Plasma Gelsolin Depletion (PGD)

After injury—either from a pathogen attack or a trauma, systemic levels of plasma gelsolin can rapidly become depleted. In cases of overwhelming injury or concurrent co-morbidities, levels can rapidly decline below a critical threshold. Because plasma gelsolin is secreted constitutively by every cell in the body, there is no emergency mechanism to increase production, leaving the body unable to prevent the spread of inflammation as well as compromising its ability to fight pathogens.

In a broad range of published human studies, PGD correlates with morbidity and mortality in both acute and chronic diseases. Depletion occurs with the onset of injury or infection and predicts increased morbidity and mortality across a broad spectrum of clinical presentations as noted below.

    Infection/Lung:

  • Pneumonia
  • Malaria
  • Sepsis, Septic Shock
  • Acute rheumatic carditis
  • Lyme Neuroborreliosis
  • Tick-borne encephalitis
  • Idiopathic Pneumonia Syndrome (IPS) after HSCT
  • Neonatal BronchoPulmonary Dysplasia

    Injury/Trauma:

  • Acute Lung Injury
  • Burns
  • Surgical Trauma
  • Trauma
  • Traumatic Brain Injury

    Inflammation/CV/Metabolic/Renal:

  • Ischemic Stroke
  • Hemorraghic Stroke
  • Diabetes Type 2
  • Rheumatoid Arthritis, SLE
  • Pre-eclampsia
  • Pre-term labor
  • Myocardial Infarction
  • Acute Liver Failure
  • Chronic Renal Disease/ESRD
  • Myonecrosis
  • Pediatric atopic disease

    Neurological:

  • Alzheimer’s Disease, Downs
  • Multiple Sclerosis

Example 1: pGSN Levels in Surgical ICU Predict Outcomes

SICU-with-fill-2

SURGICAL ICU: pGSN levels lower than 61 mg/L ( ~25% of normal values) predicted longer ICU stay, prolonged ventilator use and increased risk of death independent of APACHE II score.

Source: Lee et al, Annals of Surgery, 243:39 9-403 (2006)

For example, in a study of patients in Intensive Care Unit (ICU) after surgery, plasma gelsolin levels of all patients were below normal values and remained relatively stable over 5 days. ICU survivors had significantly higher levels of pGSN compared with ICU non-survivors (p=0.02). In multivariate analyses, only pGSN remained an independent predictor of death in surgical ICU patients (OR=36.89, p=0.04).

Other studies confirm these findings in both acute and chronic disease.

Example 2: pGSN Levels in Renal Disease Predict Outcomes

PGD is a powerful predictor for END-STAGE RENAL DISEASE patients: Greater than 3-fold increase in 1-year mortality in lowest v. highest pGSN groups, independent of other risk factors.

Source: Lee et al, Journal of the American Society of Nephrology, 20(5):1140-8 (2009)

Plasma Gelsolin: Powerful Biomarker Drives The Ability to Intervene Early

pGSN depletion provides a stable potential biomarker which may serve as an early warning system to identify patients at risk. In acute conditions where Plasma Gelsolin Deficiency is observed, the levels fall shortly after the insult and remain consistently low until death or resolution. Based on data from many studies in both animals and humans, it is clear that pGSN levels drop rapidly in acute conditions and more gradually in chronic conditions. The illustrative model below captures the likely dynamics of Plasma Gelsolin Depletion in the Acute v. Chronic situation.

Screen Shot 2015-12-10 at 11.48.25 AMScreen Shot 2015-12-10 at 11.48.40 AM

Model of time course of pGSN depletion in acute (left) v. chronic (right) conditions.

In this illustrative representation, the drop in pGSN precedes clinical complications by 6-48 hours in acute patients and up to 1 year in chronic patients. This time course provides a window of intervention which follows the assessment of status utilizing a biomarker assay in order to correct the pGSN deficiency. The extent of the drop in pGSN levels in multiple conditions has been demonstrated to be proportional to the degree of tissue damage. Moreover, there is a linear correlation of pGSN levels with the risk of poor outcomes, including death, length of time on a ventilator, length of time in the ICU, and length of time in the hospital.