Increased Membrane and Soluble P-Selectin in Atrial Fibrillation
To the Editor:
Inappropriate platelet activation and thrombus formation are frequent findings in many cardiovascular disorders and are believed to have an important pathogenic role. P-selectin, the membrane of the component of α-granule and membrane of the Weibel-Palade body, aids the adhesion of leukocytes bearing its ligand. Increased expression of P-selectin at the surface of the platelet, as defined by flow cytometry, is therefore a likely marker of the activation of these cells.1
The recent article by Minamino and colleagues2 reporting increased expression of P-selectin by platelets in subjects with atrial fibrillation (AF) is therefore in keeping with platelet activation and a prothrombotic state in AF, leading to the high risk of stroke and thromboembolism in this common condition. Nevertheless, a soluble form of P-selectin (sP-selectin) is also present in the plasma, and increasing evidence points toward elevated plasma levels among patients with thrombotic disorders, stroke, and atherosclerosis, thus providing an additional tool to study platelet activation.3 4 Similar to Minamino and colleagues,2 we hypothesised that patients with AF would have raised levels of sP-selectin.
To investigate this further, we recruited 52 consecutive patients (45 males, mean age 66 years) with chronic AF who were not taking any antithrombotic therapy and 60 age- and sex-matched healthy controls. sP-selectin was measured in citrated plasma by commercial ELISA (R&D Systems). Mean±SD levels in the patients with AF were 232±181 ng/mL compared with 161±82 ng/mL in the controls (unpaired t test P=0.015). Like Minamino and colleagues,2 we would interpret our preliminary data showing raised sP-selectin in AF as evidence of increased platelet activation in our patients.
Our findings may be applicable to other forms of atherothrombotic disorders, such as stroke, and warrant further attention in larger groups of patients with more diverse disease(s). If raised sP-selectin levels are truly a marker of platelet activation, this may possibly provide a new rationale for developing and using therapy targeting platelets. sP-selectin would also be an easily measurable index of platelet activation, allowing large-scale epidemiological and prognostic studies in AF and other disorders to be performed without encountering the limitations imposed by complex flow cytometry.
- Copyright © 1999 by American Heart Association
Minamino T, Kitakaze M, Sanada S, Asanuama A, Kurotobi T, Koretsune Y, Fukunami M, Kuzuya T, Hoki N, Hori M. Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide. Circulation. 1998;98:1721–1727.
Frijns CJM, Kappelle LJ, van Gijn J, Nieuwenhuis HK, Sixma JJ, Fijnheer R. Soluble adhesion molecules reflect endothelial cell activation in ischemic stoke and in carotid atherosclerosis. Stroke. 1997;28:2214–2218.
We thank Dr Blann and his colleagues for the important comments on the results presented in our recent publication in Circulation.R1
Our experimental and clinical data revealed that the increased expression of P-selectin on platelets with reduced nitric oxide levels was a risk factor for silent cerebral infarction in patients with atrial fibrillation (AF). Dr Blann further provided interesting data that plasma levels of soluble P-selectin in patients with AF were higher than those in age- and sex-matched controls, which seems to be consistent with our observation. However, since P-selectin is expressed in endothelial cells as well as platelets,R2 plasma soluble P-selectin is believed to be liberated from endothelial cells as well as platelets in the pathophysiological condition.R3 Therefore, the higher plasma levels of soluble P-selectin in patients with AF may be attributable to endothelial damage as well as to platelet activation in those patients. We have experimentally observed a reduction in plasma levels of nitrite and nitrate (stable end products of nitric oxide) after the onset of AF, which suggests the possibility that an irregular change in the shear stress of the cardiovascular system may impair endothelial function.R4 Indeed, Lip and colleaguesR5 reported that von Willebrand Factor (vWF), an established marker of endothelial dysfunction, is increased in patients with AF, which suggests that endothelial damage may occur in those patients. vWF is known to colocalize with P-selectin in the Weibel-Palade bodies of endothelial cells and to mobilize with P-selectin after certain stimuli. Thus, it is likely that the elevation of plasma soluble P-selectin levels may reflect both endothelial dysfunction and platelet activation in patients with AF. Since both endothelial dysfunction and platelet activation may be involved in thrombus formation in patients with AF, we agree that the measurement of plasma soluble P-selectin is promising as an integrated marker of endothelial dysfunction and platelet activation in patients with AF. It is intriguing to investigate the kinetics of soluble P-selectin in patients with AF for the prediction of cerebral infarction.
Minamino T, Kitakaze M, Sanada S, Asanuma H, Kurotobi T, Koretsune Y, Fukunami M, Kuzuya T, Hoki N, Hori M. Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide. Circulation. 1998;98:1721–1727.
Bonfanti R, Furie BC, Furie B, Wagner DD. PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells. Blood. 1989;73:1109–1112.
Koskinen PK, Lemstrom KB. Adhesion molecule P-selectin and vascular cell adhesion molecule-1 in enhanced heart allograft arteriosclerosis in the rat. Circulation. 1995;92:3304–3311.
Lip GYH, Lowe GDO, Rumley A, Dunn FD. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J. 1995;73:527–533.