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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

Extrinsic Pathway Differentiators and Relative Prothrombinase Activity.Based on the mean values of F1 + 2 and prothrombin from the three groups, HC subjects displayed higher relative prothrombinase activity than both MDD-SA and MDD-NA subjects, and MDD-SA subjects displayed a higher relative prothrombinase activity than MDD-NA subjects. *The relative mass-action ratio applied here, Γr = [F1 + 2]2/[prothrombin]x)/([F1 + 2]2MDD-NA/[prothrombin]MDD-NA, was derived from the prothrombinase reaction (i.e., prothrombin → F1 + 2 + thrombin) with a 1:1 molar equivalency of the F1 + 2 and thrombin products, leading to the [F1 + 2]-squared term. As opposed to simply comparing F1 + 2 levels, this ratio was applied as a more accurate metric of relative prothrombinase activity to control for intergroup variations in prothrombin levels. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; F1 + 2, prothrombin fragment 1 + 2.
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f6: Extrinsic Pathway Differentiators and Relative Prothrombinase Activity.Based on the mean values of F1 + 2 and prothrombin from the three groups, HC subjects displayed higher relative prothrombinase activity than both MDD-SA and MDD-NA subjects, and MDD-SA subjects displayed a higher relative prothrombinase activity than MDD-NA subjects. *The relative mass-action ratio applied here, Γr = [F1 + 2]2/[prothrombin]x)/([F1 + 2]2MDD-NA/[prothrombin]MDD-NA, was derived from the prothrombinase reaction (i.e., prothrombin → F1 + 2 + thrombin) with a 1:1 molar equivalency of the F1 + 2 and thrombin products, leading to the [F1 + 2]-squared term. As opposed to simply comparing F1 + 2 levels, this ratio was applied as a more accurate metric of relative prothrombinase activity to control for intergroup variations in prothrombin levels. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; F1 + 2, prothrombin fragment 1 + 2.

Mentions: Therefore, MDD, independent of suicidality, is associated with a proinflammatory state as evidenced by significantly higher CRP and SAA1 levels in both MDD-SA and MDD-NA relative to HC subjects (Fig. 2) accompanied by a hypothrombotic state as evidenced by significantly lower F1 + 2 levels and lower relative prothrombinase activity in MDD-SA and MDD-NA relative to HC subjects (Figs 2 and 6).


The Extrinsic Coagulation Pathway: a Biomarker for Suicidal Behavior in Major Depressive Disorder
Extrinsic Pathway Differentiators and Relative Prothrombinase Activity.Based on the mean values of F1 + 2 and prothrombin from the three groups, HC subjects displayed higher relative prothrombinase activity than both MDD-SA and MDD-NA subjects, and MDD-SA subjects displayed a higher relative prothrombinase activity than MDD-NA subjects. *The relative mass-action ratio applied here, Γr = [F1 + 2]2/[prothrombin]x)/([F1 + 2]2MDD-NA/[prothrombin]MDD-NA, was derived from the prothrombinase reaction (i.e., prothrombin → F1 + 2 + thrombin) with a 1:1 molar equivalency of the F1 + 2 and thrombin products, leading to the [F1 + 2]-squared term. As opposed to simply comparing F1 + 2 levels, this ratio was applied as a more accurate metric of relative prothrombinase activity to control for intergroup variations in prothrombin levels. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; F1 + 2, prothrombin fragment 1 + 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Extrinsic Pathway Differentiators and Relative Prothrombinase Activity.Based on the mean values of F1 + 2 and prothrombin from the three groups, HC subjects displayed higher relative prothrombinase activity than both MDD-SA and MDD-NA subjects, and MDD-SA subjects displayed a higher relative prothrombinase activity than MDD-NA subjects. *The relative mass-action ratio applied here, Γr = [F1 + 2]2/[prothrombin]x)/([F1 + 2]2MDD-NA/[prothrombin]MDD-NA, was derived from the prothrombinase reaction (i.e., prothrombin → F1 + 2 + thrombin) with a 1:1 molar equivalency of the F1 + 2 and thrombin products, leading to the [F1 + 2]-squared term. As opposed to simply comparing F1 + 2 levels, this ratio was applied as a more accurate metric of relative prothrombinase activity to control for intergroup variations in prothrombin levels. Acronyms: MDD-SA, majorly depressed suicide attempter; MDD-NA, majorly depressed non-attempter; HC, healthy control; F1 + 2, prothrombin fragment 1 + 2.
Mentions: Therefore, MDD, independent of suicidality, is associated with a proinflammatory state as evidenced by significantly higher CRP and SAA1 levels in both MDD-SA and MDD-NA relative to HC subjects (Fig. 2) accompanied by a hypothrombotic state as evidenced by significantly lower F1 + 2 levels and lower relative prothrombinase activity in MDD-SA and MDD-NA relative to HC subjects (Figs 2 and 6).

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