Muhammad Rizwan Husain, MD

Choi KH, Kim JH, Kim JM, Kang KW, Lee C, Kim JT, Choi SM, Park MS, Cho KH. d-dimer Level as a Predictor of Recurrent Stroke in Patients With Embolic Stroke of Undetermined Source. Stroke. 2021;52:2292–2301.

D-dimer levels are known to be a marker for underlying hypercoagulable state in several studies reporting raised D-dimer levels in patients with cardioembolic stroke, underling malignancy, and venous thromboembolism. However, the role of D-dimer levels to predict recurrent stroke in patients with ESUS (Embolic Stroke of Undetermined Source) is unknown.

The authors in this study evaluated the role of plasma D-dimer levels to help predict recurrent stroke (ischemic or hemorrhagic) within 1 year in patients with ESUS, as well as to evaluate possible etiologies of recurrent strokes based on D-dimer levels.

This was a single-center retrospective study that enrolled patients if they were admitted within 24 hours of acute ischemic stroke and fulfilled the diagnostic criteria for ESUS (head imaging with either a CT or MRI Brain, Intra and Extracranial imaging with a CTA or MRA, 12 lead EKG, cardiac monitoring for greater than 24 hours and a transthoracic echocardiogram). A D-dimer level was checked upon admission prior to receiving antithrombotics or reperfusion treatment. Patients were excluded if the D-dimer level was not checked upon admission, were on active cancer treatment, or were on anticoagulation for deep venous thrombosis (DVT) or pulmonary thromboembolism (PE). The normal plasma D-dimer range was 0.01-0.50 mg/L, and the range of D-dimer levels was labelled into quartiles: quartile 1 (Q1), 0.01 to 0.26 mg/L; quartile 2 (Q2), 0.27 to 0.52 mg/L; quartile 3 (Q3), 0.53 to 1.24 mg/L; and quartile 4 (Q4), >1.25 mg/L. As a control group, D-dimer levels were also checked in patients who had a non-embolic lacunar infarct. 

From January 2011 to December 2018, a total of 1431 patients with ESUS were included, of which 52 ESUS patients returned with recurrent stroke (43 ischemic and 9 hemorrhagic). Among ischemic strokes, 81.4% were embolic and 18.6% were secondary to atherosclerosis or lacunar infarcts. The mean plasma D-dimer level was 1.8 in patients with ESUS compared to 0.9 in patients with non-embolic lacunar infarcts (P<0.001). The risk of recurrent stroke was greater in the higher D-dimer quartiles (Q3 and Q4) compared to Q1 (hazard ratio, 3.12 [95% CI, 1.07−9.07], P=0.036; hazard ratio, 7.29 [95% CI, 2.59−20.52], P<0.001, respectively). An association was also noted between a raised D-dimer level above normal range and the risk of recurrent stroke (hazard ratio, 2.48 P=0.005).

Patients in the higher D-dimer quartile were found to have recurrent strokes either due to an undetermined source, occult malignancy or due to cardio-embolism. A subgroup analysis also determined a higher D-dimer level to be associated with recurrent stroke in men (P=0.039), but other variables, such as initial NIHSS, anterior vs posterior circulation strokes, age, initial reperfusion treatment or paradoxical embolism, were not associated with elevated D-dimer levels. A trend to increased incidence of MACCE (Major adverse cerebrovascular and cardiovascular events) was also noted with higher D-dimer levels (P trend 0.001). No significant difference was noted in the risk of intracerebral hemorrhage (ICH) and D-dimer quartiles.

This interesting study does provide potential evidence on the importance of measuring D-dimer levels during the initial evaluation of ischemic stroke patients, including those with ESUS, which can help determine increased risk of stroke recurrence. However, the risk of recurrent stroke was small (52 out of 1431), and, therefore, a larger patient population will be needed to confirm these findings.

An important question that arises is that if all patients with ESUS and raised D-dimer need to be anticoagulated on the assumption that most of these recurrent strokes are of etiologies that require anticoagulation like cardioembolism or malignancy. This question will still require further clinical trials, as in the current study, less than 5% of patients were on anticoagulation and a direct comparison between anticoagulation and antiplatelet therapy was not possible. Furthermore, patients already with ongoing thrombotic events such as DVT/PE or active cancer were excluded from the study, and it is unclear how likely already raised D-dimer levels might correlate in this population.

The study does provide further insight into using D-dimer levels as a biomarker for evaluation in patients with ESUS, though the use of D-dimer levels to alter management (antiplatelet vs anticoagulation) still needs further research.