopulmonary bypass is extrinsic to the platelet possibly due to the lack of an in vivo agonist [2]. Our observation that plasma separated from blood with dysfunctional platelets impaired the function of normal platelets suggests that the presence of an inhibitor is a more likely explanation. This has important clinical implications as attempts to correct the post-cardiopulmonary bypass bleeding diathesis by transfusing donor platelets, or autologous platelets collected preoperatively, may not fully restore platelet function, unless efforts are also directed towards preventing or correcting the plasma change(s).

Postoperatively, platelet macroaggregation starts to recover within half an hour of the termination of extracorporeal circulation [6], but full recovery is still not achieved even 24 hours later [6, 7]. In an earlier study, we demonstrated that ex vivo digestion of heparin with heparinase after in vivo heparinization did not restore platelet macroaggregation [4]. These findings suggest that the effect of heparin on platelet macroaggregation persists after the anticoagulant effect is reversed.

Impedance aggregometry and dilution
For optimum sensitivity, the manufacturers recommend that impedance aggregometry should be performed in saline diluted whole blood. Previous workers reported that undiluted blood gave a blunted response [10], as we note in the current study. Furthermore, dilution increases the amplitude of the oscillations of impedance [10, 11] making subtle changes more apparent, although this finding is not universal [12]. The gross changes in platelet aggregation observed during cardiopulmonary bypass, were unlikely to be obscured by reducing the sensitivity of aggregometry by diluting blood with plasma instead of saline. Although isotonic saline is a better diluent than platelet poor plasma for impedance aggregometry, plasma may be preferred when investigating ex vivo inhibitory or pro-aggregatory effects of substances found in trace amounts as saline dilution may make their effects disappear [10].

Heparin and platelet macroaggregation
Macroaggregation is essential for primary hemostasis as it gives strength to a platelet plug, so paving the way for clot retraction. The process may be irreversible and is accompanied by a reduction in the number of microaggregates, implying that coalescence of microaggregates rather than further recruitment of single platelets occurs [13]. Macroaggregation can be inhibited without affecting microaggregation [4, 5, 14], which suggests that an additional trigger is required. Platelet secretory release accompanies macroaggregation and is absent when this phase of aggregation is blocked [15]. During extracorporeal circulation, decreased platelet secretory release in shed blood and prolongation of the bleeding time both occur [2, 3]. These findings are in keeping with the observed impairment of platelet macroaggregation [4, 6, 7].

Heparin impairs primary hemostasis, at least in part, by impairing platelet function [16]. Intravenous heparinization inhibits platelet macroaggregation markedly while in vitro heparinization has a less pronounced effect only observed with concentrations far greater than those used clinically [4, 8]. Similarly, heparin inhibits platelet 5-hydroxytryptamine secretion in vivo but not in vitro [16]. Increased bleeding times after intravenous heparin correlate with lipase release [17], but are independent of heparin’s effect on plasma coagulation [16].

These findings support those of the present study and suggest that the platelet functional changes that have previously been attributed to initial contact with the extracorporeal circuit may be an indirect and delayed effect of heparin rather than a true "first pass" effect of cardiopulmonary bypass. In vivo heparin caused a gradual decline in platelet macroaggregation; the effect of plasma in vitro, however, was without delay. This suggests that the intermediate factor may act on the plasma to produce inhibitory substances rather than directly inhibiting platelets.

Some previous studies did not detect aggregatory impairment after heparinization [6, 18]. This contrast in findings may be related to the delay between heparinization and aggregometry. In many institutions, the activated clotting time, used to confirm adequacy of anticoagulation, is checked about 2 to 5 minutes after heparinization, thus the delayed indirect effect of heparin on platelets may not be detected in blood sampled at this time.

Heparin and the endothelium
Intravenous heparin in relatively low doses rapidly releases platelet factor 4 [19], superoxide dismutase [20], lipoprotein lipase, hepatic lipase [21], and other proteins [9]. Low dose continuous heparin infusions maintain the peak levels of these proteins in plasma for several hours [21]. During cardiopulmonary bypass, plasma heparin levels remain elevated following administration of large loading doses [22]. It is therefore reasonable to assume that the levels of these heparin-released endothelial proteins remain elevated.

Heparin may further impair primary hemostasis either by its direct actions on the endothelium which could impair vascular hemostatic function, or by inhibitory effects on platelets. The release of hepatic lipase and lipoprotein lipase causes acute changes in the plasma lipid profile [21]. Lipids affect platelet aggregation [23, 24].

The progressive decline of platelet macroaggregation in heparinized blood after sampling suggests an ongoing, probably enzymatic, process. Macroaggregatory impairment developed faster in vivo. This may be temperature related as we stored blood at room temperature, or it may suggest further enzyme release. Platelet poor plasma, obtained after heparinization, affected platelet macroaggregation similarly to platelet poor plasma obtained after 1 hour of extracorporeal circulation; this may be because during the separation of plasma and the setting up of the experiments, the inhibition of platelet macroaggregation proceeded to completion. We studied time-related effects in 2 patients after incremental heparin dosing and found that the macroaggregatory responses after both the initial 30 U kg^-1 and the additional 270 U kg^-1 heparin fell to nearly 0 Ohms within 2 hours, suggesting that the mediator(s) of platelet dysfunction may have already been maximally released by 30 U kg^-1 heparin.

	Acknowledgments

 
This study was supported by the Royal College of Surgeons of England. The authors thank Dr Anna Suter of Novartis Pharma AG, CH-4002 Basel, for kindly donating the recombinant hirudin; Dr Gillian M. Bernacca of the Department of Cardiac Surgery, University of Glasgow, for her assistance with the statistical analyses; and the Departments of Cardiothoracic Surgery and Anaesthesia of the Royal Infirmary, Glasgow, for their help.

	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 Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Elijah W. Muriithi Philip R. Belcher David J. Wheatley Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Muriithi, E. W. Articles by Wheatley, D. J. Search for Related Content PubMed PubMed Citation Articles by Muriithi, E. W. Articles by Wheatley, D. J.