Hypercoagulability in Pulmonary Tuberculosis: Reduced Protein C and Free Protein S Predict Pulmonary Embolism—Evidence from a Prospective Romanian Cohort

<b>Background/Objectives:</b> Pulmonary tuberculosis (TB) is accompanied by inflammation-driven hypercoagulability and increased venous thromboembolism risk. We investigated whether the natural anticoagulants protein C and free protein S are reduced in active TB and whether baseline levels are associated with bacillary burden, treatment response, CT evolution, and pulmonary embolism (PE). <b>Methods</b>: We conducted a prospective cohort study in Romania, including 63 adults with newly diagnosed, bacteriologically confirmed, drug-susceptible pulmonary TB and 30 TB-free controls (October 2024-December 2025). Venous blood was collected at baseline (before anti-TB therapy) and at 6 months to quantify inflammatory and coagulation parameters, protein C, and free protein S. Sputum AFB smear was assessed at baseline, 2 months, and 6 months; chest CT was performed at baseline and 6 months. Propensity score matching (age, sex, BMI, smoking) and multivariable regression were used to account for confounding. Logistic regression and ROC analyses evaluated the prediction of BK persistence. <b>Results</b>: Compared with controls, TB patients had substantially lower baseline protein C and free protein S levels, and higher D-dimer levels (all <i>p</i> < 0.001). In matched multivariable models, TB status remained independently associated with lower baseline natural anticoagulant levels. Lower baseline protein C and free protein S clustered with higher inflammatory markers and higher bacillary burden, and independently predicted BK persistence at 2 and 6 months (OR per 1%-point increase ~0.93-0.95 for protein C and ~0.92-0.94 for free protein S; all <i>p</i> < 0.001). Discrimination for BK persistence was high (AUCs ~0.88-0.89). Lower baseline levels of natural anticoagulants were also associated with greater residual CT abnormalities at 6 months. PE cases had significantly lower protein C and free protein S than PE-free patients. <b>Conclusions:</b> Active pulmonary TB is associated with marked depletion of protein C and free protein S. Baseline reductions identify patients with higher inflammatory/coagulation activation, higher bacillary burden, delayed microbiological clearance, more residual CT disease, and PE, supporting their potential role as adjunct risk-stratification biomarkers.