Hypercoagulability State in Predicting Severe Functional Outcome in Patients with Acute Ischemic Stroke: Cause, Consequence, or Both?

Hypercoagulability on Thromboelastography Can Predict the Functional Outcomes in Patients with Acute Ischemic Stroke

Acute ischemic stroke might be associated with hypercoagulability in approximately 30 to 40% of these patients.[1] [2] This association could be explained by the fact that the exposure of collagen in damaged vessels triggers a cascade of coagulation factors which therein forms the emboli that can occlude cerebral arteries.[3] Hypercoagulability could also be involved in early neurological deterioration which occurs in approximately 20 to 30% of patients following acute ischemic stroke.[4] In fact, most patients with early neurological deterioration have a worse outcome due to either an infarct enlargement or early recurrence. In these cases, abnormal thrombotic pathways, especially increased coagulation activity, have been suggested to play a role in the pathophysiology of neurological deterioration.[5]

Thromboelastography is a whole-blood viscoelastic assay that is widely used in the assessment of coagulation and fibrinolysis, and moreover, it can assess the hemostasis activity as a dynamic process from the time of the initial clot formation up until fibrinolysis after maximum clot strength.[6] In fact, elevated maximal clot strength is considered to be indicative of hypercoagulability and the latter can be attributed to the persistence of high platelet reactivity and the generation of thrombin on the surface of activated platelets.[7] [8] [9] Furthermore, among thromboelastography parameters, the reaction time is the time from the start of the test to the detection of the first fibrin formation; in fact, the shorter the reaction time, the greater the hypercoagulability state. Thromboelastography has been used in recent clinical studies to assess bleeding and increased transfusion requirements in hip fracture surgery,[10] and for assessment of the severity, as well as personalizing antithrombotic therapy use in COVID-19.[11] [12] [13]

In the current issue of this journal, Ryu et al[14] report that a hypercoagulability state measured with thromboelastography with a reaction time inferior of 5 was a negative predictor of functional independence. Additionally, the Ryu group reports that this hypercoagulability state was associated with the occurrence of symptomatic and asymptomatic hemorrhagic transformation and early neurological deterioration. The main results of this study are in line with those of several previous studies that reported an association between thromboelastography parameters indicating a hypercoagulability state and unfavorable functional outcome, even in patients with acute stroke treated with revascularization therapies[15] [16] [17] due to early neurological deterioration[5] or hemorrhagic transformation.[18] However, Ryu et al went one step further as they reported that the hypercoagulable state on thromboelastography was associated with atrial fibrillation and cardioembolism. Furthermore, the hypercoagulability state was also reported to be associated with worse stroke severity on admission measured with National Institutes of Health Stroke Scale.

According to Ryu et al, a hypercoagulability state was associated with worse severity of stroke, stroke event due to cardioembolism, especially in patients with atrial fibrillation, hemorrhagic transformation, neurological deterioration, and final functional outcome. The main issue with these results is that we know that cardioembolism is associated with larger ischemic lesions therein leading to a higher risk of hemorrhagic transformation and a higher risk of neurological deterioration which leads to a worse functional outcome.[19] Ryu et al used a multivariable model to evaluate the predictive factors of outcome that was correct for these types of analyses but the reported associations between hypercoagulability state and final functional outcome in patients with cardioembolism were most likely influenced by numerous potential other confounders, even if this adjusted statistical model had been used to reduce them especially when within the model several variables known to influence clinical outcome and interconnected with each other were included. Furthermore, in another study including 171 acute ischemic stroke patients treated with systemic thrombolysis, there was no reported association between thromboelastography parameters and clinical response to therapy. Therefore, a role of thromboelastography in predicting worse clinical outcome in patients with acute ischemic stroke remains controversial.[20] Another issue is that Ryu et al retain that hypercoagulability was the cause of stroke; something which had already been well documented in patients with hematological disorders, hemostatic inherited disorders, and active cancer. However, hypercoagulability might have been secondary to stroke given that hypercoagulability has been reported to be associated with more severe stroke and larger ischemic lesions.[21] In fact, a study has evidenced an increase in nitro-fibrinogen after ischemic stroke. Nitro-fibrinogen during the early stage of ischemia has a protective role by delaying clot formation, but in the long term it becomes harmful due to a production of fibrinolysis-resistant clots and the induction of neuronal damage.[22] Thus, it would be difficult to determine the origin of this vicious circle that at in the end generally leads to a worse functional outcome ([Fig. 1]). Even if prestenting thromboelastography parameters have been reported to be related to ischemic events after carotid stenting in a prospective study,[23] another study that enrolled 407 patients with acute ischemic stroke investigated for a possible relationship between thromboelastography and carotid artery plaque: after adjusting the baseline clinical data, no thromboelastography parameters were associated with predicting either plaque presence or stability and consequently subsequent stroke.[24]

Fig. 1 The vicious circle that leads to a worse functional outcome

In conclusion, thromboelastography probably has potential utility in the management of acute ischemic stroke but conclusive evidence of any role in predicting acute ischemic stroke outcome should depend upon results from future large-randomized trials.

Publication History

Article published online:
10 July 2023

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