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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

Anticoagulant Activity and Forced Swimming Test (FST) Immobility Post-Heparin Administration.(A) The effects of heparin on plasma clotting times (aPTT). (B) Immobility times in the forced swimming test (FST) between control (n = 9) and heparin-treated rats (n = 29). An asterisk (*) indicates significant change (p < 0.05). Acronyms: aPTT, activated partial thromboplastin time; CON, control group; HT, heparin-treated group. Data are presented as means ± error bars representing standard deviations (SD’s).
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f4: Anticoagulant Activity and Forced Swimming Test (FST) Immobility Post-Heparin Administration.(A) The effects of heparin on plasma clotting times (aPTT). (B) Immobility times in the forced swimming test (FST) between control (n = 9) and heparin-treated rats (n = 29). An asterisk (*) indicates significant change (p < 0.05). Acronyms: aPTT, activated partial thromboplastin time; CON, control group; HT, heparin-treated group. Data are presented as means ± error bars representing standard deviations (SD’s).

Mentions: Based on the foregoing findings, we hypothesized that heparin treatment – which inactivates the extrinsic pathway proteins thrombin, FXa, and FIXa20 – may promote depression-like behavior in rodents as measured by increased passive (immobility) behavior in the FST. Following seven days of heparin (or control saline) administration, activated partial thromboplastin time (aPTT) levels were measured in rat plasma samples to validate effective heparinization in heparin-treated rats. As expected, aPTT levels were significantly elevated in the heparin-treated subjects as compared to saline-treated control subjects (p = 0.0237; Fig. 4A). FST immobility time was significantly elevated in heparin-treated subjects as compared to saline-treated control subjects (p = 0.0295; Fig. 4B).


The Extrinsic Coagulation Pathway: a Biomarker for Suicidal Behavior in Major Depressive Disorder
Anticoagulant Activity and Forced Swimming Test (FST) Immobility Post-Heparin Administration.(A) The effects of heparin on plasma clotting times (aPTT). (B) Immobility times in the forced swimming test (FST) between control (n = 9) and heparin-treated rats (n = 29). An asterisk (*) indicates significant change (p < 0.05). Acronyms: aPTT, activated partial thromboplastin time; CON, control group; HT, heparin-treated group. Data are presented as means ± error bars representing standard deviations (SD’s).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Anticoagulant Activity and Forced Swimming Test (FST) Immobility Post-Heparin Administration.(A) The effects of heparin on plasma clotting times (aPTT). (B) Immobility times in the forced swimming test (FST) between control (n = 9) and heparin-treated rats (n = 29). An asterisk (*) indicates significant change (p < 0.05). Acronyms: aPTT, activated partial thromboplastin time; CON, control group; HT, heparin-treated group. Data are presented as means ± error bars representing standard deviations (SD’s).
Mentions: Based on the foregoing findings, we hypothesized that heparin treatment – which inactivates the extrinsic pathway proteins thrombin, FXa, and FIXa20 – may promote depression-like behavior in rodents as measured by increased passive (immobility) behavior in the FST. Following seven days of heparin (or control saline) administration, activated partial thromboplastin time (aPTT) levels were measured in rat plasma samples to validate effective heparinization in heparin-treated rats. As expected, aPTT levels were significantly elevated in the heparin-treated subjects as compared to saline-treated control subjects (p = 0.0237; Fig. 4A). FST immobility time was significantly elevated in heparin-treated subjects as compared to saline-treated control subjects (p = 0.0295; Fig. 4B).

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