VT duets: inflammation/coagulation—wall/flow

In this issue of Blood, Zirka et al¹  investigated the role of Slc44a2 in thrombosis. Specifically, they focused on determining how Slc44a2 expressing either the human neutrophil antigen (HNA)-3a or HNA-3b on neutrophils could modulate their adhesion and activation of von Willebrand factor (VWF) under certain flow conditions. Prior genome-wide association studies linked expression of HNA-3b on the Slc44a2 protein with a decreased risk of venous thrombosis (VT) in humans. Slc44a2 is a ubiquitous transmembrane protein and a receptor for VWF. The authors examined how neutrophil Slc44a2 expressing either HNA-3a or HNA-3b modulated adhesion and activation on VWF under flow. Transfected HEK293T cells or neutrophils homozygous for the HNA-3a– or the HNA-3b–coding allele were perfused in flow chambers coated with VWF, mimicking venous shear rates. HNA-3a expression was required for Slc44a2-mediated neutrophil adhesion to VWF at those shear rates. Adhesion was enhanced when neutrophils were activated with lipopolysaccharide. Specific shear conditions with high neutrophil concentrations worked like a “second hit,” inducing the formation of neutrophil extracellular traps. Neutrophil mobilization was also measured by intravital microscopy in venules. Mice lacking Slc44a2 showed a massive reduction in neutrophil recruitment in inflamed mesenteric venules.

They concluded that Slc44a2/HNA-3a is important for the adhesion and activation of neutrophils in veins during inflammation and when submitted to specific shears similar to those in veins. The authors included blood flow as part of their methodology, which is a critical component in the thrombosis process in blood vessels. Although the flow devices available have limitations, these types of tools bring blood flow into the equation. Blood flow could be even more critical as we advance in our understanding of the VT process. Investigating VT is and should be a multidisciplinary effort.²  The authors combined biology and physics, which captures a more complete picture of the disease and needs to be encouraged in basic science investigations (see figure). As part of this multidisciplinary effort, I want to encourage engineers to continue their efforts to develop tools that allow researchers to investigate the vein wall and flow conditions together. These tools are needed.

Inflammation was introduced to experimental VT in 1973.³  Since then, studies have investigated different ways to understand how inflammation is part of the VT process, from the role of P-selectin⁴  and other adhesion molecules to the recent discovery of the galectin-3.⁵  Also, inflammatory cytokines such as interleukin 6 (IL-6) were shown to have a clear role in VT,⁶  a concept unfortunately now highlighted and reinforced by the studies on COVID-19–associated thrombotic events. Several studies are confirming the role of inflammation on the COVID-19 association with VT, including the therapeutic use of anti–IL-6.⁷ 

Today, it is clear that inflammation is part of the VT process. Although it is believed that inflammation participates in all stages during the VT process (initiation, amplification, resolution), multiple questions remain unanswered. The question of whether 1 pathway can be safely targeted, or the most likely scenario that several mechanisms will be responsible for the thrombosis-inflammation intersection, needs more effort. However, this work moves the field 1 step closer on our way to map the intersection of inflammation and VT, providing evidence that could ultimately be used to improve the current outcome of our VT patients.

Last, the lesson learned is the fact that VT should not be seen as a “clotting process inside the veins” but more as a multifactorial condition that includes inflammation as a critical component of the VT process. Of course, the coagulation system's participation in VT is critical, but investigators are demonstrating a dualism, and the coagulation partner is the inflammation. VT epidemiologic data clearly show that tagging the coagulation system is essential, but it seems to be not enough. This emerging message should be spread among research and development, students, and professionals at all levels. Thinking outside the box guides us further from the coagulation system alone, and the efforts of this group lead our future research. Congratulations to the authors.