Semuloparin sodium

Clinically approved thrombolytic agents carry significant bleeding risks due to systemic plasminogen activation. Heparin analogs prevent thrombus formation but lack direct thrombolytic activity. Here, we report a previously unrecognized thrombolytic mechanism of octaparin, a synthetic heparin analog. Studies demonstrated that octaparin exhibits potent anticoagulant and thrombolytic activity both in vitro and in vivo, with a lower bleeding risk compared to conventional heparin-based agents. Octaparin directly binds fibrin monomers, altering their secondary conformation to inhibit polymerization and destabilize preformed thrombi, while preserving tissue factor-driven coagulation. In murine models of pulmonary embolism and inferior vena cava thrombosis, octaparin both prevented and dose-dependently dissolved established clots without compromising hemostatic integrity, sharply contrasting with conventional thrombolytics that induce hemorrhage. Further analyses using molecular docking, microscale thermophoresis, and spectroscopy confirmed that octaparin induces changes in fibrin monomer folding that compromise fibrin network stability. In human systems, octaparin selectively prolonged intrinsic coagulation time, reduced clot retraction, did not induce platelet activation, and its effects were reversible with protamine sulfate. This study establishes targeted fibrin destabilization as a viable therapeutic strategy, revealing a previously unrecognized thrombolytic mechanism achievable through heparin-based molecular design.

Sepsis, characterized by dysregulated immune responses and mitochondrial dysfunction, currently has few effective therapies that directly target these cellular mechanisms, and conventional heparin and related analogues provide inadequate immunomodulatory benefits. Here, we investigated the synthetic heparin analogue octaparin, which exhibits enhanced anticoagulant safety, for its potential to mitigate sepsis by targeting mitochondrial and redox pathways. Using murine models of lipopolysaccharide (LPS)-induced endotoxemia and Salmonella typhimurium-induced sepsis, along with in vitro studies performed using murine bone marrow-derived macrophages (BMDMs) and the human acute monocytic leukemia THP-1 cell line, we demonstrate that octaparin significantly improves survival and attenuates multi-organ (lung, liver, kidney) damage. Octaparin outperformed heparin, enoxaparin, and fondaparinux in suppressing systemic inflammation including TNF-α, IL-6, IL-1β and bacterial burden. Transcriptomic analysis revealed octaparin reprograms macrophage immunometabolism, suppressing pro-inflammatory pathways while enhancing phagocytosis. Crucially, octaparin inhibited both canonical and non-canonical inflammasome activation, reduced generation of the pyroptotic executor GSDMD-N-terminal fragment (GSDMD-NT), and specifically diminished mitochondrial localization of GSDMD-NT by downregulating key cardiolipin synthesis and transport genes. Furthermore, octaparin uniquely reversed LPS-induced mitochondrial dysfunction. This restoration was accompanied by improvements in mitochondrial quality and the reestablishment of redox homeostasis. Collectively, octaparin confers multifaceted protection in sepsis, positioning it as a promising redox-targeted therapeutic for sepsis.