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.

Neutropenia impairs DVT resolution by several measures, most likely by altering normal fibrinolytic activity and thrombus collagen turnover.

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Pro-angiogenic compounds increase thrombus neovascularization, but this does not correlate with smaller or less fibrotic DVT. Mechanisms other than neovascularization may be more important to hasten DVT dissolution. Clinical relevance Improved therapy for deep venous thrombosis (DVT) will ideally increase the rate of thrombus dissolution and eliminate the bleeding risks of anticoagulation. This study evaluated promoting DVT neovascularization with angiogenic chemokines, and, while successful by experimental measures, this did not translate into smaller DVT. Solely promoting thrombus neovascularization will not likely speed resolution.