The COVID‐19 pandemic has provided many challenges in the field of thrombosis and hemostasis. Among these is a novel form of coagulopathy that includes exceptionally high levels of D‐dimer. D‐dimer is a marker of poor prognosis, but does this also imply a causal relationship? These spectacularly raised D‐dimer levels may actually signify the failing attempt of the fibrinolytic system to remove fibrin and necrotic tissue from the lung parenchyma, being consumed or overwhelmed in the process. Indeed, recent studies suggest that increasing fibrinolytic activity might offer hope for patients with critical disease and severe respiratory failure. However, the fibrinolytic system can also be harnessed by coronavirus to promote infectivity and where antifibrinolytic measures would also seem appropriate. Hence, there is a clinical paradox where plasmin formation can be either deleterious or beneficial in COVID‐19, but not at the same time. Hence, it all comes down to timing.
Coagulation and innate immunity are linked evolutionary processes that orchestrate the host defence against invading pathogens and injury. The complement system is integral to innate immunity and shares numerous interactions with components of the haemostatic pathway, helping to maintain physiological equilibrium. The term 'immunothrombosis' was introduced in 2013 to embrace this process, and has become an area of much recent interest. What is less apparent in the literature however is an appreciation of the clinical manifestations of the coagulation-complement interaction and the consequences of dysregulation of either system, as seen in many inflammatory and thrombotic disease states, such as sepsis, trauma, atherosclerosis, antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH) and some thrombotic microangiopathies to name a few. The growing appreciation of this immunothrombotic phenomenon will foster the drive for novel therapies in these disease states, including anticoagulants as immunomodulators and targeted molecular therapies.
Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. The therapeutic targeting of the fibrinolytic system to date has been for two purposes: to promote plasmin generation for thromboembolic conditions, or to stop plasmin to reduce bleeding. However, both plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for over 40 years, the anti-fibrinolytic agent, tranexamic acid, has been administered for its serendipitously discovered skin whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades including complement. In addition, plasminogen, via binding to one of its dozen cell-surface receptors, can modulate cell behaviour and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. While many of these more recent findings have been derived from in vitro or animal studies, the use of anti-fibrinolytics to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its haemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that anti-fibrinolytic agents may have anti-viral benefits. Here we review the broadening role of the plasminogen activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and haemostasis.
Introduction: Acute ischemic stroke (AIS) is a potent trigger of immunosuppression, resulting in increased infection risk. While thrombolytic therapy with tissue-type plasminogen activator (t-PA) is still the only pharmacological treatment for AIS, plasmin, the effector protease, has been reported to suppress dendritic cells (DCs), known for their potent antigen-presenting capacity. Accordingly, in the major group of thrombolyzed AIS patients who fail to reanalyze (>60%), t-PA might trigger unintended and potentially harmful immunosuppressive consequences instead of beneficial reperfusion. To test this hypothesis, we performed an exploratory study to investigate the immunomodulatory properties of t-PA treatment in a mouse model of ischemic stroke. Methods: C57Bl/6J wild-type mice and plasminogen-deficient (plg −/− ) mice were subjected to middle cerebral artery occlusion (MCAo) for 60 min followed by mouse t-PA treatment (0.9 mg/kg) at reperfusion. Behavioral testing was performed 23 h after occlusion, pursued by determination of blood counts and plasma cytokines at 24 h. Spleens and cervical lymph nodes (cLN) were also harvested and characterized by flow cytometry. Results: MCAo resulted in profound attenuation of immune activation, as anticipated. t-PA treatment not only worsened neurological deficit, but further reduced lymphocyte and monocyte counts in blood, enhanced plasma levels of both IL-10 and TNFα and decreased various conventional DC subsets in the spleen and cLN, consistent with enhanced immunosuppression and systemic inflammation after stroke. Many of these effects were abolished in plg −/− mice, suggesting plasmin as a key mediator of t-PA-induced immunosuppression. Conclusion: t-PA, via plasmin generation, may weaken the immune response post-stroke, potentially enhancing infection risk and impairing neurological recovery. Due to the large number of comparisons performed in this study, additional pre-clinical work is required to confirm these significant possibilities. Future studies will also need to ascertain the functional implications of t-PA-mediated immunosuppression for thrombolyzed AIS patients, particularly for those with failed recanalization.
Background Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. Objective To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild‐type and plasminogen‐deficient (plg−/−) mice subjected to TBI. Methods Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme‐linked Immunosorbent Spot (ELISpot) assay. Fibrinolysis was determined by thromboelastography and measuring D‐dimer and plasmin‐antiplasmin complex levels. Results Plg−/− mice, but not plg+/+ mice displayed increases in both the number and activation of various antigen‐presenting cells and T cells in the cLN 1 week post TBI. Wild‐type mice treated with TXA also displayed increased cellularity of the cLN 1 week post TBI together with increases in innate and adaptive immune cells. These changes occurred despite the absence of systemic hyperfibrinolysis or coagulopathy in this model of TBI. Importantly, neither plg deficiency nor TXA treatment enhanced the autoreactivity within the CNS. Conclusion In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen‐presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.
It has long been known that the fibrinolytic system becomes activated following trauma. At first glance, this is not at all surprising and would appear to be in response to coagulation and the apparent need to remove blood clots and restore blood flow. However, in a bleeding patient, the opposite is what is actually needed. Therefore, one may ask why the fibrinolytic system gets activated in the first place or is there another purpose? Or is it that the waxing and waning of hemostasis in such severely injured patients creates a “moving target” such that the fibrinolytic system itself is constantly responding to changing circumstances? Depending on the injury modalities and the time point post injury, the fibrinolytic system could be either turned on or off. Various theories now abound that offer new insights into the turmoil and paradoxes associated with the fibrinolytic system in this unique setting and the use of antifibrinolytic agents. While this presents one conundrum, there is also another dimension to add to this discussion that has nothing to do with hemostasis per se but rather with the modulation of other critical processes that are also essential for optimal recovery following severe injury. Indeed, overwhelming data are now supporting an important role of the fibrinolytic system in the removal of necrotic tissue (mortolysis) and as a modulator of the innate immune response. Therefore, what is really going on when the fibrinolytic system decides to go into overdrive and generate plasmin, albeit even briefly after a traumatic event? Moreover, what other consequence may occur when antifibrinolytic agents are administered? This review will address this developing story and will outline a hypothesis that places the fibrinolytic system as a gateway to a myriad of processes that are not only linked to fibrin removal but are also broader players in the modulation of innate immunity.
The deposition and removal of fibrin has been the primary role of coagulation and fibrinolysis, respectively. There is also little doubt that these 2 enzyme cascades influence each other given they share the same serine protease family ancestry and changes to 1 arm of the hemostatic pathway would influence the other. The fibrinolytic system in particular has also been known for its capacity to clear various non-fibrin proteins and to activate other enzyme systems, including complement and the contact pathway. Furthermore, it can also convert a number of growth factors into their mature, active forms. More recent findings have extended the reach of this system even further. Here we will review some of these developments and also provide an account of the influence of individual players of the fibrinolytic (plasminogen activating) pathway in relation to physiological and pathophysiological events, including aging and metabolism.
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