Editorial [Hot Topic:Hemostatic Factors as Druggable Targets in Diverse Pathologies (Guest Editor: Susan A. McDowell)]

Although blood maintains a fluid state under physiologic conditions, clot formation is an immediate response to injury. The immediacy of the response is accomplished by the continuous circulation of hemostatic factors as zymogens, inactive precursors, and by the sequestration of active factors by the vessel wall, accessible only when vascular damage breaches this divide. Clot resolution, achieved by anti-coagulant and fibrinolytic factors, is central to complete restoration following injury. This balance between pro-coagulant and fibrinolytic factors is disrupted in a diverse set of pathologies, including liver and pulmonary fibrosis, sepsis, the metabolic syndrome, rheumatoid arthritis, acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Factors within the coagulation cascade and their downstream mediators are emerging as pre-clinical and clinical targets in each of these pathologies yet with varied efficacy. The emphasis for this edition will be on therapies directed at the alteration in hemostatic factors in each of these disease states, including evaluation of current and proposed therapeutics directed at factors within the coagulation cascade, their immediate downstream effectors, and cell signaling regulators of factors within the cascade. Hemostatic factors can contribute to a wide range of pathologies due in part to the circulating nature of the components and to the etiology of a number of these pathologies as a dysregulated response to injury. In this regard, therapeutic strategies directed toward hemostatic factors may have broad applicability across pathologies. This possibility is highlighted by Liang-I Kang and Wendy Mars in “Fibrinolytic factors in liver fibrosis” as they focus on the fibrinolytic side of the hemostatic equation. The authors present recent pre-clinical evidence supporting the development of fibrinolytic factors as potential therapeutics in the reversal of fibrotic liver disease, arguing from the demonstrated usefulness of such factors in the resolution of acute myocardial infarct and ischemic damage. Similar fibrotic resolution might be achievable within the lung. In their review entitled “Use of transgenic mouse models to understand the origins of familial pulmonary fibrosis”, Al Senft and Steve Glasser describe available murine models for slow-onset, slow-resolving pulmonary fibrotic disease that could prove to be useful in assessing whether a similar therapeutic regimen might provide benefit in the resolution of pulmonary fibrosis. The work from Henry Akinbi's group, “Simvastatin is protective during Staphylococcus aureus pneumonia”, demonstrates in vivo the potential for statin drugs in ameliorating dysregulated coagulation status during sepsis. Such an approach that targets multiple pathways through well-characterized pharmacology may be especially useful in the treatment of the metabolic syndrome, a complex interplay of systems that is covered in the review by Laura Michael, Veena Rao, Patrick McCollam, Mark Kowala, and John Wetterau, in “Opportunities for pharmacotherapy at the intersection of metabolic syndrome and hemostasis”. Novel therapeutics also are in need of development as reported in the review “Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome” by Sara Sebag, Julie Bastarache, and Lorraine Ware, wherein they note that clinical benefit has yet to be demonstrated in the treatment of ARDS/ALI. Harini Raghu and Matthew Flick in “Targeting the coagulation factor fibrinogen for arthritis therapy” further examine the contribution of coagulation factors in the pathogenesis and etiology of inflammatory disease. Hemostatic factors have served as biomarkers for this range of pathologies, yet their contribution to the onset of each is an emerging concept that indicates their potential usefulness as therapeutic targets. This collection of reviews examines the alternative use of well-characterized pharmacologic agents and the need for the development of novel therapeutics directed toward pro-coagulant and fibrinolytic factors as they contribute to the increasingly burdensome personal and economic impact of these disease states.