doi: 10.1161/01.ATV.0000197801.28944.41
© 2006 American Heart Association, Inc.
Letter to the Editor |
Leukocytosis, Vascular Disease, and Adenine Nucleotide Metabolism
Departments of Cardiovascular Medicine and Haematology, Queens Medical Centre, Nottingham, University of Nottingham and University Hospital NHS Trust, Nottingham, United Kingdom
To the Editor:
We read with interest the paper by Barry S. Coller on leukocytosis and its relationship with vascular disease morbidity and mortality1 and the subsequent correspondence.2,3 We are intrigued to learn that relative leukocytopenia may be associated with increased morbidity and mortality in patients with acute myocardial infarction1,4 and in those undergoing percutaneous coronary intervention.5 We note the discussion on whether leukocyte count is merely a marker of general disturbances in inflammation and general poor health, or whether leukocytes might contribute directly to thrombosis and atherosclerosis.
Although several mechanisms through which leukocytes may contribute to thrombosis and atherosclerosis were discussed,1–3 nothing has been said about the role of leukocytes in adenine nucleotide metabolism. Adenosine diphosphate (ADP) is, of course, a major contributor to the thrombotic mechanism as evidenced by the successful use of ADP antagonists which reduce ADP-induced platelet activation and aggregation and thereby act as anti-thrombotic agents.6
It was recognized that leukocytes are active in the metabolism of adenine nucleotides many years ago7 but recent papers from our own group have re-emphasized their importance.8–10 In summary, first we found that adenosine triphosphate (ATP) added to blood induces platelet aggregation via a mechanism involving leukocytes and ADP formation.8 We then found that leukocytes (all neutrophils, all monocytes and a subset of lymphocytes) test positive for an antibody to CD39, the NTPDase which converts ATP into ADP and also ADP into adenosine monophosphate (AMP).9 We also saw that leukocytosis results in modified platelet aggregation responses to both ATP and ADP; platelet aggregation in blood induced by ATP is more rapid in leukocytosis while aggregation induced by ADP is followed by rapid disaggregation. A systematic analysis of the role of blood cells and plasma enzymes in adenine nucleotide metabolism by high-performance liquid chromatography (HPLC) was then performed.10 This confirmed that leukocytes are the principle means through which ATP and ADP added to blood are broken down to ADP and AMP respectively. Thus leukocytes provide a means of metabolising adenine nucleotides that is additional to that provided by vascular endothelial cells and thus provide a clearance mechanism that is active within the blood itself as well as at the blood periphery.
In view of the current discussion on leukocytosis we show in Figure 1 the results of new experiments in which we added ATP or ADP to normal blood, blood to which autologous leukocytes had been added to increase the count from 4.4 to 26x103/µL and blood from a patient with hyperleukocytosis with a white cell count of 126x103/µL. Nucleotides and products were determined by HPLC. It can be seen that in the presence of normal numbers of leukocytes ATP was converted to ADP which peaked at about 15 minutes and was then subsequently broken down to AMP; ADP was converted directly to AMP. With added leukocytes the rate of ATP metabolism is markedly enhanced (t1/2 from &15 minutes to &4 minutes) with ADP produced more quickly, but present for a shorter duration before conversion to AMP; the rate of ADP conversion to AMP was also markedly enhanced. In hyperleukocytosis both ATP and ADP were metabolized very quickly with rapid conversion to AMP which was subsequently removed.
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It seems to us that differences in adenine nucleotide metabolism as determined by leukocyte count may well have relevance to thrombosis and also to hemostasis. On the one hand, leukocytes in blood provide a mechanism for platelet activation via ATP, as well as ADP. Further, because high leukocyte counts provide a means of converting ATP to ADP more rapidly, earlier platelet activation can occur. In this regard, leukocytes can be thought of as being prothrombotic. On the other hand, leukocytes also provide an effective means of removing ADP thus limiting platelet responses to this important nucleotide, possibly an important anti-hemostatic role.
We believe the extent to which the increased morbidity and mortality associated with leukocytosis may be a consequence of altered adenine nucleotide metabolism needs to be investigated further. Erythrocytes are a huge source of ATP which can be released physiologically in response to hypoxia11 and via cell damage. Activated platelets also release ATP as well as ADP. There is also the possibility that the increased morbidity and mortality associated with leukocytopenia in acute myocardial infarction and in percutaneous coronary intervention may be a consequence of ineffective ADP removal. In which case there would be further justification for the use of ADP antagonists in these conditions.
References
1. Coller BS. Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene? Arterioscler Thromb Vasc Biol. 2005; 25: 658–670.
2. Kaski JC, Avanzas P, Arroyo-Espliguero R. Neutrophil count and complex lesions in patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2005; 25: e112.
3. Coller BS. Neutrophil count and complex lesions in patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2005; 25: e112.
4. Grzybowski M, Welch RD, Parsons L, Ndumele CE, Chen E, Zalenski R, Barron HV. The association between white blood cell count and acute myocardial infarction in-hospital mortality: findings from the NationalRegistry of Myocardial Infarction. Acad Emerg Med. 2004; 11: 1049–1060.[CrossRef][Medline] [Order article via Infotrieve]
5. Gurm HS, Bhatt DL, Gupta R, Ellis SG, Topol EJ, Lauer MS. Preprocedural white blood cell count and death after percutaneous coronary intervention. Am Heart J. 2003; 146: 692–698.[CrossRef][Medline] [Order article via Infotrieve]
6. Hacke W. From CURE to MATCH: ADP receptor antagonists as the treatment of choice for high-risk atherothrombotic patients. Cerebrovasc Dis,. 2002; 13: 22–26.
7. Coade SB, Pearson JD. Metabolism of adenine nucleotides in human blood. Circ Res. 1989; 65: 531–537.
8. Stafford NP, Pink AE, White AE, Glenn JR, Heptinstall S. Mechanisms involved in adenosine triphosphate-induced platelet aggregation in whole blood. Arterioscler Thromb Vasc Biol. 2003; 23: 1928–1933.
9. Glenn JR, White AE, Johnson A, Fox SC, Behan MWH, Dolan G, Heptinstall S. Leukocyte count and leukocyte ecto-nucleotidase are major determinants of the effects of adenosine triphosphate and adenosine diphosphate on platelet aggregation in human blood. Platelets. 2005; 16: 159–170.[Medline] [Order article via Infotrieve]
10. Heptinstall S, Johnson A, Glenn JR, White AE. Adenine nucleotide metabolism in human blood -important roles for leukocytes and erythrocytes. J Thromb Haemost. 2005; 3: 2331–2339.[CrossRef][Medline] [Order article via Infotrieve]
11. Wang L, Olivecrona G, Götberg M, Olsson ML, Winzell MS, Erlinge D. ADP acting on P2Y13 receptors is a negative feedback pathway for ATP release from human red blood cells. Circ Res. 2005; 96: 189–196.
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