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Blood biomarkers for stroke

Blood biomarkers for stroke
Literature review current through: Jan 2024.
This topic last updated: May 31, 2022.

INTRODUCTION — This topic will discuss candidate blood biomarkers that may have a role in the evaluation and care of patients with stroke, as well as some of the more promising markers under investigation (table 1). Details about the clinical evaluation of stroke are reviewed elsewhere. (See "Overview of the evaluation of stroke".)

Specific blood biomarkers of autoimmune and hypercoagulable conditions relating to stroke are discussed separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Hypercoagulable states'.)

GENERAL CONSIDERATIONS — While measurement of blood markers of cardiac myocyte injury such as troponin has revolutionized the evaluation and management of patients with myocardial infarction, the role of blood biomarkers in stroke remains limited.

Potential roles in stroke evaluation – An ideal blood biomarker for stroke would be reliable, rapidly measured, and readily available. A suitable biomarker might assist with stroke diagnosis and determination of stroke subtype or mechanism, such as cardioembolism (see 'Cardioembolic stroke' below), large artery atherosclerosis (see 'Large artery atherosclerosis' below), and hypercoagulability (see 'Hypercoagulability' below) [1]. Other potential roles for stroke biomarkers include help in predicting response to acute therapy and in guiding specific primary and secondary prevention strategies (table 2).

Numerous biomarkers are associated with stroke outcome (see 'Stroke outcome' below), including the risk of first or recurrent stroke, though how to incorporate these markers into clinically meaningful prognostic tools remains controversial. Markers may also predict risk of early complications in stroke patients, allowing closer monitoring and earlier intervention. However, it remains uncertain how much additive value is provided beyond traditional risk assessment.

Challenges to biomarker development in stroke diagnosis – The development of diagnostic blood biomarkers for stroke, which might help distinguish stroke from mimics, faces tremendous challenges given the heterogeneity of stroke, the presence of the blood-brain-barrier, and the complexity of brain injury. Additionally, the optimal timing of measurement related to stroke is unknown, and significant variability across studies makes functional comparison challenging. To date, individual markers have lacked sufficient sensitivity and specificity for stroke diagnosis [2,3]. Panels of biomarkers may hold greater promise and are under active study, though they too have yet to demonstrate sufficient accuracy to be of clinical use [4-9].

CANDIDATE BIOMARKERS — A number of candidate biomarkers for stroke are listed in the table (table 1).

Cardiac biomarkers — Brain natriuretic peptide (BNP), also called B-type natriuretic peptide, is the main cardiac biomarker studied for its relationship with stroke.

BNP – BNP is a neurohormone initially identified in the brain but released primarily from the heart. BNP is secreted from the cardiac ventricles in response to increased wall tension (myocyte stretch) or volume overload. Physiologically, BNP has diuretic, natriuretic, and hypotensive effects (see "Natriuretic peptide measurement in heart failure", section on 'Physiologic role in HF'). It increases urinary excretion of sodium, leading to expanded volume of urine, relaxes vascular smooth muscle, and inhibits both the sympathetic and renin-angiotensin-aldosterone systems. BNP is synthesized as a prohormone (proBNP), which is cleaved after release in the circulation into the biologically active C-terminal fragment and the inactive N-terminal (NT-proBNP) fragment. The half-life and stability of NT-proBNP is several times that of BNP, leading to generally higher concentrations of NT-proBNP.

As discussed below, measurement of BNP in the setting of cryptogenic stroke is helpful to assess the likelihood of a cardioembolic source, including the presence of paroxysmal atrial fibrillation, although optimal cutoff values for individual assays are undefined. Substantially elevated BNP levels suggest the need for intensive cardiac evaluation, including echocardiography and prolonged cardiac rhythm monitoring. (See 'Cardioembolic stroke' below.)

Plasma BNP or NT-proBNP is useful as a component of the evaluation of suspected heart failure when the diagnosis is uncertain. Details of BNP use in the cardiac setting are discussed elsewhere. (See "Natriuretic peptide measurement in heart failure" and "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Natriuretic peptide'.)

Markers of stress response — Biomarkers of stress response that have been studied for their association with stroke include copeptin and cortisol.

Copeptin – Copeptin is a peptide consisting of the C-terminal part of pro-arginine vasopressin (AVP), which is released together with AVP from the pituitary in response to hemodynamic or osmotic stimuli. Copeptin has been associated with stroke risk and stroke outcome. (See 'Copeptin and stroke risk' below and 'Markers generally associated with stroke outcome' below.)

Cortisol – Acute physiologic stressors including stroke trigger activation of the hypothalamic-pituitary-adrenal axis and result in increased cortisol levels. Elevated cortisol level has been associated with stroke outcome. (See 'Markers generally associated with stroke outcome' below.)

Markers of atherogenesis/inflammation — Markers of atherogenesis and/or inflammation include C-reactive protein (CRP), fatty acid–binding protein 4 (FABP4; also known as adipocyte protein AP2), lipoprotein-associated phospholipase A2 (Lp-PLA2), mannose-binding lectin (MBL), and procalcitonin.

CRP is an acute phase reactant predominantly produced by the liver and regulated by inflammatory cytokines. It generally increases in response to injury, infection, or inflammation, and has been studied extensively as a predictor of cardiovascular disease and an indicator of underlying systemic atherosclerosis. Standardized high-sensitivity assays (hs-CRP) are widely available. CRP elevation has been associated with stroke risk and large artery atherosclerosis. (See 'CRP and stroke risk' below and 'Large artery atherosclerosis' below.)

The role of CRP in the estimation of cardiovascular risk and decision-making about statin therapy is reviewed separately. (See "C-reactive protein in cardiovascular disease".)

FABP4 is a cytosolic lipid chaperone involved in regulating cellular lipid metabolism and lipid-induced endoplasmic reticulum stress in macrophages and the role of macrophages in atherosclerosis [10]. FABP4 elevation has been associated with stroke outcome. (See 'Markers generally associated with stroke outcome' below.)

Lp-PLA2 is an enzyme expressed predominantly by leukocytes that is involved in the metabolism of low-density lipoprotein to pro-inflammatory mediators. It is a vascular-specific inflammatory biomarker highly expressed in the necrotic core of atherosclerotic plaque and is linked to plaque inflammation and instability. Both Lp-PLA2 mass and activity can be measured in serum or plasma. Diagnostic testing for Lp-PLA2 mass is available and used clinically for long-term cardiovascular risk prediction, though it is not commonly used in clinical practice for stroke evaluation. Although some studies suggest better reproducibility and reliability in vascular risk prediction over time compared with Lp-PLA2 mass [11,12], the practical performance characteristics of the Lp-PLA2 activity assay are less well-defined. Lp-PLA2 elevation has been associated with stroke risk and large artery atherosclerosis. (See 'Lp-PLA2 and stroke risk' below and 'Large artery atherosclerosis' below.)

MBL is a recognition molecule that plays a role in innate immunity and is an activator of the complement pathway [13]. Interest in MBL has increased with evidence that the complement system is involved in the cascade of events, including coagulation, that are triggered by brain ischemia [14]. MBL has been associated with stroke outcome. (See 'Markers generally associated with stroke outcome' below.)

Procalcitonin is the precursor of calcitonin and is synthesized in various inflammatory states (eg, infection, shock, trauma, surgery, burn injury, chronic kidney disease), leading to its interest in stroke. Procalcitonin has been associated with stroke outcome. (See 'Markers generally associated with stroke outcome' below.)

Procalcitonin is best known for its role as a biomarker that helps distinguish bacterial infection from other causes of infection or inflammation. (See "Procalcitonin use in lower respiratory tract infections".)

Markers of hemostasis — Markers of hemostasis include D-dimer and fibrinogen.

D-dimer is a fibrin degradation product generated during fibrinolysis, and levels are elevated in the setting of active clot formation and turnover. In clinical practice, D-dimer levels are incorporated into diagnostic algorithms used to identify patients with deep vein thrombosis and pulmonary embolism, and an elevated D-dimer level is supportive of the diagnosis of cerebral venous thrombosis. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'D-dimer' and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'D-dimer'.)

In addition, measurement of D-dimer in the setting of cryptogenic stroke may be helpful to assess the likelihood of cancer-related hypercoagulability, though optimal cutoff values for individual assays are undefined. (See 'Hypercoagulability' below.)

Similarly, elevated D-dimer levels may identify patients with cryptogenic stroke potentially attributable to coronavirus disease 2019 (COVID-19) hypercoagulability. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.)

Fibrinogen is the fundamental precursor to formation of the fibrin clot. Elevated fibrinogen levels have been shown to correlate with stroke risk, increased stroke severity, and poor outcome after stroke. A fibrinogen depletion coagulopathy may also play a role in hemorrhagic complications following use of intravenous thrombolytic therapy for acute ischemic stroke. (See 'Fibrinogen and stroke risk' below and 'Intracerebral hemorrhage' below and 'Markers generally associated with stroke outcome' below.)

Markers of brain or vascular injury — Markers of brain and or vascular injury include cellular fibronectin (c-Fn), glial fibrillary acidic protein (GFAP), matrix metalloproteinase 9 (MMP9), neuron-specific enolase (NSE), and S100 calcium binding protein B (S100B).

c-FN is a glycoprotein primarily produced by endothelial cells, particularly vascular endothelium. Elevated c-FN levels have been associated with hemorrhagic transformation. (See 'Intracerebral hemorrhage' below.)

GFAP is predominantly produced by astrocytes, making it a potential brain-specific biomarker. It is released into the blood following stroke [15] and other types of brain injury. (See 'Intracerebral hemorrhage' below.)

MMP9 is a proteolytic enzyme that specifically degrades the major components of the basal lamina surrounding cerebral blood vessels. MMP9 elevation has been associated with intracerebral hemorrhage. (See 'Intracerebral hemorrhage' below.)

NSE, an enzyme released after neuronal damage, has been studied as a marker for brain injury (see "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis", section on 'Biochemistry'), including cerebral infarction. A systematic review of 12 studies including 597 patients concluded that measurement of NSE was of limited value for diagnosis of acute ischemic stroke, even though serum NSE levels were elevated in patients with stroke compared with controls, correlated with infarct volume, and correlated with the degree of neurologic deficit [16]. Major problems with NSE as a biomarker include delayed release into the systemic circulation after brain injury such that elevations occur too late to be clinically useful, and lack of specificity for cerebral infarction. As an example, a study of 72 patients with suspected stroke found that the sensitivity and specificity of NSE for the diagnosis of stroke was only 53 and 64 percent, respectively [17].

S100B is an astroglial protein that has been studied as a serum marker for cerebral injury and disruption of the blood brain barrier. Small single-center studies have suggested S100B levels measured at multiple time points after stroke were predictive of a malignant course [18] and larger infarct volume and poor outcome [19]. It has also been investigated as an independent predictor of hemorrhagic deterioration after thrombolysis in ischemic stroke patients and as a diagnostic marker for stroke; in both of these scenarios, accuracy is too low to be clinically useful [2,20].

STROKE RISK

BNP and stroke risk — Elevated brain natriuretic peptide (BNP) levels have been associated with an increased risk of incident stroke. As examples, in data from a European consortium of population-based cohort studies, with more than 58,000 stroke-free participants followed for a median of approximately eight years, increasing levels of NT-proBNP were positively associated with the risk of ischemic and hemorrhagic stroke [21]. Subjects in the highest NT-proBNP quartile (NT-proBNP >82.2 pg/mL) had twofold greater risk of stroke than those in the lowest quartile (NT-proBNP <20.4 pg/mL), independent of other risk factors. In a subset of 1502 subjects in the population-based REGARDS study who had baseline NT-proBNP levels measured, those in the highest quartile of NT-proBNP levels had a nearly threefold increased risk of first stroke compared with those in the bottom quartile, even after adjusting for traditional vascular risk factors. Elevated BNP was particularly associated with cardioembolic stroke, with a ninefold greater risk for those in the top compared with the bottom quartile of NT-proBNP levels [22]. Another study of 381 patients admitted to a stroke unit with diagnosis of transient ischemic attack (TIA) reported that an NT-proBNP cut-off of >800 pg/mL was independently associated with higher risk of stroke over a mean follow-up of 37 months. The risk was highest in the patients with cardioembolic TIA; however, the association also held to a lesser degree for TIA of undetermined source and for atherothrombotic TIA [23].

Elevated NT-proBNP levels appear to predict stroke risk even in patients with known atrial fibrillation treated with anticoagulation. In 6189 patients with available blood samples in the RE-LY trial, which randomized patients with atrial fibrillation to warfarin or dabigatran, subjects with plasma NT-proBNP levels in the highest quartile (>1402 ng/L) had an annual stroke risk of 2 percent, while those in the lowest quartile (<387 ng/L) had an annual stroke risk of 0.8 percent [24]. NT-proBNP remained a predictor of stroke even after thromboembolic risk adjustment using the CHA2DS2-VASc risk model score (see "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'). Another study evaluated 14,892 patients with available blood samples from the ARISTOTLE trial, which randomized patients with atrial fibrillation to warfarin or apixaban; subjects with NT-proBNP levels in the highest quartile (>1250 ng/L) had an annual risk of stroke or systemic embolism of 2.2 percent, while those in the lowest quartile (≤363 ng/L) had an annual stroke risk of 0.7 percent [25]. Addition of NT-proBNP to the CHA2DS2-VASc score significantly improved prediction of embolic events.

While these data establish an increased risk of stroke associated with elevated BNP levels, it remains unclear how measurement of BNP might be incorporated into clinical practice, given that identified cut-off levels vary widely across studies. In addition, strategies for modifying treatment based on BNP levels in patients without a history of stroke have not been evaluated. However, it may be sensible to consider BNP levels in decision-making about use of oral anticoagulation for patients with otherwise low-risk atrial fibrillation.

CRP and stroke risk — Overall, available data do not suggest a clinically useful role of C-reactive protein (CRP) measurement in estimating future stroke risk for either first or recurrent stroke. A number studies have found an association between CRP and risk of first ischemic stroke in healthy adults [11,26-34], but this association is frequently attenuated after adjustment for traditional vascular risk factors, and the degree of absolute risk increase is small. As an example, a meta-analysis of 54 prospective longitudinal studies and individual records from over 160,000 patients without history of vascular disease demonstrated a significant association between CRP concentration and risk of first ischemic stroke [34]. Risk ratios per threefold higher CRP levels were 1.46 (95% CI 1.32-1.61) for ischemic stroke and 1.07 (95% CI 0.86-1.32) for hemorrhagic stroke. the association with ischemic stroke remained significant but attenuated after adjustment for conventional vascular risk factors.

The utility of CRP for predicting the risk of recurrent ischemic events after an initial transient ischemic attack or stroke is also unclear. One problem is that CRP levels increase acutely after stroke, raising uncertainty about the use of poststroke levels to predict long-term vascular risk [35]. Overall, there appears to be a modest correlation between CRP levels and recurrent stroke risk, though data are inconsistent.

In 6015 patients with prior stroke or transient ischemic attack in the PROGRESS study, CRP was associated with significantly increased risk of recurrent ischemic stroke after adjustment for other vascular risk factors [36]. The odds ratio comparing the highest tertile CRP with the lowest was 1.39 (95% CI 1.05-1.85). In 1244 patients with lacunar stroke in the SPS3 trial, those with levels the top quartile (hs-CRP >4.86 mg/L) compared with the bottom quartile had a significantly higher risk of recurrent ischemic stroke (hazard ratio 2.54, 95% CI 1.30-4.96) even after adjustment for traditional risk factors [37]. In contrast, a report of 467 patients with prior ischemic stroke in the Northern Manhattan Stroke Study found no difference in risk of recurrent stroke for those in the highest quartile of hs-CRP compared with the lowest after adjustment for traditional vascular risk factors [11].

Fibrinogen and stroke risk — Fibrinogen levels are associated with the risk of first stroke. In a meta-analysis of 31 prospective studies that included individual data from over 150,000 subjects without a prior history of stroke or cardiovascular disease, fibrinogen had a moderately strong association with risk of any stroke [38]. The hazard ratio for stroke was 2.06 for every 1 g/L increase in fibrinogen (95% CI 1.83-2.33), with only a modest attenuation of the effect after adjustment for other vascular risk factors. The relationship between fibrinogen and stroke risk was strongest in younger participants (age 40 to 59 years).

The association between fibrinogen and risk of recurrent stroke is less clear. In 472 patients with ischemic stroke included in a substudy of the PROGRESS trial, those in the top tertile of fibrinogen levels (>4.04 g/L) compared with the bottom tertile (<3.32 g/L) had a significantly increased recurrent stroke risk (odds ratio 1.34, 95% CI 1.01-1.78) [36]. However, in 817 subjects with ischemic stroke in the Edinburgh Stroke Study, no clear relationship between fibrinogen and risk of recurrent stroke was seen [39].

Overall, these data suggest that fibrinogen measurement might be used in moderate-risk patients with no history of stroke, particularly younger patients, to assist with decisions about whether to implement prevention strategies. However, there is no defined threshold level for fibrinogen, and the incremental additive value in improving risk reclassification has not been established. For patients with prior stroke, fibrinogen measurement is unlikely to impact treatment decisions.

Lp-PLA2 and stroke risk — A meta-analysis of 79,036 subjects in 32 prospective studies found that elevations in Lp-PLA2 mass and activity were associated with an increased risk for ischemic stroke after adjustment for other predictors of vascular risk [40]. The association was strongest for Lp-PLA2 mass; for each standard deviation increase in Lp-PLA2 mass level, the risk of ischemic stroke increased 14 percent. In one population-based study, the risk of incident stroke was doubled in patients in the highest compared with lowest quartile of Lp-PLA2 levels [41]. Another population-based longitudinal study with over 1900 participants and a median follow-up of 11 years found that the association between Lp-PLA2 level and stroke risk varied by race and ethnicity; Lp-PLA2 was associated with an increased risk of atherosclerotic stroke in non-Hispanic White subjects but not in Hispanic or Black subjects [42]. Further study is needed to determine if the relationship of Lp-PLA2 and stroke risk differs according to race and ethnicity.

These data suggest the potential for using Lp-PLA2 measurement to determine whether to implement primary prevention strategies, such as antiplatelet or statin therapy, in patients otherwise at intermediate risk of stroke where uncertainty about the benefit of these therapies exists. An Lp-PLA2 mass level of 235 ng/mL has been suggested as a reasonable threshold for identifying those at increased cardiovascular risk [43]. However, measurement of Lp-PLA2 is not appropriate in low-risk patients (ie, those with no or minimal vascular risk factors) or high-risk patients (ie, those with known cardiovascular disease risk factors, including prior stroke), as it would be unlikely to change management.

Elevated Lp-PLA2 activity levels may predict short-term risk of recurrent cerebrovascular events, even after adjustment for clinical predictors [44-47]. However, Lp-PLA2 measurement appears unlikely to impact treatment decisions for secondary prevention in patients with prior stroke; the change in risk assessment in this setting does not appear sufficient to alter management.

Copeptin and stroke risk — In a population-based study of over 1000 patients with ischemic stroke or TIA, increased copeptin was associated with recurrent cerebrovascular and other vascular events [48]. Another report of 100 patients admitted with TIA found that copeptin levels were higher in patients with recurrent cerebrovascular events [49].

STROKE MECHANISM

Cardioembolic stroke — The strongest evidence for blood biomarkers linked with cardioembolic stroke supports an association with brain natriuretic peptide (BNP) and midregional pro-atrial natriuretic peptide (MR-proANP); lesser evidence suggests an association with D-dimer.

BNP – Elevated plasma BNP levels are associated both with heart failure and with atrial fibrillation (AF) [50], two important cardioembolic stroke mechanisms with specific management implications. Measurement of BNP may thus help focus the stroke evaluation on the most likely etiologic mechanism. Identification of paroxysmal AF is a particular challenge, as detection rates of AF vary significantly based upon the monitoring strategy used. Paroxysmal AF, if transient, infrequent, and largely asymptomatic, may be undetected on standard cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors. More prolonged cardiac event monitoring (eg, for several weeks) can significantly increase the detection of AF in patients with transient ischemic attack or acute ischemic stroke (see "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'). Measurement of BNP can be a useful adjunct to determining which patients are most likely to harbor occult AF.

The association of elevated plasma BNP with cardioembolic stroke is supported by the results of several systematic reviews and meta-analyses [51-53]. In one of the larger individual studies, which evaluated 707 patients with acute ischemic stroke or transient ischemic attack, a plasma BNP >76 pg/mL was an independent predictor of a cardioembolic mechanism (odds ratio 2.3, 95% CI 1.4-3.7) [54]. The sensitivity and specificity of BNP >76 pg/mL for identification of a cardioembolic mechanism was 72 and 68 percent, respectively.

Two studies evaluated NT-proBNP for identification of patients most likely to benefit from prolonged cardiac monitoring. In a study of 429 patients with ischemic stroke, including 103 with stroke attributed to AF, NT-proBNP ≥505 pg/mL had a sensitivity of 93 percent and specificity of 72 percent for identifying AF-related versus noncardioembolic stroke mechanism [55]. A study of 398 stroke patients from the Find-AF Randomized trial cohort with sinus rhythm on presenting EKG and no history of AF found that those with BNP ≥100 pg/mL benefited more from prolonged cardiac monitoring than those with BNP <100 pg/mL with a number needed to screen of 3 versus 18, respectively [56].

Further evidence supporting BNP as a predictor of cardioembolic stroke comes from a post-hoc analysis of WARSS, a randomized trial that compared warfarin and aspirin in the prevention of recurrent ischemic stroke in patients with presumed noncardioembolic stroke. Among a cohort of 1028 patients in WARSS for whom blood samples were available, those with plasma NT-proBNP concentrations in the top 5 percent (>750 pg/mL) had a significant reduction in the composite endpoint of stroke or death favoring warfarin (hazard ratio 0.30, 95% CI 0.12-0.84) [57]. In contrast, no benefit of warfarin over aspirin was seen in those with NT-proBNP levels ≤750 pg/mL. These findings suggest that elevated NT-proBNP concentrations identified a subgroup of patients with an occult cardioembolic stroke mechanism (eg, from atrial fibrillation or heart failure) who benefited from anticoagulation. However, WARSS was performed prior to widespread use of prolonged cardiac monitoring for acute stroke, and occult atrial fibrillation may have been underdiagnosed.

Taken in its entirety, the data support a role for BNP as a predictor of cardioembolic stroke, particularly cardioembolism due to heart failure and atrial fibrillation. While various threshold levels have been identified in different studies, comparison across studies is difficult due to the use of different assays and variable measurement of BNP versus NT-proBNP. Nevertheless, it appears that the likelihood of cardioembolism rises linearly with BNP, such that markedly elevated levels in the setting of cryptogenic stroke should raise suspicion for a cardioembolic source with more aggressive diagnostic pursuit of heart failure and paroxysmal atrial fibrillation.

MR-proANP – Several reports have found that elevated levels of MR-proANP were associated with cardioembolic stroke and atrial fibrillation [58-60]. As an example, a study of over 1700 patients with acute ischemic stroke found that elevated levels of MR-proANP, collected within 24 hours of symptom onset, were associated with cardioembolic stroke and newly diagnosed atrial fibrillation [59].

D-dimer – D-dimer is typically elevated in patients with stroke due to a cardioembolic source, though levels of elevation are usually more modest compared with cancer hypercoagulability. As an example, in a study of 707 prospectively evaluated patients with acute ischemic stroke, D-dimer levels were significantly higher in stroke classified as cardioembolic (1.1 mcg/mL) compared with stroke classified as atherothrombotic (0.5 mcg/mL), lacunar (0.6 mcg/mL), or undetermined (0.8 mcg/mL) [54]. Similar results have been seen in a number of other smaller studies [61-64]. Given this, the ability of D-dimer to discriminate between cardioembolic and non-cardioembolic stroke in individual patients is limited.

Large artery atherosclerosis — CRP and Lp-PLA2 may be predictive of carotid artery and other large artery atherosclerosis.

CRP – In a longitudinal study of 179 patients, CRP was an independent predictor for the development and rate of progression of early carotid atherosclerosis [65]. Progression intensified with increasing CRP levels even within the normal range, implicating a possible direct pro-inflammatory and prothrombotic vascular interaction. However, CRP concentration is more predictive of early carotid atherosclerotic activity and development than the extent of atherosclerosis or the degree of carotid stenosis [65,66]. Elevated CRP levels have not been shown to be useful as a diagnostic marker for identifying stroke or transient ischemic attack patients with significant carotid stenosis (>50 percent) [44].

Lp-PLA2 – A population-based longitudinal study with over 1900 participants and a median follow-up of 11 years found that Lp-PLA2 mass levels were associated with stroke due to large artery atherosclerosis [42]. In two earlier studies evaluating patients with acute transient ischemic attack, each with approximately 165 patients, elevated Lp-PLA2 activity was associated with a large artery atherosclerotic mechanism causing the cerebrovascular event [44,45]. However, the discriminatory value of Lp-PLA2 measurement was not sufficient to allow its use as a diagnostic test for this purpose.

Cerebral venous thrombosis — Similar to its role in deep vein thrombosis, D-dimer may be useful for evaluation of patients with suspected cerebral venous sinus thrombosis (CVT). This issue is discussed separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Laboratory tests'.)

Hypercoagulability

With cancer – While relatively infrequent, cancer-associated hypercoagulability is an important stroke mechanism. Some experts, including one author of this topic, measure the D-dimer level routinely in patients with otherwise cryptogenic stroke and pursue aggressive diagnostic testing for occult malignancy in those with very elevated D-dimer levels.

Although there is significant variability in D-dimer assays and specific cut-off values across studies [67], available data suggest that D-dimer elevation is useful for identifying patients at high-risk of having cancer hypercoagulability as a stroke mechanism [68-76]. As examples, in a report of 140 patients with ischemic stroke and active cancer, D-dimer levels were higher in patients with no identified cause of stroke aside from potential cancer hypercoagulability compared with those who had a determined, conventional stroke mechanism (8.4 versus 3.9 mcg/mL) [68]. In a case-control study of patients 204 with ischemic stroke, D-dimer levels were higher in 104 patients with active cancer compared with 100 patients with inactive cancer (5.7 versus 1.0 mcg/mL, versus 0.6 mcg/mL in 408 control patients with ischemic stroke but no history of cancer) [69]. In the active cancer group, elevated D-dimer levels were also associated with absence of a conventional stroke mechanism and the presence of multiple ischemic lesions in different vascular territories.

In a retrospective report, the group of 71 patients with cryptogenic stroke and active cancer had significantly higher plasma D-dimer levels than the group of 277 patients with cryptogenic stroke without cancer or the control group of 33 patients with active cancer but no stroke (10.7 versus 0.5 versus 0.7 mcg/mL) [70]. Using a data-derived D-dimer cutoff of 2.15 mcg/mL, the sensitivity and specificity for identifying cancer hypercoagulability as the stroke mechanism was 74 and 97 percent, respectively. Among 10 patients without known active cancer who had multifocal lesions in different vascular territories and who exceeded the D-dimer cutoff, all had occult malignancy on further work-up.

With COVID-19 – The relationship of elevated D-dimer levels and hypercoagulability associated with COVID-19 as a potential stroke mechanism is discussed separately. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.)

Intracerebral hemorrhage — Glial fibrillary acid protein (GFAP), cellular fibronectin (c-Fn), fibrinogen, and matrix metalloproteinase 9 (MMP9) levels have been associated with acute intracerebral hemorrhage or hemorrhagic transformation.

GFAP – Acute intracerebral hemorrhage may cause sudden destruction of astroglial cells and an early increase in serum GFAP levels, whereas ischemic stroke results in a slower breakdown of astroglial cells and a delayed increase in GFAP levels [77]. Several studies and meta-analyses have demonstrated that GFAP levels are significantly higher in patients with intracerebral hemorrhage compared with ischemic stroke when measured in the acute period (two to six hours after symptom onset), suggesting a potential role in determining stroke subtype [77-85]. However, a number of factors may affect the diagnostic performance of GFAP, including specimen type, measurement method, hemorrhage location (lobar versus deep), hemorrhage volume, and population studied [81,86]. In addition, the sensitivity of GFAP for intracerebral hemorrhage is suboptimal compared with CT scan [86]. These obstacles hinder clinical use of GFAP in this scenario.

c-FN – Prospective studies reported that high pretreatment cellular fibronectin (c-Fn) levels predicted the risk of hemorrhagic transformation after intravenous thrombolysis for acute ischemic stroke [87,88]. A 2020 systematic review identified several small studies suggesting that c-FN is associated with hemorrhagic transformation, severe brain edema, and poor functional outcome [89]. However, a rapid assay that could be used for decision making prior to thrombolysis is not clinically available.

Fibrinogen – Fibrinogen levels decrease and fibrinogen degradation products (FDP) increase significantly within two hours of administration of intravenous thrombolysis for acute ischemic stroke [90,91]. This depletion of fibrinogen and subsequent formation of fibrinogen degradation products can cause an early fibrinogen degradation coagulopathy. While one report of 114 patients found that baseline pretreatment fibrinogen levels did not predict symptomatic intracerebral hemorrhage following intravenous thrombolysis for acute ischemic stroke [92], changes in fibrinogen and FDP may be predictive of hemorrhage.

As examples, a study of 547 patients with acute ischemic stroke treated with intravenous rt-PA found that a ≥200 mg/dL decrease in fibrinogen over the first six hours after thrombolysis was associated with a fourfold increased risk of symptomatic intracerebral hemorrhage compared with a smaller decrease in fibrinogen [93]. In a similar cohort of 157 patients, an increase in fibrinogen degradation products >200 mg/L at two hours after thrombolysis was associated with a nearly fivefold increase in the risk of early (within 24 hours) parenchymal intracerebral hemorrhage [91]. Early hematomas were significantly predictive of poor prognosis at three months.

While these data suggest a potential role of serial fibrinogen measurement for assessing risk of post-thrombolysis hemorrhage, it is unclear how this might impact the decision to start intravenous thrombolysis treatment.

MMP9 – In several small studies, MMP9 was an independent predictor of hemorrhagic transformation associated with acute ischemic stroke, both in patients treated with intravenous thrombolytic therapy [88,94] and in those not treated with thrombolysis [95,96].

STROKE OUTCOME — A number of blood biomarkers have been evaluated for association with stroke outcome. While the strength of supporting evidence varies, none of the biomarkers is sufficiently validated for predicting outcome after stroke in routine clinical use.

Markers generally associated with stroke outcome

BNP – Elevated brain natriuretic peptide (BNP) levels are associated with increased poststroke mortality [97], although the incremental clinical utility of BNP measurement for predicting death after stroke is likely small. In a meta-analysis of individual data from 2258 patients with stroke, the addition of NT-proBNP to clinical variables resulted in a small improvement in prediction of mortality after stroke, reclassifying 8 percent of patients into more accurate risk categories [98]. Data on the association between BNP and functional outcome after stroke are inconsistent [97,99,100].

Copeptin – A systematic review published in 2021 found that copeptin levels were associated with poor outcome in all seven higher-quality studies where it was evaluated [97]. As an example, the multicenter CoRisk study evaluated 788 patients with acute ischemic stroke and measured copeptin levels within 24 hours of symptom onset [101]. The median copeptin levels for those with a favorable and unfavorable outcome were 9.6 and 32.2 pmol/L, respectively. A 10-fold increase in copeptin levels independently predicted unfavorable functional outcome (odds ratio 2.17, 95% CI 1.46-3.22) and mortality (hazard ratio 2.40, 95% CI 1.60-3.60) at 90 days, irrespective of acute treatment including thrombolysis. A risk reclassification analysis showed that copeptin significantly improved risk prediction beyond that achieved using the National Institutes of Health Stroke Scale (NIHSS) score and age. In a further refinement, the investigators derived and validated the CoRisk score, which incorporates four elements (treatment with or without thrombolysis, copeptin level, NIHSS score on admission, and age) to predict outcome at three months after ischemic stroke [102].

Cortisol – In a 2021 systematic review, three of four higher-quality studies assessing cortisol found that higher levels were associated with poor outcome [97]. An earlier systematic review (2014) concluded that elevated cortisol levels after stroke were associated with morbidity and mortality, but the evidence was insufficient to determine if this association was independent of stroke severity [103].

D-dimer – Early stroke progression or recurrence has been associated with increased thrombin generation and fibrin turnover, suggesting that D-dimer levels may help to identify patients at highest risk. D-dimer has been associated with poor stroke outcome in multiple studies [97].

FABP4 – Fatty acid–binding protein 4 (FABP4) levels were associated with poor outcome in several higher-quality studies assessing FAB4 [97].

MBL – Two studies have found that elevated mannose-binding lectin (MBL) levels were associated with poor outcome [97].

Procalcitonin – Three high-quality studies have found that increased procalcitonin levels were associated with poor outcome [97].

Markers inconsistently associated with stroke outcome

CRP – The association of C-reactive protein (CRP) levels and outcome has been inconsistent across multiple studies [97]. Given these results, measurement of CRP for prediction of stroke outcome is not recommended.

Fibrinogen – Fibrinogen levels have been associated with poor outcome after stroke in some reports [90,91,104,105]; however, higher-quality studies have not confirmed this association [97].

MMP9 – The evidence for MMP9 in stroke outcome is inconsistent [89,97]. A 2020 systematic review of cohort or case-control studies with computed tomographic or magnetic resonance imaging and functional outcome data at three months after stroke onset identified 11 studies with over 5000 patients and found no association of MMP9 levels with outcome [89]. There was a very high level of heterogeneity among the included studies, which lowers the reliability of the results.

SUMMARY AND RECOMMENDATIONS

Ideal blood biomarkers for stroke would be reliable, rapidly measured, and readily available, and might assist with diagnosis, determination of stroke subtype or mechanism, or prediction of outcome or response to therapy (table 2). Numerous biomarkers and panels of biomarkers have been studied to improve the early diagnosis of stroke, but none have sufficient sensitivity or specificity for routine clinical use. Several biomarkers are associated with stroke outcome, but it remains uncertain how much additive value is provided beyond traditional risk assessment. Two biomarkers, NT-proBNP and D-dimer, may have the strongest data to support clinical use in differentiating stroke mechanism in particular. (See 'General considerations' above.)

Candidate biomarkers for stroke diagnosis (table 1) include the following, though none have shown sufficient sensitivity or specificity to be clinically useful:

Brain natriuretic peptide (BNP) (see 'Cardiac biomarkers' above)

Copeptin and cortisol (see 'Markers of stress response' above)

C-reactive protein (CRP), fatty acid–binding protein 4 (FABP4), lipoprotein-associated phospholipase A2 (Lp-PLA2), mannose-binding lectin (MBL), and procalcitonin (see 'Markers of atherogenesis/inflammation' above)

D-dimer and fibrinogen (see 'Markers of hemostasis' above)

Cellular fibronectin (c-Fn), glial fibrillary acidic protein (GFAP), matrix metalloproteinase 9 (MMP9), neuron-specific enolase (NSE), and S100 calcium binding protein B (S100B) (see 'Markers of brain or vascular injury' above)

Elevated levels of BNP, CRP, fibrinogen, and Lp-PLA2 have been associated with an increased risk of stroke. (See 'Stroke risk' above.)

Elevated levels of some biomarkers have been associated with specific stroke mechanisms or complications, including BNP (cardioembolic stroke), CRP and Lp-PLA2 (large artery atherosclerosis), D-dimer (cerebral venous thrombosis and hypercoagulability), and GFAP, c-FN, fibrinogen, and MMP9 (intracerebral hemorrhage or hemorrhagic transformation). (See 'Stroke mechanism' above.)

Significant elevations in NT-proBNP may be clinically useful in targeting prolonged cardiac monitoring for those patients with cryptogenic embolic stroke most likely to have undetected paroxysmal atrial fibrillation and in targeting echocardiography at those most likely to have underlying severe heart failure as the stroke mechanism. (See 'Cardioembolic stroke' above.)

Very elevated levels of D-dimer in patients with cryptogenic stroke should raise suspicion of occult malignancy causing cancer hypercoagulability and prompt thorough cancer screening. Elevated D-dimer levels in patients with cryptogenic stroke and COVID-19 may also suggest hypercoagulability as a possible stroke mechanism. (See 'Hypercoagulability' above and "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.)

Biomarkers with the best evidence of an association with stroke outcome include BNP, copeptin, cortisol, D-dimer, FABP4, MBL, and procalcitonin. However, none is sufficiently validated for routine clinical use. (See 'Stroke outcome' above.)

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Topic 96239 Version 19.0

References

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