Molecular mechanisms of thrombosis and immunothrombosis
In our laboratory we strive to understand the pathophysiological mechanisms that lead to thrombosis and immunothrombosis, an innate immune response that links coagulation to the recognition, containment and destruction of microbial pathogens. In this context, autoimmune disorders such as Antiphosholipid Syndrome (APS) are of particular relevance. APS is characterized by venous and arterial thrombosis as well as pregnancy morbidity. One of the most serious complications of APS occurs when a clot forms in the brain and causes a stroke. 30% of strokes in individuals younger than age 50 are due to APS. Other neurological symptoms include chronic headaches, dementia (similar to the dementia of Alzheimer’s disease), and seizures. APS is challenging to diagnose and it has no specific cure. The current treatment relies on long-term oral anticoagulant medications such as warfarin or the combination of heparin and aspirin, which requires careful adjustment of the dosage and continuous monitoring to avoid life threatening side effects. Our focus is to elucidate structural and functional aspects of proteins that are mistakenly targeted by autoantibodies. In particular we investigate how the antigen-antibody recognition occurs at the molecular level, what is the role of the conformational plasticity in the target proteins and what are the molecular pathways behind the clinical manifestations of the disease. To achieve our goals, we apply a unique combination of biochemistry, protein engineering, X-ray crystallography, single molecule fluorescence biophysics (smFRET and FCS) and surface plasmon resonance (SPR).