Serotonergic Mechanisms in Haemostasis: A Connection between Major Depression and Thrombotic Risk.

Serotonergic mechanisms implied in both neuronal and platelet functions have been pointed out as a possible link between depressive disorders and cardiovascular risk. Recent studies suggest serotonin (5-HT) as a key element in the generation of a subpopulation of platelets with elevated procoagulant properties (coated-platelets). We have investigated the implication of serotonergic mechanisms in platelet and coagulation activation in samples from healthy donors or from patients suffering major depression. Furthermore, we evaluated the possible prothrombotic role of serotonergic mechanisms and the potential antithrombotic effect of selective serotonin reuptake inhibitors (SSRI) in vitro and compared results with those observed in a group of patients with major depression. Different experimental strategies were used to evaluate platelet function and the activation of coagulation system including standard aggregometry, flow cytometry, perfusion studies with circulating blood to evaluate platelet interaction and fibrin deposition on damaged vessels. Levels of tissue factor (TF) in whole blood and prothrombin fragment F1+2 in plasma samples were also determined. Aggregation studies did not reveal marked differences between control and patients with major depression. The presence of SSRI in plasma decreased up to 30% of the aggregation induced by ADP potentiated with 5-HT. Flow cytometry studies revealed that platelets from patients with major depression showed an enhanced expression of platelet antigens: FV, fibrinogen, CD63, GPIV, GPIb, as well as elevated exposure of anionic phospholipids (p<0.05 vs. controls). Treatment of patients with the SSRI normalized the expression of these antigens vs. control samples. Studies performed under flow conditions only showed a significant increase of the fibrin formation on vascular damaged vessels of patients with major depression vs. controls (71.1±9.5 % vs. 45.8±5.3 %, p<0.05) with corresponding elevations in F1+2 levels. In vitro incubation of blood samples with a SSRI was followed by a 30% of reduction in fibrin formation. Similar tendencies were confirmed in studies performed along clinical treatment of patients with SSRI. A decrease of 20% and 80% of covered surface by fibrin was observed after 8 and 24 weeks of treatment respectively. Levels of whole blood TF of patients suffering depression were found elevated vs. control samples (1.3±0.4 ng/ml vs. 1.0± 0.4 ng/ml respectively) and tended to decrease during the treatment (p<0.05). Our results reveal a more thrombogenic state in patients diagnosed of major depression associated to serotonergic mechanisms. Strategies aimed to control serotonergic mechanisms in platelets may offer a potential therapy for the regulation of the prothrombotic state of patients with major depression, but also in patients with cardiovascular risk.