Abstract 36: Alpha 2-antiplasmin Prevents the Resolution of Deep Vein Thrombosis

Introduction: Deep venous thrombosis is a major cause of death and disability. Despite anticoagulation treatment, venous thrombi persist for months, causing chronic venous obstruction, inflammatory remodeling and post-thrombotic syndrome. The mechanisms responsible for impaired clearance of venous thrombi are poorly understood. Alpha 2-antiplasmin (a2AP) is the primary physiological inhibitor of plasmin and a key regulator of the fibrinolytic pathway. The role of a2AP in the resolution of venous thrombosis has not been determined. Hypothesis: We tested the hypothesis that a2AP prevents the resolution of experimental deep venous thrombi. Methods and Results: Thrombus resolution and content were examined in a2AP +/+ and a2AP -/- mice using a well-established, fibrinolytic-resistant, stasis model induced by ligation of the inferior vena cava (IVC). Thrombus weight and composition were determined after 7 days. Data was analyzed by one-way ANOVA with Neumann-Keul’s correction. Thrombus weight was reduced in a2AP -/- mice by >90% when compared to a2AP +/+ mice (p<0.001); there was no significant difference between a2AP -/- mice and shams. Histochemical and immunofluorescence staining showed significant reductions in IVC fibrin content, neutrophil recruitment and matrix metalloproteinase-9 expression in a2AP -/- mice (p<0.001) vs. a2AP +/+ mice. The relative effect of plasminogen activation and a2AP on resolution of preformed venous thrombi was examined in wild-type a2AP +/+ mice treated 24 h after IVC ligation with tissue plasminogen activator (TPA) (1.2 or 5 mg/kg) or a monoclonal antibody inactivating a2AP (10 mg/Kg). By comparison to 7 day old venous thrombi in untreated mice, treatment with TPA at 1.2 mg/kg or 5 mg/kg did not decrease thrombus size after 7 days. In contrast, a2AP inactivation significantly reduced thrombus weight vs. untreated and TPA-treated mice (p<0.01 to p<0.001). Conclusions: In experimental venous thrombosis, a2AP was required for the persistence of venous thrombi 7 days after formation. Venous thrombi resisted TPA, but were sensitive to resolution after a2AP inactivation. This suggests that a2AP may be responsible for the persistence of clinical venous thrombosis in humans.

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Cellular Fibronectin Promotes Deep Vein Thrombosis in Obese Mice

Blood ◽

10.1182/blood-2020-141441 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 19-20

Author(s):

Nirav Dhanesha ◽

Manish Jain ◽

Prakash Doddapattar ◽

Anetta Undas ◽

Anil K Chauhan

Keyword(s):

Deep Vein Thrombosis ◽

Venous Thrombosis ◽

Conflicts Of Interest ◽

Vena Cava ◽

Significant Risk ◽

Comorbid Condition ◽

Vein Thrombosis ◽

Deep Vein ◽

Cellular Fibronectin

Objective: Obesity is a significant risk factor for deep vein thrombosis (DVT). The mechanisms of increased DVT in preexisting comorbid condition of obesity remain poorly understood. Cellular fibronectin containing extra domain A (Fn-EDA), an endogenous ligand for toll-like-receptor 4 (TLR4), is known to contribute to thrombo-inflammation in the experimental models. However, the role of Fn-EDA in modulation of venous thrombosis in context of obesity is not elucidated yet. Approach and Results: We found that cellular Fn-EDA levels were significantly elevated in plasma of venous thromboembolism (VTE) patients that positively correlated with body mass index (BMI). To investigate whether Fn-EDA promotes venous thrombosis in obese condition, WT and Fn-EDA-/- mice were either fed a control or high-fat diet (HF-diet) for 12-weeks. DVT was induced by inferior vena cava stenosis and evaluated after 48 hours. We found that HF diet-fed WT mice exhibited increased DVT susceptibility compared with control diet-fed WT mice. In contrast, HF-fed Fn-EDA-/- mice exhibited significantly reduced thrombus weight and decreased incidence (%) of DVT compared with HF-fed WT mice that was concomitant with improved blood flow, reduced neutrophil content and citrullinated histone H3-positive cells (a marker of NETosis) in IVC thrombus. Exogenous Fn-EDA potentiated NETosis in neutrophils stimulated with thrombin-activated platelets via TLR4. Genetic deletion of TLR4 in Fn-EDAfl/fl mice, which constitutively express Fn-EDA, reduced DVT compared with Fn-EDAfl/fl mice. Conclusion: These results demonstrate a previously unknown role of Fn-EDA in the modulation of DVT, which may be an important mechanism promoting DVT in the setting of obesity. Figure Disclosures No relevant conflicts of interest to declare.

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Venous Thrombosis in Acquired Hemophilia: The Complex Management of Competing Pathologies

TH Open ◽

10.1055/s-0039-1698414 ◽

2019 ◽

Vol 03 (04) ◽

pp. e325-e330 ◽

Cited By ~ 2

Author(s):

Manu Chhabra ◽

Zhen Wan Stephanie Hii ◽

Joseph Rajendran ◽

Kuperan Ponnudurai ◽

Bingwen Eugene Fan

Keyword(s):

Venous Thrombosis ◽

Vena Cava ◽

Cost Effective ◽

Major Surgery ◽

High Dose ◽

Acquired Hemophilia ◽

Vein Thrombosis ◽

Associated Conditions ◽

Activated Prothrombin Complex Concentrates ◽

Deep Vein

Abstract Introduction Venous thrombosis is rare in the setting of factor VIII (FVIII) deficiency. Cases of deep vein thrombosis (DVT) have been described in hemophiliacs after recent major surgery, or in association with the administration of FVIII concentrate and activated prothrombin complex concentrates, but occurrence of spontaneous DVT is even more uncommon. Aim We describe the challenging management of extensive DVT in a patient with acquired hemophilia A with concurrent hemorrhagic manifestations and review similar published cases. Methods We summarize a series of 10 cases with the following demographics: 6 males and 4 females; median age at presentation of 65 (21–80); mean inhibitor titer of 68.5 Bethesda Units (BU 1.9 to BU 350). Results Four cases were idiopathic and six had associated conditions (cancer [two cases], recent pregnancy [two cases], and recent surgery [two cases]). Three cases had an inferior vena cava filter inserted for acute lower limb DVT/pulmonary embolism. Inhibitor eradication was achieved with high-dose steroids with or without cyclophosphamide, and adjunct Rituximab administration was used in three cases. One patient received concurrent therapeutic plasma exchange (TPE). Inhibitor eradication was fastest with concurrent TPE at 6 days (range: 6–733 days). The 30-day survival was 90%. Conclusions There was adequate response of inhibitors to immunosuppression with steroids and cyclophosphamide therapy. For more refractory disease, Rituximab is emerging as a beneficial and cost-effective adjunct with better rates of complete remission, and the threshold for its use may be lowered in this complex cohort with dual competing pathologies.

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Role of Anticoagulation in Patients with Inferior Vena Cava Filter but with No Risk Factor or History of DVT/PE

Blood ◽

10.1182/blood.v118.21.4317.4317 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4317-4317

Author(s):

Mustapha A. Khalife ◽

Vrushali S. Dabak ◽

Marwa Hammoud ◽

Karim Arnaout

Keyword(s):

Inferior Vena ◽

Vena Cava ◽

Ivc Filter ◽

Vein Thrombosis ◽

History Of ◽

Group 2 ◽

Deep Vein ◽

Group 1

Abstract Abstract 4317 Introduction: Inferior Vena Cava (IVC) filters have been available for almost 40 years but their clinical utility and safety have not been completely evaluated in patients with no previous history of deep vein thrombosis (DVT) or pulmonary embolism (PE). The role of anticoagulation in patients with IVC filter with no history of DVT/PE is questionable. In this study, we try to determine if there is a role or benefit from anticoagulation in patients with an IVC filter placed but without any other risk factor for deep vein thrombosis (DVT) or pulmonary embolism (PE). Methods: we retrospectively reviewed the charts of 562 patients who had an IVC filter placed between 2003 and 2005. 442 patients were excluded because they had a history of DVT/PE, or because of a hypercoagulable state (genetic predisposition, prolonged hospitalization/immobilization, surgery, or malignancy). Of the 120 remaining patients included in this study, 6 had their IVC filter removed. And therefore we only analyzed the charts of 114 patients who had a permanent IVC filter placed for prophylactic reasons. Group 1 consisted of 17 patients who received different forms of anticoagulation (subcutaneous heparin, low molecular weight heparin or coumadin). Group 2 consisted of the remaining 97 patients who did not receive any form of anticoagulation. Results: 2 out of 17 patients in group 1 had a DVT and 14 out of 97 patients in group 2 had a DVT. The incidence of DVT was 11.8% in group 1 versus 14.4% in group 2 (p-value 0.770). The median onset of DVT/PE after IVC filter placement was 31 days. The median time of follow up was 77.33 months. Conclusion: Patients who had a permanent prophylactic IVC filter placed but with no history or risk factors for DVT/PE appear to be at an elevated risk for new DVT/PEs. In these patients, the role of anticoagulation is questionable. With a median 6 year follow up, anticoagulation seemed to non significantly lower the risk of DVT/PE. Larger randomized prospective trials are needed to examine the efficacy and duration of anticoagulation in patients with a prophylactic IVC filter placed. Disclosures: No relevant conflicts of interest to declare.

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the NADPH Oxidase Catalytic Subunit Nox2 Displays Differential Roles in Arterial Vs. Venous Thrombosis

Blood ◽

10.1182/blood.v128.22.4907.4907 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4907-4907

Author(s):

Vijay Sonkar ◽

Melissa J Jensen ◽

Steven R. Lentz ◽

Sanjana Dayal

Keyword(s):

Nadph Oxidase ◽

Venous Thrombosis ◽

Platelet Activation ◽

Vena Cava ◽

Catalytic Subunit ◽

Advisory Committees ◽

Small Vessels ◽

Fibrinogen Binding ◽

Significant Difference

Abstract NADPH oxidase is a major superoxide generating enzyme in vascular tissues. Deficiency of the Nox2 (gp91phox) catalytic subunit of NADPH oxidase is a genetic cause of X-linked chronic granulomatous disease. These patients are prone to infection due to loss of oxidant production by neutrophils, and recent evidence suggests they also have a defect in platelet adhesion to collagen. However, the role of Nox2 in thrombosis is controversial, with one study demonstrating no effect of murine Nox2 deficiency on platelet activation and another study implicating Nox2 in platelet aggregation as well as thrombosis in small vessels. Given that Nox2 may be important for both platelet activation as well as release of neutrophil extracellular traps (NETs, a mediator of venous thrombosis), we hypothesized that genetic deficiency in murine Nox2 leads to decreased susceptibility to experimental thrombosis in both arterial and venous systems. We studied male Nox2 deficient (Cybb-/y) mice and wild type (Cybb +/y) littermates at 10-14 weeks of age. There were no differences in platelet count (921.9±33.6 x103/µl vs. 978±85.2 x103/µl), hematocrit (36.5±0.6% vs. 38.7±0.8% ) or white blood cell count (5.5±0.3 x103/µl vs. 6.1±0.6 x103/µl) between Cybb+/y and Cybb-/y mice. We next, examined platelet activation in response to thrombin (0.05 and 0.2 U/ml) or collagen (80 and 320 ng/ml) using flow cytometry. We observed similar levels of integrin α2bβ3 activation, fibrinogen binding, and intra-platelet levels of H2O2 in platelets from Cybb+/y and Cybb-/y mice after activation with either agonist, which suggests no alteration in platelet inside-out signaling due to loss of Nox2. No significant difference in susceptibility to carotid artery thrombosis in a photochemical injury model was observed between Cybb+/y and Cybb-/- mice (time to stable occlusion 21.97±4.7 vs 27.6±4.2, P>0.4). In contrast, Cybb-/y mice demonstrated significant decreases in the weight and length of venous thrombi in the inferior vena cava after 48 hours of stenosis (P<0.05). Our findings suggest that Nox2 is not a major mediator of platelet activation or arterial thrombosis but contributes to the development of venous thrombi. Future studies are warranted to examine the role of NETs and the prothrombotic effects of Nox2 in association with other cardiovascular risk factors. Disclosures Lentz: Novo Nordisk: Consultancy, Research Funding; Celgene: Equity Ownership; Opko: Membership on an entity's Board of Directors or advisory committees.

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IS IT POSSIBLE TO PREDICT THE EFFICIENCY OF THE FIBRINOLYTIC AND SURGICAL TREATMENT OF DEEP VEIN THROMBOSIS BY ULTRASOUND IMAGING AND DOPPLER ?

10.1055/s-0038-1643003 ◽

1987 ◽

Author(s):

A Elias ◽

J L Bouvier ◽

G Le Corff ◽

A Serradimigni

Keyword(s):

Surgical Treatment ◽

Venous Thrombosis ◽

Inferior Vena ◽

Vena Cava ◽

Complete Obstruction ◽

Complete Occlusion ◽

Vein Thrombosis ◽

Floating Thrombus ◽

Deep Vein ◽

Total Disappearance

The sucess of the fibrinolytic or surgical treatment of venous thrombosis depends largely on how old the thrombosis is.To study the therapeutic predictibility of the ultrasonographic signs,their pretherapeutic aspects were compared to the results of the fibrinolytic treatment during 3 days or to the anatomic aspects intra-operatively. This prospective study was carried out on 21 patients presenting an isolated venous thrombosis confirmed by venography. 65 involved venous segments from the popliteal to the inferior vena cava were studied.The following are analyzed : 1) The C.W. Doppler signal when there is a complete obstruction of the femoral iliac junction : absence or presence of flow (MEDAS0NICS BF4A 5.3MHZ).2)The morphological and dynamic aspects of the vein, the thrombus and the flow using echographic test (DIASONICS DRF 400. 10-7.5-5MHZ) were retained as predictible signs of sucessfull treatment a hypodens^homogeneous thrombus with major venous dilation (about twice the controlateral vein) where there is a total obstruction, and a free floating thrombus or even “elastic”,soft,compressible when there is a partial obstruction.The opposite signs were interpreted as predicting a therapeutic failure : a dense heterogeneous adherent and hard thrombus.The criteria for thrombolysis efficiency is the total disappearance of the thrombus when there was a partial obstruction,or a recanalization (>50%)where there was a complete occlusion.The ultrasonographic predictible signs compared with the effective results are indicated in the following tables.Ultrasonography enables most cases tne recognition or a “recent” thrombus from an “old” one and allows talcing thus a cal-lated risk. If the evaluation of the echotexture of the thrombus is subjective and technique dependant, and if an objective measurement of the density distribution insight the clot as reported is preferable, a combined study of the other ultrasonographic parameters seems to be essential.

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Management of Acute Iliofemoral Deep Vein Thrombosis

DeckerMed Surgery ◽

10.2310/surg.3084 ◽

2018 ◽

Author(s):

Albeir Y Mousa

Keyword(s):

Pulmonary Embolism ◽

Deep Vein Thrombosis ◽

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Inferior Vena ◽

Vena Cava ◽

External Compression ◽

Vein Thrombosis ◽

Surgical Thrombectomy ◽

Deep Vein

Acute deep venous thrombosis (DVT) of iliofemoral segment is one of the most dreaded presentations of venous thromboembolism, as it can not only compromise the function of the extremity but may also result in pulmonary embolism and even death. There are many causes for acute iliofemoral DVT, including underdiagnosed May-Thurner syndrome, hypercoagulable syndrome, and external compression on iliocaval segment. The available treatment depends on the acuity of the symptoms. Acute iliofemoral DVT can be treated with medical anticoagulation, pharmacomechanical therapy, including thrombolysis or surgical thrombectomy. Chronic iliofemoral occlusion may be treated with recanalization of the occluded segments with angioplasty stenting. This review contains 4 Figures, 4 Tables and 63 references Key Words: acute, angioplasty, deep venous thrombosis, iliofemoral, inferior vena cava, pharmacomechanical therapy, occlusion, stent

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Management of Acute Iliofemoral Deep Vein Thrombosis

10.2310/vasc.3084 ◽

2018 ◽

Author(s):

Albeir Y Mousa

Keyword(s):

Pulmonary Embolism ◽

Deep Vein Thrombosis ◽

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Inferior Vena ◽

Vena Cava ◽

External Compression ◽

Vein Thrombosis ◽

Surgical Thrombectomy ◽

Deep Vein

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Deep Venous Thrombosis Associated With Inferior Vena Cava Abnormalities And Hypoplastic Kidney In Siblings

Acta Medica Marisiensis ◽

10.1515/amma-2016-0011 ◽

2016 ◽

Vol 62 (2) ◽

pp. 266-268 ◽

Cited By ~ 6

Author(s):

Carmen Duicu ◽

Gabriela Bucur ◽

Iunius Simu ◽

Florin Tripon ◽

Oana Marginean

Keyword(s):

Deep Vein Thrombosis ◽

Inferior Vena Cava ◽

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Inferior Vena ◽

Vena Cava ◽

Vein Thrombosis ◽

Reduced Frequency ◽

Angio Ct ◽

Deep Vein

AbstractCongenital inferior vena cava anomalies have a reduced frequency in general population, many times being an asymptomatic finding. Patients caring such anomalies are at risk to develop deep vein thrombosis. In this paper, we present 2 siblings with deep venous thrombosis and inferior vena cava abnormalities, with a symptomatic onset at similar age. The inferior vena cava abnormality was documented by an angio-CT in each case. The thrombophilic workup was negative. Patients were treated with conservative therapy: low molecular weight heparin anticoagulants converted later to oral anticoagulant with resolution of symptoms and disappearance of the thrombus. Finally, in the absence of any risk factor in a young patient admitted with deep vein thrombosis investigations to exclude inferior vena cava anomalies are mandatory.

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Prostaglandin-endoperoxide synthase-2 deletion affects the natural trafficking of Annexin A2 in monocytes and favours venous thrombosis in mice

Thrombosis and Haemostasis ◽

10.1160/th16-12-0968 ◽

2017 ◽

Vol 117 (08) ◽

pp. 1486-1497 ◽

Cited By ~ 8

Author(s):

Patrizia Amadio ◽

Eva Tarantino ◽

Leonardo Sandrini ◽

Elena Tremoli ◽

Silvia Barbieri

Keyword(s):

Venous Thrombosis ◽

Thrombus Formation ◽

Vena Cava ◽

Peritoneal Macrophages ◽

Mutant Mice ◽

Nuclear Accumulation ◽

Prostaglandin Endoperoxide ◽

Vein Thrombosis ◽

Prostaglandin Endoperoxide Synthase

SummaryDeep-vein thrombosis (DVT) is a common condition that often leads to pulmonary thromboembolism (VTE) and death. The role of prostaglandin-endoperoxide synthase (PTGS)2 in arterial thrombosis has been well established, whereas its impact in venous thrombosis remains unclear. Here, we showed that PTGS2 deletion predisposes to venous thrombosis as suggested by greater clot firmness and clot elasticity, by higher plasma levels of functional fibrinogen, factor VIII and PAI-1 activity, and proved by bigger thrombi detected after inferior vena cava ligation (IVCL) compared to WT mice. PTGS2-/- thrombi have greater fibrin content, higher number of F4/80+, TF+ and ANXA2+ cells, and lower S100A10+ cells. Remarkably, monocyte depletion reduced thrombus size in mutant mice, suggesting an important role of PTGS2-/- monocytes in this experimental setting. Interestingly, PTGS2 deletion reduced membrane ANXA2, and total S100A10, promoted assembly of ANXA2/p50NF-kB complex and its nuclear accumulation, and induced TF in peritoneal macrophages, whereas ANXA2 silencing decreased dramatically TF. Finally, Carbaprostacyclin treatment prevented venous thrombus formation induced by IVCL in mutant mice, reduced the ANXA2 binding to p50NF-kB subunit and its nuclear trafficking, and decreased TF in PTGS2-/- macrophages. PTGS2 deletion, changing the natural distribution of ANXA2 in monocytes/macro-phages, increases TF expression and activity predisposing to venous thrombosis. Interestingly, Carbaprostacyclin treatment, inhibiting nuclear ANXA2 trafficking, controls monocyte TF activity and prevents DVT occurrence. Our data are of help in elucidating the mechanisms by which PTGS2 inhibition increases DVT risk, and suggest a new role for ANXA2 in venous thrombosis.Supplementary Material to this manuscript is available online at www.thrombosis-online.com.

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Controversies in the management of venous thromboembolism

Journal of Precision Respiratory Medicine ◽

10.2500/jprm.2019.190001 ◽

2019 ◽

Vol 2 (1) ◽

pp. 48-52

Author(s):

James P. Lamberti

Keyword(s):

Venous Thromboembolism ◽

Inferior Vena Cava Filter ◽

Inferior Vena ◽

Recent Literature ◽

Vena Cava ◽

Vein Thrombosis ◽

Outpatient Settings ◽

Deep Vein ◽

Acute Pe

Background: Venous thromboembolism (VTE) includes pulmonary embolism (PE) and deep vein thrombosis (DVT), and is frequently encountered in both inpatient and outpatient settings. Methods: This review examines three significant controversies in the management of VTE. Results: Thrombolytic therapy has been available for >50 years, yet its role in the management of acute PE remains controversial. The role of interruption of the venous system by insertion of an inferior vena cava filter into a VTE is a therapeutic challenge for hospital-based physicians. The duration of anticoagulation as therapy for VTE is a challenge for many outpatient physicians. Conclusion: Review of recent literature will guide clinicians in the management of venous thromboembolism.

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