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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.


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Western Blotting Validation of Differential Proteins.A total of 25 differential proteins (Supplementary Table 3) were analyzed by Western blotting for significant changes in individual MDD-SA, MDD-NA, and HC samples (n = 12 each). Only 4 of these 25 differential proteins – SAA1, CRP, FX, and PCI – displayed significant dysregulation by Western blotting. (A,B) SAA1 and CRP were significantly upregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (C,D) FX and PCI expression were significantly downregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (E) Total protein staining by Coomassie Blue employed as the loading control. A single asterisk (*) indicates significant change with p < 0.05, ** indicates p < 0.01, and *** indicates p = 0.000. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; SAA1, serum amyloid A protein 1; CRP, C-reactive protein; FX, coagulation factor X; PCI, protein C inhibitor. Data are presented as means ± error bars representing standard deviations (SD’s).
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f2: Western Blotting Validation of Differential Proteins.A total of 25 differential proteins (Supplementary Table 3) were analyzed by Western blotting for significant changes in individual MDD-SA, MDD-NA, and HC samples (n = 12 each). Only 4 of these 25 differential proteins – SAA1, CRP, FX, and PCI – displayed significant dysregulation by Western blotting. (A,B) SAA1 and CRP were significantly upregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (C,D) FX and PCI expression were significantly downregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (E) Total protein staining by Coomassie Blue employed as the loading control. A single asterisk (*) indicates significant change with p < 0.05, ** indicates p < 0.01, and *** indicates p = 0.000. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; SAA1, serum amyloid A protein 1; CRP, C-reactive protein; FX, coagulation factor X; PCI, protein C inhibitor. Data are presented as means ± error bars representing standard deviations (SD’s).

Mentions: From these 28 differential proteins with established coagulatory and/or inflammatory functions, 25 candidate differential proteins were selected for Western blotting validation based on the commercial availability of antibodies (Supplementary Table 3). Consistent with 2-DE-MALDI-TOF/TOF MS findings, only four proteins – SAA1, CRP, FX, and PCI – demonstrated significantly altered levels in MDD-SA subjects relative to both MDD-NA and HC subjects, but did not show any significant differentiation between MDD-NA and HC subjects (Fig. 2). The differential expression of the other proteins found by 2-DE-MALDI-TOF/TOF MS or iTRAQ-LC-MS/MS did not reach statistical significance (data not shown).


The Extrinsic Coagulation Pathway: a Biomarker for Suicidal Behavior in Major Depressive Disorder
Western Blotting Validation of Differential Proteins.A total of 25 differential proteins (Supplementary Table 3) were analyzed by Western blotting for significant changes in individual MDD-SA, MDD-NA, and HC samples (n = 12 each). Only 4 of these 25 differential proteins – SAA1, CRP, FX, and PCI – displayed significant dysregulation by Western blotting. (A,B) SAA1 and CRP were significantly upregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (C,D) FX and PCI expression were significantly downregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (E) Total protein staining by Coomassie Blue employed as the loading control. A single asterisk (*) indicates significant change with p < 0.05, ** indicates p < 0.01, and *** indicates p = 0.000. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; SAA1, serum amyloid A protein 1; CRP, C-reactive protein; FX, coagulation factor X; PCI, protein C inhibitor. Data are presented as means ± error bars representing standard deviations (SD’s).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5015115&req=5

f2: Western Blotting Validation of Differential Proteins.A total of 25 differential proteins (Supplementary Table 3) were analyzed by Western blotting for significant changes in individual MDD-SA, MDD-NA, and HC samples (n = 12 each). Only 4 of these 25 differential proteins – SAA1, CRP, FX, and PCI – displayed significant dysregulation by Western blotting. (A,B) SAA1 and CRP were significantly upregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (C,D) FX and PCI expression were significantly downregulated in MDD-SA subjects as compared to both MDD-NA and HC subjects. (E) Total protein staining by Coomassie Blue employed as the loading control. A single asterisk (*) indicates significant change with p < 0.05, ** indicates p < 0.01, and *** indicates p = 0.000. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; SAA1, serum amyloid A protein 1; CRP, C-reactive protein; FX, coagulation factor X; PCI, protein C inhibitor. Data are presented as means ± error bars representing standard deviations (SD’s).
Mentions: From these 28 differential proteins with established coagulatory and/or inflammatory functions, 25 candidate differential proteins were selected for Western blotting validation based on the commercial availability of antibodies (Supplementary Table 3). Consistent with 2-DE-MALDI-TOF/TOF MS findings, only four proteins – SAA1, CRP, FX, and PCI – demonstrated significantly altered levels in MDD-SA subjects relative to both MDD-NA and HC subjects, but did not show any significant differentiation between MDD-NA and HC subjects (Fig. 2). The differential expression of the other proteins found by 2-DE-MALDI-TOF/TOF MS or iTRAQ-LC-MS/MS did not reach statistical significance (data not shown).

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&thinsp;=&thinsp;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&thinsp;=&thinsp;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