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Indolic uremic solutes enhance procoagulant activity of red blood cells through phosphatidylserine exposure and microparticle release.

Gao C, Ji S, Dong W, Qi Y, Song W, Cui D, Shi J - Toxins (Basel) (2015)

Bottom Line: However, the effect of uremic solutes indoxyl sulfate (IS) and indole-3-acetic acid (IAA) on procoagulant activity (PCA) of erythrocyte is unclear.Our results suggest that RBC eryptosis in uremic solutes IS and IAA plays an important role in thrombus formation through releasing RMPs and exposing PS.Lactadherin acts as an efficient anticoagulant in this process.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, 39 Xinyang Road, Gaoxin District, Daqing 163319, China. gaochunyan1234@163.com.

ABSTRACT
Increased accumulation of indolic uremic solutes in the blood of uremic patients contributes to the risk of thrombotic events. Red blood cells (RBCs), the most abundant blood cells in circulation, may be a privileged target of these solutes. However, the effect of uremic solutes indoxyl sulfate (IS) and indole-3-acetic acid (IAA) on procoagulant activity (PCA) of erythrocyte is unclear. Here, RBCs from healthy adults were treated with IS and IAA (mean and maximal concentrations reported in uremic patients). Phosphatidylserine (PS) exposure of RBCs and their microparticles (MPs) release were labeled with Alexa Fluor 488-lactadherin and detected by flow cytometer. Cytosolic Ca(2+) ([Ca(2+)]) with Fluo 3/AM was analyzed by flow cytometer. PCA was assessed by clotting time and purified coagulation complex assays. We found that PS exposure, MPs generation, and consequent PCA of RBCs at mean concentrations of IS and IAA enhanced and peaked in maximal uremic concentrations. Moreover, 128 nM lactadherin, a PS inhibitor, inhibited over 90% PCA of RBCs and RMPs. Eryptosis or damage, by indolic uremic solutes was due to, at least partially, the increase of cytosolic [Ca(2+)]. Our results suggest that RBC eryptosis in uremic solutes IS and IAA plays an important role in thrombus formation through releasing RMPs and exposing PS. Lactadherin acts as an efficient anticoagulant in this process.

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Mechanism diagram of indolic solutes-induced PCA of erythrocytes. IS and IAA triggered PS externalized on the outer membrane of RBC and accompanied with RMPs shedding. Externalized PS on RBCs and PS-bearing RMPs provided binding sites for FXa and prothrombinase complexes, increased thrombin production and enhanced thrombus formation. PS, phosphatidylserine; RMPs, RBC derived MPs; IS, Indoxyl sulfate; IAA, indoxyl-3-acetate acid; PCA, procoagulant activity.
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toxins-07-04390-f006: Mechanism diagram of indolic solutes-induced PCA of erythrocytes. IS and IAA triggered PS externalized on the outer membrane of RBC and accompanied with RMPs shedding. Externalized PS on RBCs and PS-bearing RMPs provided binding sites for FXa and prothrombinase complexes, increased thrombin production and enhanced thrombus formation. PS, phosphatidylserine; RMPs, RBC derived MPs; IS, Indoxyl sulfate; IAA, indoxyl-3-acetate acid; PCA, procoagulant activity.

Mentions: In this study, we have found that indolic uremic solutes (IS or IAA) induced a procoagulant phenotype on RBC through increased PS exposure and RMP release. Exposed PS of RBCs and RMPs supports the assembly of intrinsic FXa and prothrombinase, moreover, blockade of PS with lactadherin inhibits activity of procoagulant enzyme complexes and consequently decreases the PCA of RBCs and RMPs (Figure 6). Furthermore, we showed that PS translocation to the RBC surface within indolic uremic solutes is at least partially due to increased cytosolic Ca2+ concentration.


Indolic uremic solutes enhance procoagulant activity of red blood cells through phosphatidylserine exposure and microparticle release.

Gao C, Ji S, Dong W, Qi Y, Song W, Cui D, Shi J - Toxins (Basel) (2015)

Mechanism diagram of indolic solutes-induced PCA of erythrocytes. IS and IAA triggered PS externalized on the outer membrane of RBC and accompanied with RMPs shedding. Externalized PS on RBCs and PS-bearing RMPs provided binding sites for FXa and prothrombinase complexes, increased thrombin production and enhanced thrombus formation. PS, phosphatidylserine; RMPs, RBC derived MPs; IS, Indoxyl sulfate; IAA, indoxyl-3-acetate acid; PCA, procoagulant activity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663509&req=5

toxins-07-04390-f006: Mechanism diagram of indolic solutes-induced PCA of erythrocytes. IS and IAA triggered PS externalized on the outer membrane of RBC and accompanied with RMPs shedding. Externalized PS on RBCs and PS-bearing RMPs provided binding sites for FXa and prothrombinase complexes, increased thrombin production and enhanced thrombus formation. PS, phosphatidylserine; RMPs, RBC derived MPs; IS, Indoxyl sulfate; IAA, indoxyl-3-acetate acid; PCA, procoagulant activity.
Mentions: In this study, we have found that indolic uremic solutes (IS or IAA) induced a procoagulant phenotype on RBC through increased PS exposure and RMP release. Exposed PS of RBCs and RMPs supports the assembly of intrinsic FXa and prothrombinase, moreover, blockade of PS with lactadherin inhibits activity of procoagulant enzyme complexes and consequently decreases the PCA of RBCs and RMPs (Figure 6). Furthermore, we showed that PS translocation to the RBC surface within indolic uremic solutes is at least partially due to increased cytosolic Ca2+ concentration.

Bottom Line: However, the effect of uremic solutes indoxyl sulfate (IS) and indole-3-acetic acid (IAA) on procoagulant activity (PCA) of erythrocyte is unclear.Our results suggest that RBC eryptosis in uremic solutes IS and IAA plays an important role in thrombus formation through releasing RMPs and exposing PS.Lactadherin acts as an efficient anticoagulant in this process.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, 39 Xinyang Road, Gaoxin District, Daqing 163319, China. gaochunyan1234@163.com.

ABSTRACT
Increased accumulation of indolic uremic solutes in the blood of uremic patients contributes to the risk of thrombotic events. Red blood cells (RBCs), the most abundant blood cells in circulation, may be a privileged target of these solutes. However, the effect of uremic solutes indoxyl sulfate (IS) and indole-3-acetic acid (IAA) on procoagulant activity (PCA) of erythrocyte is unclear. Here, RBCs from healthy adults were treated with IS and IAA (mean and maximal concentrations reported in uremic patients). Phosphatidylserine (PS) exposure of RBCs and their microparticles (MPs) release were labeled with Alexa Fluor 488-lactadherin and detected by flow cytometer. Cytosolic Ca(2+) ([Ca(2+)]) with Fluo 3/AM was analyzed by flow cytometer. PCA was assessed by clotting time and purified coagulation complex assays. We found that PS exposure, MPs generation, and consequent PCA of RBCs at mean concentrations of IS and IAA enhanced and peaked in maximal uremic concentrations. Moreover, 128 nM lactadherin, a PS inhibitor, inhibited over 90% PCA of RBCs and RMPs. Eryptosis or damage, by indolic uremic solutes was due to, at least partially, the increase of cytosolic [Ca(2+)]. Our results suggest that RBC eryptosis in uremic solutes IS and IAA plays an important role in thrombus formation through releasing RMPs and exposing PS. Lactadherin acts as an efficient anticoagulant in this process.

Show MeSH
Related in: MedlinePlus