“Going with the flow” in modeling fibrinolysis

Funding CSW and NJM are supported by the British Heart Foundation (PG/20/17/35050) and a NC3Rs-British Heart Foundation Studentship (NC/W001810/1).Peer reviewedPublisher PD

uPA-mediated plasminogen activation is enhanced by polyphosphate

Funding This research was supported by grants FS/11/2/28579 (NJM) and PG/11/1/28461 (NJM, CSW) from the British Heart Foundation.Peer reviewedPublisher PD

All tangled up: interactions of the fibrinolytic and innate immune systems

The hemostatic and innate immune system are intertwined processes. Inflammation within the vasculature promotes thrombus development, whilst fibrin forms part of the innate immune response to trap invading pathogens. The awareness of these interlinked process has resulted in the coining of the terms “thromboinflammation” and “immunothrombosis.” Once a thrombus is formed it is up to the fibrinolytic system to resolve these clots and remove them from the vasculature. Immune cells contain an arsenal of fibrinolytic regulators and plasmin, the central fibrinolytic enzyme. The fibrinolytic proteins in turn have diverse roles in immunoregulation. Here, the intricate relationship between the fibrinolytic and innate immune system will be discussed

Location, location, location : Fibrin, cells, and fibrinolytic factors in thrombi

Funding Information: Figures were created with BioRender.com.Peer reviewedPublisher PD

The Efficacy of Fibrinogen Concentrates in Relation to Cryoprecipitate in Restoring Clot Integrity and Stability against Lysis

Funding: This work was supported in part by Tenovus Scotland Grampian (G17.03) and Friends of Anchor (SC025332). C.S.W. and N.J.M. were supported by the British Heart Foundation (PG/15/82/31721and PG/20/17/35050). Acknowledgments: We thank the NHS Grampian Haematology department for kindly performing the Clauss assay to measure the fibrinogen concentration in the cryoprecipitate. We thank the University of Aberdeen Microscopy and Histology facility for their advice and the use of their facilities. We thank Linda Robertson and Megan Simpson for their technical assistance.Peer reviewedPublisher PD

Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID‐19

The global pandemic of coronavirus disease 2019 (COVID‐19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID‐19 patients show elevated D‐dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI‐1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID‐19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre‐existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue‐type plasminogen activator (tPA), to treat COVID‐19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID‐19 patients to degrade fibrin and improving oxygenation in critically ill patients

Location, location, location: Fibrin, cells, and fibrinolytic factors in thrombi

Thrombi are heterogenous in nature with composition and structure being dictated by the site of formation, initiating stimuli, shear stress, and cellular influences. Arterial thrombi are historically associated with high platelet content and more tightly packed fibrin, reflecting the shear stress in these vessels. In contrast, venous thrombi are generally erythrocyte and fibrin-rich with reduced platelet contribution. However, these conventional views on the composition of thrombi in divergent vascular beds have shifted in recent years, largely due to recent advances in thromboectomy and high-resolution imaging. Interestingly, the distribution of fibrinolytic proteins within thrombi is directly influenced by the cellular composition and vascular bed. This in turn influences the susceptibility of thrombi to proteolytic degradation. Our current knowledge of thrombus composition and its impact on resistance to thrombolytic therapy and success of thrombectomy is advancing, but nonetheless in its infancy. We require a deeper understanding of thrombus architecture and the downstream influence on fibrinolytic susceptibility. Ultimately, this will aid in a stratified and targeted approach to tailored antithrombotic strategies in patients with various thromboembolic diseases

“Super” SERPINs—A stabilizing force against fibrinolysis in thromboinflammatory conditions

The superfamily of serine protease inhibitors (SERPINs) are a class of inhibitors that utilise a dynamic conformational change to trap and inhibit their target enzymes. Their powerful nature lends itself well to regulation of complex physiological enzymatic cascades, such as the haemostatic, inflammatory and complement pathways. The SERPINs α2-antiplasmin, plasminogen-activator inhibitor-1, plasminogen-activator inhibitor-2, protease nexin-1, and C1-inhibitor play crucial inhibitory roles in regulation of the fibrinolytic system and inflammation. Elevated levels of these SERPINs are associated with increased risk of thrombotic complications, obesity, type 2 diabetes, and hypertension. Conversely, deficiencies of these SERPINs have been linked to hyperfibrinolysis with bleeding and angioedema. In recent years SERPINs have been implicated in the modulation of the immune response and various thromboinflammatory conditions, such as sepsis and COVID-19. Here, we highlight the current understanding of the physiological role of SERPINs in haemostasis and inflammatory disease progression, with emphasis on the fibrinolytic pathway, and how this becomes dysregulated during disease. Finally, we consider the role of these SERPINs as potential biomarkers of disease progression and therapeutic targets for thromboinflammatory diseases

A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo

Funded by Medical Research Council. Grant Number: 74804 NHS Grampian Endowments Research Trust. Grant Number: 12/16 Kidney Research UK. Grant Number: RP1/2012 Cunningham Trust. Grant Number: ACC/KWF/CT08/03Peer reviewedPublisher PD

Monocytes Expose Factor XIII-A and Stabilize Thrombi against Fibrinolytic Degradation

Acknowledgments: We acknowledge the University of Aberdeen Microscopy and Histology Facility and the Iain Fraser Cytometry for use of facilities and advice. Funding: The work presented here was funded the University of Aberdeen Development Trust and by project grants from Friend of Anchor (RS2015 006), the British Heart Foundation (PG/15/82/31721), Royal Embassy of Saudi Arabia Cultural Bureau (KFMCS74) and a British Heart Foundation Fellowship (FS/11/2/28579) awarded to N.J.M.Peer reviewedPublisher PD