Meghana Srinivas, MD
@SrinivasMeghana

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.

Embolic stroke of underdetermined source is used to identify patients with nonlacunar embolic cryptogenic strokes with a more restrictive inclusion criteria for strokes of cryptogenic origin and complete diagnostic workup in comparison to classic cryptogenic strokes.

Patients with a diagnosis of ESUS at the time of their index stroke carry a high risk of recurrent strokes, which is approximately twice as compared to cryptogenic stroke other than ESUS. Given this incidence, it is important to identify the underlying mechanism and cause of strokes for secondary stroke prevention. Although the most common mechanism in ESUS is embolism with covert atrial fibrillation being the most common cause, recent randomized control trials have shown that non-vitamin antagonist oral anticoagulants (OACs) are not superior to aspirin in preventing recurrence of strokes in patients with ESUS. This can be explained by the heterogeneity among the potential causes of ESUS, which can be covert AF and hidden malignancy to patients with ipsilateral carotid stenosis of less than 50% and aortic arch atherosclerosis. As in the name, it is unknown at least at the time of initial presentation. It is important to identify factors which can predict the risk of recurrent stroke in patients with ESUS and use the right secondary preventative measures.

In this single-center retrospective study using a prospective registry, Kang-Ho Choi et al. investigated the value of plasma d-dimer levels as a marker for predicting and identifying underlying causes of recurrent strokes in patients with ESUS. The investigators looked into the plasma d-dimer levels collected immediately at the time of index stroke admission. They divided the plasma d-dimer levels into quartile ranges: 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. The primary outcome measure was the occurrence of recurrent stroke according to baseline d-dimer levels over 1 year.

The authors used the Kaplan-Meier analysis to show that the risk of recurrent stroke increased significantly in patients with ESUS as the baseline d-dimer quartiles increased (P=0.001). The incidence rate of recurrent stroke in Q4 was 8.43 per 100 person-years, while that in Q1 was 1.54 per 100 person-years.

In total, 52 out of 1431 patients with ESUS developed recurrent strokes over one year follow up. Ischemic events were noted in 43 patients; 35 (81.4%) of them developed embolic stroke, out of which 20 (46.5%) patients had recurrent ESUS; newly discovered AF, active cancer and large artery atherosclerosis were identified during the recurrent event. Analysis using the Multivariable Cox regression, after adjusting for confounders, revealed that patients in Q3 and Q4 had a significantly increased risk of future recurrent stroke than that of patients in Q1 (hazard ratio [HR], 3.12 [95% CI, 1.07−9.07], P=0.036 and HR, 7.29 [95% CI, 2.59−20.52], P<0.001).The risk of recurrent ischemic stroke, vascular death, and MACCE (a composite of stroke, acute myocardial infarction, or vascular death) also increased significantly with the increasing of the baseline d-dimer quartiles (P=0.008, P=0.004, and P<0.001, respectively), which were the secondary outcome measures.

Figure 1. Subject enrollment and outcome measurements.
Figure 1. Subject enrollment and outcome measurements.

Plasma d-dimer levels are a marker of hypercoagulable states related to thrombus formation and resolution; thrombus formation causes embolism, which is the most commonly identified mechanism in ESUS. A study by Nahab et al.1 showed that markers of coagulation and hemostatic activation can help identify patients with ESUS who are more likely to have new malignancy, venous thromboembolism, or hypercoagulable states and may be useful in the direct evaluation of underlying causes of ESUS.

Why is this important? The study gives an insight into an improved understanding of the role of high d-dimer levels elucidated by their finding; this might enable the creation of novel and tailored antithrombotic strategies for secondary stroke prevention of strokes in patients with ESUS. This can partly be supported by recent studies in patients with coronavirus disease 2019 (COVID-19) who developed stroke and were classified as having ESUS. The first line of investigation was measuring d-dimer and commencing anticoagulation therapy in patients with high d-dimer levels in order to reduce the risk of thromboembolism and mortality. 

This study comes with limitations. The investigators did not collect information on any improvement in d-dimer levels during follow up, and the number of patients who received OAC therapy was small compared to antiplatelet therapy. Other potential causes for elevation of d-dimer levels, such as deep vein thrombosis, pulmonary thromboembolism, or other hematologic diseases—except hematologic cancer, were not accounted for, and the sample size of recurrent strokes was small, and, therefore, the impact of higher d-dimer levels could not be confirmed.

This study, although retrospective in nature, shows that obtaining a baseline d-dimer level can prove to be a potential risk assessment biomarker in not only predicting the risk of future recurrence of stroke in patients with ESUS, but also in identifying the appropriate measures for secondary stroke prevention.

References:

1. Nahab F, Sharashidze V, Liu M, Rathakrishnan P, El Jamal S, Duncan A, Hoskins M, Marmarchi F, Belagaje S, Bianchi N, et al. Markers of coagulation and hemostatic activation aid in identifying causes of cryptogenic stroke. Neurology. 2020;94:e1892–e1899.