Antithrombotic effect of grape seed proanthocyanidins extract in a rat model of deep vein thrombosis

ObjectiveProanthocyanidins are abundantly found in grape seeds and have been suggested to inhibit the pathogenesis of systemic diseases. We investigated the antithrombotic effects of proanthocyanidins in a rat model of deep vein thrombosis (DVT) and examined the underlying mechanisms.MethodsDVT was induced in rat model by inferior vena cava (IVC) ligation. Grape seed proanthocyanidins extract (GSPE, 400 mg/kg/d) dissolved in saline (2 mL) was orally administered to the experimental rats. Control rats were administrated saline (2 mL) only. The thrombi were harvested and weighed. The IVC was analyzed histologically and by transmission electron microscopy. The cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay. Expression of cellular adhesion molecules (CAMs) in thrombi was examined by Western blot.ResultsGSPE significantly reduced thrombus length and weight (P < .01) and protected the integrity of the endothelium. GSPE inhibited thrombogenesis-promoting factors P-selectin, von Willebrand factor, and CAMs, and promoted thrombogenesis-demoting factors CD34, vascular endothelial growth factor receptor-2, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type one motif, member 13). Compared with the control, GSPE significantly lowered the cytokines IL-6 (74.19 ± 13.86 vs 189.54 ± 43.76 pg/mL; P < .01), IL-8 (80.71 ± 21.42 vs 164.56 ± 39.54 pg/mL; P < .01), and TNF-α (43.11 ± 17.58 vs 231.84 ± 84.11 pg/mL; P < .01).ConclusionsGSPE significantly inhibited the propagation of thrombus induced by IVC ligation in a rat model. The antithrombotic properties of proanthocyanidins are likely to be directly associated with endothelial protection and regeneration, platelet aggregation, and inhibition of inflammatory cell and thrombus adhesion. Thus, proanthocyanidins may have a clinical application in DVT treatment.

Clinical RelevanceThe major presenting symptoms of deep vein thrombosis (DVT) are pain, swelling, and sometimes intractable venous ulceration. These are mainly caused by intravenous thrombosis occlusion and local inflammatory reaction. Two recent clinical studies reported that the levels of inflammatory markers such as interleukin-6, intercellular adhesion molecule 1 (ICAM-1), and C-reactive protein were associated with the development of postthrombotic syndrome (PTS). Our current results show that grape seed proanthocyanidins extract (GSPE) inhibited interleukin-6 release and ICAM-1 expression, which may suggest that prompt administration of GSPE is instrumental to thrombus clearance, removal of venous outflow obstruction, and attenuation of venous endothelium loss in PTS. Clinically, oral anticoagulants, heparin, and urokinase/streptokinase regimens are routinely used for treating DVT patients. These medicines are effective in correcting bloodstream stasis and hypercoagulable state; however, they are unable to cure endothelium injury caused by preceding thrombus occlusion that induces endothelial inflammation, compression, and hypoxia. This pathology may contribute to the recurrence of DVT, PTS, and other complications. Therefore, it is necessary to find a novel regimen that is effective and safe for the treatment of DVT. GSPE may be such a promising candidate.