The Coagulation Cascade in Cirrhosis Dougald M. Monroe, PhD a , Maureane Hoffman, MD, PhD a,b,c, * In the 1960s, two groups proposed a ‘‘waterfall’’ or ‘‘cascade’’ model of coagulation composed of a sequential series of steps in which activation of one clotting factor led to the activation of another, finally leading to a burst of thrombin generation. 1,2 Each clotting factor was thought to exist as a precursor that could be converted pro- teolytically into an active enzyme. 3 The original models were modified to eventually become the familiar Y-shaped scheme that we call the ‘‘coagulation cascade’’ today (Fig. 1). The two arms of the ‘‘Y’’ are the ‘‘intrinsic’’ and ‘‘extrinsic’’ pathways initiated by factor XII (FXII) and FVIIa/tissue factor (TF), respectively. The pathways converge on a ‘‘common’’ pathway at the level of the FXa/FVa (prothrombinase) complex. This ‘‘cascade’’ was not proposed as a literal model of hemostasis in vivo, but rather as a scheme of how the many identified coagulation factors interact biochemically. However, the lack of any other clear and predictive model of physiologic hemostasis has meant that most physicians view the ‘‘cascade’’ as a model of physiology by default. This view has been reinforced by the fact that screening coagulation tests (prothrombin time [PT] and activated partial thromboplastin time [aPTT]) are often used as though they were predictive of clinical bleeding. Many people recognized that the ‘‘cascade’’ model had serious failings as a model of physiologic coagulation, and that the intrinsic and extrinsic systems could not operate as independent and redundant pathways as implied by this model. It was also recognized from the earliest studies of coagulation that cells are important partic- ipants in the process 4,5 and that normal hemostasis is not possible in the absence of cell-associated tissue factor (TF) and platelets. It is therefore logical that substituting the role of cells in in vitro coagulation tests with phospholipid vesicles 6 in the PT and PTT assays overlooks their active roles in hemostasis in vivo. Therefore, we proposed a Carolina Cardiovascular Biology Center, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA b Pathology and Laboratory Medicine Service, Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27705, USA c Department of Pathology, Duke University Medical Center, Durham, NC, USA * Corresponding author. Pathology and Laboratory Medicine Service (113), Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC. E-mail address: maureane@med.unc.edu (M. Hoffman). KEYWORDS  Hemostasis  Hemorrhage  Thrombin  Platelets  Coagulation factors Clin Liver Dis 13 (2009) 1–9 doi:10.1016/j.cld.2008.09.014 liver.theclinics.com 1089-3261/08/$ – see front matter. Published by Elsevier Inc.