James A Russell1. 1. Division of Critical Care Medicine, Department of Medicine and UBC McDonald Research Laboratories, St. Paul's Hospital, Vancouver, BC, Canada.
Abstract
OBJECTIVES: To review the role of coagulation and of single nucleotide polymorphisms of coagulation factors in acute lung injury. DATA SOURCES AND STUDY SELECTION: MEDLINE search of selected basic and clinical studies in English literature. CONCLUSIONS: Exuberant coagulation relative to anticoagulation and fibrinolysis in the lung and the systemic circulation are important in the pathophysiology of acute lung injury. In the early stages of acute lung injury, fibrin is deposited in the alveoli, and fibrin in the alveoli increases the inflammatory response. Sepsis, trauma, and aspiration are risk factors for acute lung injury. They are also potent stimuli for increased coagulation because inflammatory stimuli activate coagulation and proinflammatory cascades. There is "cross-talk" amplification of the coagulation and inflammatory cascades. Inflammatory mediators activate coagulation. Tumor necrosis factor-alpha, interleukin-1, and interleukin-6 increase tissue factor and inhibit fibrinolysis, thereby activating the extrinsic pathway. Conversely, intravascular coagulation induces an inflammatory response. Coagulation of blood in vitro increases the production of tumor necrosis factor-alpha, interleukin-1, and interleukin-8 by monocytes. Factor Xa, alpha-thrombin, and fibrin increase synthesis of interleukin-6 and interleukin-8. Genetic predisposition could increase the tendency to intravascular and intraalveolar coagulation. Single nucleotide polymorphisms and single nucleotide polymorphism haplotypes of coagulation factor genes increase coagulation and impair anticoagulation and fibrinolysis, which could tip the balance in favor of coagulation. For example, procoagulant and antifibrinolytic single nucleotide polymorphisms in the promoter and coding regions have been reported for alpha-thrombin, fibrinogen, factor V, protein C, endothelial protein C receptor, and plasminogen activator inhibitor-1. Single nucleotide polymorphisms of protein C, factor V (e.g., factor V Leiden), and plasminogen activator inhibitor-1 are associated with an increased risk of deep venous thrombosis, pulmonary emboli, acute myocardial infarction, and stroke. These and other single nucleotide polymorphisms could be associated with increased risk of coagulation relative to anticoagulation/fibrinolysis in the vascular spaces and airspaces of the lung, thus increasing the risk of acute lung injury in patients with sepsis, trauma, aspiration, and other precursors of acute lung injury.
OBJECTIVES: To review the role of coagulation and of single nucleotide polymorphisms of coagulation factors in acute lung injury. DATA SOURCES AND STUDY SELECTION: MEDLINE search of selected basic and clinical studies in English literature. CONCLUSIONS: Exuberant coagulation relative to anticoagulation and fibrinolysis in the lung and the systemic circulation are important in the pathophysiology of acute lung injury. In the early stages of acute lung injury, fibrin is deposited in the alveoli, and fibrin in the alveoli increases the inflammatory response. Sepsis, trauma, and aspiration are risk factors for acute lung injury. They are also potent stimuli for increased coagulation because inflammatory stimuli activate coagulation and proinflammatory cascades. There is "cross-talk" amplification of the coagulation and inflammatory cascades. Inflammatory mediators activate coagulation. Tumor necrosis factor-alpha, interleukin-1, and interleukin-6 increase tissue factor and inhibit fibrinolysis, thereby activating the extrinsic pathway. Conversely, intravascular coagulation induces an inflammatory response. Coagulation of blood in vitro increases the production of tumor necrosis factor-alpha, interleukin-1, and interleukin-8 by monocytes. Factor Xa, alpha-thrombin, and fibrin increase synthesis of interleukin-6 and interleukin-8. Genetic predisposition could increase the tendency to intravascular and intraalveolar coagulation. Single nucleotide polymorphisms and single nucleotide polymorphism haplotypes of coagulation factor genes increase coagulation and impair anticoagulation and fibrinolysis, which could tip the balance in favor of coagulation. For example, procoagulant and antifibrinolytic single nucleotide polymorphisms in the promoter and coding regions have been reported for alpha-thrombin, fibrinogen, factor V, protein C, endothelial protein C receptor, and plasminogen activator inhibitor-1. Single nucleotide polymorphisms of protein C, factor V (e.g., factor V Leiden), and plasminogen activator inhibitor-1 are associated with an increased risk of deep venous thrombosis, pulmonary emboli, acute myocardial infarction, and stroke. These and other single nucleotide polymorphisms could be associated with increased risk of coagulation relative to anticoagulation/fibrinolysis in the vascular spaces and airspaces of the lung, thus increasing the risk of acute lung injury in patients with sepsis, trauma, aspiration, and other precursors of acute lung injury.
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