Background
Hepatitis C virus (HCV) infection is estimated to affect 170 million people worldwide, with about one-fourth of these patients developing liver cirrhosis through chronic infection [
1]. Thrombocytopenia, which is frequently observed in HCV-infected patients [
2,
3], is thought to be caused by complex mechanisms, which can include increased destruction of platelets and their decreased production in bone marrow [
4]. Platelet destruction is increased by hypersplenism, which is caused by HCV infection-associated portal hypertension and autoimmunity [
4]. Hypersplenism is regarded as the main factor contributing to thrombocytopenia, the frequency of which increases as liver fibrosis progresses or cirrhosis develops [
2,
5]. In addition, thrombocytopenia is associated with an increased risk of bleeding occurring during invasive procedures [
3].
HCV eradication with interferon (IFN) or direct-acting antivirals (DAA) has been shown to improve liver fibrosis and extrahepatic manifestations of HCV infection [
6,
7]. IFN eradication of HCV was found to increase platelet counts, which persisted for several years after HCV eradication [
8]. DAA eradication of HCV was also found to improve thrombocytopenia, beginning 4 weeks after DAA initiation [
9,
10]. IFN itself, however, can induce thrombocytopenia and have various immune-modulatory effects [
11], suggesting that the difference in effects of IFN and DAA on thrombocytopenia improvement may be caused by the pharmacological effects of IFN. DAA treatment can reduce HCV-RNA viral loads immediately and eradicate infection, generally within 4 weeks, with little effect on bone marrow and host immunity [
12,
13]. Thus the effects of DAA on thrombocytopenia may directly reflect the pathogenesis of HCV-induced thrombocytopenia.
Although the short-term, 12-week effects of DAA treatment on thrombocytopenia following HCV eradication have been assessed [
9,
10,
14], the long term effects of DAA treatment on thrombocytopenia and its association with hypersplenism remain uncertain. The present study evaluated changes in platelet and leukocyte counts and spleen size in DAA-treated, cirrhotic HCV-infected patients for 5 years.
Discussion
The present study showed that DAA treatment of patients rapidly improved leukocytopenia and thrombocytopenia, with a 20% increase within 4 weeks, in patients with HCV-associated cirrhosis, followed by a gradual reduction in splenomegaly. The rapid increase in platelet count was followed by gradual yearly increases, with platelet counts being nearly 40% higher 5 years after DAA treatment than at baseline. DAA treatment resulted in yearly improvements in liver fibrosis, accompanied by improvements in thrombocytopenia and hypersplenism. Platelet transfusions have limited effects in patients with HCV cirrhosis and thrombocytopenia, with platelet counts increasing only 20% after transfusion [
19]. Cirrhotic patients with thrombocytopenia have been treated with thrombopoietin (TPO) receptor agonists such as lusutrombopag a few weeks before invasive procedures [
19,
20], markedly reducing the need for platelet transfusion. Although several weeks are required for DAA to increase platelet counts, the effects of HCV eradication by DAA are comparable to those of platelet transfusion.
DAA treatment has been shown to rapidly improve thrombocytopenia, with effects observed within 4 weeks [
9,
10]. TPO concentration before DAA treatment was found to be associated with increased platelet counts after DAA treatment [
14]. However, DAA treatment did not alter TPO concentrations within 48 weeks [
10], suggesting that TPO is not a main contributor to thrombocytopenia in patients with HCV cirrhosis. The present study also showed that DAA treatment improved leukocytopenia within 4 weeks, with white blood cell counts maintained for 5 years. These findings suggest that leukocytopenia in HCV-cirrhosis is mostly caused by HCV-induced myelosuppression. HCV-RNA has been detected in bone marrow of patients with chronic HCV infection, with viral RNA inducing bone marrow suppression [
21,
22]. The rapid increase in hematological parameters after DAA treatment may therefore be caused by a reduction in HCV-induced myelosuppression. Further studies are needed to determine the precise mechanism by which DAA treatment suppresses leukocytopenia.
The present study also found that DAA-associated HCV eradication improved splenomegaly. Thrombocytopenia in HCV-infected patients is thought to be due to portal hypertension-induced splenomegaly, resulting in the splenic pooling of platelets [
23]. Spleen size and thrombocytopenia are thought to be associated, and meta-analyses have shown that splenectomy in addition to hepatectomy or liver transplantation improved thrombocytopenia and/or leukocytopenia compared with hepatectomy or liver transplantation alone [
24,
25]. Reduced portal hypertension following trans-jugular intrahepatic portosystemic shunt was also found to improve thrombocytopenia [
26,
27]. Liver transplantation has been reported to normalize platelet and leukocyte counts, reduce splenomegaly and improve portal hypertension [
28,
29]. Collectively, HCV-induced liver inflammation and fibrosis contribute to portal hypertension and splenomegaly, with splenomegaly also contributing to thrombocytopenia and leukocytopenia. Therefore HCV eradication with DAA could improve this sequence of events.
DAA treatment was also shown to result in rapid and significant improvements in liver elasticity [
30‐
32], suggesting that liver elasticity, as determined by liver elastography, was largely affected by liver inflammation. Liver elasticity is dependent on the elastography method, with acoustic radiation force impulse (ARFI) regarded as a better determinant of liver fibrosis than transient elastography [
33]. DAA eradication of HCV has been shown to improve liver elasticity within 12 weeks, as determined by transient elastography. ARFI, however, showed improvements in liver elasticity, and maintenance of spleen elasticity, for 3 years after DAA [
34]. Although few studies to date have evaluated changes in spleen size after DAA, a case study showed that spleen size was reduced 2 years after DAA eradication of HCV [
35], a finding consistent with the present results. Collectively, these findings show that splenomegaly may be improved by clearance of hepatic inflammation within 2 years after DAA treatment, with further improvements resulting from a decrease in hepatic fibrosis.
The present study had several limitations. First, the number of patients included in the study was limited and varied, and the retrospective design may have led to selection bias and some errors in the measurement of SI. Liver fibrosis progression by liver biopsy or elastography could be assessed only in some of these patients, with cirrhosis diagnosed by individual physicians, not centrally. Second, splenomegaly in these patients was assessed by measuring SI with area. Spleen volume or spleen elasticity may better reflect hypersplenism, as these measures are more objective and functional than SI. Third, serum TPO concentration and HCV-RNA titers in bone marrow could not be evaluated in the present study, making it difficult to determine whether thrombocytopenia was due to myelosuppression or platelet destruction. Fourth, studies have shown that treatment of patients with advanced liver fibrosis and/or severe portal hypertension does not result in full recovery of liver function or complete abrogation of portal hypertension [
36‐
38]. In the present study, liver fibrosis could not be quantified and portal hypertension could not be determined. Future detailed studies are required.
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