Circulating Extracellular Vesicle Tissue Factor Activity During Orthohantavirus Infection Is Associated With Intravascular Coagulation

Schmedes, Clare M.; Grover, Steven P.; Hisada, Yohei; Goeijenbier, Marco; Hultdin, Johan; Nilsson, Sofie; Thunberg, Therese; Ahlm, Clas; Mackman, Nigel; Connolly, Anne-Marie Fors

doi:10.1093/infdis/jiz597

Cited by 18 publications

(20 citation statements)

References 38 publications

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“…While tPA and uPA share only about 40% amino acid similarity, their basic structure is highly similar ( 31 ). The basal circulating levels of tPA and uPA are low compared to other circulating proteins, with tPA reported in the range of ~1–10 ng/mL and uPA at 2–10x lower levels (~0.1–0.3 ng/mL) ( 32 – 36 ). Synthesis of tPA occurs in abundance in both the vasculature and the central nervous system.…”

Section: Overview Of the Fibrinolytic Machinerymentioning

confidence: 99%

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Yaron

Zhang

Guo

et al. 2021

Front. Cardiovasc. Med.

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The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and complex relationship of sequentially activated serine proteases and their regulatory inhibitors in the circulating blood. The proteases and inhibitors interact continuously throughout all branches of the cardiovascular system in the human body, representing one of the most abundant groups of proteins in the blood. There is an intricate interaction of the coagulation cascades with endothelial cell surface receptors lining the vascular tree, circulating immune cells, platelets and connective tissue encasing the arterial layers. Beyond their role in control of bleeding and clotting, the thrombotic and thrombolytic cascades initiate immune cell responses, representing a front line, “off-the-shelf” system for inducing inflammatory responses. These hemostatic pathways are one of the first response systems after injury with the fibrinolytic cascade being one of the earliest to evolve in primordial immune responses. An equally important contributor and parallel ancient component of these thrombotic and thrombolytic serine protease cascades are the serine protease inhibitors, termed serpins. Serpins are metastable suicide inhibitors with ubiquitous roles in coagulation and fibrinolysis as well as multiple central regulatory pathways throughout the body. Serpins are now known to also modulate the immune response, either via control of thrombotic and thrombolytic cascades or via direct effects on cellular phenotypes, among many other functions. Here we review the co-evolution of the thrombolytic cascade and the immune response in disease and in treatment. We will focus on the relevance of these recent advances in the context of the ongoing COVID-19 pandemic. SARS-CoV-2 is a “respiratory” coronavirus that causes extensive cardiovascular pathogenesis, with microthrombi throughout the vascular tree, resulting in severe and potentially fatal coagulopathies.

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Section: Overview Of the Fibrinolytic Machinerymentioning

confidence: 99%

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Yaron

Zhang

Guo

et al. 2021

Front. Cardiovasc. Med.

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“… 8 – 12 Notably, levels of EV TF activity are associated with thrombosis in patients with pancreatic cancer and patients infected with Puumala orthohantavirus. 9 , 13 , 14 This suggests that EV TF activity can be used as a biomarker to assess induction of TF expression in patients and thrombotic risk.…”

mentioning

confidence: 99%

Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report

Rosell

Havervall

Meijenfeldt

et al. 2021

ATVB

Self Cite

180

188

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Objective: Patients with coronavirus disease 2019 (COVID-19) have a high rate of thrombosis. We hypothesized that severe acute respiratory syndrome coronavirus 2 leads to induction of TF (tissue factor) expression and increased levels of circulating TF-positive extracellular vesicles (EV) that may drive thrombosis. Approach and Results: We measured levels of plasma EV TF activity in 100 patients with COVID-19 with moderate and severe disease and 28 healthy controls. Levels of EV TF activity were significantly higher in patients with COVID-19 compared with controls. In addition, levels of EV TF activity were associated with disease severity and mortality. Finally, levels of EV TF activity correlated with several plasma markers, including D-dimer, which has been shown to be associated with thrombosis in patients with COVID-19. Conclusions: Our results indicate that severe acute respiratory syndrome coronavirus 2 infection induces the release of TF-positive EVs into the circulation that are likely to contribute to thrombosis in patients with COVID-19. EV TF activity was also associated with severity and mortality.

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“…Thrombin generation may also take place in the shed microparticles in vivo, although no difference in the procoagulant activity of MPs in peripheral circulating blood could be detected when comparing the acute and recovery stages of PUUV infection [ 41 , 97 ]. In a recent study, increased circulating extracellular vesicle (i.e., microparticle) TF activity was observed during NE, which was significantly associated with plasma levels of tPA and PAI-1 [ 98 ]. Particularly, the extracellular TF activity was shown to peak in patients with DIC compared with patients who did not have DIC.…”

Section: Coagulopathy In Puuv Infectionmentioning

confidence: 99%

Coagulopathy in Acute Puumala Hantavirus Infection

Koskela

Mäkelä

Strandin

et al. 2021

Viruses

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Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein–kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis.

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Circulating Extracellular Vesicle Tissue Factor Activity During Orthohantavirus Infection Is Associated With Intravascular Coagulation

Cited by 18 publications

References 38 publications

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report

Coagulopathy in Acute Puumala Hantavirus Infection

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