Why is blood group a risk marker for myocardial infarction?

Background: Glycoprotein (GP)Ib, expressed on the surface of platelets, and its ligand, von Willebrand Factor (VWF) both express covalently linked ABO(H) blood group carbohydrate determinants. VWF is secreted by endothelial cells and circulates in the plasma in a coiled confirmation that is cryptic to platelet binding until it anchors to collagen exposed at sites of vascular damage. Blood group O is associated with an increased risk of bleeding whereas non-O is associated with increased risk of myocardial infarction. Aims: We set out to characterise platelet function from donors with blood group O and non-O. Methods: Parallel plate perfusion chamber assays were used to characterise platelet interactions with VWF. Novel surfaces were developed for the perfusion assays that allowed the capture of autologous VWF on the chamber surface. Platelet interaction with both captured autologous VWF and exogenous pooled, plasma derived VWF was assessed at 1500s-1. P-Selectin expression, annexin V binding and number of disappearing platelets were used to determine functional responses to shear using a cone and plate viscometer. Platelet aggregation in response to Arachidonic Acid, Collagen, ADP, Epinephrine, Ristocetin and TRAP-6 was assessed using a 96-well plate assay. Conclusion: We have established the basis of an assay that will provide information as to how platelets interact with autologous VWF. We have provided evidence that VWF can be captured from flowing blood by a nano-topographical interface of 50nM. VWF captured in this manner is able to support platelet adhesion and thrombus build up. Using an alternative antibody based system to coat our flow chambers with autologous VWF we have shown that platelets from donors with blood group O have more platelet tracks, stably adhered and translocating platelets on VWF compared to non-O donors. In contrast, when our flow chambers were coated with exogenous VWF, Type O platelets travelled further and faster across the pooled, plasma-derived VWF surface, taking longer to form stable bonds. Coupled with the observation that ristocetin and TRAP-6 induced aggregation are both lower in donors with blood Type O, these results provide evidence that ABO(H) glycans modulate platelet function and may explain the increased risk of myocardial infarction associated with non-O blood groups.</p

Identification of physicochemical properties that modulate nanoparticle aggregation in blood

Inorganic materials are receiving significant interest in medicine given their usefulness for therapeutic applications such as targeted drug delivery, active pharmaceutical carriers and medical imaging. However, poor knowledge of the side effects related to their use is an obstacle to clinical translation. For the development of molecular drugs, the concept of safe-by-design has become an efficient pharmaceutical strategy with the aim of reducing costs, which can also accelerate the translation into the market. In the case of materials, the application these approaches is hampered by poor knowledge of how the physical and chemical properties of the material trigger the biological response. Hemocompatibility is a crucial aspect to take into consideration for those materials that are intended for medical applications. The formation of nanoparticle agglomerates can cause severe side effects that may induce occlusion of blood vessels and thrombotic events. Additionally, nanoparticles can interfere with the coagulation cascade causing both pro-and anti-coagulant properties. There is contrasting evidence on how the physicochemical properties of the material modulate these effects. In this work, we developed two sets of tailored carbon and silica nanoparticles with three different diameters in the 100-500 nm range with the purpose of investigating the role of surface curvature and chemistry on platelet aggregation, activation and adhesion. Substantial differences were found in the composition of the protein corona depending on the chemical nature of the nanoparticles, while the surface curvature was found to play a minor role. On the other hand, large carbon nanoparticles (but not small carbon nanoparticles or silica nanoparticles) have a clear tendency to form aggregates both in plasma and blood. This effect was observed both in the presence or absence of platelets and was independent of platelet activation. Overall, the results presented herein suggest the existence of independent modes of action that are differently affected by the physicochemical properties of the materials, potentially leading to vessel occlusion and/or formation of thrombi in vivo

Identification of the physical-chemical properties that modulate the nanoparticles aggregation in blood

Inorganic materials are receiving significant interest in medicine given their usefulness for therapeutic applications such as targeted drug delivery, carriers of active pharmaceutical and medical imaging. However, the poor knowledge of the side effects related to their use is an obstacle to their clinical translation. For the molecular drug development, safe-by-design has become as a novel pharmaceutical strategy that allows a reduction of the costs and an acceleration of the translation of research to market. In the case of materials, the application of such approaches is hampered by a poor knowledge of how the physical and chemical properties of the material trigger biological response. Hemocompatibility is a crucial factor for those materials that are intended for medical applications. In particular, the formation of agglomerates is a serious side effect that may induce occlusion of blood vessels and thrombotic events. Additionally, nanoparticles can interfere with the coagulation cascades where they have been reported to induce both pro- and anti-coagulant properties where their properties like size, shape and surface charge have been see to be critical parameters.   Here, we developed two sets of tailored carbon and silica nano/submicron-particles with three different sizes (100-500 nm) with the purpose of investigating the role of surface curvature and chemistry on platelet aggregation, activation and adhesion. We show that that large carbon nanoparticles, but not small carbon nanoparticles or silica nanoparticles, have a strong tendency to form aggregates both in plasma and blood, as a consequence of the formation of a protein corona and not of platelets activation. Substantial differences were found in the composition of the protein corona depending upon the chemical nature of the nanoparticles, while the surface curvature plays a minor role. On the other hand, coagulation proteins were abundant in the corona of both silica and carbon nanoparticles.  The results presented herein suggest that vessel occlusion and formation of thrombi in vivo may occur through independent mode of action (MoA), differently affected by the physico-chemical properties of the materials

Levels of sGPVI in patients with seropositve RA vs seronegative RA vs controls.

<p>Levels of sGPVI in patients with seropositve RA vs seronegative RA vs controls.</p

Characteristics of patients with seropositive RA vs seronegative RA.

<p>Characteristics of patients with seropositive RA vs seronegative RA.</p