In vivo monitoring of impaired hemorheology in circulatory diseases by cellular quantitative ultrasound – HEMO

In circulatory disorders, impaired deformability and aggregation of red blood cells (RBCs) are frequent findings, which contribute to alterations in macro- and micro-circulatory blood flow. Such disorders may affect tissue perfusion and result in functional deteriorations. For instance, in sickle cell disease (SCD), the loss of RBC deformability results in a rise of blood viscosity, which can yield frequent painful vaso-occlusive crises in SCD patients. Moreover, increased RBC aggregation participates to vaso-occlusive crisis process in SCD. SCD patients are normally experiencing chronic anemia, and frequent blood transfusions may be required. Currently, the indices of RBC deformability and aggregation can only be measured in vitro on patients’ blood samples obtained by venipuncture. However, a technique based on venipuncture is impossible to apply when frequent monitoring and rapid medical decision are required.
In the context of SCD, the continuous monitoring of RBC pathological states associated with circulatory disorders (i.e., loss of RBC deformability and/or impaired aggregation) with a non-invasive technique would thus offer a major advantage for the management of SCD patients. The HEMO project aims to develop a novel cellular Quantitative UltraSound (QUS) technique for the continuous and non-invasive monitoring of the RBC pathological states through in vivo measurements of RBC suspension microstructure. We propose to use the QUS technique to measure the changes in RBC deformability and aggregation in flowing blood under in vivo conditions in real time. The medical outcome of this study will be beneficial in the daily monitoring of SCD patients to predict and prevent painful vaso-occlusive crises, to assess response to treatments and to manage the frequency of blood transfusion.

Our consortium has recently developed an anisotropic QUS approach able to probe the microstructure in opaque concentrated suspensions. The suspension microstructure (i.e., the spatial arrangement of the particles relative to each other in a flow) provides quantitative information on the particle properties and the interactions they undergo. With this cutting-edge QUS approach, it is possible, for the first time, to consider probing the anisotropic microstructure of concentrated RBC suspensions under shear flow in order to detect abnormal alteration in RBC deformability and aggregation.
Before assessing the performance of this QUS approach for pathophysiological human studies, its ability to detect a change in RBC properties needs to be evaluated and understood. To achieve this goal, developments of original experimental setups together with numerical simulations will allow us to
1. Test the QUS technique and its ability to detect changes in microstructure induced by a change in shape, stiffness or adhesion of particles in transparent model suspensions whose microstructure can be directly measured by suspension imaging (WP1);
2. Develop novel anisotropic QUS parameters and evaluate their ability to characterize the average deformability index of RBCs in flowing RBC suspensions (WP2);
3. Understand the physical mechanisms underlying the microstructure anisotropy in RBC suspensions and its change with the RBC deformability levels, by determining the relation between the individual dynamics of RBC, RBC-RBC interactions, microstructure and resulting rheology (WP3);
4. Evaluate if the proposed anisotropic QUS approach can detect abnormal alteration in RBC deformability and/or RBC aggregation in animal models of sickle cell disease (WP4).

To achieve this program, the interdisciplinary HEMO project brings together 4 French academic laboratories with complementary skills: LMA Marseille (quantitative ultrasound investigation of microstructure), InPhyNi Nice (rheology and imaging of concentrated suspensions), IMAG Montpellier (numerical simulations of RBC suspensions), and LIBM Lyon (clinical hemorheology and sickle cell disease).