Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration.

Autor:	Byrnes JR; Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Lee T; Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Sharaby S; Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Campbell RA; Molecular Medicine Program, Department of Internal Medicine, The University of Utah, Salt Lake City, UT., Dobson DA; Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Holle LA; Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Luo M; Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Kangro K; Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Homeister JW; Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Aleman MM; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Luyendyk JP; Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI., Kerlin BA; Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio.; Division of Pediatric Hematology/Oncology/Blood & Marrow Transplantation, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio., Dumond JB; Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC., Wolberg AS; Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Feb 01; Vol. 143 (5), pp. 444-455.
DOI:	10.1182/blood.2023022042
Abstrakt:	Abstract: Transglutaminase factor XIII (FXIII) is essential for hemostasis, wound healing, and pregnancy maintenance. Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively. The subunits associate tightly in circulation as FXIII-A2B2. FXIII-B2 stabilizes the (pro)active site-containing FXIII-A subunits. Interestingly, people with genetic FXIII-A deficiency have decreased FXIII-B2, and therapeutic infusion of recombinant FXIII-A2 (rFXIII-A2) increases FXIII-B2, suggesting FXIII-A regulates FXIII-B secretion, production, and/or clearance. We analyzed humans and mice with genetic FXIII-A deficiency and developed a mouse model of rFXIII-A2 infusion to define mechanisms mediating plasma FXIII-B levels. Like humans with FXIII-A deficiency, mice with genetic FXIII-A deficiency had reduced circulating FXIII-B2, and infusion of FXIII-A2 increased FXIII-B2. FXIII-A-deficient mice had normal hepatic function and did not store FXIII-B in liver, indicating FXIII-A does not mediate FXIII-B secretion. Transcriptional analysis and polysome profiling indicated similar F13b levels and ribosome occupancy in FXIII-A-sufficient and -deficient mice and in FXIII-A-deficient mice infused with rFXIII-A2, indicating FXIII-A does not induce de novo FXIII-B synthesis. Unexpectedly, pharmacokinetic/pharmacodynamic modeling of FXIII-B antigen after rFXIII-A2 infusion in humans and mice suggested FXIII-A2 slows FXIII-B2 loss from plasma. Accordingly, comparison of free FXIII-B2 vs FXIII-A2-complexed FXIII-B2 (FXIII-A2B2) infused into mice revealed faster clearance of free FXIII-B2. These data show FXIII-A2 prevents FXIII-B2 loss from circulation and establish the mechanism underlying FXIII-B2 behavior in FXIII-A deficiency and during rFXIII-A2 therapy. Our findings reveal a unique, reciprocal relationship between independently synthesized subunits that mediate an essential hemostatic protein in circulation. This trial was registered at www.ClinicalTrials.com as #NCT00978380. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu