Serial Measurement of Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 in Serum of Patients With Acute Ischemic Stroke
To the Editor:
Slevin et al1 reported on elevated serum levels of vascular endothelial growth factor (VEGF) in patients with acute ischemic stroke. They claim to demonstrate a relationship between stroke volume and circulating VEGF (tissue damage, hypoxia, and VEGF expression) and concluded from their data that VEGF may play an important role in the pathogenesis of ischemic stroke and could be of value in future treatment strategies. A moderate correlation between peripheral blood leukocyte counts and serum levels of VEGF was noted.
These findings are interesting. However, in our opinion, several points need to be considered in order to interpret these results more accurately. Under physiological conditions virtually no soluble VEGF is present in the blood. The main transporter of VEGF in the blood stream are thrombocytes,2 and unfortunately no data on platelet counts are reported in the article by Slevin and colleagues. Platelets contain large amounts of VEGF (approximately 1,74 pg/106 platelets), and there is a tight correlation between blood platelet counts and serum VEGF,3 slightly influenced by the mean platelet volume.4 Thus, in serum samples, VEGF predominantly released from platelets during the in vitro clotting process is measured. When citrated plasma samples are analyzed instead (where platelets remain intact), only very low VEGF levels can be found.2 In patients with a massive platelet activation and destruction in vivo (eg, those suffering from idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura), we found elevated VEGF levels in both serum samples and citrated plasma (71 pg/106 platelets and 93 pg/106 platelets, respectively). Also, patients with acute myocardial infarction have high levels of circulating VEGF, most likely as a result of platelet activation in vivo (authors’ own unpublished data). Thus, soluble VEGF measured in serum or plasma samples from patients with chronic vascular disease might reflect platelet activation and destruction. Activation and destruction of platelets occurs frequently in patients with cerebrovascular events,5 and therefore it seems likely that the elevated VEGF levels in stroke patients described by Slevin et al merely reflect this phenomenon, notwithstanding the fact that patients with stroke may have elevated platelet counts.6 Also, their finding that patients with coronary heart disease have the highest VEGF levels fits well into this assumption. Therefore, for a more accurate interpretation of their data on VEGF blood levels in patients with stroke, the appropriate control samples should be taken from patients with atherosclerosis instead of age-matched healthy individuals.
Finally, we would favor another interesting point, that is, the use of elevated VEGF blood levels as a screening parameter for fatal events in patients with chronic vascular disease. This issue is currently being evaluated.
- Copyright © 2001 by American Heart Association
Slevin M, Krupinski J, Slowik A, Kumar P, Szczudlik A, Gaffney J. Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke. 2000;31(8):1863–1870.
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Gunsilius et al suggest that patients suffering from acute ischemic stroke may have increased expression of blood platelets which could account for the increase in vascular endothelial growth factor (VEGF) concentration observed in serum, following in vitro clotting. Although we did not measure this parameter, blood platelet concentration has been measured in several studies in patients suffering from stroke. These studies demonstrated either a reduction in platelet expressionR1 or showed no statistical difference between control, healthy volunteers and stroke patients.R2 A similar study showed a reduction in platelet concentration in patients suffering from large infarct (Li) compared with small infarct (Si), suggesting that greater tissue damage and stroke volume might in fact result in a reduction in circulating platelets.R3 Furthermore, the authors went on to show that serum expression of TGF-β, also known to be synthesized in platelets, was not related to stroke or its severity. It is not likely, therefore, that increased expression of VEGF described in stroke patients in our study is associated with changes in blood platelet concentration.
Gunsilius et al also claim that the VEGF concentration in human platelets is approximately 1.74 pg/106; however, a figure of 0.56 pg/106 was reported recently, suggesting difficulty in accurate measurement of this parameter.R4
It is possible that increased activation and destruction of platelets in and around the infarcted area may contribute to the overall increase in serum VEGF, as Gunsilius et al suggest; however, there are many other well-documented sources. For example, VEGF expression is upregulated in neurons, endothelial cells, and astrocytes in the penumbra region after stroke.R5 Similarly, activated macrophages and neutrophils associated with the acute inflammatory response also express and release significant quantities of VEGF.R6 We believe that increased VEGF expression occurs as a result of a combination of these factors, and furthermore, the same argument may be applied to patients suffering from chronic vascular diseases such as atherosclerosis, where in the latter stages the inflammatory response coupled with platelet aggregation could result in generation of larger-than-normal quantities of VEGF. The pathological and biochemical changes that occur during atherosclerotic plaque formation are currently under investigation in our laboratories.
D’Erasmo E, Celi FS, Acca M, Mazzuoli G. Relationship between platelet and white blood cell counts during the early phase of cerebral infarction. Stroke. 1991:22;283. Letter.
Kim JS, Yoon SS, Kim YH, Ryu JS. Serial measurement of interleukin-6, transforming growth factor-β, and S-100 protein in patients with acute stroke. Stroke. 1996;27:1553–1557.