Elevated thrombopoietin and platelet indices confirm active thrombopoiesis but fail to predict clinical severity of puumala hantavirus infection

Laine, Outi; Joutsi-Korhonen, Lotta; Lassila, Riitta; Huhtala, Heini; Vaheri, Antti; Mäkelä, Satu; Mustonen, Jukka

The most evident finding of our study was the 4-fold elevated level of serum TPO during acute PUUV infection compared with the recovery phase. Elevated platelet indices MPV and IPF% imply that bone marrow response to the TPO stimulus is adequate, and decreased platelet count observed during the acute phase of the disease is contributed by factors other than impaired platelet production. The association of high TPO with decreased platelet functions measured both with PFA-100 and Multiplate was observed during thrombocytopenia. It suggests that active thrombopoiesis, though able to provide with clinical hemostasis, is not sufficient to overcome the diminished functional capacity noted in vitro. TPO did not associate with AKI, the major outcome of HFRS. The markedly increased F1 + 2 and D-dimer further support the idea of platelet consumption in the vasculature by ongoing coagulation and fibrinolysis. Their association with variables reflecting AKI is a novel finding in Finnish PUUV-patients, but in line with a previous observation of high D-dimer under severe disease condition in Swedish patients. [3] We could not detect any increase in MPs' procoagulant activity during acute PUUV infection. That finding, however, needs to be explored in more detail, but MPs have been shown to bind to fibrin surfaces, [13] which may be the case during the hantavirus infection. TPO is a humoral growth factor characterized for its ability to stimulate the production and differentiation of megakaryocytes. TPO is mainly produced in the liver and kidneys, and binding of TPO with its receptor c-mPl on platelet surface initiates intracellular signaling including activation of JAK2/signal transducers and activators of transcription (STAT) pathway. Plasma TPO concentrations vary usually inversely with the platelet count, but mechanisms other than platelet count that affect TPO have also been identified. [14] High plasma concentration of TPO and low platelet count have been reported in patients with Puumala hantavirus, dengue virus, and human immunodeficiency virus (HIV) infection. [9, 15, 16] In HIV-infected patients, c-mPl expression per platelet is elevated, and recombinant human megakaryocytic growth factor reduces the c-mPl expression and restores platelet count to normal level. [16] In a macaque model of HIV, transforming growth factor b (TGFb) downregulates TPO, and combined antiretroviral therapy corrects both plasma TGFb level and platelet count. [17] In severe acute respiratory syndrome induced by a novel coronavirus, TGFb inhibits the effect of high TPO on megakaryocytopoiesis. [18] Inflammatory mediator interleukin 6 (IL-6), however, increases TPO production both in vitro and in vivo. [14] Our finding of high TPO during acute PUUV infection is in line with a previous observation [9] and consistent with both low platelet count and high plasma IL-6 in acute PUUV infection . [19] High plasma level of TPO is suggested to predict sepsis severity in the early disease phase. [20] We now noted an association between plasma level of TPO and the length of hospital stay, the latter variable describing overall disease severity. However, in this study, TPO had no association with any of the variables reflecting AKI that is the major clinical determinant of hantavirus-induced HFRS.