Computational modeling of hypercoagulability in COVID-19.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 100 million people worldwide and claimed millions of lives. While the leading cause of mortality in COVID-19 patients is the hypoxic respiratory failure from acute respiratory distress syndrome, there is accumulating evidence that shows excessive coagulation also increases the fatalities in COVID-19. Thus, there is a pressing demand to understand the association between COVID-19-induced hypercoagulability and the extent of formation of undesired blood clots. Mathematical modeling of coagulation has been used as an important tool to identify novel reaction mechanisms and to identify targets for new drugs. Here, we employ the coagulation factor data of COVID-19 patients reported from published studies as inputs for two mathematical models of coagulation to identify how the concentrations of coagulation factors change in these patients. Our simulation results show that while the levels of many of the abnormal coagulation factors measured in COVID-19 patients promote the generation of thrombin and fibrin, two key components of blood clots, the increased level of fibrinogen and then the reduced level of antithrombin are the factors most responsible for boosting the level of fibrin and thrombin, respectively. Altogether, our study demonstrates the potential of mathematical modeling to identify coagulation factors responsible for the increased clot formation in COVID-19 patients where clinical data is scarce.

An In Vivo Model for Elucidating the Role of an Erythroid-Specific Isoform of Nuclear Export Protein Exportin 7 (Xpo7) in Murine Erythropoiesis.

Erythroid nuclear condensation is a complex process in which compaction to one-tenth its original size occurs in an active nucleus simultaneously undergoing transcription and cell division. We previously found that the nuclear exportin Exportin7 (Xpo7), which is erythroid- specific and highly induced during terminal erythropoiesis, facilitates nuclear condensation. We also identified a previously unannotated, erythroid-specific isoform of Xpo7 (Xpo7B) containing a novel first exon Xpo7-1b expressed only in late Ter119+ erythroblasts. To better understand the functional difference between the erythroid Xpo7B isoform and the ubiquitous isoform (Xpo7A) containing the original first exon Xpo7-1a, we created gene-targeted mouse models lacking either exon Xpo7-1a or Xpo7-1b, or both exons 4 and 5, which are completely null for Xpo7 expression. We found that deficiency in Xpo7A does not affect steady-state nor stress erythropoiesis. In contrast, mice lacking the erythroid isoform, Xpo7B, exhibit a mild anemia as well as altered stress erythropoiesis. Complete Xpo7 deficiency resulted in partially penetrant embryonic lethality at the stage when definitive erythropoiesis is prominent in the fetal liver. Inducible complete knockdown of Xpo7 confirms that both steady-state erythropoiesis and stress erythropoiesis are affected. We also observe that Xpo7 deficiency downregulates the expression of important stress response factors, such as Gdf15 and Smad3. We conclude that the erythroid-specific isoform of Xpo7 is important for both steady-state and stress erythropoiesis in mice.