Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNF^Met/Met) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha_2A-adrenergic receptor (α_2A-ADR) overexpression found in BDNF^Met/Met mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The α₂-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNF^Met/Met mice and reduces procoagulant activity and platelet generation in cells transfected with BDNF^Met plasmid or exposed to pro-BDNF^Met peptide. Finally, we show that homozygous BDNF^Met/Met CAD patients have hyper-reactive platelets overexpressing abundant α_2A-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNF^Val/Val patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α_2A-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α_2A-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.