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Open AccessArticle

Elevated Cytokines, Thrombin and PAI-1 in Severe HCPS Patients Due to Sin Nombre Virus

1
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
2
Clinical and Translational Science Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
3
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10031, USA
4
Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
5
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-5644, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Eric O. Freed
Viruses 2015, 7(2), 559-589; https://doi.org/10.3390/v7020559
Received: 6 November 2014 / Accepted: 3 February 2015 / Published: 10 February 2015
(This article belongs to the Section Animal Viruses)
Sin Nombre Hantavirus (SNV, Bunyaviridae Hantavirus) is a Category A pathogen that causes Hantavirus Cardiopulmonary Syndrome (HCPS) with case fatality ratios generally ranging from 30% to 50%. HCPS is characterized by vascular leakage due to dysregulation of the endothelial barrier function. The loss of vascular integrity results in non-cardiogenic pulmonary edema, shock, multi-organ failure and death. Using Electric Cell-substrate Impedance Sensing (ECIS) measurements, we found that plasma samples drawn from University of New Mexico Hospital patients with serologically-confirmed HCPS, induce loss of cell-cell adhesion in confluent epithelial and endothelial cell monolayers grown in ECIS cultureware. We show that the loss of cell-cell adhesion is sensitive to both thrombin and plasmin inhibitors in mild cases, and to thrombin only inhibition in severe cases, suggesting an increasing prothrombotic state with disease severity. A proteomic profile (2D gel electrophoresis and mass spectrometry) of HCPS plasma samples in our cohort revealed robust antifibrinolytic activity among terminal case patients. The prothrombotic activity is highlighted by acute ≥30 to >100 fold increases in active plasminogen activator inhibitor (PAI-1) which, preceded death of the subjects within 48 h. Taken together, this suggests that PAI-1 might be a response to the severe pathology as it is expected to reduce plasmin activity and possibly thrombin activity in the terminal patients. View Full-Text
Keywords: hantavirus; PAI-1; ECIS; cell barrier function; hemostasis; proteomics hantavirus; PAI-1; ECIS; cell barrier function; hemostasis; proteomics
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Bondu, V.; Schrader, R.; Gawinowicz, M.A.; McGuire, P.; Lawrence, D.A.; Hjelle, B.; Buranda, T. Elevated Cytokines, Thrombin and PAI-1 in Severe HCPS Patients Due to Sin Nombre Virus. Viruses 2015, 7, 559-589.

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