Table 3.

Biomarkers of inflammation and vascular function

Biomarker	Sample source	Observations
Tumor necrosis factor alpha (TNF-α)	Serum	Elevated TNF-α throughout post-SAH days 0–14 is independently associated with poor long-term outcome [27] Serum TNF-α is not associated with angiographic vasospasm [27] Neither TNF-α nor TNF-α genotype is associated with DCI or poor outcome [82]
	CSF	Elevated CSF TNF-α on post-SAH days 4–10 is associated with poor outcome [28] CSF TNF-α does not show statistical association with outcome [29]
Leukocyte and neutrophil counts	Blood	Elevated blood leukocyte throughout post-SAH days 0–14 is associated with angiographic vasospasm [26] Elevated blood neutrophil count on post-SAH days 2–3 is associated with poor SAH 3-month outcome [26] Two retrospective studies show elevated leukocyte counts on admission are associated with mortality and elevated leukocyte counts during the course of SAH are associated with symptomatic vasospasm [23–25]
Interleukin 6 (IL-6)	Serum	IL-6 is not associated with SAH outcome or angiographic vasospasm [27] Higher IL-6 levels in the early phase (days 3–7) are associated with DIND and unfavorable outcome (GOS 1–3) [25, 30] IL-6 levels elevated over 2 weeks after bleeding, correlate with SAH severity grade [30–32] and vasospasm [30] IL-6 levels are increased with increasing age, intraventricular and intracerebral hemorrhage, seizures, vasospasm, DIND, chronic hydrocephalus, and pneumonia [31] IL-6 on admission is elevated in SAH compared to unruptured aneurysm [31] Higher IL-6 is associated with higher Fisher grade, severe EBI, susceptibility to pneumonia [31]
	CSF	IL-6 is higher in CSF than in serum in SAH [29] CSF IL-6 post-SAH day 5 is elevated in poor outcome group [29]
Plasma-type gelsolin (pGSN)	CSF, serum	Serum and CSF pGSN are decreased in SAH patients compared to controls [35, 36] Blood pGSN is negatively associated with WFNS and Fischer grade and is an independent predictor of poor functional outcome [36]
Metalloproteinase-9 (MMP-9)	CSF, plasma	Elevated MMP-9 in CSF post-SAH days 2–3 is associated with poor 3-month outcome [26] Plasma and CSF MMP9 within 48 h of admission are associated with DCI [33] Elevated serum MMP9 is associated with higher HH grade, vasospasm, and poor outcome [30] One study found no association between MMP9 on post-SAH days 1, 4, 7, 10, and 14 and DCI [34]
Soluble intercellular adhesion molecule-1 (sICAM1)	Serum	sICAM1 is elevated in SAH patients compared to controls Patients with poor outcome (mRS 4–6) have higher sICAM1 levels over first 2 weeks post-SAH compared to patients with good outcome (mRS 0–3) [37] No association between time course of sICAM1 and DCI [34]
C-reactive protein (CRP)	Serum, CSF	No association between blood and CSF CRP time course and DCI in SAH [34] CRP levels are significantly higher after a SAH [38] Higher CRP is associated with EBI and Hunt and Hess grades and increased susceptibility to pneumonia [32, 38] Higher CRP is associated with death or severe disability at 3 months
Interleukin 10 (IL-10)	Serum	Higher Fisher grade on admission results in higher IL-10 Higher IL-10 and CRP are associated with severe EBI and increased susceptibility to pneumonia [38]
Interleukin 1β (IL-1β)	CSF	IL-1β is higher in CSF than in serum in SAH patients [38]
Interleukin 1R antagonist (IL-1Ra)	CSF	IL-1Ra is higher in patients with poor SAH (HH grades 3–4) [28] Elevated IL-1Ra on post-SAH days 4–10 is associated with poor outcome [28]
Monocyte chemoattractant protein-1 (MCP-1)	Serum, CSF	Serum MCP-1 concentrations correlate with poor outcome, but not with angiographic vasospasm [41] CSF MCP-1 is significantly higher in patients with angiographically demonstrated vasospasm [41]
Toll-like receptor 4 (TLR4) expression	Plasma	Patients with SAH show significantly higher TLR4 levels on days 1, 3, and 7 after admission compared to healthy controls [42] Patients with DCI show significantly higher TLR4 levels than those without DCI [42] Admission (day 1) TLR4 level is as an independent factor to predict patients at risk of DCI and/or 3-month poor clinical outcome [42]
Thioredoxin (Trx)	Serum	Trx is a potent antioxidant that modulates inflammation. Elevated plasma Trx levels at admission (within 24 h after initial bleeding) correlate with severity grade (WFNS, Fisher) and poor prognosis after 6 months [45]
Inflammatory cytokines	Serum	Serum samples analyzed at: < 24 h, 24–48 h, and 3–5 and 6–8 days after SAH [43] Systemic inflammatory activity peaked at 24–48 h post-SAH [43] Platelet-derived growth factors (PDGF)-AA, PDGF-AB/BB, soluble CD-40 ligand, TNF-α increased overtime [43] Participants with higher clinical severity had increased levels of pro and antiinflammatory cytokines: IL-6, CC chemokines CCL2, CCL11, colony-stimulating factor (CSF) 3, IL-8, IL-10, CX chemokines CX3CL1, and TNF-α compared to lower-severity patients [43]
Galectin-3	Plasma	Gal-3 plays a role in macrophage activation, angiogenesis, cell-cell adhesion, cell-matrix interactions, and metastasis. Gal-3 is an independent determinant for poor outcome [47] Gal-3 levels on days 1–3 correlate with DCI and infarction, but not with angiographic vasospasm and chronic hydrocephalus [47] ROC indicates cutoff value of 3.30 predicting DCI development (specificity, 62.5%; sensitivity, 90.9%) [47]
Osteopontin (OPN)	Plasma	OPN binds to integrin receptors expressed by leukocytes and induces immune cell adhesion, migration, and survival. OPN levels measured on days 1–3, 4–6, 7–9, and 10–12 correlated with 90-day poor outcome [44] Based on ROC curves, OPN levels at days 10–12 are most useful to predict poor outcome [44] Levels higher at certain days are associated with delayed cerebral ischemia, cerebral infarctions, and hydrocephalus [44]
Von Willebrand factor (vWF)	Serum	vWF levels > 94.5 nmol/L are independently associated with poor 3-month outcome [48] Plasma vWF antigen and activity were higher in SAH patients versus controls. No significant difference between survivors and non-survivors in SAH [49]
Asymmetric and symmetric dimethylarginine (ADMA and SDMA)	Plasma, serum, CSF	ADMA and SDMA inhibit nitric oxide production from L-arginine. ADMA was significantly lower and peak arginine/ADMA ratio was higher in patients with HH 1–2 compared to HH 3–5 [32] Baseline plasma arginine/ADMA ratio is significantly lower in patients with DCI [51] CSF ADMA is associated with DCI and CSF SDMA with 30-day poor neurological outcome [51]
Platelet activation	Plasma	Patients with DCI have more platelet activation compared to those without DCI within 72 h of ictus. At 3 months: death or severe disability is more likely with higher platelet activation [83]
ADAMTS13	Plasma	A zinc-containing metalloprotease that cleaves vWF Plasma ADAMTS13 activity post-bleed days 0, 1, 3, 5, 7, and 10 significantly is lower in SAH than in healthy controls [49]
Neuropeptide Y (NPY)	CSF	NPY is a potent vasoconstrictor that regulates cerebral vascular diameter and cerebral blood flow CSF NPY is significantly higher in SAH compared to controls and CSF NPY from post-SAH days 4–10 is higher in patients with vasospasm [52]

CSF cerebrospinal fluid, DCI delayed cerebral ischemia, DIND delayed ischemic neurological deficit, EBI early brain injury, GOS Glasgow Outcome Score, HH Hunt and Hess grade, SAH subarachnoid hemorrhage, WFNS World Federation of Neurosurgical Societies