British Journal of Anaesthesia, 2000, Vol. 85, No. 6 896-898
© 2000 The Board of Management and Trustees of the British Journal of Anaesthesia
Increased pre-operative platelet counts are a possible predictor for reduced sensitivity to heparin
Department of Anaesthesia, Papworth Hospital, Papworth Everard, Cambridge CB3 8RE, UK 1Present address: Department of Anaesthesia, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK*Corresponding author
Accepted for publication: July 21, 2000
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Abstract |
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We investigated a possible relationship between pre-operative platelet count and reduced sensitivity to heparin in 87 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Sensitivity to heparin was determined by measuring the slope of the heparin dose response (HDR) before surgery. Pre-operative platelet counts were measured as part of routine analysis of the patients’ coagulation status. Patients with an HDR slope of <80 s u. ml–1, were considered to have a reduced sensitivity to heparin and activated clotting time data were collected from these patients before and after heparin administration before CPB. A significant correlation was determined between pre-operative platelet levels and HDR slope (P<0.001). Platelet counts were significantly greater in heparin-resistant patients compared with those who had the expected response to the anticoagulant (P<0.05). This could be caused by an increased capacity to produce platelet factor 4, which neutralizes heparin.
Br J Anaesth 2000; 85: 896–8
Keywords: blood, platelets; blood, anticoagulants, heparin
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Introduction |
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In patients having cardiac surgery with extracorporeal circulation, sensitivity to heparin is important, because inadequate anticoagulation can disturb haemostatic mechanisms. Possible factors that contribute to heparin resistance include intra-aortic balloon pumping and pre-operative intravenous nitroglycerin therapy.1 2 However, the most common reason is heparin treatment before operation, which can reduce concentrations of the coagulation inhibitor antithrombin III.1
Platelet counts are greater in heparin-resistant patients before operation, compared with those who are heparin-sensitive.1 3 We studied the relationship between pre-operative platelet levels and the response to heparin in a population of patients undergoing cardiac surgery.
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Methods and results |
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After local ethics committee approval and informed consent, eighty-seven patients presenting for either coronary artery bypass surgery (n=73), valve surgery (n=8) or a combination of both (n=6) were included in this study. Patients with pre-existing coagulopathy or who had received either warfarin (within 3 days of surgery), streptokinase (within 48 h), tissue-type plasminogen activator (within 48 h) or any antifibrinolytic agent (within 24 h) were excluded.
Platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured as part of the routine pre-operative evaluation of the patients’ coagulation state. In addition, before surgery, the heparin dose response (HDR) for each patient was determined by the use of the Hepcon® Hemostasis Management System (Medtronic Inc, Minneapolis, MA, USA). This system carries out three dual channel clotting tests simultaneously by comparing a patient’s blood with zero heparin in two channels, 1.5 u. ml–1 heparin in another two channels and 2.5 u. ml–1 heparin in the final two channels. As the response to heparin is linear up to 8 u. ml–1, the three clotting times can be plotted on a graph to produce an HDR curve. The HDR slope (in seconds per unit heparin per ml of blood) is the value that the ACT will increase by, for every unit of heparin given per unit of ml blood volume. Patients with an HDR slope of <80 s u. ml–1 were considered to have a reduced heparin sensitivity and were studied further. Intra-operative administration of heparin was standardized in all patients and anticoagulation capacity was assessed by determination of ACT by the use of the Automated Coagulation Timer II® system (Medtronic Inc, Minneapolis, MA USA). If administration of 300 u. kg–1 heparin failed to achieve an ACT of 
480 s, then a further 100 u. kg–1 of heparin was given. Patients were considered heparin-resistant if the ACT was <480 s after the second dose of heparin.
The Mann–Whitney U test was used to compare patient data. Where appropriate results are expressed as median (interquartile range). Correlation analysis was with Spearman’s rank sum correlation.
Thirty patients from the original 87, had an HDR slope of >80 s u. ml–1 (group A). Of the remaining 57 patients, 42 achieved an ACT of 480 s after the first dose of heparin (group B), eight achieved an ACT of 480 s after the second dose of heparin (group C) and seven were heparin-resistant (Group D). Median (interquartile range) age and sex ratio (male: female) for each group were as follows: Group A (69 (62.5–73.8), 7:1); group B (68 (60–73), 5:1); group C (67 (65–78.8), 1:1) and group D (67 (64–70.5), 1:1).
A significant correlation was found between increased pre-operative platelet levels and a reduced sensitivity to heparin (as measured by the HDR slope) (P<0.001; Fig. 1). No correlation was observed for either the baseline ACT or the ACT after the first dose of heparin with pre-operative platelet levels. Pre-operative platelet count was significantly greater in patients in groups C (252 (221–270)x109 litre–1) and D (262 (222–314)x109 litre–1) compared with 194 (165–223)x109 litre–1 in group A (P<0.05). However, none of the patients had a pre-operative platelet count which was greater than normal levels (i.e. >400x109 litre–1).
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PT and aPTT values were within the normal range for all patients studied.
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Comment |
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We found a significant correlation between pre-operative platelet count and a reduced sensitivity to heparin. In addition, pre-operative platelet counts were significantly higher in groups C and D compared with those in group A, although in these cases, platelet counts were within the normal range.
Platelets themselves are thought to influence the ACT, since anti-platelet agents can prolong clotting times. For example, abciximab, which binds to the platelet membrane glycoprotein IIb/IIIa receptor to inhibit platelet activation, can prolong ACT measurements in healthy volunteers.4 However, in this study, there was no correlation between pre-operative platelet count and the initial ACT measurement suggesting that the baseline coagulation state of the patients was unaffected. In any case, low baseline ACT measurements are now not thought to be a predictor of heparin response.1
Patients with thrombocytosis, who have had surgery with CPB, require extra heparin to achieve adequate anticoagulation.5 When activation of platelets takes place, they release platelet factor 4 and this neutralizes heparin. In fact, recombinant platelet factor 4 has been used in clinical trials as a possible alternative to protamine for antagonizing the anticoagulant effect of heparin.6 Thus, patients with a higher platelet count would have a greater capacity to produce platelet factor 4 upon activation, which would have a heparin neutralizing effect. This would explain the correlation between pre-operative platelet counts and heparin response observed in this study.
However, heparin resistance is multifactorial and a high platelet count may indirectly reflect other processes. The high platelet count could be an indirect reflection of more complex mechanisms related to ischaemic heart disease. These mechanisms may also induce a degree of heparin resistance that cannot be attributed to platelet factor 4 alone. Further studies are needed to allow a better understanding of the various components ultimately responsible for heparin resistance.
In conclusion, these findings present the possibility of using the assessment of pre-operative platelet counts could indicate patients who might have a reduced sensitivity to heparin.
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References |
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1 Staples MH, Dunton RF, Karlson KJ, Leonardi HK, Berger RL. Heparin resistance after preoperative heparin therapy or intraaortic balloon pumping. Annal Thorac Surg 1994; 57: 1211–16[Abstract]
2 Habbab M, Haft JI. Heparin resistance induced by intravenous nitroglycerine. A word of caution when both drugs are used concomitantly. Arch Intern Med 1987; 147: 857–60
3 Cazzanga A, Soro G, Isgrò G, Ranucci M. Predictors for heparin resistance in CABG operations. Br J Anaesth 1999; 82 (Suppl 2): A57
4 Ammar T, Scudder LE, Coller BS. In vitro effects of the platelet glycoprotein IIb/IIIa receptor antagonist c7E3 Fab on the activated clotting time. Circulation 1997; 95: 614–7
5 Wilds SL, Camerlengo LJ, Dearing JP. Activated clotting time and cardiopulmonary bypass. III. Effect of high platelet count on heparin management. J Extracorpor Technol 1987; 19: 36–8
6 Levy JH, Michelsen LG. Heparin neutralisation by recombinant platelet factor 4 and heparinase. Anaesth Pharmacol Rev 1995; 3: 112–7
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