Thrombocytopenia, encountered frequently among patients with HCV-related chronic hepatitis and cirrhosis, is usually aggravated during IFN-based antiviral therapy. In several large-scale clinical trials, the incidence of severe on-treatment thrombocytopenia was 3-5% among all patients with chronic hepatitis C [2–4]. In the current study, severe thrombocytopenia occurred more frequently (12.8%) in patients with baseline thrombocytopenia. Roomer et al. (2010) documented that patients with baseline thrombocytopenia were vulnerable to severe thrombocytopenia . This group also found that severe thrombocytopenia was significantly associated with bleeding events. In the present study, severe thrombocytopenia did occur in some patients during antiviral therapy, but it was not followed by mortality or major morbidity. Instead, severe thrombocytopenia was associated with higher rates of premature discontinuation of therapy.
Thrombocytopenia is one of the extrahepatic manifestations of HCV infection. Several mechanisms have been proposed to account for thrombocytopenia in patients with CHC [12–15]. Hypersplenism in the cirrhosis stage, autoantibodies or immune complexes directed against platelets, direct infection of platelets and megakaryocytes by HCV, decreased level or activity of thrombopoietin (TPO), and virus-induced bone marrow suppression or direct platelet suppression are linked to the low platelet counts in HCV-infected patients before antiviral therapy [12–27]. In the present study, 22% of patients with baseline thrombocytopenia had splenomegaly. In these patients, hypersplenism might account for thrombocytopenia; however, the other 78% of patients with baseline thrombocytopenia did not have splenomegaly; other causes such as decreased level or activity of TPO, autoimmune reaction to platelets, and direct infection of platelets and megakaryocytes by HCV might contribute to the thrombocytopenia.
The proposed mechanisms of treatment-related thrombocytopenia include inhibition of proliferation of megakaryocytes from IFN-α ; and, less commonly, autoimmune reactions  and impaired TPO production . Direct repression of megakaryopoiesis by IFN-α by inhibiting TPO-induced signaling was demonstrated in one in vitro study . In contrast, ribavirin also plays a role in thrombocytopenia because ribavirin is associated with reactive thrombocytosis . Determinants of severity of thrombocytopenia during antiviral therapy may be numerous, and the interaction between these factors may be complicated. Detection of some factors, such as TPO and anti-platelet antibodies, is rarely conducted clinically, and is not practical. Hence, the authors of the current study hypothesized that early platelet dynamics, which could represent the summation of a variety of factors, was a relevant factor. Among the limited reports, the search for predisposing factors for severe thrombocytopenia during antiviral therapy disclosed discrepancies between these studies. For example, Roomer et al. (2010) found baseline thrombocytopenia and cirrhosis , whereas Nachnani et al. (2010) reported that lower white blood cell counts, higher alkaline phosphatase, and higher iron level, were associated with severe thrombocytopenia during antiviral therapy . The present study was aimed at finding factors associated with severe thrombocytopenia in patients with baseline thrombocytopenia, and observed that baseline platelet counts < 100,000/μL and rapid early platelet decline (> 30% decline of platelets 2 weeks after initiation of therapy) were strong factors for predicting the development of severe thrombocytopenia during antiviral therapy. Lower baseline platelet counts, which reportedly correlate with decreased liver function and lower TPO level , account for lower on-treatment platelet counts. Alternatively, rapid early platelet decline may represent higher repression of megakaryopoiesis, or increased platelet consumption. Further studies assessing megakaryocytes, autoimmune anti-platelet antibodies, and virological response during combination therapy are warranted to elucidate factors associated with rapid early platelet decline, and consequent development of severe thrombocytopenia.
The other factor, cirrhosis, reported by Roomer et al. (2010) as a significant factor in severe thrombocytopenia during antiviral therapy in the general population with chronic hepatitis C, was not relevant in the current study. Although low pretreatment platelet count and albumin level, suggestive of cirrhosis status, were significant on univariate analysis, the significance of cirrhosis in prediction of on-treatment severe thrombocytopenia may be restricted by small sample size. In addition, the majority of patients without cirrhosis in the present study were classified as having advanced hepatic fibrosis (F3). It is reasonable to postulate that the increased susceptibility to thrombocytopenia in these patients may also decrease the difference in the rate of severe thrombocytopenia in patients with cirrhosis compared with the rate in those without cirrhosis.
In patients with pretreatment thrombocytopenia, it is possible to select a group at low risk for severe on-treatment thrombocytopenia by means of baseline platelet count before antiviral therapy. For pretreatment platelet count ≥ 100,000/μL, the NPV for severe on-treatment thrombocytopenia was 95.1%, i.e., the on-treatment incidence of severe thrombocytopenia in the patients with baseline platelet count ≥ 100,000/μL was only 4.9%, which is comparable to that of the general population with chronic hepatitis C during antiviral therapy (which was reportedly 3-5%). In high-risk patients, it is still possible to identify those with a relatively low-risk (8.3%) of severe thrombocytopenia by lack of rapid early platelet decline (11 among 12 (91.7%) patients with baseline moderate thrombocytopenia and platelet decline ≤ 30%).
In contrast, patients with platelet count < 100,000/μL before treatment and a rapid early platelet decline during antiviral therapy were at very high risk (100%) for severe thrombocytopenia (positive predictive value was 100%). For this group of patients, modification of antiviral therapy, close monitoring, and salvage therapy for thrombocytopenia were needed. A TPO-mimetic agent may be beneficial in these high-risk patients. An emerging TPO-mimetic agent, eltrombopag, reportedly increases the proportion of baseline-thrombocytopenic, HCV-infected patients completing the initial 12 weeks of antiviral therapy, from 36% to 65% (compared with 6% in the control group) in a phase II study . Eltrombopag is not yet licensed for treatment of thrombocytopenia in patients with chronic liver disease because the risk of portal venous thrombosis (PVT) increased substantially when this drug was administered at 75 mg daily for 14 days . Subsequent PVT had never been reported in patients undergoing combination therapy with peg-IFN-α and ribavirin, except in those having undergone splenectomy or partial splenic embolization prior to treatment [34, 35]. Hence, eltrombopag was believed to be responsible for PVT, and such conditions were different from those assessed in the current study. Nevertheless, cautious use of this drug at a low dose was recommended in concert with close monitoring of patients . Still under investigation is the use of other TPO-mimetic agents, including romiplostim (which has been approved for treatment of immunological thrombocytopenic purpura) in patients with chronic liver disease and thrombocytopenia,.
The study presented here has several limitations. First, the choice between peg-IFN-α-2a and peg-IFN-α-2b was not randomized; however, this study demonstrated that the choice of peg-IFN-α-2a or peg-IFN-α-2b was not an independent factor related to severe thrombocytopenia. A meta-analysis study conducted by Alavian SM et al. also failed to find significantly different rates of thrombocytopenia (platelet count < 50,000/μL) between both types of peg-IFN-α (odds ratio 1.37, 95% CI 0.73-2.58) . Second, the number of patients with baseline thrombocytopenia was relatively small; therefore, factors not demonstrated to be significant in this study may become significant in larger studies. Third, due to the retrospective nature of our study, further prospective investigations are needed.