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BACKGROUND

The EA 3801 HERVI Unit aims to explore the links between haemostasis and ischemia-reperfusion in order to establish new therapeutic methods of vascular remodeling.

Research in Hemostasis has largely improved our knowledge in the understanding of the mechanisms leading to atherosclerosis, and, subsequently, to vascular obstruction and ischemia. It is well-accepted that venous thrombosis is the consequence of an imbalance in plasmatic coagulation whereas arterial thrombosis is rather a consequence of platelet activation. In both arterial and venous thromboses, the endothelial cells play a crucial role, notwithstanding large specificities depending on the characteristics of the vessels and flow.
Being focused on the biology of Tissue Factor (TF), the main trigger of coagulation, our team has extensively worked on the role of leucocytes in haemostasis: TF expression by monocytes and neutrophils, regulating effects of cytokines on TF expression and thrombin generation, relationship between haemostasis and inflammation.

As far as pharmacology is concerned, the prevention of thrombosis currently uses either antiplatelet of anticoagulant drugs. These drugs are not intended for restoring blood flow. Thrombolysis, conversely, allows the dissolution of the clot, with a rapid efficacy as long as the clot is fresh and therefore sensitive to lysis. Thrombolysis is the primary emergency care in acute ischemia such as stroke, in order to restore arterial blood flow as rapidly as possible, and to limit tissue damage. It is still poorly understood why ischemia and reperfusion can be deleterious and may activate coagulation. Nowadays, no medicine seeks to prevent or limit the consequences of ischemia.

Arterial vascular disease is most frequently the consequence of a vascular atherothrombotic process. This process is considered to be inherent to the individual's aging but many individual situations, both genetic and related to the environment, promote the development and progression of the atherosclerotic lesions.

Arterial risk factors are mainly age, metabolic diseases (diabetes, lipid disorders), high blood pressure, kidney failure, and tobacco use. The clinical manifestations of ischemia can result from the obstruction of coronary arteries, brain vessel network or limb vascularization. If the basic mechanisms are the same, the consequences are obviously very different between organs. In the heart, a short sequence of ischemia and reperfusion before prolonged ischemia can activate a protection pathway to limit ischemia-reperfusion injury. This paradigm of an endogenous protective effect has been described under the term of "ischemic preconditioning". On the opposite, a short sequence of ischemia and reperfusion after a prolonged ischemia refers to the mechanisms of post-conditioning which also protect cells and tissues against ischemia and reperfusion injury. Post-conditioning, but also pre-conditioning, may be emphasized by a pharmacological intervention.

Vascular imaging uses non invasive and invasive techniques. These latter allow to obtain a topographic diagnosis and to cure the patient in a same procedure time. The endovascular restorations of the flow use different methods of remodeling thanks to dedicated dilation devices, coils and stents. Whenever appropriate, thrombectomy is a first-line treatment to cure stroke, in addition to thrombolysis or when this latter is contra-indicated. When an intravascular device is placed during the procedure, it is mandatory to provent both immediate and delayed thrombosis with an acceptable of, at best, no increase of bleeding risk. On a long term basis, an endothelization of the devices is expected but never assessed in current practice.

Many pharmacological studies and clinical trials have been achieved in the field of coronary angioplasty. Most protocols used in neuro-angioplasty are extrapolated from the literature published in cardiology, in the absence of spectific date. As a consequence, these management procedures may not take into account the specificity of neurovascular remodeling: assessement of the bleeding risk and of the risk of recurrence, consequences of the ischemia and of the reperfusion on hemostasis and tissue damage.
In the field of peripheral arterial disease of the lower limbs, it is striking to notice the lack of pharmacological studies, in spite of the fact that critical limb ischemia leads to the amputation of the lower limb and subsequently generates disability as stroke does. When any technique of revascularization (stenting or surgical revascularization) cannot be proposed due to poor distal vascularization, amputation is the sole option, but it is generally associated with high risk of mortality. In these "no-option patients", it is an interesting alternative that we have explored and developed these recent past years.

SCIENTIFIC GOAL

The goal of the Unit is to analyze the relationship between ischemia, revascularization and haemostasis, in order to improve vascular remodeling. As atherothrombosis commonly affects in a same patient the vascularization of the myocardium, the brain and the lower limb, it is a major issue to understand the common basic mechanisms and, in the same time, to depict and analyze the spectificities of each organ and tissue.

To achieve these objectives, EA 3801 HERVI conducts fondamental and clinical research on various themes:

• Biology of tissue factor, regulation of thrombin generation.
• Structure of the clot: Identification of structural components, evaluation of a structural characterization method by microspectroscopy.
• The potential of cell therapy (and alternative approaches): Efficacy of cell therapy in endovascular revascularization to improve distal peripheral angiogenesis.
• Endothelial protection during hypoxia and hypoxia-reoxygenation: Complementary role of P1 and P2 receptors.
• Mechanisms of ischemia and cardioprotection.