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Factor XIII activity mediates red blood cell retention in venous thrombi.

ABSTRACT: Venous thrombi, fibrin- and rbc-rich clots triggered by inflammation and blood stasis, underlie devastating, and sometimes fatal, occlusive events. During intravascular fibrin deposition, rbc are thought to become passively trapped in thrombi and therefore have not been considered a modifiable thrombus component. In the present study, we determined that activity of the transglutaminase factor XIII (FXIII) is critical for rbc retention within clots and directly affects thrombus size. Compared with WT mice, mice carrying a homozygous mutation in the fibrinogen ? chain (Fib?390-396A) had a striking 50% reduction in thrombus weight due to reduced rbc content. Fibrinogen from mice harboring the Fib?390-396A mutation exhibited reduced binding to FXIII, and plasma from these mice exhibited delayed FXIII activation and fibrin crosslinking, indicating these residues mediate FXIII binding and activation. FXIII-deficient mice phenocopied mice carrying Fib?390-396A and produced smaller thrombi with fewer rbc than WT mice. Importantly, FXIII-deficient human clots also exhibited reduced rbc retention. The addition of FXIII to FXIII-deficient clots increased rbc retention, while inhibition of FXIII activity in normal blood reduced rbc retention and produced smaller clots. These findings establish the FXIII-fibrinogen axis as a central determinant in venous thrombogenesis and identify FXIII as a potential therapeutic target for limiting venous thrombosis.

SUBMITTER: Aleman MM

PROVIDER: S-EPMC4109540 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Project description:BackgroundPostpartum hemorrhage is a leading cause of maternal morbidity and mortality worldwide. Contradictory information exists regarding the relevance of prepartum platelet count on postpartum hemorrhage. We have shown prepartum coagulation factor XIII to be associated with postpartum blood loss; however, little is known about the association of platelet count with factor XIII activity. Our objectives were, first, to evaluate the impact of prepartum platelet count on measured postpartum blood loss in the context of prepartum measurements of coagulation factors I, II, and XIII and, second, to evaluate the association of platelet count with coagulation factor XIII, both pre- and postpartum.Material and methodsThis is a secondary analysis of a prospective cohort study (PPH 1,300 study) which analyzed the impact of prepartum blood coagulation factors on postpartum blood loss in 1,300 women. Blood loss was quantified using a validated technique. The impact of prepartum platelet count on measured blood loss was assessed by continuous outcome logistic regression; the association of platelet count with factor XIII activity by Spearman rank correlation.ResultsPrepartum platelet count was significantly associated with measured postpartum blood loss: every one unit (G/L) increase in prepartum thrombocytes was associated with an odds ratio of 1.002 (95% confidence interval, 1.001-1.004, p = 0.005) to keep blood loss below any given cut-off level. This means that the probability of postpartum hemorrhage decreases with increasing prepartum platelet levels. Moreover, a significant association of platelet count with factor XIII activity was shown (Spearman rank correlation coefficient for prepartum values 0.228, p < 0.001, and for postpartum values 0.293, p < 0.001).Discussion/conclusionThe significant association of prepartum platelet count and postpartum blood loss as well as the association of platelet count with blood coagulation factor XIII activity support the likely role of platelets in preventing postpartum hemorrhage and support the new guidelines for the treatment of postpartum hemorrhage in Germany, Austria, and Switzerland, which calls for optimizing platelet counts peripartally in case of postpartum hemorrhage. A possible effect of platelets on the level of circulating factor XIII cannot be ruled out and should prompt further investigation.

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Factor XIII activity mediates red blood cell retention in venous thrombi.

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