Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

Abstract

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-associated HCC involves both viral and host factors. The latter include a functionally inefficient CD8 + T-cell response that fails to clear the infection from the liver but sustains a chronic necroinflammatory process that contributes to the development of HCC. According to this scenario, amelioration of immune-mediated chronic liver injury may prevent HCC. Because platelets facilitate immune-mediated liver injury by promoting the hepatic accumulation of virus-specific CD8 + T cells, we evaluated the long-term consequences of antiplatelet therapy in an HBV transgenic mouse model of chronic immune-mediated necroinflammatory liver disease that progresses to HCC. Treatment with aspirin and clopidogrel during the chronic phase of the disease diminished the number of intrahepatic HBV-specific CD8 + T cells and HBV-nonspecific inflammatory cells, the severity of liver fibrosis, and the development of HCC. Antiplatelet therapy improved overall survival without causing significant side effects. In contrast, the same antiplatelet regimen had no antitumor effect when HCC was induced nonimmunologically by chronic exposure to a hepatotoxic chemical. The unprecedented observation that antiplatelet therapy inhibits or delays immune-mediated hepatocarcinogenesis suggests that platelets may be key players in the pathogenesis of HBV-associated liver cancer and supports the notion that immune-mediated necroinflammatory reactions are an important cause of hepatocellular transformation during chronic hepatitis.

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

“…The spectrum of feasible therapies include cyclooxygenase inhibitors, proteaseactivated receptor inhibitors, and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors. (6,12,(34)(35)(36) HCC patients with mild thrombocytopenia are likely better candidates until more scientific data on the safety of those therapies accumulate because such patients can have less bleeding diathesis and greater metastasis risk. In addition, the stable late posttransplant phase might provide another time window for targeting the latent metastasis with less concern about bleeding complications or graft regeneration.…”

“…Preoperative PLT was negatively associated with the amount of transfused platelets during surgery (coefficient -0.49; P < 0.001), during the first week after surgery (coefficient -0.55; P < 0.001), and between 1 and 2 weeks after surgery (coefficient -0.21; P < 0.001). Accordingly, the amount of transfused platelets during surgery, during the first week after surgery, and between 1 and 2 weeks after surgery was 0 (0-6), 9 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and 0 (0-0) units in the low platelet group and 0 (0-0), 0 (0-4), and 0 (0-0) units in the high platelet group, respectively, where 1 unit of apheresis platelets was considered to be equivalent to 6 units of platelets, as described previously. (22) Minimum PLT measured at each postoperative day during the first 2 weeks after transplantation was consistently <30 3 10 9 /L in median within the subgroup of recipients who underwent platelet transfusion on each corresponding day, indicating that platelet transfusion was performed according to our standardized protocol targeting PLT >30 3 10 9 /L (Supporting Fig.…”

“…(6,7,10,11) A previous study in hepatitis B virus (HBV) transgenic mice clearly demonstrated that antiplatelet treatment reduced intrahepatic inflammatory response and HCC development with improved longterm survival. (12) Thus, we hypothesized that the risk of HCC recurrence after living donor liver transplantation is affected by platelets. In this study, we sought to evaluate the relationship between preoperative PLT and posttransplant HCC recurrence using a robust matching method.…”

Measuring and interpreting platelet-leukocyte aggregates

“…Platelets are further involved in both acute and chronic viral hepatitis as shown by attenuated accumulation of CD8 + T cells and virus-nonspecific inflammatory cells into the liver upon anti-platelet therapy (using aspirin and clopidogrel) (101,102). Similarly, platelet inhibition in clinically relevant sterile liver inflammation, such as ischemia/reperfusion injury (as observed following transplantation) reduces liver damage via blocking platelet- and P-selectin-dependent CD4 + , but not CD8 + T cell recruitment to post-ischemic sinusoids (58).…”

Therapeutic potential of phages in autoimmune liver diseases

“…Anti‐platelet therapy prevents the development of hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B 51. It is also known that fibrinogen deposits are observed in liver injury which form a matrix attracting and inducing proliferation of inflammatory cells 52.…”