TF pathway inhibitors
TF and factor VIIa levels are elevated in the bronchoalveolar lavage fluid of patients with severe pneumonia, and the central role of TF for initiating coagulation makes it an attractive target for therapeutic intervention against the potential negative consequences of coagulation activation. Tissue factor pathway inhibitor (TFPI) is a central endogenous regulator of TF pathway activity and thrombin generation. This glycoprotein is mainly expressed by endothelial cells and platelets and acts by directly inhibiting factor Xa. The Xa-TFPI complex subsequently also inhibits the TF-VIIa complex. In preclinical non-human primate models of endotoxaemia, blockade of TF-VIIa, using a competitive inhibitor of TF (site-inactivated factor VIIa), inhibits the TF pathway and reduces lung inflammation and deposition of fibrin [35, 36]. A phase II clinical trial of recombinant human TFPI (rhTFPI; Tifacogin) in patients with severe sepsis decreased concentrations of IL-6, an important pro-inflammatory cytokine that is increased in COVID-19 pneumonia and a major target in ongoing clinical trials [37, 38]. However, in the Optimised Phase III Tifacogin (rTFPI) in Multicenter International Sepsis Trial (OPTIMIST phase III) for patients with severe sepsis with a high international normalised ratio (≥1.2), rhTFPI did not improve 28-day mortality, despite reducing evidence of inflammation [39]. Administration of rhTFPI and heparin concomitantly was associated with increased bleeding, although a post hoc analysis did suggest rhTFPI improved survival in patients with severe community-acquired pneumonia (CAP) for whom the microbiological aetiology was known and heparin had not been given [40]. However, the subsequent Recombinant Tissue Factor Pathway Inhibitor in Severe Community-Acquired Pneumonia (CAPTIVATE) trial [41] did not demonstrate improved survival for patients with severe CAP treated with rhTFPI. Although TFPI was largely disappointing in the setting of sepsis, the advantages of targeting the TF pathway in preventing the development of capillary microthrombi, as well as inflammation, might outweigh potential risks.