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

Abstract

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.

Figure 1

Fixed effect meta-analysis to assess the effect of admission TIMP-1 and hematoma volume in ICH patients. Beta coefficients were adjusted for location, hypertension and NIHSS in both cohorts (Cohort 1 = CHN and Cohort 2 = VdH).

Figure 2

TIMP-1 effects in mice experimental tail bleeding. (a) Bleeding time of animals treated with saline (n = 5), TIMP-1 (0.05 mg/Kg, n = 4) and TIMP-1 (0.2 mg/Kg, n = 3). (b) Blood lost obtained after experimental bleeding model. **p < 0.01 and *p < 0.05 vs. Saline.