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Anesth Analg 2000;91:528-532
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Heparin Induces Release of Phospholipase A2 into the Splanchnic Circulation

Hartmut Kern, MD*, Wolfram Johnen, MD*, Jan Braun, MD*, Bettina Frey*, Bernd Rüstow, PhD{dagger}, Wolfgang J. Kox, MD, PhD, FRCP*, and Michael Schlame, MD, PhD, DEAA*

Departments of *Anesthesiology and Intensive Care Medicine and {dagger}Neonatology, University Hospital Charité, Humboldt University, Berlin, Germany

Address correspondence and reprint requests to Michael Schlame, MD, PhD, DEAA, Department of Anesthesiology and Intensive Care Medicine, University Hospital Charité, 10117 Berlin, Germany, Schumannstr. 20/21. Address e-mail to schlamem{at}hss.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Cardiopulmonary bypass results in increased plasma activity of phospholipase A2 (PLA2) that appears to be caused by the administration of heparin. High PLA2 activity may be responsible for increased production of eicosanoids and, thus, may be implicated in various pathophysiologic events associated with cardiac surgery. To investigate the site of PLA2 secretion, blood samples were simultaneously collected from the radial artery, the pulmonary artery, and the hepatic vein at 2, 4, 6, and 20 min after systemic heparinization (350 U/kg). Within 2 min of the heparin injection, plasma activity of PLA2 increased 4- to 9-fold and remained so for at least 20 min. Two minutes after the heparin injection, PLA2 was significantly higher in the hepatic vein than in the radial artery (P < 0.01). No such difference was detected between pulmonary and radial arteries. When heparin was added to blood samples in vitro (5–100 U/mL), plasma activity of PLA2 did not increase, which suggests that the enzyme was not secreted by blood cells.

Implications: Heparin, given in the dosage required for cardiopulmonary bypass, caused release of phospholipase A2 into the splanchnic circulation.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Plasma phospholipase A2 (PLA2) is an acute phase reactant that is involved in the generation of proinflammatory mediators (1). PLA2 activity has been shown to be markedly enhanced by large-dose heparin given in preparation for cardiopulmonary bypass (CPB) (2,3). It was suggested that increased PLA2 activity may be responsible for increased production of eicosanoids during cardiac surgery (2). Eicosanoids, in turn, have been implicated in various pathological states pertinent to cardiac surgery (4). For instance, it was hypothesized that pulmonary vasoconstriction, occasionally seen during protamine infusion, can be caused by a sudden reversal of plasma PLA2 activity, shifting the balance from vasodilating 6-keto-prostaglandin F1{alpha} to vasoconstricting thromboxane B2 (2). In animal experiments and various clinical trials, increased activities of circulating PLA2 were associated with critical conditions, such as severe acute pancreatitis (5), septic shock (6), adult respiratory distress syndrome (7), multiple organ failure (8), multiple injuries (9), and rheumatoid arthritis (10).

PLA2 is a lipolytic enzyme that hydrolyzes phospholipids to the corresponding lysocompounds and free fatty acids. Three types of PLA2 are known in humans: one intracellular 85-kDa enzyme and two secretory enzymes with a molecular mass of 14 kDa (1). Intracellular PLA2 translocates to and acts on cell membranes to release arachidonic acid for eicosanoid synthesis (11). In contrast, the secretory isoenzymes of PLA2 seem to have different functions. Group I secretory PLA2 is present in the mammalian pancreas and in cobra and sea snake venoms, whereas Group II secretory PLA2 is found in several mammalian cell types and in rattlesnake and viper venoms. Group I and Group II secretory enzymes are characterized by specific amino acid sequences. Postheparin PLA2 in human plasma is a Group II secretory enzyme (2).

Because heparin is widely used and one of its side effects is the induction of plasma PLA2, we investigated where this enzyme is released into the circulation, i.e., where it is expected to cause the most significant damage. This question has not been addressed, perhaps because of the ubiquitous occurrence of PLA2, including pancreatic tissue and juice, stomach, intestine, spleen, heart, liver, lung, brain, chondrocytes, vascular smooth muscle cells, polymorphonuclear leukocytes, macrophages, erythrocytes, platelets, inflammatory exudates, ascitic fluid, and seminal plasma (1). Previous data suggested that heparin can release the enzyme from polymorphonuclear leukocytes (2), and that endotoxin can induce secretion of PLA2 from liver Kupffer cells (12). Despite this evidence, no consensus has been established about the origin of PLA2 found in the plasma of patients subjected to extracorporal circulation.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After we obtained approval by the institutional review board and written, informed consent, 25 adult cardiac surgical patients were investigated, of which 16 had coronary artery bypass grafting (CABG), 3 had aortic valve replacement, and 3 had mitral valve replacement. Two patients had a combined CABG and mitral valve replacement, and one patient had a CABG and resection of a myocardial aneurysm.

Clinical Management
Patients (7 women, 18 men, mean age: 65 ± 9 yr, range: 52–87 yr.) were premedicated with midazolam (0.1 mg/kg). Etomidate (0.2 mg/kg), pancuronium (0.1 mg/kg), and fentanyl (1–5 µg/kg) were used for the induction of anesthesia. Anesthesia was maintained by using fentanyl (0.1–0.3 µg · kg-1 · min-1) and either isoflurane (0.1–0.8 vol%) or sevoflurane (0.5–1 vol%). Emergency patients were excluded from this study, as were patients treated with heparin before surgery.

Heparin was injected IV at a dose of 350 U/kg. Activated clotting time increased to more than 480 s. Blood samples were obtained at various time intervals (0–20 min) after heparinization but before the initiation of CPB (Biomedicus Centrifugal PumpTM; Metronic, MN). After separation from CPB, heparin was antagonized by protamine, adjusting activated clotting time at about 120 s. The plasma concentration of heparin was determined as previously described (13).

Plasma PLA2 gradients across the pulmonary and hepatosplanchnic circulation were determined separately in different groups of patients. Because transorgan gradients were expected to exist only temporarily during the period of PLA2 secretion, rapid sampling was necessary. Therefore, we limited the measurements to two samples per time point. The radial artery was cannulated in all patients for hemodynamic monitoring. In six patients, nonheparinized thermodilution fiberoptic catheters (OpticathTM 7.5F, 110 cm; Abbott Critical Care Systems, North Chicago, IL) were inserted into the pulmonary artery via the right jugular vein. In another six patients, catheters of the same type were advanced into the right hepatic vein through a 8.5F sheath inserted into the right femoral vein. Under fluoroscopic guidance, the tip of the catheter was positioned in the inferior vena cava approximately 4 inches below the diaphragm. The patient was asked to cough to optimize the angle of the vessels, so the tip of the catheter could be moved approximately 3 inches into the right hepatic vein. Positioning was documented by radiograph, and the catheter was fixed. There was no bleeding or other catheter-related complications in these patients.

Blood Sampling
Blood samples (3 mL) were drawn into syringes filled with EDTA (1.6 mg/mL blood). Before sampling, 5 mL was removed from each line to avoid dilution. Immediately after sampling, blood was spun for 5 min at 2000 rpm in a table-top centrifuge, and plasma was collected from the supernatant. In one set of samples, EDTA was omitted to check for potential side effects of this substance. In this case, blood was drawn into blank syringes, solely relying on the anticoagulating effect of heparin.

Effect of Heparin In Vivo and In Vitro
To investigate whether PLA2 can be released from blood cells, we added heparin to freshly drawn blood in vitro. The samples were incubated at 37°C in plastic syringes for 15 min in the presence of heparin (5 U/mL). In control samples, protamine (5 U/mL) was added with heparin. After incubation, blood was spun to obtain plasma for the determination of PLA2 activity. The same patients who donated blood for heparinization in vitro, received heparin (350 U/kg) IV, allowing for a direct comparison between the effect of heparin in vivo and in vitro. After 15 min of treatment, blood was collected and plasma was obtained for PLA2 analysis. Blood was also analyzed after treating the patient with protamine when separation from CPB had occurred. Finally, a control experiment was performed in which blood was treated with increasing concentrations of heparin (0–100 U/mL) in vitro, by using the conditions described above.

Effect of Heparin on Polymorphonuclear Leukocytes
Polymorphonuclear leukocytes were isolated from human blood by density gradient centrifugation as described (14). Isolated cells were resuspended in Krebs-Ringer phosphate buffer containing 11 mmol/L glucose, 1 mmol/L phenylmethylsulfonylfluoride, and different concentrations of heparin ranging from 0 to 100 U/mL. Cells were incubated for 15 min at 37°C. Subsequently, the leukocytes were sedimented by centrifugation, and PLA2 was measured in the supernatant. A similar experiment was performed with the incubation buffer used by Nakamura et al. (2), containing 0.25 mol/L sucrose, 0.05 mol/L HEPES buffer (pH 7.5), 0.02 mmol/L leupeptin, and 100 U/mL aprotinin. Results in both incubation systems were identical.

PLA2 Assay
Plasma samples were stored frozen at -80°C before measurement. PLA2 was assayed by the method of Kim and Bonventre (15), measuring the release of fatty acid from radiolabeled phosphatidylethanolamine. Plasma was diluted fivefold in incubation medium (75 mmol/L Tris, pH 8.5; 5 mmol/L CaCl2), and an aliquot of 98 µL of diluted plasma was mixed with 0.5 nmol of 1-palmitoyl-2-[1'-14C]-arachidonoyl-sn-glycero-3-phosphorylethanolamine (specific radioactivity 100 Ci/mol), added in 2 µL dimethylsulfoxide. The mixture was incubated at 37°C for 1 h. The reaction was stopped by the addition of 0.56 mL of Dole’s reagent (16). Released fatty acids were extracted by adding 0.11 mL of water, followed by vortexing and brief centrifugation (2000g, 5 min). An aliquot of 0.15 mL of the supernatant was transferred to a fresh tube containing 25 mg of silica and 0.85 mL of n-heptane. Tubes were vortexed and centrifuged again (2000g, 5 min). Released radioactivity was measured in 0.8 mL of the supernatant by using liquid scintillation counting.

All results were presented as means with SEM. Data were statistically analyzed by using a Student’s t-test for paired samples and by one-way analysis of variance by using the software program SigmaPlot 3.03 (Jandel Scientific, San Rafael, CA). A P value less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Infusion of heparin (350 U/kg) caused a significant increase of PLA2 activity in blood plasma, which was entirely reversible by infusion of protamine (Figure 1). The surgical procedure did not affect PLA2 levels because the enzyme was measured before the institution of CPB. Also, we did not observe a different response to heparin between patients with valve disease and those with coronary disease.



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  		Figure 1. Phospholipase A2 (PLA2) activity in blood plasma after the addition of heparin in vivo and in vitro. Blood was treated with heparin either in vivo (IV application of heparin, open columns) or in vitro (addition of heparin to freshly drawn blood in a test tube, hatched columns). In either protocol, concentration of heparin was 5 U/mL blood and PLA2 activity was measured 15 min after the heparin injection. Protamine (5 U/mL) was added to antagonize the effect of heparin. The same patients were used for measurements in vivo and in vitro (n = 7). Heparin-induced activities were compared with control by using paired t-tests. *In a separate group (n = 6), blood was collected in the absence of EDTA, solely relying on the anticoagulating effect of heparin. This was done to demonstrate that EDTA did not interfere with secretion and measurement of PLA2. NS = not significant.

 
We investigated the possibility that circulating blood cells were the source of heparin-induced PLA2. For this purpose, blood was incubated with heparin in vitro, adjusting the same heparin concentration used in vivo. The concentration of heparin in vivo was 7.5 ± 1.0 U/mL plasma 2 min after the injection, and 6.9 ± 0.8 U/mL plasma 10 min after the injection of heparin (n = 5). Considering the hematocrit, this corresponded to 4–5 units of heparin per mL of whole blood. Although this concentration of heparin caused a significant increase of plasma PLA2 in vivo, it did not elicit a similar response in vitro (Figure 1). Even at larger doses of heparin (10, 20, and 100 U/mL), we did not find any significant release of PLA2 in vitro, i.e., the activities remained below 20 pmol · h-1mL-1, which was not different from baseline activity (n = 3). Furthermore, we tested the ability of isolated polymorphonuclear leukocytes to release PLA2 in response to heparin: After 15 min of incubation, the secreted activity of PLA2 was 2.6 ± 0.4, 3.3 ± 1.0, and 2.4 ± 2.0 pmol/h per 106 leukocytes in the presence of 0, 10, and 100 U/mL of heparin, respectively (n = 4). Thus, isolated polymorphonuclear leukocytes did not release PLA2 under conditions chosen for this experiment. The data suggested that blood cells alone were not able to secrete PLA2 when stimulated by heparin.

In vivo heparin induced a rapid increase of plasma PLA2. The increase occurred within 2 min, and the activity stayed increased until patients were treated with protamine. PLA2 activity during CPB was 96% ± 21% of prebypass activity (n = 5). We did not find a significant difference in PLA2 activity between systemic arterial and pulmonary arterial blood in the period of enzyme release and beyond, which suggests that the enzyme was not secreted into the pulmonary circulation (Figure 2). In contrast, 2 min after heparin addition, PLA2 activity was significantly higher in the hepatic vein compared with the radial artery. Four minutes after heparinization, there was still a small, but significant, difference in PLA2 activity. This difference disappeared 6 min after the infusion of heparin. The venous-arterial difference in PLA2 suggested a net increase of the plasma activity during perfusion of the splanchnic region (Figure 3).



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  		Figure 2. Difference in heparin-induced phospholipase A2 (PLA2) between the radial and pulmonary arteries. Open circles represent the difference in plasma PLA2 activity between radial artery and pulmonary artery as a function of time elapsed after the heparin injection. Filled circles represent absolute PLA2 activities in the radial artery. Measurements were made in six patients before institution of cardiopulmonary bypass. Data were analyzed for time-dependent change by using one-way analysis of variance. NS = not significant.

 


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  		Figure 3. Difference in heparin-induced phospholipase A2 (PLA2) between the hepatic vein and radial artery. Open circles represent the difference in plasma PLA2 activity between the hepatic vein and radial artery as a function of time elapsed after the heparin injection. Filled circles represent absolute PLA2 activities in the radial artery. Measurements were made in six patients before institution of cardiopulmonary bypass. Data were analyzed for time-dependent change by using one-way analysis of variance.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Large-dose heparin, given for CPB, may induce imbalance in the relative synthesis of prostaglandins and thromboxanes, which may result in depressed renal, pulmonary, and cardiac function as well as thrombocytopenia after cardiac surgery (2,4). With the advent of hirudin (17) and danaparoid (18) as alternatives to heparin, it became time to revisit benefits and side effects of this drug. This has spurred new interest in the various pharmacologic actions of heparin, one of which is a sudden increase of PLA2 activity in plasma. Consistent with the results of Nakamura et al. (2), Bruins et al. (3) demonstrated that the enhancement of plasma PLA2 in cardiac surgical patients was the result of systemic heparinization rather than CPB. The present data support the idea that heparinization itself induces PLA2 activity in plasma, because increased activity was observed before institution of CPB, and the activity did not change significantly during extracorporeal circulation. It is not known, however, which tissue or cell type releases PLA2 in this setting.

Nakamura et al. (2) suggested that heparin-induced PLA2 was derived from polymorphonuclear leukocytes. However, conflicting evidence has been published regarding the potential capability of polymorphonuclear cells to release PLA2. There was no in situ hybridization signal for PLA2 messenger ribonucleic acid in polymorphonuclear leukocytes (19), and there was no correlation between white blood cell counts and serum PLA2 activities in patients with inflammatory diseases (20). PLA2 concentrations increased in the sera of febrile leukemia patients with treatment-induced neutropenia (21). In addition, immunohistochemical reaction with an anti-PLA2 antibody was negative in inflammatory cells of rheumatic synovial tissue (22), and the concentration of PLA2 was small in homogenates of blood leukocytes (23). In this study, polymorphonuclear leukocytes did not secrete PLA2 in response to heparin.

Bruins et al. (3) demonstrated a dose-dependent effect of heparin on the plasma level of PLA2 in blood samples incubated in vitro. At a heparin concentration comparable to the one in Figure 1, they detected an approximately twofold increase of PLA2 by enzyme-linked immunosorbent assay. This finding was in conflict with our study, in which we did not observe any secretion of PLA2 up to a heparin concentration of 100 U/mL. The data of Bruins et al. (3) were obtained in blood from a single volunteer only. It is possible that the enzyme leaked from cell debris or that blood cells did indeed secrete small levels of PLA2. It is further possible that the enzyme-linked immunosorbent assay was more sensitive than the present measurement of enzyme activity. In any case, even a twofold increase of PLA2 in vitro was negligible compared with the strong effect of heparin in vivo. Thus, blood cells did not seem to be the source of heparin-induced PLA2.

Kim et al. (7) demonstrated increased PLA2 activities in bronchoalveolar lavage fluids of patients with adult respiratory distress syndrome. Because lung tissue is known to produce a variety of mediators, we studied whether it can release PLA2 in response to systemic heparin treatment. We did not find a significant PLA2 gradient across the pulmonary circulation (Figure 2); hence, it appeared unlikely that lung tissue contributed to plasma PLA2 in heparinized patients.

Further, it was proposed that PLA2 is an acute phase protein secreted by the liver (24). Several cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-{alpha}, induced synthesis and secretion of PLA2 in cultured hepatocytes (24,25). In a case report, a patient with a liver tumor had vastly increased levels of circulating PLA2 (19). The authors suggested that hepatocytes are an important source of this enzyme in vivo (19). Hatch et al. (12) demonstrated that liver macrophages (Kupffer cells) are the source of endotoxin-induced serum Group II PLA2 associated with bacterial infection and trauma. In our study, the venous-arterial difference of PLA2 activity in the splanchnic region (Figure 3) was consistent with secretion of the enzyme by the liver. However, a PLA2 gradient could also be generated by interaction of blood cells with splanchnic endothelium or with signaling compounds released by gut or liver tissue. Xu et al. (26) suggested a relation between shock-induced mucosal injury and increased plasma activity of PLA2. Gut mucosa contains large concentrations of PLA2, which can be activated in the presence of splanchnic hypoperfusion and may generate proinflammatory mediators such as lysophospholipids and arachidonic acid (27). In addition, Paneth cells of the intestinal mucosa showed strong expression of the enzyme in vitro (28). Thus, the present data suggest heparin-induced release of PLA2 from the splanchnic region, but they do not allow any conclusion about the specific cellular origin in the liver and/or the intestine.


   Acknowledgments
 
This work was supported, in part, by a grant from the Deutsche Forschungsgemeinschaft (Schl 307/4-1).

We are grateful to Dr. S. Ziemer (Hospital Charite, Berlin) for determination of heparin in blood plasma.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 26, 2000.




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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