Box 1.

Peripheral blood vascular health analytes

Fibrinogen is a protein commonly associated with coagulation (Pretorius et al., 2022), but is also a classic acute phase reactant in that inflammatory insults drive significantly increased liver expression and concentration in general blood circulation (Luyendyk et al., 2019). Furthermore, fibrinogen specifically induces a sustained glial response at the perivascular spaces surrounding neurovasculature, a process worsened by blood–brain barrier disruption during neuroinflammation (Davalos et al., 2012).

α2-macroglobulin is an extracellular macromolecule mainly known for its role as a broad-spectrum protease inhibitor, but also has a role facilitating immune cell migration to vasculature. For example, α2-macroglobulin aids neutrophils through stimulation of their capacity to migrate and bind to vascular endothelial cells, and to phagocytose and kill pathogens (Vandooren & Itoh, 2021).

Orosomucoid (also called alpha-1-acid glycoprotein or AGP) is known as an acute phase protein synthesized by liver, but can also be synthesized by several other tissues including brain under different physiological conditions as well as pathological conditions such as stroke and metabolic syndrome (Li et al., 2019). In a well-characterized in vitro blood-brain barrier model, human orosomucoid showed a dose-dependent effect on the permeability of microvessel endothelial cells (Zhang & Mark, 2012).

Fetuin A was previously called pp63 or countertrypin and is a multifunctional protein made by the liver and some secretory tissues. Its role in cardiovascular health is multifactorial including protective effects such as mitigation of calcification but it is also associated with worse prognosis in cardiovascular disease and diabetes. Fetuin A may act as an endogenous ligand for TLR4 receptors (Abebe et al. 2022).

sL-selectin (soluble leukocyte selectin) is also called CD62L and is a cell adhesion molecule that is expressed on most circulating leukocytes and facilitates endothelial adhesion and transendothelial migration of activated immune cells (Ivetic et al., 2019; Seekamp et al., 2001), which in turn would activate local glia. A study of acute COVID patients found that patients with severe COVID-19 had greater frequencies of CD4+ T cells expressing CD62L, in particular severe patients with hypertension (Lesteberg et al., 2023).

Pentraxin-2 (also called serum amyloid P component or SAP) is a short pentraxin protein like C-reactive protein and is a component of the humoral arm of the innate immune system, involved in infection resistance and tissue remodeling. Pentraxin-2 binds to organisms such as viruses, bacteria, and fungi (Doni et al. 2021). In mice it was also found to regulate the interaction between macrophage activation and coagulation cascades and is thought to be involved in the pathogenic buildup of amyloid fibrils by reducing normal proteolytic cleavage (Muczynsk et al. 2017 28213380).

Haptoglobin protein circulating in plasma scavenges extracellular hemoglobin and is thought to have a protective effect against hemoglobin-induced vasoconstriction, however in murine models vascular endothelial dysfunction prevents this function (Graw et al., 2017). The gut permeability marker zonulin, which is reduced in the post-acute-COVID condition multisystem inflammatory syndrome in children (MIS-C) (Yonker et al. 2021) is the precursor for haptoglobin-2.