Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitis C

Abstract

Thrombocytopenia is common in advanced-stage liver disease and is partly caused by inadequate thrombopoietin (TPO) production in the failing liver. Treatment of chronic hepatitis C with interferon alfa (IFN-␣) often induces thrombocytopenia, sometimes even leading to discontinuation of treatment. TPO regulation in response to IFN-␣-induced thrombocytopenia was studied in patients with chronic hepatitis C with and without cirrhosis (Child A). An in vitro culture system with HepG2 cells was used to demonstrate any direct effects of IFN-␣ on TPO mRNA expression, TPO synthesis, or TPO secretion from liver cells. Thrombocyte count was lower (U test: P F .05) in patients with hepatitis C cirrhosis compared with patients with chronic hepatitis C without cirrhosis before IFN therapy, and decreased in both patient groups (Wilcoxon matched-pairs test: P F .05) on IFN therapy, the median decrease in both groups being comparable (noncirrhotic patients, 35%; cirrhotic patients, 32%; U test: P ‫؍‬ .57). TPO levels rose in noncirrhotic patients (Wilcoxon matchedpairs test: P F .05), but not in patients with cirrhosis (noncirrhotic patients' median increase: 43% vs. cirrhotic patients' median decrease: 5%; U test: P F .001). Even in patients without cirrhosis, the increase in TPO levels was relatively small for the decrease in platelet count. No effect of IFN-␣ could be demonstrated on TPO mRNA expression in vitro, but TPO secretion from liver cells was significantly reduced. Lower platelet counts but similar TPO levels in patients with chronic hepatitis C and cirrhosis compared with noncirrhotic patients and a moderate increase in TPO levels in noncirrhotic patients with a missing increase in cirrhotic patients during IFN-␣-induced thrombocytopenia provide further evidence for an impairment of TPO production in patients with cirrhosis and during IFN therapy.Recombinant human TPO could be of value in patients developing severe thrombocytopenia under IFN-␣ therapy. (HEPATOLOGY 1998;28:1424-1429.)Interferon alfa (IFN-␣) therapy is the current treatment of choice for chronic hepatitis C. Although well tolerated in many cases, IFN therapy has its side-effects, one of them being the development of thrombocytopenia. 1-3 Thrombocytopenia is mild in most cases, amounting to a decrease in peripheral platelet count between 10% and 50%, but when severe, can lead to bleeding complications 4,5 and discontinuation of IFN treatment. 6 Bone marrow suppression by IFN seems to be the main mechanism leading to thrombocytopenia in these patients, 7-9 and discontinuation of IFN therapy usually leads to restitution of a normal peripheral platelet count within 2 weeks.We recently described that inadequate thrombopoietin (TPO) production is at least partly responsible for thrombocytopenia in cirrhosis. 10 Because TPO is the key hematopoietic growth factor for full megakaryocyte maturation and thrombocyte production, 11 and the liver is the main source for TPO in humans, 12 a reduced production of TPO in the failing liver would lead to a lower peripher...

Hepatic thrombopoietin mRNA levels in acute and chronic liver failure of childhood

“…8,9,19,20 Furthermore, Ishikawa et al 20 measured in weekly intervals the TPO mRNA/GAPDH mRNA ratios in livers from rats treated with dimethylnitrosamine, which causes cirrhosis. The authors noted a progressive decrease in hepatic TPO mRNA levels for the 4-week observation period, which was related to reduced TPO mRNA expression by parenchymal cells as well as the loss of hepatocytes.…”

Laparoscopic splenectomy with peginterferon and ribavirin therapy for patients with hepatitis C virus cirrhosis and hypersplenism

“…Because of bone marrow suppression, IFN therapy tends to reduce the platelet and white blood cell counts [5,6]. The effect, which is dose dependent, usually occurs within the first few weeks after IFN therapy and necessitates dose reductions or withdrawal from therapy for up to 25% of patients [5,[7][8][9]. The decreased platelet count can be reversed by splenectomy in patients with HCV cirrhosis, usually in combination with portal hypertension [11][12][13].…”

“…Treatment with IFN alone can decrease peripheral platelet and leukocyte counts [7][8][9]. Therefore, patients with severe baseline thrombocytopenia and leukocytopenia due to hypersplenism generally are not considered candidates for IFN therapy, much less a full course of peg-IFN ?…”

Era of direct acting antivirals in chronic hepatitis C: Who will benefit?

“…These include those who are intolerant to IFN or have hypersensitivity to polyethylene glycol, have underlying autoimmune hepatitis or other severe autoimmune disorders [40,41] , history of significant psychiatric disorder such as depression [42] , and pre-existing cardiac disease [43] . Those patients with significant anemia, neutropenia, or thrombocytopenia may also be contra-indicated, as therapy with IFN can potentially compound the preexisting cytopenic state [44][45][46] . Patients with established severe liver disease are also contra-indicated for IFNbased therapy, as there is a risk of decompensation and liver failure with the use of IFN [47] .…”