The pathophysiology of thrombocytopenia in chronic liver disease

Abstract

Thrombocytopenia is the most common hematological abnormality encountered in patients with chronic liver disease (CLD). In addition to being an indicator of advanced disease and poor prognosis, it frequently prevents crucial interventions. Historically, thrombocytopenia has been attributed to hypersplenism, which is the increased pooling of platelets in a spleen enlarged by congestive splenomegaly secondary to portal hypertension. Over the past decade, however, there have been significant advances in the understanding of thrombopoiesis, which, in turn, has led to an improved understanding of thrombocytopenia in cirrhosis. Multiple factors contribute to the development of thrombocytopenia and these can broadly be divided into those that cause decreased production, splenic sequestration, and increased destruction. Depressed thrombopoietin levels in CLD, together with direct bone marrow suppression, result in a reduced rate of platelet production. Thrombopoietin regulates both platelet production and maturation and is impaired in CLD. Bone marrow suppression can be caused by viruses, alcohol, iron overload, and medications. Splenic sequestration results from hypersplenism. The increased rate of platelet destruction in cirrhosis also occurs through a number of pathways: increased shear stress, increased fibrinolysis, bacterial translocation, and infection result in an increased rate of platelet aggregation, while autoimmune disease and raised titers of antiplatelet immunoglobulin result in the immunologic destruction of platelets. An in-depth understanding of the complex pathophysiology of the thrombocytopenia of CLD is crucial when considering treatment strategies. This review outlines the recent advances in our understanding of thrombocytopenia in cirrhosis and CLD.

Keywords: cirrhosis; thrombocytopenia; thrombopoietin.

Figure 1

Factors that contribute to the development of thrombocytopenia in patients with cirrhosis. Note: The factors can be categorized as those that result in decreased production, splenic sequestration, and increased destruction. Abbreviations: DITP, drug-induced thrombocytopenia; HCV, hepatitis C virus; ITP, idiopathic thrombocytopenia purpura; TPO, thrombopoietin.

Figure 2

Normal thrombopoiesis. Notes: The liver secretes TPO at a constant rate into the circulation, where it binds to c-mpl ligands on both platelets and megakaryocytes. TPO bound to platelets is internalized and degraded, and TPO bound to megakaryocytes stimulates platelet production. Abbreviation: TPO, thrombopoietin.

Figure 3

Increased thrombopoietin levels in thrombocytopenia lead to increased platelet production. Note: In states of thrombocytopenia in the absence of chronic liver disease, there is decreased TPO binding and degradation by circulating platelets, leading to higher levels that are available for increased megakaryocyte stimulation and platelet production. Abbreviation: TPO, thrombopoietin.

Figure 4

Decreased thrombopoietin levels in cirrhosis lead to decreased platelet production. Notes: In patients with chronic liver disease, circulating TPO levels are decreased due to impaired production and secretion and increased internalization and degradation by platelets sequestered in the enlarged spleen. Reduced TPO levels result in decreased megakaryocyte stimulation and platelet production. Adapted with permission from Pacific Health and Wellness. Reproduced with permission from Cognition Studio, Inc. Abbreviation: TPO, thrombopoietin.