ArticleJournal of thrombosis and haemostasis : JTH2025
Protease domain exosites regulate extravascular binding of factor IX(a).
Article in Journal of thrombosis and haemostasis : JTH, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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Who cites it
3 citing papers in PubMed.
- Extravascular factor IX: a semicentennial narrative review.Research and practice in thrombosis and haemostasis · 2026Review
- Extravascular distribution of factor IX-review of experimental and clinical evidence, and relevance for hemophilia B replacement therapy.Research and practice in thrombosis and haemostasis · 2026Review
- Nine areas with outstanding challenges for hemophilia B research.Therapeutic advances in hematology · 2026Review
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Authors and funding
7 authors.
Funding
Abstract
backgroundFactor (F)IX is unique among the vitamin K-dependent coagulation factors in that a substantial portion is bound to extravascular sites.
objectivesDetermine the impact of exosites in the human FIX protease domain on clearance, tissue distribution, and activity in hemophilic mice.
methodsHuman FIX(a) variants with protease domain substitutions in the antithrombin (R150A), heparin (K126A/K132A), and FIX-Padua (R170A) exosites were evaluated in hemophilia B (zymogen) and A (protease) mice. Pharmacokinetic modeling of FIX(a) clearance, select tissue content, and in vivo activity were determined.
resultsFIX wild-type (WT) demonstrated poor plasma recovery, biphasic clearance, and heterogeneous tissue binding. FIX WT was predominantly found in liver, followed by plasma, kidney, heart, and brain. Equimolar FIX variants were similar except for FIX K126A/K132A, which demonstrated 2.3-fold higher plasma recovery and reduced liver content. FIXa WT was cleared more rapidly than zymogen, but also had poor recovery, biphasic clearance, and heterogeneous tissue binding. FIXa-Glu-Gly-Arg-chloromethyl ketone accelerated clearance from all compartments in the distribution phase but prolonged the terminal phase relative to FIXa. FIXa K126A/K132A, R150A, and R170A demonstrated 2- to 3-fold higher plasma recovery than WT, with reduced liver content for FIXa K126A/K132A. Despite reduced coagulant activity, FIX K126A/K132A and R150A demonstrated intact or enhanced potency relative to FIX WT in the saphenous vein bleeding and FeCl
conclusionProtease exosites regulate in vivo clearance, distribution, and FIX(a) activity. Human FIX(a) demonstrates extensive tissue-specific binding to extravascular sites.
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