Table 3.

Summary of evidence—List of biomarkers.

Biomarker	Has Role in Risk Stratification?	Has Role in Diagnosis/Detection?	Has Role in Outcome?	Has Therapeutic Role? Or Is It Affected by Stroke Treatment?
C-reactive protein (CRP)	YES, high values are associated with increased risk of stroke and TIA, as well as increased risk of recurrence.	UNCLEAR, although high values appear in acute phases of stroke.	YES, high values are associated with poor outcomes, both in the short and long term. In addition, high values are associated with increased mortality.	YES, statins have been observed to reduce hs-CRP levels.
Thrombin-antithrombin complex (TAT)	Not enough data is available.	UNCLEAR, although higher values have been found in acute ischemic stroke patients.	YES, higher values are associated with poor outcomes.	YES, lower values are associated with better rt-PA success rates.
Alpha2-plasmin inhibitor (a2-PI)	YES, high plasma values are associated with increased stroke recurrence risk.	YES, higher values have been detected in patients with atherothrombotic stroke.	UNCLEAR, although in experimental studies, there was a slight reduction of brain lesion volume by administering human plasmin in order to inhibit a2-PI effects.	YES, higher values are associated with lower rt-PA success rates.
Plasminogen activator inhibitor-1 (PAI-1)	YES, high values are linked to stroke risk and stroke recurrence risk.	UNCLEAR, although higher PAI-1 levels can be found in stroke patients.	UNCLEAR, even if no statistically significant difference was found regarding PAI-1 polymorphism, there is an increased risk of hemorrhagic transformation.	YES, PAI-1 5G/5G is associated with an increased risk of hemorrhage after rt-PA treatment.
Soluble P-selectin (sP-selectin)	UNCLEAR, although increased values are found in patients with aortic atherosclerosis.	YES, high values have been found in stroke patients, with a decrease in value after three months.	YES, high values were found in progressive ischemic stroke.	YES, patients that received statin treatment showed a decrease in blood values of sP-selectin.
E-selectin	YES, genetic polymorphism is associated with increased stroke risk. Alleles association increases the risk even more.	Not enough data is available.	YES, independent predictor of poor three-month outcome	NEED FURTHER EVIDENCE. Experimental studies on mice showed improved outcomes after administering anti-E-selectin monoclonal antibodies.
Adiponectin (APN)	YES, higher values are associated with a lower prevalence of carotid atherosclerotic plaques.	YES, low values can be found at admission in stroke patients compared to control patients.	UNCLEAR, patients with higher levels at admission were more likely to have a poor outcome and increased mortality risk. However, low levels were associated with increased five-year mortality rates.	UNCLEAR. Further studies regarding a viable agonist of APN could hold the answer.
Leptin	YES, higher leptin values were associated with increased stroke incidence. Leptin/Adiponectin ratio could offer additional predictive value for subclinical atherosclerotic changes.	YES, both ischemic and hemorrhagic stroke patients had higher leptin values compared to healthy ones.	YES, patients with stroke history that had higher leptin values had an increased risk of recurrence. A high Leptin/Adiponectin ratio is associated with good outcomes.	YES, leptin values can be decreased by healthy lifestyle changes, statins, and antidiabetic drugs.
Resistin	YES, higher values of resistin are a risk factor for atherothrombotic stroke. The risk is further increased when diabetes or hypertension are present. Specific genotypes such as -420(C>G) are an additional risk factor.	YES, higher values have been found in the early phase of stroke. Experimental studies on mice showed resistin peak values around 12 h from the onset.	YES, high values of resistin were associated with increased stroke severity, increased disability after stroke, and a higher five-year mortality rate.	UNCLEAR. Additional studies need to be performed to confirm the evidence from experimental studies, where resistin was able to decrease brain edema.
D-Dimer (DDs)	YES, increased DDs value is associated with increased risk of ischemic stroke.	UNCLEAR, although in specific etiological subtypes of stroke, like occult cancer or undetected atrial fibrillation, it was shown that higher values of DD could be found. Because of the poor specificity and sensitivity of DD in stroke, the role is still unclear.	YES, higher DD values have been associated with progressive stroke. Also, combined with other biomarkers, it can be used as a predictive factor for the poor outcome of stroke patients.	UNCLEAR, although patients that had poor outcomes after rt-PA treatment had higher values compared to those who had good outcomes post rt-PA. This is suggestive of a decrease in the success rate of rt-PA in high D-dimers level patients.
Homocysteine (Hcy)	YES, high levels are associated with increased stroke risk. Also, patients that already had a stroke and high plasma values have an increased risk of recurrence.	YES, higher values were detected in stroke patients.	YES, higher blood values were correlated with higher severity of stroke using NIHSS score.	YES, a decrease in stroke risk was shown in groups of patients treated with folic acid in order to lower the total Hcy levels. Further studies are required to show the benefits in the general population.
Asymmetric dimethylarginine (ADMA)	YES, several studies showed that ADMA could be linked with the atherosclerosis process and with increased stroke risk.	YES, higher blood values of ADMA can be found in the acute phase of the stroke.	YES, higher values of ADMA have been associated with poor outcomes at 90 days after stroke.	UNCLEAR, rt-PA seems to decrease ADMA levels. A decrease in ADMA value was also seen in patients who received folic acid and B12 vitamin supplements.
Lipoprotein(a) (Lp (a))	YES, Lp (a) is a risk factor for both atherosclerosis and stroke, especially in young patients. High values are also associated with an increased risk of recurrence after a first-time stroke.	YES, higher values were found in stroke patients compared to healthy subjects.	YES, high values of Lp (a) are associated with poor short-term outcomes.	UNCLEAR, but increased values of Lp (a) were documented in patients that received statin treatment.
Lipoprotein lipase (LPL)	YES, polymorphism of LPL is a direct influence on the risk of developing ischemic stroke. Genetic variants have different effects in different ethnic populations, ranging from increasing stroke risk to having a protective effect. There is suggestive data showing LPL proatherogenic effect.	Not enough data.	Not enough data.	Not enough data.
Lipoprotein-associated phospholipase A2 (Lp-PLA2)	YES, high values are strongly associated with large-vessel disease and risk of transient ischemic attack, and also with a high risk of stroke reoccurrence.	YES, high values were found in patients with TIA and in stroke patients with arterial stenosis, especially intracranial stenosis.	YES, high values are associated with increased one-year mortality rates.	Not enough data.
Haptoglobin (Hp)	YES, Hp2 allele and its Hp2-2 genotype are associated with carotid atherosclerosis leading to potential strokes and TIA.	YES, high levels of Hp in the first 12 h of onset are strongly associated with atherothrombotic stroke.	YES, Hp2 allele is associated with premature cardiovascular deaths in patients with first-time ischemic stroke.	UNCLEAR, however, in the Hp2-2 genotype, there was an observed decrease of cardiovascular events after administering Vitamin E.
Serum amyloid A (SAA)	YES, in arteriopathic children with atherothrombotic stroke, SAA correlated with both occurrence and recurrence of stroke.	YES, high values of SAA in the first 12 h were associated with atherothrombotic stroke.	YES, patients with increased SAA at admission are more likely to develop infections, thus increasing mortality.	Not enough data.
Microalbuminuria (MAU)	YES, patients with MAU have an increased incidence of large vessel disease and recurrence of stroke.	UNCLEAR; however, MAU was detected in one-third of stroke patients.	YES, patients with MAU have a worse short-term and long-term prognosis.	UNCLEAR for stroke patients, but angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to reduce MAU in patients with cardiovascular comorbidities.
Pregnancy-associated plasma protein-A (PAPP-A)	YES, PAPP-A has been associated with atherosclerosis, especially unstable atherosclerotic plaques.	YES, high PAPP-A levels are found in stroke patients that have coronary artery disease.	YES, patients with increased levels of PAPP-A have increased stroke severity and are more likely to have a poor outcome.	UNCLEAR, although statin treatment can decrease PAPP-A levels.
Matrix metalloproteinases (MMPs)	YES, high MMPs values are correlated with the presence of unstable atherosclerotic plaques. Also, specific genotypes have proven to be independent risk factors for ischemic stroke.	YES, high values of MMPs can be found in the acute phase of stroke.	YES, increased values of MMPs at admission are associated with poor outcomes and increased mortality risk.	YES, inhibition of MMPs activity in the acute phase of the stroke could be a viable treatment strategy. Statins are a drug class capable of decreasing MMPs activity. Other specific inhibitors could be used in future studies, such as minocycline alongside rt-PA, as a possibility to increase the therapeutic window and also reduce its secondary effects, such as brain hemorrhage. Another specific inhibitor could be phytochemicals derived from Withaniasomnifera, which have the ability to inhibit specifically MMP-2 and MMP-9 and have a potential neuroprotective effect against stroke.
Endostatin	YES, high endostatin values are associated with subclinical atherosclerosis changes.	YES, increased endostatin values can be found in stroke patients.	YES, increased endostatin values are associated with severe disability, increased mortality risk, and three-month cognitive impairment.	Not enough data.
VEGF	YES, low values of VEGF are correlated with intracranial arterial stenosis.	YES, High values of VEGF have been found in the acute phase of atherothrombotic stroke but with no correlation with atherosclerotic changes, such as IMT.	YES, high values of VEGF have been correlated with good clinical outcomes. The endostatin/VEGF ratio is another predictor for good outcomes.	UNCLEAR, administering VEGF-C to mice showed increased plaque stability. Acid folic affects VEGF DNA methylation and slows down the atherosclerotic process.