Noting that the 75 amino acid N-terminal acidic extension of heparin cofactor II (HCII), a thrombin-specific inhibitory serpin, had no counterpart in API [1], we fused HCII 1-75 to API M358R, and demonstrated a > 5-fold increase in the rate of thrombin inhibition [24,28], and a superior ability to limit thrombus size in murine arterial and venous thrombosis models, relative to API M358R [29]. The gene discussed is SERPIND1; the disease is Venous thrombosis.