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Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates

Shinji Yokoyama, MD^_*, Hisao Ikeda, MD, PhD^_*,_*, Nobuya Haramaki, MD, PhD^_*, Hideo Yasukawa, MD, PhD^_*, Toyoaki Murohara, MD, PhD and Tsutomu Imaizumi, MD, PhD, FACC^_*

^_* Department of Internal Medicine III and the Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Manuscript received November 4, 2004; revised manuscript received November 24, 2004, accepted December 21, 2004.

^_* Reprint requests and correspondence: Dr. Hisao Ikeda, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. (Email: ikeda_hisao{at}kurume-u.ac.jp).

OBJECTIVES: We investigated the role of P-selectin in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates.

BACKGROUND: Plaque rupture followed by thrombus formation is a fundamental pathophysiology of acute coronary syndromes. Although the adhesive interaction between platelets and leukocytes via P-selectin is known to mediate platelet-rich thrombi, the true function of P-selectin in thrombus formation in vivo is unknown.

METHODS: In wild-type (P^+/+) and P-selectin-deficient (P^–/–) mice with ferric chloride (FeCl₃)-induced carotid arterial thrombosis model, we measured in vivo platelet P-selectin expression and adenosine diphosphate (ADP)-induced ex vivo platelet aggregation. We also measured ex vivo ADP-induced whole blood aggregations and their size distribution by flow cytometry.

RESULTS: Time to thrombotic occlusion was longer in P^–/– mice than in P^+/+ mice. Spontaneous reflow after total thrombotic occlusion was observed in 8 of 10 P^–/– mice but not in any P^+/+ mice. ADP-induced ex vivo platelet aggregation was not different between the two groups. However, ADP-induced ex vivo whole blood aggregation was inhibited in P^–/– mice compared to P^+/+ mice. FeCl₃ application increased in vivo expressions of platelet P-selectin in P^+/+ mice but not in P^–/– mice. The number of leukocytes within thrombi was less in P^–/– mice than in P^+/+ mice. In flow cytometric analysis of size distribution of ADP-induced whole blood aggregates, the number of large aggregates was less in P^–/– mice than in P^+/+ mice. Using platelet and leukocyte fluorescence makers, the large aggregates were confirmed as platelet-leukocyte aggregates.

CONCLUSIONS: Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates.

Abbreviations and Acronyms   ADP = adenosine diphosphate   FeCl3 = ferric chloride   FITC = fluorescein isothiocyanate   PPP = platelet-poor plasma   PRP = platelet-rich plasma   P–/– mice = P-selectin-deficient mice   P+/+ mice = wild-type mice   PSGL-1 = P-selectin glycoprotein ligand-1

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