Therapeutic Potential of Targeting Plasminogen Activator Inhibitor-1 in COVID-19

Kellici, Tahsin F.; Pilka, E.S.; Bodkin, Michael J.

doi:10.1016/j.tips.2021.03.006

Cited by 24 publications

(19 citation statements)

References 20 publications

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“…The most distinct difference between COVID-19 (+) and COVID-19 (−) non-survivors was a decrease in plasmin generation in COVID-19 (+) patients. This observation may suggest a COVID-19-induced impairment in fibrinolysis mediated by plasminogen activator inhibitor 1 (PAI-1) ( 62 , 63 ), consistent with greater expression of the inhibitor in adipose tissue ( 64 ) and endothelium ( 65 ).…”

Section: Discussionmentioning

confidence: 86%

The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients

et al. 2022

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Aging and obesity independently contribute toward an endothelial dysfunction that results in an imbalanced VWF to ADAMTS13 ratio. In addition, plasma thrombin and plasmin generation are elevated and reduced, respectively, with increasing age and also with increasing body mass index (BMI). The severity risk of Corona Virus Disease 2019 (COVID-19) increases in adults older than 65 and in individuals with certain pre-existing health conditions, including obesity (>30 kg/m2). The present cross-sectional study focused on an analysis of the VWF/ADAMTS13 axis, including measurements of von Willebrand factor (VWF) antigen (VWF:AG), VWF collagen binding activity (VWF:CBA), Factor VIII antigen, ADAMTS13 antigen, and ADAMTS13 activity, in addition to thrombin and plasmin generation potential, in a demographically diverse population of COVID-19 negative (−) (n = 288) and COVID-19 positive (+) (n = 543) patient plasmas collected at the time of hospital presentation. Data were analyzed as a whole, and then after dividing patients by age (<65 and ≥65) and independently by BMI [<18.5, 18.5–24.9, 25–29.9, >30 (kg/m2)]. These analyses suggest that VWF parameters (i.e., the VWF/ADAMTS13 activity ratio) and thrombin and plasmin generation differed in COVID-19 (+), as compared to COVID-19 (−) patient plasma. Further, age (≥65) more than BMI contributed to aberrant plasma indicators of endothelial coagulopathy. Based on these findings, evaluating both the VWF/ADAMTS13 axis, along with thrombin and plasmin generation, could provide insight into the extent of endothelial dysfunction as well as the plasmatic imbalance in coagulation and fibrinolysis potential, particularly for at-risk patient populations.

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Section: Discussionmentioning

confidence: 86%

The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients

et al. 2022

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“…PAI-1 inhibitors significantly enhance the bronchoalveolar fibrinolytic system and relieve symptoms of COVID-19 by increasing fibrinolytic protein levels that effectively remove fibrin. 447 There is increasing evidence that complement is involved in SARS-CoV-2 pathology, and that complement inhibitors may reduce the severity of COVID-19 complications and the number of intensive care or deaths, especially with ekuzumab showing preliminary efficacy. 448 Defibrotide can counteract endothelial activation and hypercoagulability induced by NETs and histone H4, promote endothelial remodeling and prevent endothelial dysfunction.…”

Section: The Implication For Therapeuticsmentioning

confidence: 99%

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

Ning

Wang

et al. 2022

Sig Transduct Target Ther

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The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

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“…Currently, therapeutic approaches are symptomatic and include empirical immunosuppressive and anti-inflammatory tactics (dexamethasone)[ 128 ], interferons[ 129 ], targeting of individual cytokines (IL-6: Tocilizumab/statins/heparin; PAI-1: Statins, and numerous target substances in development)[ 75 , 130 - 132 ] and correction of isolated laboratory abnormalities ( e.g. , sodium disturbances)[ 133 ].…”

Section: Therapeutic Considerationsmentioning

confidence: 99%

Age and genotype dependent erythropoietin protection in COVID-19

Papadopoulos

Sutheesophon

Manipalviratn³

et al. 2021

WJSC

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Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a “bait” for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.

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Therapeutic Potential of Targeting Plasminogen Activator Inhibitor-1 in COVID-19

Cited by 24 publications

References 20 publications

The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients

The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

Age and genotype dependent erythropoietin protection in COVID-19

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