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Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice.

ABSTRACT: Platelets and myeloid cells cooperate to promote deep vein thrombosis (DVT). Here we evaluated the role of kindlin-3, a key integrin activator in these cells, in regulating stenosis-induced DVT in mice. DVT was significantly suppressed in mice that express a kindlin-3 mutant defective for integrin binding, showing that kindlin-3-mediated integrin signaling in blood cells is required for DVT. While platelet-specific deficiency of kindlin-3 in Kindlin-3fl/flPF4-Cre mice significantly suppressed DVT, deficiency of kindlin-3 specifically in myeloid cells in Kindlin-3fl/flLysM-Cre mice remarkably enhanced the early development of DVT, indicating that kindlin-3 in platelets and myeloid cells can play distinct roles in regulating DVT. Mechanistically, the levels of neutrophil extracellular traps (NETs) in plasma, a key DVT facilitator, were significantly elevated in Kindlin-3fl/flLysM-Cre mice upon the IVC stenosis; and treatment with either DNase I or PAD4 inhibitor could effectively compromise the enhancement of DVT in these mice, suggesting that kindlin-3 in neutrophils may affect DVT via restraining NET release. In addition, we found that the kindlin-3-integrin ?IIb?3 signaling in platelets was required to promote NET release. Together, our studies reveal that kindlin-3 in platelets and myeloid cells can differentially regulate DVT through orchestrating NET release, thus providing further mechanistic insights into DVT.

SUBMITTER: Yan Y

PROVIDER: S-EPMC6756892 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice.

Yan Yanyan Y Yang Hongqin H Hu Xiao X Zhang Zeping Z Ge Shushu S Xu Zhen Z Gao Juan J Liu Junling J White Gilbert C GC Ma Yan-Qing YQ

Aging 20190831 17

Platelets and myeloid cells cooperate to promote deep vein thrombosis (DVT). Here we evaluated the role of kindlin-3, a key integrin activator in these cells, in regulating stenosis-induced DVT in mice. DVT was significantly suppressed in mice that express a kindlin-3 mutant defective for integrin binding, showing that kindlin-3-mediated integrin signaling in blood cells is required for DVT. While platelet-specific deficiency of kindlin-3 in Kindlin-3<sup>fl/fl</sup>PF4-Cre mice significantly su ...[more]

PMID: 31477636

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Project description:BACKGROUND:The post-thrombotic syndrome frequently develops in patients with proximal deep-vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter-directed thrombolysis (hereafter "pharmacomechanical thrombolysis") rapidly removes thrombus and is hypothesized to reduce the risk of the post-thrombotic syndrome. METHODS:We randomly assigned 692 patients with acute proximal deep-vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post-thrombotic syndrome between 6 and 24 months of follow-up. RESULTS:Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P=0.09). Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanical-thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups. CONCLUSIONS:Among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT ClinicalTrials.gov number, NCT00790335 .).

Dataset Information

Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice.

Publications

Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice.

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