In this issue of Blood, Kravtsov and colleagues provide conclusive evidence for factor XII-independent activation of factor XI in plasma. Even though nearly 20 years have passed since thrombin-mediated factor (f)XI activation was first described, the relevance of this feedback activation for coagulation remains controversial. In the activated partial thromboplastin time, fXI becomes activated by fXIIa due to contact activation-initiated coagulation. However, the relevance of fXIIa-mediated fXI activation in hemostasis is questionable because individuals with fXII deficiency do not show signs of a bleeding tendency. In contrast, fXI deficiency is associated with a mild to moderate bleeding tendency, especially in tissues with a high local fibrinolytic activity. Alternative pathways for activation of fXI should therefore exist. Besides fXIIa, thrombin, meizothrombin, and fXIa (auto-activation) were shown to activate fXI. Upon initiation of coagulation with low concentrations of tissue factor, the presence of fXI contributed to (further) thrombin generation. The extra generation of thrombin via this pathway resulted in clot resistance to fibrino-lysis, providing an explanation for the bleeding tendency of fXI-deficient individuals.3 Although feedback activation in coagulation has been described by many laboratories using different techniques, skepticism about its relevance remained. The most recent study that tried to disprove feedback activation of fXI was a study by Pedicord and colleagues in the Proceedings of the National Academy of Sciences. This study could not demonstrate fXIa generation when thrombin or tissue factor was added to plasma. As with all scientific findings, it is much more difficult to prove the absence of an effect than the presence thereof. Also, the technology that was used in this study was clearly inferior compared with earlier publications. However, the authors justifiably concluded that the reagents used in (some of) the previous studies may have contained traces of fXIa that could have led to the erroneous conclusion that fXI activation occurred independent of fXII. Instead of ignoring the conclusions of this paper, Kravtsov et al decide to do one better and demonstrate feedback activation of fXI in plasma. With their report in this issue of Blood, they convincingly succeed.
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