Objective-To determine the role of CXCR2, the receptor for cysteine-X-cysteine (CXC) chemokines, and its primary effector cell, the neutrophil (PMN), on deep venous thrombosis (DVT) resolution. Methods and Results-DVT in BALB/c, anti-CXCR2 antibody-treated, and BALB/c CXCR2 Ϫ/Ϫ mice were created by infrarenal inferior vena cava (IVC) ligation and the thrombus harvested at various time points over 21 days. The CXCR2 Ϫ/Ϫ mice had significantly larger thrombi at early time points (days 2 to 8), and significantly decreased intrathrombus PMNs, monocytes, and neovascularization as compared with controls. Thrombus KC/CXCL1 was significantly higher at 2 days in CXCR2 Ϫ/Ϫ thrombi as measured by enzyme-linked immunosorbent assay. Fibrin content was significantly higher, with less uPA gene expression at 4 days in CXCR2 Ϫ/Ϫ thrombi. Late fibrotic maturation of the thrombus was delayed in the CXCR2Ϫ/Ϫ mice, with significantly decreased 8 day MMP-2 activity, whereas MMP-9 activity was elevated as compared with controls. Similar impairment in DVT resolution was found at 8 days with anti-CXCR2 inhibition. However, systemic neutropenia, unlike CXCR2 deletion, did not increase the thrombus size as compared with controls. Conclusions-Normal DVT resolution involves CXCR2-mediated neovascularization, collagen turnover, and fibrinolysis, and it is probably primarily monocyte-dependent.

This study demonstrates that high circulating levels of P-selectin are associated with increased thrombosis, whereas a lack of P-selectin and E-selectin is associated with a lessening of thrombosis. Additionally, leukocyte MPs are associated with venous thrombus formation. These data suggest the importance of selectins to venous thrombogenesis and show that P-selectin and leukocyte-derived MPs should be good targets to limit venous thrombus formation.

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rPSGL-Ig, LMWH, and tPA showed equal DVT resolution efficacy over 7 days. However, only rPSGL-Ig was associated with a decrease in vein wall fibrosis, suggesting that purely accelerating DVT resolution may not decrease long-term vein scarring.

These data demonstrate that variations in aortic MMP-9 expression and activity result from regional factors affecting the aorta rather than intrinsic aortic wall differences. Increases in abdominal aortic MMP-9 may contribute to the predilection for aneurysm to develop in the infrarenal aorta.