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Lancet. 2015 Feb 26;385 Suppl 1:S39. doi: 10.1016/S0140-6736(15)60354-3.

Use of a novel floxed mouse to characterise the cellular source of plasma coagulation FXIII-A.

Author information

1
Leeds Institute of Cardiovascular & Metabolic Medicine, University of Leeds, Leeds, UK. Electronic address: Kgriffin@doctors.org.uk.
2
Leeds Institute of Cardiovascular & Metabolic Medicine, University of Leeds, Leeds, UK.
3
Division of Experimental Medicine, University of Montreal, Montreal, QC, Canada.
4
Department of Haematology, University of Cambridge, Cambridge, UK.
5
Division of Cancer and Haematology, Walter and Eliza Hall Institute, Melbourne, VIC, Australia.

Abstract

BACKGROUND:

Coagulation factor XIII-A has a crucial role in thrombus stabilisation and tissue repair. Factor XIII-A deficiency causes a severe bleeding phenotype and impaired wound healing, but the cellular origin of Factor XIII-A is unknown. To identify the cells that maintain the plasma pool, we generated a mouse floxed in coding exon7 of the factor XIII-A gene (F13A1). These mice were crossed with mice transgenic for Pf4-Cre-recombinase (thrombopoietic deletion) or Cd11b-Cre-recombinase (myeloid deletion). The resultant mice were compared with a Mpl-/- (thrombopoietin receptor knockout) thrombocytopenic murine model.

METHODS:

Factor XIII-A recombination was evaluated by quantitative PCR assay of genomic DNA from liver and spleen. Factor XIII-A enzyme activity was measured in plasma and platelets with a biotin incorporation assay. quantitative PCR was performed to determine factor XIII-A mRNA levels in aortic and cardiac tissue. Factor XIII-A transcripts were assayed in human umbilical blood haemopoietic cell lineages.

FINDINGS:

Selectivity of Pf4-Cre and Cd11b-Cre mediated deletion was confirmed in liver and spleen. A 40% decrease in factor XIII-A plasma activity was observed in Cd11b mice, whereas plasma activity was decreased by 85% and absent in platelets from Pf4 mice. By contrast, plasma factor XIII-A was normal in Mpl mice. Cd11b mice showed no reduction in factor XIII-A mRNA in cardiac tissue and a 54·6% reduction in aorta. A major decrease in factor XIII-A mRNA was observed in the aorta (91·6%) and heart (99·2%) of Pf4 mice, but there was no change in expression in either tissue from Mpl mice. In a human stem-cell study, factor XIII-A mRNA transcription increased as common myeloid progenitors committed to become granulocyte-macrophage progenitors and as megakaryocyte-erythroid progenitors differentiated to both megakaryocytes and erythroblasts.

INTERPRETATION:

These results raise the possibility that a unique Pf4-dependent, Mpl-independent progenitor cell is the major source of the plasma pool. These findings might have implications for the management of factor XIII-A deficiency states.

FUNDING:

British Heart Foundation.

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