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Figure 5 Detection of Vulnerable, Thrombogenic Plaques by Radiolabeled Platelet GPVI

(A) Pathophysiology of platelet adhesion, secretion, and thrombus formation at sites of injured vascular endothelium with exposed extracellular matrix. 1) Within the intact vessel, platelets do not adhere to the endothelial monolayer under physiological conditions. 2) At site of atherosclerotic lesions, subendothelial proteins such as von Willebrand factor (vWF) and collagen are exposed to blood flow. Platelet adhesion receptors glycoprotein Ib (GPIb) and glycoprotein VI (GPVI) mediate tethering of platelets. 3) After activation of the integrins ₂β₁ (collagen receptor) and _IIbβ₃ (fibrinogen receptor), platelets firmly adhere via interaction of these receptors with extracellular matrix proteins. 4) Subsequently, platelets get activated and secrete distinct mediators resulting in: 5) platelet aggregation via fibrinogen bridges between 2 _IIbβ₃ receptors and thrombus formation. (B) A soluble dimeric form of human platelet GPVI conjugated to an Fc-fragment was used, which was radiolabeled with ¹²⁴I. Glycoprotein VI is essential to establish the first interaction of platelets with an exposed collagen surface. Therefore, we made use of this natural mechanism to detect thrombogenic and, thus, vulnerable plaques. (C and D) Apolipoprotein E^–/– mice were analyzed with ¹²⁴IGPVI-Fc using an animal microPET scanner (MicroPET Focus 120, Siemens, Knoxville, Tennessee) (left). Images were acquired 24 h after administration of the tracer and imaging time was 20 min. Positron emission tomography (PET) images were correlated with computed tomographic (CT) data (right) to verify anatomical structures. (C) Shows transverse sections of these experiments. (D) Ex vivo nuclear imaging was performed to evaluate tracer activity in the aortic arch (top). The bottom shows the specimen after staining with sudan III. Activity of ¹²⁴IGPVI-Fc correlated well with plaque extension (left). The signal could be nearly abolished, when nonlabeled GPVI-Fc was injected before application of ¹²⁴IGPVI-Fc (right).