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The Extrinsic Coagulation Pathway: a Biomarker for Suicidal Behavior in Major Depressive Disorder

View Article: PubMed Central - PubMed

ABSTRACT

Although an association between major depressive disorder (MDD) and suicide exists, most depressed patients never attempt suicide. An improved understanding of the factors contributing to suicidal risk in MDD can provide direction for suicide predictor development. In MDD suicide attempters (MDD-SA), MDD non-attempters (MDD-NA), and healthy controls (HC) (n = 12 each group), complementary plasma proteomics identified 45 differential proteins mapped to coagulation and inflammation, 25 of which underwent Western blotting. In another cohort including antidepressant-treated patients (n = 49 each group), seven additional extrinsic pathway proteins were selected for ELISA. Two inflammatory proteins and eight coagulatory proteins demonstrated alterations in MDD-SA relative to MDD-NA and HC. Applying a relative mass-action ratio, MDD-SA subjects displayed a higher relative prothrombinase activity than MDD-NA subjects, while healthy controls displayed higher relative prothrombinase activity than both MDD-SA and MDD-NA subjects. Consistent with our human findings, we found that heparin treatment significantly increased forced swimming test (FST) immobility time in rodents. MDD, independent of suicidality, is associated with a proinflammatory state accompanied by a hypothrombotic state. Suicidal behavior in MDD is associated with a more pronounced proinflammatory and prothrombotic phenotype accompanied by extrinsic pathway activation, revealing an extrinsic pathway biomarker that can be applied in predicting and monitoring suicidal risk.

No MeSH data available.


Related in: MedlinePlus

Inflammation-Coagulation Crosstalk and Extrinsic Pathway Activation in Majorly Depressed Suicide Attempters.Inflammatory cytokines induce endothelial cells to express soluble TF. More potent upregulation of CRP and SAA1 in MDD-SA subjects induces increased monocytic expression of cell-bound TF, which catalyzes the conversion of increased soluble TF and circulating FVII to generate the TF-FVIIa complex that efficiently converts the increased FX to FXa. FXa and thrombin then mediate the activation of increased FV to form FVa, which, in turn, binds to FXa to form prothrombinase (FVa-FXa complex). TFPI upregulation indicates inhibition of the TF-FVIIa complex and FXa. PCI downregulation indicates disinhibition of FXa. APC upregulation is likely a result of PCI downregulation. The cumulative effect of these differential changes in protein expression yields increased relative prothombinase activity in MDD-SA relative to MDD-NA subjects (Fig. 6). Acronyms: MDD, major depressive disorder; MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; TNF-alpha, tumor necrosis factor-alpha; IL-1, interleukin-1; IL-6, interleukin-6; CRP, C-reactive protein; SAA1, serum amyloid A protein 1; TF, tissue factor; FVII, coagulation factor FVII; FVIIa, activated coagulation factor FVII; FX, coagulation factor X; FXa, activated coagulation factor X; FV, coagulation factor V; FVa, activated coagulation factor V; TFPI, tissue factor pathway inhibitor; PCI, protein C inhibitor; APC, activated protein C.
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f5: Inflammation-Coagulation Crosstalk and Extrinsic Pathway Activation in Majorly Depressed Suicide Attempters.Inflammatory cytokines induce endothelial cells to express soluble TF. More potent upregulation of CRP and SAA1 in MDD-SA subjects induces increased monocytic expression of cell-bound TF, which catalyzes the conversion of increased soluble TF and circulating FVII to generate the TF-FVIIa complex that efficiently converts the increased FX to FXa. FXa and thrombin then mediate the activation of increased FV to form FVa, which, in turn, binds to FXa to form prothrombinase (FVa-FXa complex). TFPI upregulation indicates inhibition of the TF-FVIIa complex and FXa. PCI downregulation indicates disinhibition of FXa. APC upregulation is likely a result of PCI downregulation. The cumulative effect of these differential changes in protein expression yields increased relative prothombinase activity in MDD-SA relative to MDD-NA subjects (Fig. 6). Acronyms: MDD, major depressive disorder; MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; TNF-alpha, tumor necrosis factor-alpha; IL-1, interleukin-1; IL-6, interleukin-6; CRP, C-reactive protein; SAA1, serum amyloid A protein 1; TF, tissue factor; FVII, coagulation factor FVII; FVIIa, activated coagulation factor FVII; FX, coagulation factor X; FXa, activated coagulation factor X; FV, coagulation factor V; FVa, activated coagulation factor V; TFPI, tissue factor pathway inhibitor; PCI, protein C inhibitor; APC, activated protein C.

Mentions: Soluble TF, FVII, FX, and FV – all protein constituents of the coagulation cascade (Fig. 5) – were shown to be increased in MDD-SA relative to MDD-NA and HC subjects. At the initiation of the extrinsic pathway, cell-bound TF on monocytes catalyze the generation of the TF-FVIIa complex from endothelium-released soluble TF and circulating FVII. This complex efficiently converts FX to FXa. Then, FXa and thrombin mediate the activation of FV to form FVa, which, in turn, binds to FXa to form prothrombinase (FVa-FXa complex), which promotes coagulation by cleaving prothrombin to generate thrombin3536.


The Extrinsic Coagulation Pathway: a Biomarker for Suicidal Behavior in Major Depressive Disorder
Inflammation-Coagulation Crosstalk and Extrinsic Pathway Activation in Majorly Depressed Suicide Attempters.Inflammatory cytokines induce endothelial cells to express soluble TF. More potent upregulation of CRP and SAA1 in MDD-SA subjects induces increased monocytic expression of cell-bound TF, which catalyzes the conversion of increased soluble TF and circulating FVII to generate the TF-FVIIa complex that efficiently converts the increased FX to FXa. FXa and thrombin then mediate the activation of increased FV to form FVa, which, in turn, binds to FXa to form prothrombinase (FVa-FXa complex). TFPI upregulation indicates inhibition of the TF-FVIIa complex and FXa. PCI downregulation indicates disinhibition of FXa. APC upregulation is likely a result of PCI downregulation. The cumulative effect of these differential changes in protein expression yields increased relative prothombinase activity in MDD-SA relative to MDD-NA subjects (Fig. 6). Acronyms: MDD, major depressive disorder; MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; TNF-alpha, tumor necrosis factor-alpha; IL-1, interleukin-1; IL-6, interleukin-6; CRP, C-reactive protein; SAA1, serum amyloid A protein 1; TF, tissue factor; FVII, coagulation factor FVII; FVIIa, activated coagulation factor FVII; FX, coagulation factor X; FXa, activated coagulation factor X; FV, coagulation factor V; FVa, activated coagulation factor V; TFPI, tissue factor pathway inhibitor; PCI, protein C inhibitor; APC, activated protein C.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5015115&req=5

f5: Inflammation-Coagulation Crosstalk and Extrinsic Pathway Activation in Majorly Depressed Suicide Attempters.Inflammatory cytokines induce endothelial cells to express soluble TF. More potent upregulation of CRP and SAA1 in MDD-SA subjects induces increased monocytic expression of cell-bound TF, which catalyzes the conversion of increased soluble TF and circulating FVII to generate the TF-FVIIa complex that efficiently converts the increased FX to FXa. FXa and thrombin then mediate the activation of increased FV to form FVa, which, in turn, binds to FXa to form prothrombinase (FVa-FXa complex). TFPI upregulation indicates inhibition of the TF-FVIIa complex and FXa. PCI downregulation indicates disinhibition of FXa. APC upregulation is likely a result of PCI downregulation. The cumulative effect of these differential changes in protein expression yields increased relative prothombinase activity in MDD-SA relative to MDD-NA subjects (Fig. 6). Acronyms: MDD, major depressive disorder; MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; TNF-alpha, tumor necrosis factor-alpha; IL-1, interleukin-1; IL-6, interleukin-6; CRP, C-reactive protein; SAA1, serum amyloid A protein 1; TF, tissue factor; FVII, coagulation factor FVII; FVIIa, activated coagulation factor FVII; FX, coagulation factor X; FXa, activated coagulation factor X; FV, coagulation factor V; FVa, activated coagulation factor V; TFPI, tissue factor pathway inhibitor; PCI, protein C inhibitor; APC, activated protein C.
Mentions: Soluble TF, FVII, FX, and FV – all protein constituents of the coagulation cascade (Fig. 5) – were shown to be increased in MDD-SA relative to MDD-NA and HC subjects. At the initiation of the extrinsic pathway, cell-bound TF on monocytes catalyze the generation of the TF-FVIIa complex from endothelium-released soluble TF and circulating FVII. This complex efficiently converts FX to FXa. Then, FXa and thrombin mediate the activation of FV to form FVa, which, in turn, binds to FXa to form prothrombinase (FVa-FXa complex), which promotes coagulation by cleaving prothrombin to generate thrombin3536.

View Article: PubMed Central - PubMed

ABSTRACT

Although an association between major depressive disorder (MDD) and suicide exists, most depressed patients never attempt suicide. An improved understanding of the factors contributing to suicidal risk in MDD can provide direction for suicide predictor development. In MDD suicide attempters (MDD-SA), MDD non-attempters (MDD-NA), and healthy controls (HC) (n = 12 each group), complementary plasma proteomics identified 45 differential proteins mapped to coagulation and inflammation, 25 of which underwent Western blotting. In another cohort including antidepressant-treated patients (n = 49 each group), seven additional extrinsic pathway proteins were selected for ELISA. Two inflammatory proteins and eight coagulatory proteins demonstrated alterations in MDD-SA relative to MDD-NA and HC. Applying a relative mass-action ratio, MDD-SA subjects displayed a higher relative prothrombinase activity than MDD-NA subjects, while healthy controls displayed higher relative prothrombinase activity than both MDD-SA and MDD-NA subjects. Consistent with our human findings, we found that heparin treatment significantly increased forced swimming test (FST) immobility time in rodents. MDD, independent of suicidality, is associated with a proinflammatory state accompanied by a hypothrombotic state. Suicidal behavior in MDD is associated with a more pronounced proinflammatory and prothrombotic phenotype accompanied by extrinsic pathway activation, revealing an extrinsic pathway biomarker that can be applied in predicting and monitoring suicidal risk.

No MeSH data available.


Related in: MedlinePlus