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Platelet desialylation is a novel mechanism and a therapeutic target in thrombocytopenia during sepsis: an open-label, multicenter, randomized controlled trial.

ABSTRACT: BACKGROUND:Studies in murine models suggested that platelet desialylation was an important mechanism of thrombocytopenia during sepsis. METHODS:First, we performed a prospective, multicenter, observational study that enrolled septic patients with or without thrombocytopenia to determine the association between platelet desialylation and thrombocytopenia in patients with sepsis, severe sepsis, and septic shock. Gender- and age-matched healthy adults were selected as normal controls in analysis of the platelet desialylation levels (study I). Next, we conducted an open-label randomized controlled trial (RCT) in which the patients who had severe sepsis with thrombocytopenia (platelet counts ?50?×?109/L) were randomly assigned to receive antimicrobial therapy alone (control group) or antimicrobial therapy plus oseltamivir (oseltamivir group) in a 1:1 ratio (study II). The primary outcomes were platelet desialylation level at study entry, overall platelet response rate within 14 days post-randomization, and all-cause mortality within 28 days post-randomization. Secondary outcomes included platelet recovery time, the occurrence of bleeding events, and the amount of platelets transfused within 14 days post-randomization. RESULTS:The platelet desialylation levels increased significantly in the 127 septic patients with thrombocytopenia compared to the 134 patients without thrombocytopenia. A platelet response was achieved in 45 of the 54 patients in the oseltamivir group (83.3%) compared with 34 of the 52 patients in the control group (65.4%; P?=?0.045). The median platelet recovery time was 5 days (interquartile range 4-6) in the oseltamivir group compared with 7 days (interquartile range 5-10) in the control group (P?=?0.003). The amount of platelets transfused decreased significantly in the oseltamivir group compared to the control group (P?=?0.044). There was no difference in the overall 28-day mortality regardless of whether oseltamivir was used. The Sequential Organ Failure Assessment score and platelet recovery time were independent indicators of oseltamivir therapy. The main reason for all of the mortalities was multiple-organ failure. CONCLUSIONS:Thrombocytopenia was associated with increased platelet desialylation in septic patients. The addition of oseltamivir could significantly increase the platelet response rate, shorten platelet recovery time, and reduce platelet transfusion. TRIAL REGISTRATION:Chinese Clinical Trial Registry, ChiCTR-IPR-16008542 .

SUBMITTER: Li MF

PROVIDER: S-EPMC5426054 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Platelet desialylation is a novel mechanism and a therapeutic target in thrombocytopenia during sepsis: an open-label, multicenter, randomized controlled trial.

Li Mei-Feng MF Li Xiao-Li XL Fan Kai-Liang KL Yu Ying-Yi YY Gong Jing J Geng Shu-Ying SY Liang Ya-Feng YF Huang Ling L Qiu Ji-Hua JH Tian Xing-Han XH Wang Wen-Ting WT Zhang Xiao-Lu XL Yu Qing-Xia QX Zhang Yuan-Feng YF Lin Peng P Wang Li-Na LN Li Xin X Hou Ming M Liu Lu-Yi LY Peng Jun J

Journal of hematology & oncology 20170511 1

<h4>Background</h4>Studies in murine models suggested that platelet desialylation was an important mechanism of thrombocytopenia during sepsis.<h4>Methods</h4>First, we performed a prospective, multicenter, observational study that enrolled septic patients with or without thrombocytopenia to determine the association between platelet desialylation and thrombocytopenia in patients with sepsis, severe sepsis, and septic shock. Gender- and age-matched healthy adults were selected as normal controls ...[more]

PMID: 28494777

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Project description:Thrombocytopenia and platelet dysfunction are commonly observed in patients with dengue virus (DENV) infection and may contribute to complications such as bleeding and plasma leakage. The etiology of dengue-associated thrombocytopenia is multifactorial and includes increased platelet clearance. The binding of the coagulation protein von Willebrand factor (VWF) to the platelet membrane and removal of sialic acid (desialylation) are two well-known mechanisms of platelet clearance, but whether these conditions also contribute to thrombocytopenia in dengue infection is unknown. In two observational cohort studies in Bandung and Jepara, Indonesia, we show that adult patients with dengue not only had higher plasma concentrations of plasma VWF antigen and active VWF, but that circulating platelets had also bound more VWF to their membrane. The amount of platelet-VWF binding correlated well with platelet count. Furthermore, sialic acid levels in dengue patients were significantly reduced as assessed by the binding of Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL-II) to platelets. Sialic acid on the platelet membrane is neuraminidase-labile, but dengue virus has no known neuraminidase activity. Indeed, no detectable activity of neuraminidase was present in plasma of dengue patients and no desialylation was found of plasma transferrin. Platelet sialylation was also not altered by in vitro exposure of platelets to DENV nonstructural protein 1 or cultured DENV. In contrast, induction of binding of VWF to glycoprotein 1b on platelets using the VWF-activating protein ristocetin resulted in the removal of platelet sialic acid by translocation of platelet neuraminidase to the platelet surface. The neuraminidase inhibitor oseltamivir reduced VWF-induced platelet desialylation. Our data demonstrate that excessive binding of VWF to platelets in dengue results in neuraminidase-mediated platelet desialylation and platelet clearance. Oseltamivir might be a novel treatment option for severe thrombocytopenia in dengue infection.

Project description:IntroductionThe pathogenesis of thrombocytopenia in patients with sepsis is not fully understood. The aims of this study were to investigate changes in thrombopoietic activity over time by using absolute immature platelet counts (AIPC) and to examine the impact of platelet production on thrombocytopenia and mortality in patients with sepsis.MethodsThis retrospective observational study included adult patients with sepsis admitted to the intensive care unit at a university hospital. Two hundred five consecutive sepsis patients were stratified into four groups according to nadir platelet count: severe (nadir ?40×103/?L), moderate (41-80×103/?L), or mild thrombocytopenia (81-120×103/?L), or normal-increased platelet count (>120×103/?L). The development of thrombocytopenia was assessed during the first week; mortality was assessed at day 28.ResultOf the 205 patients included, 61 (29.8%) developed severe thrombocytopenia. On admission, AIPC did not differ among the four groups. In patients with severe thrombocytopenia, AIPC decreased significantly from days 2 to 7, but remained within or above the normal range in the other three groups (overall group comparison, P<0.0001). Multivariate analysis including coagulation biomarkers revealed that AIPC was independently associated with the development of severe thrombocytopenia (day 3 AIPC, odds ratio 0.49 [95% confidence interval (CI) 0.35-0.66], P<0.0001; day 5 AIPC, 0.59 [95% CI 0.45-0.75], P<0.0001). AIPC was a significant predictor of 28-day mortality in Cox hazard models adjusted for Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores (day 3 AIPC, hazard ratio 0.70 [95% CI 0.52-0.89], P = 0.0029; day 5 AIPC, 0.68 [95% CI 0.49-0.87], P = 0.0012).ConclusionsThrombopoietic activity was generally maintained in the acute phase of sepsis. However, a decrease in AIPC after admission was independently associated with the development of severe thrombocytopenia and mortality, suggesting the importance of suppressed thrombopoiesis in the pathophysiology of sepsis-induced thrombocytopenia.

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Platelet desialylation is a novel mechanism and a therapeutic target in thrombocytopenia during sepsis: an open-label, multicenter, randomized controlled trial.

Publications

Platelet desialylation is a novel mechanism and a therapeutic target in thrombocytopenia during sepsis: an open-label, multicenter, randomized controlled trial.

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