Elevated cytokines, thrombin and PAI-1 in severe HCPS patients due to Sin Nombre virus

Viruses. 2015 Feb 10;7(2):559-89. doi: 10.3390/v7020559.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Chlorocebus aethiops
  • Cytokines / blood*
  • Cytopathogenic Effect, Viral
  • Endothelial Cells / metabolism
  • Endothelial Cells / virology
  • Hantavirus Pulmonary Syndrome / blood*
  • Hantavirus Pulmonary Syndrome / diagnosis
  • Hantavirus Pulmonary Syndrome / immunology
  • Hantavirus Pulmonary Syndrome / virology*
  • Humans
  • Models, Biological
  • Plasminogen Activator Inhibitor 1 / blood*
  • Proteome
  • Proteomics / methods
  • Retrospective Studies
  • Severity of Illness Index
  • Sin Nombre virus / physiology*
  • Thrombin / metabolism*
  • Vero Cells


  • Blood Proteins
  • Cytokines
  • Plasminogen Activator Inhibitor 1
  • Proteome
  • Thrombin