Low protein C and incidence of ischemic stroke and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study

J Thromb Haemost. 2009 Nov;7(11):1774-8. doi: 10.1111/j.1538-7836.2009.03577.x. Epub 2009 Aug 19.


Background: Protein C is an important plasma natural anticoagulant. Although protein C deficiency increases risk of venous thrombosis, it remains uncertain whether low protein C increases risk of atherothrombosis.

Objective: To examine whether low protein C may be a risk factor for ischemic stroke or coronary events in a prospective population-based study.

Patients/methods: The Atherosclerosis Risk in Communities Study assessed protein C antigen by ELISA at baseline in 1987-89 and followed participants (n = 13 879) for incident ischemic stroke or coronary events through 2005.

Results: Over a median of 16.9 years of follow-up, 613 ischemic strokes and 1257 coronary heart disease events occurred. Protein C was inversely associated with incidence of ischemic stroke. Adjusted for multiple risk factors, the rate ratios (95% CIs) from highest to lowest quintiles were 1.0, 1.16 (0.90-1.50), 1.22 (0.94-1.58), 1.18 (0.90-1.55) and 1.52 (1.17-1.98). This inverse association was stronger for non-lacunar and cardioembolic stroke than for lacunar stroke. In contrast, there was a positive association between protein C and coronary heart disease in incompletely adjusted models, but no association after adjustment for plasma lipids.

Conclusions: In this cohort study, low protein C was a risk factor for incident ischemic stroke but not coronary heart disease. Levels of protein C associated with stroke risk were not restricted to the traditional 'deficient' range for protein C (< 0.5 percentile), suggesting that other etiologies for a lower protein C, or genetic variants associated with more subtle changes in protein C, are playing a role in disease pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain Ischemia / epidemiology
  • Brain Ischemia / etiology*
  • Cohort Studies
  • Coronary Disease / epidemiology
  • Coronary Disease / etiology*
  • Female
  • Follow-Up Studies
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Prospective Studies
  • Protein C / analysis*
  • Risk Factors
  • Stroke / epidemiology
  • Stroke / etiology*


  • Protein C