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

Abstract

We evaluated the mechanisms of thrombocytopenia and procoagulant changes in relation with clinical variables in a cohort of patients with acute hantavirus disease.Blood samples of 33 prospectively recruited, consecutive, hospitalized patients with acute Puumala virus–induced hemorrhagic fever with renal syndrome (HFRS) were collected acutely and at the recovery visit (control). Serum thrombopoietin (TPO) and activity of plasma microparticles (MPs) from various cell sources were measured with enzyme-linked immunosorbent assay-based methods. The results were related to data on platelet indices and functions, coagulation variables, and clinical disease.Serum TPO was nearly 4-fold higher acutely compared with the control (median 207 pg/mL, range 56–1258 pg/mL vs. median 58 pg/mL, range 11–241 pg/mL, P < 0.001) and coincided with high mean platelet volume (MPV) and immature platelet fraction (IPF%). Prothrombin fragments and D-dimer were high acutely compared with the control (F1 + 2 median 704 pmol/L, range 284–1875 pmol/L vs. median 249 pmol/L, range 118–556 pmol/L, P < 0.001; d-dimer median 2.8 mg/L, range 0.6–34.0 mg/L vs. median 0.4 mg/L, range 0.2–1.1 mg/L, P < 0.001), and associated with low platelet count and severe acute kidney injury (AKI). MPs’ procoagulant activity was high acutely only among patients with mild AKI (plasma creatinine below the median at the time of the measurement).Upregulated TPO together with high MPV and IPF% confirm active thrombopoiesis, but do not predict severity of HFRS. Simultaneously, elevated prothrombin fragments and d-dimer suggest increased consumption of platelets in patients with severe AKI. Activity of platelet-derived MPs in HFRS should be studied with flow cytometry in a larger cohort of patients.

Mesenteric Vein Thrombosis Following Platelet Transfusion in a Patient with Hemorrhagic Fever with Renal Syndrome: A Case Report

“…Platelet activation markers were higher in HFRS patients with thrombosis compared with those who did not have a thrombosis. 10 Furthermore, thrombocytopenia during HFRS is not caused by decreased thrombopoiesis 10 15 but presumably by platelet consumption potentially by adhesion to activated/infected endothelial cells. 16 17 In addition, Puumala virus–infected endothelial cells themselves have a procoagulatory phenotype with increased tissue factor expression.…”

Coagulopathy in Acute Puumala Hantavirus Infection

“…Bone marrow examinations have shown an increased amount and size of megakaryocytes during acute NE [ 40 ]. An increased mean platelet volume and immature platelet fraction, together with an elevated thrombopoietin level, also refer to an active thrombopoiesis in the bone marrow [ 19 , 20 , 41 ]. An enlarged spleen is a frequently detected lymphoid organ involvement in NE patients.…”

“…Increased circulating prothrombin fragments 1+2 (F1+2), the fibrin degradation product D-dimer, and diminished amounts of physiologic anticoagulants, antithrombin (AT), protein C (PC), and protein S (PS), indicate enhanced in vivo thrombin formation [ 12 , 14 , 96 ]. Thrombin generation may also take place in the shed microparticles in vivo, although no difference in the procoagulant activity of MPs in peripheral circulating blood could be detected when comparing the acute and recovery stages of PUUV infection [ 41 , 97 ]. In a recent study, increased circulating extracellular vesicle (i.e., microparticle) TF activity was observed during NE, which was significantly associated with plasma levels of tPA and PAI-1 [ 98 ].…”

Hypopituitarism after Orthohantavirus Infection: What is Currently Known?

“…On the other hand, thrombopoietin, procoagulant activity, coagulation variables, and platelet indices, e.g., mean platelet volume, are shown not to be predictive of the severity of renal insufficiency and hypotension due to PUUV infection. This further questions the correlation between pituitary damage and the severity of infection [46]. However, thrombocytopenia has shown to be associated with the severity of inflammation, e.g., expressed as a C-reactive protein (CRP), and severity of capillary leakage in acute PUUV infection [47].…”