Fibrinolysis and Inflammation in Venous Thrombus Resolution

Mukhopadhyay, Subhradip; Johnson, Tierra A.; Duru, Nadire; Buzza, Marguerite S.; Pawar, Nisha R.; Sarkar, Rajabrata; Antalis, Toni M.

doi:10.3389/fimmu.2019.01348

Cited by 99 publications

(76 citation statements)

References 185 publications

(185 reference statements)

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“…This phenomenon is the result of interaction between activated leukocytes and cellular adhesion molecules on the vein wall [ 23 – 30 ]. Inflammatory mechanisms up-regulate procoagulant factors, down-regulate natural anticoagulants and inhibit fibrinolytic activity [ 31 ]. In particular, as Marongiu et al .…”

Section: Discussionmentioning

confidence: 99%

Venous thromboembolism and COVID-19: a single center experience from an academic tertiary referral hospital of Northern Italy

et al. 2020

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Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score > 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p < 0.0001) or lactate dehydrogenase (LDH) (p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p < 0.0001). Platelet-to-lymphocyte ratio significantly correlated with CRP (p < 0.0001). The majority of VTE patients was male and younger compared to non-VTE patients (p = 0.002 and p = 0.005, respectively). No significant difference was found in d-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE.

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Section: Discussionmentioning

confidence: 99%

Venous thromboembolism and COVID-19: a single center experience from an academic tertiary referral hospital of Northern Italy

et al. 2020

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“…The initial thrombus is rich in fibrin and as the thrombus matures, it undergoes fibrinolysis mediated by factors largely secreted by thrombus associated macrophages. Maturation of the thrombus is also characterized by collagen deposition and remodeling [60]. Thrombus associated leukocytes secrete various cytokines and regulatory factors that modulate the processes that are required for venous thrombus resolution [36].…”

Section: Discussionmentioning

confidence: 99%

Depletion of CD4 and CD8 Positive T Cells Impairs Venous Thrombus Resolution in Mice

Mukhopadhyay

Gabre

Chabasse

et al. 2020

IJMS

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Resolution of deep venous thrombosis involves coordinated inflammatory processes. T cells regulate inflammation in vivo and modulate vascular remodeling in other settings, but their role in venous thrombus resolution remains undefined. To determine the role of T cells in venous thrombus resolution in vivo, stasis induced thrombi were created by vena cava ligation in outbred CD-1 mice. CD4 and CD8 positive T cells, as determined by flow cytometry, were present in thrombi both during thrombus formation and resolution. Depletion of the CD4 and CD8 positive T cells by antibody treatment selectively impaired thrombus resolution compared to animals treated with isotype control antibodies, without an effect on venous thrombus formation. Quantitation of intra-thrombus macrophage numbers, fibrinolytic marker expression, and gelatinolytic activity by zymography revealed that T cell depletion decreased the number of macrophages, reduced the expression of fibrinolytic marker urokinase plasminogen activator (uPA), and decreased the activity of matrix metalloprotinease-9 (MMP-9). These data implicate CD4 and CD8 positive T cells in functionally contributing to venous thrombus resolution, thus representing a potential therapeutic target, but also underscoring potential risks involved in T cell depletion used clinically for solid organ and hematopoietic transplantation procedures.

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“…Cell free DNA is seen in the sera of COVID-19 patients, indicating NETs formation [30]. Macrophages are also recruited to fibrin thrombi and work to remodel the thrombus as part of the normal healing process [32]. Macrophages within the fibrin clot generate plasmin, which degrades fibrin to produce D-Dimers.…”

Section: Infiltration Of Neutrophils and Macrophagesmentioning

confidence: 99%