Pathophysiology and management of bleeding and thrombosis in patients with liver disease

Abstract

Patients with liver disease often develop complex changes in their haemostatic system. Frequently observed changes include thrombocytopaenia and altered plasma levels of most of the proteins involved in haemostasis. Although liver disease was historically classified as a haemostasis-related bleeding disorder, it has now been well established that the antihaemostatic changes that promote bleeding are compensated for by prohaemostatic changes. Conventional coagulation tests however do not accurately reflect these prohaemostatic changes, resulting in an underestimation of haemostatic potential. Novel coagulation tests, such as viscoelastic tests (VETs) and thrombin generation assays (TGAs) better reflect the net result of the haemostatic changes in patients with liver disease, and demonstrate a new, "rebalanced" haemostatic status. Although rebalanced, this haemostatic status is more fragile than in patients without liver disease. Patients with liver disease are therefore not only at risk of bleeding but also at risk of thrombosis. Notably, however, many haemostatic complications in liver disease are not related to the haemostatic failure. It is, therefore, crucial to identify the cause of the bleed or thrombotic complication in order to provide adequate treatment. In this paper, we will elaborate on the haemostatic changes that occur in liver disease, reflect on laboratory and clinical studies over the last few years, and explore the pathophysiologies of bleeding and thrombosis in this specific patient group.

Keywords: bleeding; coagulation; haemostasis; liver disease; thrombosis.

FIGURE 1

Schematic presentation of the rebalanced haemostasis in patients with liver disease. In healthy individuals (A), haemostasis is in solid balance. In patients with liver disease (B and table) both pro‐ and antihaemostatic changes result in a “rebalance” of the haemostatic system. This new balance is however more fragile, and may therefore more easily tip towards bleeding or thrombosis. Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; PAI‐1, plasminogen activator inhibitor‐1; TAFI, thrombin activatable fibrinolysis inhibitor; tPA, Tissue plasminogen activator; VWF, von Willebrand factor. Modified from Warnaar et al. with permission from Wolters Kluwer Health

FIGURE 2

Depiction of various types of bleeding that a patient with cirrhosis might experience. Some bleeding sources are related to vascular trauma, some to excessive portal hypertension, and some to haemostatic failure. Other common sources not shown include portal hypertensive enteropathy/colopathy, rectal varices (portal hypertensive), epistaxis (mechanical or haemostatic), and menorrhagia (haemostatic). Figure from Northup et al., used with permission

FIGURE 3

Martius scarlet blue (MSB)‐stained sections of extrahepatic portal vein samples removed during liver transplantation. (A) A portal vein thrombus consisting of a focally thickened intimal layer of the vessel wall with some haemorrhage but without a fibrin‐rich thrombus. (B) A Portal vein thrombus consisting of a circumferential thickened intimal layer of the vessel wall with a fibrin‐rich thrombus on top. Figure from Driever et al., used with permission.