Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production

Abstract

Thrombopoietin (TPO) deficiency has been proposed as an important etiologic factor for thrombocytopenia in advanced-stage liver disease. To clarify the contributions of platelet production, platelet consumption, coagulation activation, and splenic sequestration to thrombocytopenia in liver disease, we studied TPO serum levels and markers of platelet production, platelet activation, and coagulation activation before and 14 days after orthotopic liver transplantation (OLT) in 18 patients with advanced liver cirrhosis. Thrombocytopenia before transplantation occurred with low-normal serum levels of TPO, normal levels of platelet and coagulation activation markers, and no increase in bone marrow production of platelets. TPO serum levels increased significantly on the first day after OLT, preceding the increase of reticulated platelets by 3 days and peripheral platelets by 5 days. Normalization of the peripheral platelet count occurred in most patients within 14 days of OLT, irrespective of the change in spleen size assessed by computed tomography volumetry. Normalization of platelet counts was not hampered by a certain degree of platelet activation observed during the steepest increase in the peripheral platelet count. Bone marrow production of platelets increased significantly within 2 weeks of transplantation. Low TPO serum levels with low platelet counts and without platelet consumption suggests low TPO production in end-stage liver disease. The rapid increase in TPO serum levels after transplantation induces an increase in the bone marrow production of platelets. Decreased TPO production in the cirrhotic liver is an important etiologic factor for thrombocytopenia in liver disease that is rapidly reversed by transplantation.

ADAMTS13 activity may predict the cumulative survival of patients with liver cirrhosis in comparison with the Child‐Turcotte‐Pugh score and the Model for End‐Stage Liver Disease score

“…The plasma levels of von Willebrand factor antigen (VWF: Ag), the substrate for ADAMTS13, substantially increases as the liver disease progresses, 21,22 and thrombocytopenia is commonly seen in patients with advanced LC. [23][24][25] Previous studies revealed a significant reduction in the ADAMTS13 activity (ADAMTS13:AC) in advanced LC, 26,27 while the ADAMTS13 activity was unchanged in another study. 28 Subsequently, we demonstrated that both the plasma ADAMTS13 activity and antigen levels decreased as the severity of cirrhosis increased, and an imbalance between the decreased ADAMTS13:AC and the increased levels of its substrate may reflect a state that predisposes the patients with advanced LC to platelet thrombus formation.…”

Thrombocytopenia in chronic liver disease

“…38,39 As TPO is synthesized in the liver, impaired hepatic function may reduce TPO production. 8,40,41 TPO production in various stages of cirrhosis cannot be estimated from TPO serum levels, with conflicting reports of lower, similar and slightly elevated levels (all within the normal range) compared with control patients. [41][42][43][44] This can easily be explained by the "end-organ" regulation of TPO levels through removal by platelets and megakaryocytes.…”

“…45,46 Thus, TPO serum levels in CLD are inappropriately low for the actual degree of thrombocytopenia. 40,[43][44][45] The study by Koike et al 45 showed that the gradual decline in liver function in the patients with cirrhosis and thrombocytopenia was accompanied by a gradual decline in TPO production. This resulted in a low platelet production rate by the bone marrow, ruling out a high turnover state caused by increased platelet destruction in cirrhosis.…”

The circulating platelet count is not dictated by the liver, but may be determined in part by the bone marrow: analyses from human liver and stem cell transplantations

“…Indeed, patients with liver disease frequently have a reduced platelet count, which is partly ascribed to TPO deficiency [12]. Rapid normalization of thrombocytopenia in a patient with liver disease occurs after a successful liver transplantation, and this is associated with normalization of plasma TPO levels [13].…”