Circulating TIMP-1 is associated with hematoma volume in patients with spontaneous intracranial hemorrhage

Sci Rep. 2020 Jun 25;10(1):10329. doi: 10.1038/s41598-020-67250-9.


Matrix metalloproteinases (MMPs) are proteolytic zinc-endopeptidases regulated by tissue Inhibitors of matrix metalloproteinases (TIMPs). We evaluated the potential of MMPs and TIMPs as clinical tools for Intracranial Haemorrhage (ICH). Spontaneous non-traumatic ICH patients were recruited from two hospitals: Complejo Hospitalario de Navarra (CHN = 29) and Vall d´Hebron (VdH = 76). Plasmatic levels of MMP-1, -2, -7, -9, -10 and TIMP-1 and their relationship with clinical, radiological and functional variables were evaluated. We further studied the effect of TIMP-1 (0.05-0.2 mg/Kg) in an experimental tail-bleeding model. In CHN, TIMP-1 was associated with admission-hematoma volume and MMP-7 was elevated in patients with deep when compared to lobar hematoma. In VdH, admission-hematoma volume was associated with TIMP-1 and MMP-7. When data from both hospitals were combined, we observed that an increase in 1 ng/ml in TIMP-1 was associated with an increase of 0.14 ml in haemorrhage (combined β = 0.14, 95% CI = 0.08-0.21). Likewise, mice receiving TIMP-1 (0.2 mg/Kg) showed a shorter bleeding time (p < 0.01). Therefore, the association of TIMP-1 with hematoma volume in two independent ICH cohorts suggests its potential as ICH biomarker. Moreover, increased TIMP-1 might not be sufficient to counterbalance MMPs upregulation indicating that TIMP-1 administration might be a beneficial strategy for ICH.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Biomarkers / blood
  • Disease Models, Animal
  • Female
  • Head / diagnostic imaging
  • Hematoma / blood
  • Hematoma / diagnosis*
  • Hematoma / drug therapy
  • Hematoma / etiology
  • Humans
  • Intracranial Hemorrhages / blood
  • Intracranial Hemorrhages / complications
  • Intracranial Hemorrhages / diagnosis*
  • Intracranial Hemorrhages / drug therapy
  • Male
  • Matrix Metalloproteinase 7 / blood
  • Mice
  • Prospective Studies
  • Severity of Illness Index
  • Tissue Inhibitor of Metalloproteinase-1 / blood*
  • Tissue Inhibitor of Metalloproteinase-1 / therapeutic use
  • Tomography, X-Ray Computed


  • Biomarkers
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • MMP7 protein, human
  • Matrix Metalloproteinase 7