Thrombotic occlusion of blood vessels, which leads to myocardial infarctions, strokes and venous thromboembolisms, is the major cause of death in the western hemisphere. Therefore, it is of critical importance to understand mechanisms preventing thrombus formation. A new study by the research group of Christoph Binder, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor at the Medical University of Vienna, now explains the important role of immunoglobulin-M (IgM) antibodies in preventing thrombosis.
The study published in the journal Blood shows that these antibodies recognize microvesicles, which are membrane blebs shed by cells and recognized for their critical role in thrombosis, and therefore prevent their pro-thrombotic effects. These results provide a novel approach to reduce the risk of thrombosis by using IgM antibodies.
Antibodies are an important component of the immune system. On the one hand, these proteins serve in the body to defend against microbes, and on the other hand to remove the body's own "cell waste". Naturally occurring antibodies which are present from birth and mostly of the immunoglobulin-M (IgM) type, play an essential role in these processes. In the context of thrombosis, earlier studies demonstrated that people with a low number of IgM antibodies have an increased risk of thrombosis.
A research group led by Christoph Binder, Professor of Atherosclerosis Research at the Medical University of Vienna and Principal Investigator at CeMM , previously demonstrated in a study published in 2009 that a high percentage of natural IgM antibodies bind oxidation-specific epitopes, molecular structures that are present on dying cells and serve as "remove-me signals" for the immune system. In this study, Binder's research group identified the mechanisms explaining anti-thrombotic effects of natural IgM antibodies.
IgM antibodies bind procoagulant microvesicles
Microvesicles, blebs shed from the membrane of cells, are critical mediators of blood coagulation and thrombus formation. The study authors Georg Obermayer and Taras Afonyushkin from Binder's research group, both affiliated with CeMM and the Medical University of Vienna, have now demonstrated that natural IgM antibodies that bind oxidation-specific epitopes can prevent coagulation and thrombosis induced by microvesicles. This provides a mechanistic explanation for the previously published observation that low levels of these antibodies are associated with an increased risk of thrombosis.
"We assume that natural IgM antibodies recognize microvesicles that are particularly proinflammatory and procoagulant," say the scientists. Both in experiments on the mouse model and directly on human blood samples, the scientists were able to show that the addition of IgM antibodies inhibited blood clotting caused by specific microvesicles and protected mice from lung thrombosis. Conversely, it was also shown that depletion of the IgM antibodies increased blood clotting.
Possible starting point for future therapies
The study authors explain: "The study for the first time provides an explanation why people with a low number of natural IgM antibodies have an increased risk of thrombosis."
The results offer high potential for novel treatments to reduce the risk of thrombosis. Influencing IgM antibody levels in high-risk patients could be a viable addition to the previously established blood thinning treatment, as this is also known to be associated with side effects such as an increased tendency to bleed in the case of injuries."
Christoph Binder, Project Leader
In addition, the study makes an important contribution to the basic understanding of factor modulating thrombus formation. "Microvesicles are already recognized as an important component of blood coagulation. However, our study created a novel possibility of targeting them therapeutically for the first time," says Christoph Binder.
Obermayer, G., et al. (2020) Natural IgM antibodies inhibit microvesicle-driven coagulation and thrombosis. Blood. doi.org/10.1182/blood.2020007155.