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.

Serum glucose and potassium ratio as a predictive factor for prognosis of acute intracerebral hemorrhage

“…19 However, hypokalemia was not associated with a poor functional outcome after ICH. 2 Post-stroke hyperglycemia has been confirmed to be related to hematoma GPR, glucose/potassium ratio. Combination indicates the combination of the serum glucose/potassium ratio and hematoma volume expansion, presence, and severity of intraventricular extension, perihematomal edema, and poor clinical outcome in patients with acute ICH.…”

“…19 However, hypokalemia was not associated with a poor functional outcome after ICH. 2 Post-stroke hyperglycemia has been confirmed to be related to hematoma Results are presented as odds ratios (95% confidence interval) according to a binary logistic regression analysis. [20][21][22][23][24] The exact pathophysiological mechanism underlying the relationship between post-stroke hyperglycemia and severe neurological deficit or poor outcome in patients with ICH remains unclear.…”

“…1 In recent decades, researchers have given increasing attention to recognition of prognostic biomarkers because early prognosis prediction can aid in the modification of therapeutic strategies and further improve ICH outcomes. Inflammatory biomarkers (such as circulating matrix metalloproteinases and monomeric C-reactive protein levels), 2,3 immune parameters (for instance, the serum neutrophil-to-lymphocyte and lymphocyte-to-monocyte ratios), 4,5 and metabolic or homeostatic indices (e.g., serum magnesium and serum calcium levels) 6,7 have been extensively studied to assess their ability to predict hematoma growth after ICH. However, those indices have not been applied clinically because they are typically unavailable or because of their insignificant clinical value for prognostic prediction.…”

CM-352 Efficacy in a Mouse Model of Anticoagulant-Associated Intracranial Hemorrhage

“…MMPs inhibition has been hypothesized as a promising strategy for the treatment of ICH 30 . In fact, our group previously demonstrated the effectiveness and safety of CM-352 after experimental collagenase-ICH in rats, and discarded any effect of CM-352 on…”

“…(2) PCC reduced hematoma volume and functional decline in experimental ICH associated with warfarin or rivaroxaban; and (3) MMP-10-deficient animals showed smaller hematoma MMP inhibition has been hypothesized as a promising strategy for the treatment of ICH. 30 In fact, our group previously demonstrated the effectiveness and safety of CM-352 after experimental collagenase-induced ICH in rats, and discarded any effect of CM-352 on collagenase activity. 27 In line with these results, the current study shows that CM-352 successfully reduces brain hemorrhage and prevents neurological decline in collagenase-induced ICH in mice.…”