Preoperative systemic immunothrombotic state class is associated with microvascular invasion and early recurrence after curative resection for hepatocellular carcinoma

Background Microvascular invasion (MVI) and early recurrence limit durable benefit after curative resection for hepatocellular carcinoma (HCC). We assessed whether an outcome-blinded preoperative systemic immunothrombotic state was associated with pathological MVI and 24-month recurrence and examined NET-associated circulating and tissue markers. Methods This observational cohort included 520 patients undergoing curative-intent HCC resection. Three systemic immunothrombotic state classes were derived without outcome information from six preoperative immune-coagulation components; a continuous principal-component burden score was examined supportively. MVI was evaluated using multivariable logistic regression with 30-fold multiple imputation. Twenty-four-month recurrence was analyzed using Fine-Gray competing-risk models, treating death without recurrence as a competing event. Circulating H3Cit and MPO-DNA were measured in 302 patients with valid paired assays. A balanced nested tissue subset of 72 patients selected by state class and MVI status underwent quantitative H3Cit/MPO and CD8 spatial assessment. Results High versus low state class was associated with MVI (OR 2.51, 95% CI 1.42–4.43; P = 0.002) and 24-month recurrence (sHR 1.87, 95% CI 1.28–2.74; P = 0.001), whereas the intermediate class was not significantly associated with either outcome. The continuous burden score showed supportive associations with both outcomes. Circulating H3Cit and MPO-DNA increased across state classes, but neither was independently associated with MVI after multivariable adjustment. In the tissue subset, high state class was associated with greater peritumoral and intratumoral H3Cit/MPO-positive density. Circulating H3Cit remained associated with peritumoral H3Cit/MPO density after adjustment for state class, MVI, and age, whereas corresponding MPO-DNA and intratumoral associations were weaker. CD8 spatial exclusion did not differ significantly by state class. Conclusion A high preoperative systemic immunothrombotic state was associated with pathological MVI and 24-month recurrence after HCC resection. The clearest blood-tissue concordance involved circulating H3Cit and peritumoral H3Cit/MPO density. The state class added only modest internal discrimination, supporting external validation before clinical application and further mechanistic work to define the role of NET-associated activity.