Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration
© 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..
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.
Errataetall: |
CommentIn: Blood. 2024 Feb 1;143(5):385-387. - PMID 38300613 |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:143 |
---|---|
Enthalten in: |
Blood - 143(2024), 5 vom: 01. Feb., Seite 444-455 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Byrnes, James R [VerfasserIn] |
---|
Links: |
---|
Themen: |
9013-56-3 |
---|
Anmerkungen: |
Date Completed 06.02.2024 Date Revised 24.03.2024 published: Print ClinicalTrials.gov: NCT00978380 CommentIn: Blood. 2024 Feb 1;143(5):385-387. - PMID 38300613 Citation Status MEDLINE |
---|
doi: |
10.1182/blood.2023022042 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM363758933 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM363758933 | ||
003 | DE-627 | ||
005 | 20240324234834.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1182/blood.2023022042 |2 doi | |
028 | 5 | 2 | |a pubmed24n1344.xml |
035 | |a (DE-627)NLM363758933 | ||
035 | |a (NLM)37883802 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Byrnes, James R |e verfasserin |4 aut | |
245 | 1 | 0 | |a Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 06.02.2024 | ||
500 | |a Date Revised 24.03.2024 | ||
500 | |a published: Print | ||
500 | |a ClinicalTrials.gov: NCT00978380 | ||
500 | |a CommentIn: Blood. 2024 Feb 1;143(5):385-387. - PMID 38300613 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 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. | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 7 | |a Factor XIII |2 NLM | |
650 | 7 | |a 9013-56-3 |2 NLM | |
650 | 7 | |a Factor XIIIa |2 NLM | |
650 | 7 | |a EC 2.3.2.13 |2 NLM | |
650 | 7 | |a Hemostatics |2 NLM | |
700 | 1 | |a Lee, Taek |e verfasserin |4 aut | |
700 | 1 | |a Sharaby, Sherif |e verfasserin |4 aut | |
700 | 1 | |a Campbell, Robert A |e verfasserin |4 aut | |
700 | 1 | |a Dobson, Dre'Von A |e verfasserin |4 aut | |
700 | 1 | |a Holle, Lori A |e verfasserin |4 aut | |
700 | 1 | |a Luo, Michelle |e verfasserin |4 aut | |
700 | 1 | |a Kangro, Kadri |e verfasserin |4 aut | |
700 | 1 | |a Homeister, Jonathon W |e verfasserin |4 aut | |
700 | 1 | |a Aleman, Maria M |e verfasserin |4 aut | |
700 | 1 | |a Luyendyk, James P |e verfasserin |4 aut | |
700 | 1 | |a Kerlin, Bryce A |e verfasserin |4 aut | |
700 | 1 | |a Dumond, Julie B |e verfasserin |4 aut | |
700 | 1 | |a Wolberg, Alisa S |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Blood |d 1946 |g 143(2024), 5 vom: 01. Feb., Seite 444-455 |w (DE-627)NLM000014761 |x 1528-0020 |7 nnns |
773 | 1 | 8 | |g volume:143 |g year:2024 |g number:5 |g day:01 |g month:02 |g pages:444-455 |
856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood.2023022042 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 143 |j 2024 |e 5 |b 01 |c 02 |h 444-455 |