VWF-ADAMTS13 imbalance bridges infection to stroke

In this issue of Blood Advances, Patel et al¹ present results from their study designed to investigate how respiratory tract infection by either Staphylococcus aureus bacteria or the mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus exacerbates cerebral injury and neurological deficits in mice subjected to experimental ischemic stroke. In the study, mice deficient in either von Willebrand factor (VWF) or ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13) and their wild-type littermates were preconditioned with the bacteria or virus through the intranasal route before being subjected to right middle cerebral artery occlusion (a model of ischemic stroke). They were then evaluated for the severity of cerebral injuries and neurological deficits.

The authors report that VWF deficiency reduced the severity of ischemic stroke, whereas ADAMTS13 deficiency exacerbated it, demonstrating the role of hyperadhesive VWF in the pathogenesis of ischemic stroke. There are 2 strains of ADAMTS13-deficient mice available which are on C57BL/6J and CASA/RK backgrounds. A phenotypic difference between the 2 strains is that plasma levels of VWF are comparable to those of C57BL/6J mice in the former but significantly elevated in the latter.² This study evaluated ADAMTS13-deficient mice on C57BL/6J background, but results from this study would suggest that those on CASA/RK background likely develop even worse neurological deficits on stroke induction.

VWF is the largest adhesive ligand in the blood, primarily binds the platelet glycoprotein Ib-IX-V complex and integrin, and circulates as multimers of different sizes, with large multimers being more active in hemostasis.³ It is constitutively released from endothelial cells during homeostasis but also rapidly released from the storage granules of endothelial cells on pathological insults to the endothelium.⁴ VWF multimers released on induction are enriched in ultralarge forms that are hyperadhesive and prothrombotic by forming high-strength bonds with receptors on platelets and other cells. On their release, these ultralarge VWF multimers are quickly cleaved by ADAMTS13 into smaller forms that remain active in hemostasis but are no longer prothrombotic.

This study is important for several reasons. First, it validates extensive clinical observations that infection acts as a significant triggering event for stroke, propagates its progression, and worsens its outcome.⁵ Second, it identifies the dysregulated VWF-ADAMTS13 axis as a key pathway linking infections to exacerbated cerebral injuries and neurological deficits during acute ischemic stroke. Third, although tested in mice with ADAMTS13 or VWF deficiency, which are rare conditions found in patients with thrombotic thrombocytopenic purpura (TTP) or von Willebrand disease (VWD), the study suggests more broadly that infections induce acquired ADAMTS13 deficiency caused by releasing an excessive amount of ultralarge VWF multimers without a parallel increase in ADAMTS13 release. The molar ratio of circulating VWF and ADAMTS13 in healthy subjects is ∼7:1, which ensures sufficient hemostasis without causing spontaneous thrombosis, as found in patients with TTP, or bleeding, as found in patients with VWD. Infection disrupts this balance, resulting in acquired ADAMTS13 deficiency. It is not known whether the S aureus bacteria or SARS-CoV-2 virus induce a systemic inflammatory state, which is known to cause VWF release from endothelial cells,⁶ or directly affect the adhesive activity of VWF or the enzymatic activity of ADAMTS13. The available evidence supports both causes. For example, the study found elevated levels of the proinflammatory interleukin-6 (IL-6), C-X-C motif chemokine ligand-1, and monocyte chemoattractant protein-1 in mice challenged by S aureus bacteria or SARS-CoV-2 virus, suggesting a systemic inflammatory state. However, IL-6 not only stimulates endothelial cells to release ultralarge VWF multimers but also directly blocks ADAMTS13 to cleave VWF under flow conditions.⁷ Regardless of its causes, the acquired ADAMTS13 deficiency allows insufficiently cleaved and hyperadhesive VWF multimers to accumulate in the blood and on the endothelium to cause more severe cerebral microvascular occlusion.

Acquired ADAMTS13 deficiency has been extensively reported not only in infections and stroke, but also in trauma, traumatic brain injury, autoimmune disease, myocardial infarction, atherosclerosis, and cancer. As an acute-phase reactant, more adhesive VWF multimers are quickly released to enhance hemostasis against trauma-induced bleeding. However, reasons for this acquired ADAMTS13 deficiency to occur in other conditions are far more complex. Although diverse in their causes, these diseases share the common pathology of inflammation, which induces the excessive release of VWF from endothelial cells. In contrast, ADAMTS13 is primarily synthesized in stellate cells of the liver,⁸ which are often impaired during acute severe infection and inflammation. The endothelial cells synthesize ADAMTS13,⁹ but its contribution to plasma ADAMTS13 is unknown. Despite its synthesis in different cells, a longitudinal study reports that increasing plasma levels of VWF during aging is associated with increasing levels of ADAMTS13 to maintain a steady state of VWF cleavage in the general population.¹⁰ This study suggests that the synthesis and release of VWF and ADAMTS13 are intrinsically coordinated during homeostasis but disrupted during infections and other disease states. This acquired ADAMTS13 deficiency also calls into question whether a backup system is in place to regulate VWF adhesive activity in disease states. There is increasing evidence that VWF can also be cleaved by granzyme, plasmin, elastase, proteinase 3, cathepsin G, and matrix metalloprotease 9. All these enzymes are at least partially associated with infection and inflammation. However, we do not yet know what triggers VWF cleavage by these enzymes, what regulates the cleavage by them, and whether the cleavage alters the adhesive activity of VWF.

Conflict-of-interest disclosure: The authors declare no competing financial interests.