The inhibition of FXII as means to inhibit the thromboinflammatory response incited by severe COVID-19 appears an attractive and rational therapeutic target. Activation of the contact pathway is initiated by FXII activation by negatively charged molecules such as NETs, which are increased in severe COVID-19 patients, and platelet-derived PolyP.100 This leads to the generation of thrombin and the activation of bradykinin, of which the latter in particular results in downstream complement activation and the production of inflammatory cytokines.149 Importantly, therapeutic inhibition of FXIIa demonstrates protection from occlusive thrombus formation in animal models of thrombosis without impeding hemostasis.150 Treatment with an inhibitory FXIIa antibody in animal models of systemic inflammatory response syndrome, using a lethal E coli challenge, have shown that FXIIa inhibition improves survival and decreases a number of inflammatory markers including complement activation, neutrophil degranulation, and IL-6.151–153 Importantly, the potential safety of FXII inhibitors is highlighted by the fact that FXII-deficient individuals display no bleeding phenotype, and there is no known effect on immune function.154 A FXIIa inhibitory antibody has recently entered clinical trials for the treatment of hereditary angioedema and therefore represents a promising novel combination of antithrombotic and anti-inflammatory drugs (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03712228).