Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA

AbstractThrombotic complications are still a major health risk worldwide. Our view on the pathophysiology of thrombosis has significantly changed since the discovery of neutrophil extracellular traps (NETs) and their prothrombotic characteristics. Generated by neutrophils that release their decondensed chromatin as a network of extracellular fibers, NETs promote thrombus formation by serving as a scaffold that activates platelets and coagulation. The thrombogenic involvement of NETs has been described in various settings of thrombosis, including stroke, myocardial infarction, and deep vein thrombosis. The aim of this review is to summarize existing evidence showing the presence of NETs in human thrombus material. Following an introduction on NETs and their role in thrombus formation, the authors address studies showing the presence of NETs in arterial or venous thrombi. In addition, they focus on potential novel therapeutic opportunities to resolve or prevent thrombosis by targeting NETs.

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Neutrophil extracellular traps and inflammasomes cooperatively promote venous thrombosis in mice

Blood Advances ◽

10.1182/bloodadvances.2020003377 ◽

2021 ◽

Vol 5 (9) ◽

pp. 2319-2324

Author(s):

Joana Campos ◽

Tatyana Ponomaryov ◽

Alexandra De Prendergast ◽

Katharine Whitworth ◽

Christopher W. Smith ◽

...

Keyword(s):

Neutrophil Extracellular Traps ◽

Simultaneous Formation ◽

Vein Thrombosis ◽

Extracellular Traps ◽

Caspase 1 ◽

Histone 3 ◽

Adhesive Surface ◽

Deep Vein ◽

Active Caspase

Abstract Deep vein thrombosis (DVT) is linked to local inflammation. A role for both neutrophil extracellular traps (NETs) and the assembly of inflammasomes (leading to caspase-1–dependent interleukin-1β activation) in the development of DVT was recently suggested. However, no link between these 2 processes in the setting of thrombosis has been investigated. Here, we demonstrate that stimulation of neutrophils induced simultaneous formation of NETs and active caspase-1. Caspase-1 was largely associated with NETs, suggesting that secreted active caspase-1 requires NETs as an adhesive surface. NETs and their components, histones, promoted robust caspase-1 activation in platelets with the strongest effect exerted by histones 3/4. Murine DVT thrombi contained active caspase-1, which peaked at 6 hours when compared with 48-hour thrombi. Platelets constituted more than one-half of cells containing active caspase-1 in dissociated thrombi. Using intravital microscopy, we identified colocalized NETs and caspase-1 as well as platelet recruitment at the site of thrombosis. Pharmacological inhibition of caspase-1 strongly reduced DVT in mice, and thrombi that still formed contained no citrullinated histone 3, a marker of NETs. Taken together, these data demonstrate a cross-talk between NETs and inflammasomes both in vitro and in the DVT setting. This may be an important mechanism supporting thrombosis in veins.

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Prevention of Pulmonary Embolism by Inferior Vena Cava Filter in Patients With Proximal Deep Vein Thrombosis

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(97)85281-3 ◽

1998 ◽

Vol 31 (2) ◽

pp. 362A

Author(s):

R Faivre

Keyword(s):

Pulmonary Embolism ◽

Deep Vein Thrombosis ◽

Inferior Vena Cava ◽

Inferior Vena Cava Filter ◽

Inferior Vena ◽

Vena Cava ◽

Vena Cava Filter ◽

Proximal Deep Vein Thrombosis ◽

Vein Thrombosis ◽

Deep Vein

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Incidence of Deep Vein Thrombosis After Varicose Vein Surgery

Yearbook of Vascular Surgery ◽

10.1016/s0749-4041(08)70279-3 ◽

2006 ◽

Vol 2006 ◽

pp. 363-364

Author(s):

G.L. Moneta

Keyword(s):

Deep Vein Thrombosis ◽

Varicose Vein ◽

Varicose Vein Surgery ◽

Vein Thrombosis ◽

Deep Vein

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Feasibility Study of Catheter-directed Thrombolysis with Recombinant Staphylokinase in Deep Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614936 ◽

1998 ◽

Vol 79 (03) ◽

pp. 517-519 ◽

Cited By ~ 13

Author(s):

Stephane Heymans ◽

Raymond Verhaeghe ◽

Luc Stockx ◽

Désiré Collen

Keyword(s):

Deep Vein Thrombosis ◽

Continuous Infusion ◽

High Speed ◽

Minor Bleeding ◽

Vein Thrombosis ◽

Catheter Directed Thrombolysis ◽

Long Term Follow Up ◽

Valve Function ◽

Rotating Impeller ◽

Deep Vein

SummaryThe feasibility of catheter-directed thrombolysis with recombinant staphylokinase was evaluated in six selected patients with deep vein thrombosis. The patients underwent intrathrombus infusion of recombinant staphylokinase (2 mg bolus followed by a continuous infusion of 1 mg/h). Heparin was given via the catheter as a bolus (5000 U) and as a continuous infusion (1000 U/h). Complete lyis was obtained in five patients and partial lysis in one patient. Complications consisted of minor bleeding in four subjects. Symptomatic reocclusion occurred in one. Debulking of the thrombus mass by a high speed rotating impeller (n = 1) and stenting (n = 3) were used as additional interventions. An underlying anatomical abnormality was present in two patients. Long term follow up revealed normal patency in all patients and normal valve function in four patients. Symptomatic venous insufficiency with valve dysfunction was present in the two with a second thrombotic episode.Thus catheter-directed infusion of recombinant staphylokinase in patients with deep vein thrombosis appears feasible and may be associated with a high frequency of thrombolysis. Larger studies to define the clinical benefit of this treatment appear to be warranted.

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Deep Vein Thrombosis and Fibrinolysis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646432 ◽

1991 ◽

Vol 66 (04) ◽

pp. 426-429 ◽

Cited By ~ 16

Author(s):

Marcel Levi ◽

Anthonie W A Lensing ◽

Harry R Büller ◽

Paolo Prandoni ◽

Gerard Dooijewaard ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Controlled Study ◽

First Episode ◽

Control Group ◽

Vein Thrombosis ◽

Type Plasminogen Activator ◽

Deep Vein

SummaryIn the present study 57 consecutive patients with a first episode of venographically proven deep vein thrombosis were investigated to evaluate the release of tissue-type plasminogen activator (t-PA) and of urokinase-type plasminogen activator (u-PA) in response to DDAVP stimulation as well as the resting plasminogen activator inhibitor (PAI) concentration, comparing this to the results obtained in 66 similar patients with a clinical suspicion of thrombosis but with a normal venogram. All assays were performed without knowledge of the patient's status.Four patients in the deep vein thrombosis-group (7%) had an absent u-PA antigen response upon DDAVP infusion, while a normal response was observed in all control subjects. Patients and controls showed similar increases in t-PA antigen level upon DDAVP. High resting PAI antigen levels were encountered in 5 patients in the deep vein thrombosis-group (9%) and in 6 subjects in the control group (9%).The results from this controlled study indicate that a defective release of u-PA may occur in patients with deep vein thrombosis and may have pathogenetic significance. Furthermore it is concluded that elevation of PAI levels cannot be considered as a specific risk factor for venous thrombosis.

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Confirmation of the Failure of Computerized Impedance Plethysmography in the Diagnostic Management of Patients with Clinically Suspected Deep-Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646500 ◽

1991 ◽

Vol 66 (06) ◽

pp. 744-744

Author(s):

Anthonie W A Lensing ◽

Harry R Büller ◽

Jan Wouter ten Cate ◽

Paolo Prandoni

Keyword(s):

Deep Vein Thrombosis ◽

Impedance Plethysmography ◽

Vein Thrombosis ◽

Diagnostic Management ◽

Deep Vein

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Acute Deep Vein Thrombosis Treated with Porcine Plasmin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647715 ◽

1974 ◽

Vol 32 (02/03) ◽

pp. 468-482 ◽

Cited By ~ 2

Author(s):

O Storm ◽

P Ollendorff ◽

E Drewsen ◽

P Tang

Keyword(s):

Deep Vein Thrombosis ◽

Lower Limb ◽

Initial Dose ◽

Treated Group ◽

Allergic Reactions ◽

Double Blind ◽

Vein Thrombosis ◽

Thrombolytic Effect ◽

Acute Deep Vein Thrombosis ◽

Deep Vein

SummaryThe thrombolytic effect of pig plasmin was tested in a double blind trial on patients with deep venous thrombosis in the lower limb. Only patients with not more than three days old thrombi were selected for this study. The diagnosis of deep vein thrombosis was made clinically and confirmed by phlebography. Lysofibrin Novo (porcine plasmin) or placebo (porcine plasminogen) was administered intravenously to the patients. The enzyme and the placebo were delivered as lyophilized powder in labelled bottles - the contents of the bottles were unknown to the doctor in charge of the clinical administration of the trial. An initial dose of plasmin/plasminogen of 30 unit per kg body weight given slowly intravenously (1-1% hours infusion) was followed by a maintenance dosis of 15 per cent the initial dose per hour for the following 5-7 hours. In most cases a similar maintenance dosis was given the next day. In all patients heparin was administered after ending the plasmin/plasminogen infusion. The results of the treatment was evaluated clinically as well as by control phlebo- grams the following days.A statistically significant improvement was found in the plasmin treated group compared with the placebo (plasminogen) treated group. Thrombolysis was obtained clinically and phlebographically in 65 per cent of the plasmin treated group, but only in 15 per cent of the control patients were improvements found.This study has thus demonstrated that plasmin treatment according to a standard scheme was able to induce thrombolysis. There were only a few and insignificant side effects. Allergic reactions have not been seen and only very simple tests are required.

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