Immunothrombosis and the molecular control of tissue factor by pyroptosis: prospects for new anticoagulants

Abstract

The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional ‘waterfall’ model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1β and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.

Endothelial dysfunction and immunothrombosis in sepsis

“…Numerous studies depicted in Table 4 suggest that pathogens induce monocyte-derived TF expression and release in the circulation, which in turn activates the extrinsic coagulation pathway. The binding of LPS to transmembrane receptors such as TLR4 in monocytes induces TF mRNA expression via NF-κB activation ( 166 ). Moreover, the interaction of pathogen components either with TLRs or directly with intracellular pathways in monocytes can result in inflammasome activation and subsequent TF release via pyroptosis ( 163 , 166 ).…”

Immunothrombosis: Molecular Aspects and New Therapeutic Perspectives

“…In conclusion, clinical and experimental evidence establish cellular death mediated by inflammasomes as a key trigger for immunothrombosis and microvascular thrombosis [ 22 ]. Two key signals are required for the coagulation activation mediated by the inflammasome: induction of TF protein and inflammatory caspase activation that induce TF release through pyroptosis [ 23 ] ( Figure 1 ).…”

“…Several studies have shown that hemostasis can be spared with effective thromboprotection, among them it has been demonstrated that a modified heparin without anticoagulant activity blocks HMGB1, inhibiting the caspase-11 mediated pyroptosis, preventing sepsis, thrombosis, and mortality in mice, without increasing hemorrhagic risk [ 65 ]. It is possible that coagulopathy may be better prevented by inflammasome inhibition of the TF induction rather than by the coagulation factor inhibition [ 17 , 23 ].…”

Innate immune signaling and immunothrombosis: New insights and therapeutic opportunities

“…TF is a 47-kDa membrane glycoprotein and receptor and the key trigger of infection-and injury-induced coagulation [5,[22][23][24]. TF is critical for survival, as deletion in mice leads to universal embryonic death [25][26][27], and defects in TF gene expression are associated with differing clinical outcomes in patients with severe sepsis [28].…”