Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Background and Objective. Bronchoalveolar coagulopathy is a characteristic feature of pulmonary inflammation. We compared bronchoalveolar and systemic levels of coagulation in patients who did and patients who did not develop ventilator-associated lung injury (VALI). Methods. Secondary analysis of a randomized controlled trial evaluating the effect of lower tidal volumes versus conventional tidal volumes in patients without acute lung injury or acute respiratory distress syndrome at the onset of mechanical ventilation. Results. Ten patients with VALI and 10 random control patients without lung injury during the course of mechanical ventilation, but all ventilated with conventional tidal volumes, were compared. Patients who developed VALI showed both bronchoalveolar activation of coagulation (increase in thrombin-antithrombin complex levels P < 0.001 versus baseline) and inhibition of fibrinolysis (decline in plasminogen activator activity P < 0.001 versus baseline). The later seemed to be dependent on higher levels of plasminogen activator inhibitor type 1 (P = 0.001 versus baseline). Patients who developed VALI also showed elevated systemic thrombin-antithrombin complex levels and decreased systemic plasminogen activator activity levels. Conclusions. VALI is characterized by bronchoalveolar coagulopathy. Systemic and bronchoalveolar coagulopathy at the onset of mechanical ventilation may be a risk factor for developing VALI in patients ventilated with conventional tidal volumes.
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PMID:Bronchoalveolar Activation of Coagulation and Inhibition of Fibrinolysis during Ventilator-Associated Lung Injury. 2257 Jul 75

Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho-alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator-induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ARDS and pneumonia.
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PMID:Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome. 2311 8

A 21-year old female, recently diagnosed with osteosarcoma of right humerus, presented to the emergency with history of fever, productive cough, chest pain and progressive respiratory distress for six days. Initial investigations suggested pneumonia but she did not respond to parenteral antibiotics. CT pulmonary angiogram revealed bilateral pulmonary artery embolism. Thrombolysis was performed using alteplase, which failed to improve the clinical condition. In view of underlying malignancy, a possibility of tumour-embolism was considered and she was started on chemotherapy for osteosarcoma. There was dramatic improvement in her respiratory symptoms after the first chemotherapy cycle, along with radiological resolution of the embolism. This case highlights the importance of suspecting tumour embolism in a known case of malignancy with respiratory distress.
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PMID:Treatment of Pulmonary Embolism with Chemotherapy in a Case of Newly Diagnosed Osteosarcoma. 3129 47

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.
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PMID:Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. 3232 46

The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold mechanism responsible for causing acute coronary events in patients with COVID-19 infection: Cytokine storm leading to rapid onset formation of new coronary plaques along with destabilization of pre-existing plaques and direct myocardial injury secondary to acute systemic viral infection. A well-coordinated immune response is the first line innate immunity against a viral infection. However, an uncoordinated response and hypersecretion of cytokines and chemokines lead to immune related damage to the human body. Human Coronavirus (HCoV) infection causes infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules causing endothelial damage, disruption of fibrous cap and initiation of formation of thrombus. Systemic viral infections also cause vasoconstriction leading to narrowing of vascular lumen and stimulation of platelet activation via shear stress. The resultant cytokine storm causes secretion of hypercoagulable tissue factor without consequential increase in counter-regulatory pathways such as AT-III, activated protein C and plasminogen activator type 1. Lastly, influx of CD4+ T-cells in cardiac vasculature results in an increased production of cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products leading to advancement of fatty streaks to advanced atherosclerotic lesions. Direct myocardial damage and cytokine storm leading to destabilization of pre-existing plaques and accelerated formation of new plaques are the two instigating mechanisms for acute coronary syndromes in COVID-19.
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PMID:Possible mechanisms responsible for acute coronary events in COVID-19. 3276 57

Background: Coronavirus Disease 2019 (COVID-19)-associated coagulopathy is characterized by a prothrombotic state not yet comprehensively studied. We investigated the coagulation pattern of patients with COVID-19 acute respiratory distress syndrome (ARDS), comparing patients who survived to those who did not. Methods: In this prospective cohort study on 20 COVID-19 ARDS patients, the following biomarkers were measured: thrombin generation (prothrombin fragment 1 + 2 (PF 1 + 2)), fibrinolysis activation (tissue plasminogen activator (tPA)) and inhibition (plasminogen activator inhibitor 2 (PAI-2)), fibrin synthesis (fibrinopeptide A) and fibrinolysis magnitude (plasmin-antiplasmin complex (PAP) and D-dimers). Measurements were done upon intensive care unit (ICU) admission and after 10-14 days. Results: There was increased thrombin generation; modest or null release of t-PA; and increased levels of PAI-2, fibrinopeptide A, PAP and D-dimers. At baseline, nonsurvivors had a significantly (p = 0.014) higher PAI-2/PAP ratio than survivors (109, interquartile range (IQR) 18.1-216, vs. 8.7, IQR 2.9-12.6). At follow-up, thrombin generation was significantly (p = 0.025) reduced in survivors (PF 1 + 2 from 396 pg/mL, IQR 185-585 to 237 pg/mL, IQR 120-393), whereas it increased in nonsurvivors. Fibrinolysis inhibition at follow-up remained stable in survivors and increased in nonsurvivors, leading to a significant (p = 0.026) difference in PAI-2 levels (161 pg/mL, IQR 50-334, vs. 1088 pg/mL, IQR 177-1565). Conclusion: Severe patterns of COVID-19 ARDS are characterized by a thrombin burst and the consequent coagulation activation. Mechanisms of fibrinolysis regulation appear unbalanced toward fibrinolysis inhibition. This pattern ameliorates in survivors, whereas it worsens in nonsurvivors.
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PMID:Covid-19-Associated Coagulopathy: Biomarkers of Thrombin Generation and Fibrinolysis Leading the Outcome. 3312 72


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