{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSERPINC1 encodes antithrombin—a member of the serpin family that plays a central role in the regulation of hemostasis. The mature protein functions as a potent inhibitor of key coagulation proteases by undergoing a dramatic conformational activation upon binding to glycosaminoglycans such as heparin. Structural studies have detailed how specific amino acid residues and hydrophobic interactions govern its high‐affinity binding to the heparin pentasaccharide, triggering the reactive center loop to reposition for optimal protease inhibition. Moreover, biochemical analyses have revealed that subtle structural alterations, including those leading to conformational polymerization, are critical determinants of its function and stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nExtensive genetic investigations have demonstrated that diverse mutations in SERPINC1 underlie both quantitative (type I) and qualitative (type II) antithrombin deficiencies, which predispose to venous and, in some instances, arterial thrombotic events. In many patient cohorts, point mutations, small insertions/deletions, splice‐site changes and large genomic rearrangements have been characterized, revealing significant genotype–phenotype correlations. Certain variants—such as those affecting the heparin‐binding site—lead to aberrant conformational changes, increased polymerization, or altered secretion, thereby impairing the anticoagulant capacity of circulating antithrombin. These molecular defects correlate with variable clinical manifestations, ranging from early‐onset thrombotic episodes in children to subtler functional anomalies detectable only through comprehensive genetic screening."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "34"}, {"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in coagulation, antithrombin exhibits important anti‐inflammatory properties and modulates vascular as well as organ‐protective functions. Its actions extend to counteracting endotoxin‐induced hypotension, reducing ischemia/reperfusion injury in the liver and kidneys, and even contributing to the regulation of angiogenesis in cancer. These diverse clinical implications underscore why even subtle variations in SERPINC1 expression or structure may have significant pathophysiological outcomes. Understanding these multifaceted roles not only aids in risk stratification for thrombotic disorders but also opens avenues for therapeutic intervention across a spectrum of diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masayuki Yamasaki, Wei Li, Daniel J D Johnson, et al. 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