Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis

Payne, Holly; Ponomaryov, Tatyana; Watson, Steve P.; Brill, Alexander

doi:10.1182/blood-2016-09-742999

Cited by 157 publications

(180 citation statements)

References 46 publications

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“…The ideal targets for LEDVT therapies are eliminating the embolic capacity of existing thrombi, reconstructing unobstructed blood flow, maintaining venous valve function, and preventing further thrombosis . However, the molecular mechanism of LEDVT remains unclear, which greatly limits the screening for LEDVT diagnostic markers …”

Section: Introductionmentioning

confidence: 99%

Overexpressed microRNA‐103a‐3p inhibits acute lower‐extremity deep venous thrombosis via inhibition of CXCL12

et al. 2019

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Studies have shown that microRNAs (miRNAs) participate in almost all pathological and physiological processes including acute lower‐extremity deep venous thrombosis (LEDVT). Here, this study was designed to elucidate the possible function of miR‐103a‐3p in acute LEDVT. Expression of miR‐103a‐3p and chemokine C‐X‐C motif ligand 12 (CXCL12) was initially quantified in plasma collected from 81 LEDVT patients. Then LEDVT mouse models were established by injection with 3% sodium pentobarbital. The interaction between miR‐103a‐3p and CXCL12 was identified by dual‐luciferase reporter gene assay. After gain‐ and loss‐of‐function studies, interleukin‐6 (IL‐6) and IL‐8 and tissue factor (TF) levels, and expression of plasminogen activator inhibitors (PAIs), von Willebrand factor (vWF), thromboxane A2 (TH‐A2), F4/80, IL‐12, Arginase‐1 (Arg‐1) and CD206 were determined using enzyme‐linked immunosorbent assay (ELISA), reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and western blot analysis, respectively. miR‐103a‐3p was downregulated, while CXCL12 was upregulated in patients and mice with LEDVT. miR‐103a‐3p targets CXCL12 and inhibited its expression. Overexpressed miR‐103a‐3p or downregulated CXCL12 decreased expression of IL‐6, IL‐8, TF, PAIs, vWF, TH‐A2, M1 markers (IL‐6 and IL‐12), yet increased expression of M2 markers (Arg‐1 and CD206) in LEDVT mice. Additionally, upregulated miR‐103a‐3p or silencing CXCL12 suppressed thrombosis in LEDVT mice. However, overexpression of CXCL12 reversed the tendency mentioned above. Altogether, miR‐103a‐3p can potentially downregulate CXCL12 expression to disrupt inflammatory response and thrombosis, ultimately preventing the development of LEDVT. Our findings underscore a possible alternative therapeutic strategy to limit LEDVT.

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Section: Introductionmentioning

confidence: 99%

Overexpressed microRNA‐103a‐3p inhibits acute lower‐extremity deep venous thrombosis via inhibition of CXCL12

et al. 2019

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“…Podoplanin is a sialomucin‐like glycoprotein and has the ability to induce platelet aggregation via interacting with the C‐type lectin‐like receptor (CLEC)‐2 on platelets . Recent experimental studies using mouse models confirmed the important role of podoplanin in the pathophysiology of VTE . Based on these observations, podoplanin‐induced platelet aggregation might be a major driver of brain tumor‐associated VTE.…”

Section: Introductionmentioning

confidence: 99%

Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism

Nazari

Riedl

Preusser

et al. 2018

Journal of Thrombosis and Haemostasis

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Essentials Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging.Patients with IDH1 wildtype and high podoplanin expression have a 6‐month VTE risk of 18.2%.Patients with IDH1 mutation and no podoplanin expression have a 6‐month VTE risk of 0%. IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive. SummaryBackgroundVenous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk.ObjectivesTo investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development.Patients/MethodsIn a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2‐year follow‐up.ResultsAll brain tumors that expressed podoplanin to a medium‐high extent showed also an IDH1 wild‐type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild‐type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6‐month risk 18.2% vs. 0%).Conclusions IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild‐type tumors is strongly linked to podoplanin expression levels.

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“…However, the mechanisms underlying the association between pCLEC‐2 and death or recurrence of vascular diseases are still unclear and more studies, especially animal experiments, are needed to explore them. Recently, another role of thromboinflammation of CLEC‐2 has been reported . As AIS may be in fact a thrombo‐inflammatory disorder, the thromboinflammation role of CLEC‐2 may be crucial in the development and pathogenesis of ischaemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Plasma C‐type lectin‐like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke

Zhang

et al. 2019

Euro J of Neurology

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Background and purpose C‐type lectin‐like receptor 2 (CLEC‐2) has prominent involvement in platelet activation, which is increased in coronary heart disease and acute ischaemic stroke (AIS) and is associated with stroke progression and stroke prognosis. Here, the aim was to examine the prognostic value of CLEC‐2 in death and vascular event recurrence in AIS patients. Methods In all, 352 patients with AIS were studied prospectively. All patients were followed up for 1 year. Death for all vascular events and a combination of death and vascular diseases (recurrent stroke, myocardial infarction, hospitalized and treated angina, hospitalized and treated peripheral arterial disease) were recorded. Results During 1 year of follow‐up, 46 patients (14.2%) experienced death or combined end‐points (23 death and 46 combined end‐points). Plasma CLEC‐2 (pCLEC‐2) was significantly associated with an increased risk of death and combined events of death and vascular diseases after adjusting for age, sex, history of hypertension, diabetes mellitus and coronary artery disease, and National Institutes of Health Stroke Scale scores. Each 1 SD higher log‐transformed pCLEC‐2 was associated with a 4.27‐fold (hazard ratio 4.27, 95% confidence interval 1.71–10.65) increased risk for death and a 2.42‐fold increased risk for combined end‐points (hazard ratio 2.42, 95% confidence interval 1.52–3.86). The optimal cut‐off point of pCLEC‐2 for predicting death was 184.38 pg/ml. Conclusions Higher pCLEC‐2 levels at admission were associated with increased risk of death and combined events of death and vascular diseases in patients with AIS, which indicated that pCLEC‐2 is an important prognostic factor for AIS.

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Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis

Abstract: Key Points Absence of CLEC-2 abrogates venous thrombosis. Podoplanin expression is upregulated in the vessel wall and correlates with the degree of thrombosis.

Cited by 157 publications

References 46 publications

Overexpressed microRNA‐103a‐3p inhibits acute lower‐extremity deep venous thrombosis via inhibition of CXCL12

Overexpressed microRNA‐103a‐3p inhibits acute lower‐extremity deep venous thrombosis via inhibition of CXCL12

Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism

Plasma C‐type lectin‐like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke

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