Vertebral artery dissection (VAD) is defined as the penetration of blood from the vertebral artery (VA) lumen through a damaged intimal layer into the vessel wall, with subsequent propagation of blood between the arterial layers [1]. VAD can be either spontaneous or traumatic [2]. The clinical presentation of VAD ranges from an asymptomatic course to severe stroke and even fatal outcomes due to complete arterial rupture [3]. However, the most frequent clinical manifestations of VAD in the acute phase are cephalalgia, neck pain, and dizziness [4]. Given the potential for non-traumatic VAD to present with an absence of clinical symptoms, its precise incidence remains unknown. Nevertheless, within the population of trauma patients, who typically undergo a diagnostic workup sufficient to detect VAD, this pathology is identified in 70–77% of patients with cervical spine fractures and in approximately 20% of victims with traumatic brain injury (TBI) [5, 6]. VAD most frequently occurs in individuals who have experienced falls and road traffic accidents [7].

In 1999, the Denver classification of VAD was proposed, based on the morphological characteristics of the arterial injury (Table 1) [8].

Table 1. Denver Classification of Vertebral Artery Dissection

GradeMorphological CharacteristicsIDissection with less than 25% luminal stenosisIIDissection/intramural hematoma with more than 25% luminal stenosis, with intraluminal thrombosis or intimal flapIIIPseudoaneurysmIVVessel occlusionVTransection

The incidence of acute ischemic stroke (AIS) secondary to VAD is reported by various authors to range from 5% to 24%, with these rates increasing with higher grades of dissection severity [6, 9]. Stroke resulting from VAD can occur not only in the hyperacute phase but also in a delayed manner [10]. The established causes of delayed ischemic stroke in patients with VAD are arterio-arterial thromboembolism and the progression of VA thrombosis with an increase in its extent [11].

A cornerstone in the management of patients with VAD, including for the secondary prevention of delayed stroke, is the timely administration of adequate antiplatelet therapy [12]. Theoretically, genetic resistance to antiplatelet agents could be one potential cause of delayed ischemic stroke in patients with VAD. However, a review of the available literature revealed no data addressing this issue. This clinical case report describes a patient with VAD and genetic resistance to antiplatelet agents.

A 35-year-old male patient (Mr. Ch.) experienced a sudden onset of severe cephalalgia and neck pain during a sharp turn of his head while driving. The patient self-administered non-steroidal anti-inflammatory drugs and sought medical attention only on the third day, after the onset of dizziness and intensification of neck pain. He was admitted to the A.I. Burnazyan Federal Medical and Biophysical Center with a referral diagnosis of "Vertebrobasilar arterial system syndrome."

Upon admission, the patient was conscious but presented with cerebellar dysarthria and vestibulo-atactic syndrome. No other focal neurological deficits were detected. Doppler ultrasound of the major neck vessels revealed a dissection of the left vertebral artery. Contrast-enhanced magnetic resonance imaging (MRI) of the brain confirmed a dissection in the V4 segment of the left vertebral artery. No cerebral ischemic foci were identified (Fig. 1).

Fig. 1. Dopplerography of the main vessels of the neck.

No indications for surgical intervention were present. Pathogenetic dual antiplatelet therapy (DAPT) with acetylsalicylic acid (100 mg) and clopidogrel (75 mg) was initiated, alongside anticoagulant therapy with enoxaparin for the prevention of venous thromboembolic complications. The patient was managed in the neuro-intensive care unit for two days and was subsequently transferred to the neurology department in a stable condition.

On the 5th day of hospitalization in the neurology department, the patient's blood pressure increased to 190/100 mm Hg. He developed numbness in the right limbs, dysphagia, dysarthria, worsening ataxia, left-sided ptosis, and right-sided hemiparesis and hemihypoesthesia. A follow-up MRI of the brain revealed an ischemic focus in the medulla oblongata (Fig. 2).

Fig. 2. MRI examination of the brain.

The patient was transferred back to the intensive care unit. Pharmacogenetic testing was performed using real-time polymerase chain reaction (PCR) to investigate genetic resistance to antiplatelet agents by determining the polymorphic variants rs4244285*2, rs4986893*3, and rs12248560*17 of the CYP2C19 gene. The analysis revealed that the patient was a carrier of the CT genotype for polymorphic variant rs12248560, the GA genotype for rs4244285, and the GG genotype for rs4986893 of the CYP2C19 gene. This genotype corresponds to an intermediate metabolizer phenotype with an uncertain response to clopidogrel. A correction of the antiplatelet therapy was deemed necessary. Clopidogrel was replaced with prasugrel at a maintenance dose of 10 mg, with the decision to forgo a loading dose. Therapy with aspirin in combination with prasugrel, as well as prophylactic anticoagulation with enoxaparin, was continued.

Over the next three days, no progression of neurological symptoms was observed, hemodynamics stabilized, and the patient was transferred back to the neurology department. Over the subsequent two weeks, the focal neurological symptoms regressed, and the patient was discharged from the hospital in a satisfactory condition.

This case is unique as it illustrates an association between genetic resistance to clopidogrel and the development of delayed ischemic stroke in a patient with VAD. Although VAD is a common cause of stroke in the posterior cerebral circulation, this pathology receives insufficient attention from clinicians and in terms of the quantity and quality of research dedicated to it. Consequently, the pathogenesis of stroke in VAD remains poorly understood in many aspects, particularly concerning delayed stroke. While AIS in the hyperacute phase of VAD typically results from severe VA injury and subsequent cessation of blood flow [13], its occurrence likely requires additional anatomical risk factors, such as hypoplasia of the contralateral VA, an incomplete circle of Willis, underdeveloped cerebral arterial anastomoses, or severe atherosclerosis of cerebral arteries [15]. In any case, the pathogenesis of hyperacute stroke in VAD is relatively clear, which cannot be said for delayed stroke.

According to the literature, delayed stroke in VAD is attributed to either arterio-arterial embolism or the propagation of thrombosis [16]. An increase in the size of the intramural hematoma, the dissected area, or the zone of detached intima can lead to the extension of VA thrombosis. Currently, there are limited technical means to prevent these complications [17]. The administration of dual antiplatelet therapy is fundamental in preventing both arterio-arterial embolism and the extension of thrombosis [18].

The first-line drugs for DAPT in VAD are a combination of acetylsalicylic acid and clopidogrel [19]. In some clinical situations, adequate suppression of platelet reactivity is not achieved, which may be due to impaired absorption, distribution, metabolism, or elimination of the antiplatelet agents [20]. While altered absorption, distribution, and elimination are more characteristic of critically ill patients, impaired metabolism of antiplatelet agents can occur in any patient, regardless of their condition, due to genetic polymorphisms causing genetic resistance [20].

The prevalence of genetic resistance to acetylsalicylic acid ranges from 5% to 45%, and to clopidogrel from 20% to 45% [21]. Single nucleotide polymorphisms involving COX-1, COX-2, and other platelet-related genes can alter the antiplatelet effect of acetylsalicylic acid [22]. Resistance to clopidogrel is primarily associated with polymorphic variants of the CYP2C19 gene [14]. The CYP2C19 gene, part of the cytochrome P450 family, is involved in the bioactivation of clopidogrel [23]. Carriers of the rs4244285 and rs4986893 alleles of the CYP2C19 gene often fail to achieve adequate platelet inhibition [23]. Conversely, the presence of the rs12248560 allele of the CYP2C19 gene enhances the metabolism of clopidogrel and increases the risk of bleeding.

Currently, there are no specific guidelines regarding the testing for genetic resistance to antiplatelet agents in patients with VAD. The routine use of genetic analysis is likely not feasible. However, given the high risk of delayed stroke in VAD, it is prudent to search for reliable laboratory markers, routinely used in clinical practice, that could help suspect genetic resistance. In the population of patients with ST-elevation myocardial infarction (STEMI), the CT-EXTEM parameter in rotational thromboelastometry has been proposed as such a marker [24]. In this context, further research is needed to identify similar criteria for VAD patients.

Aspirin is an inhibitor of COX-1 and COX-2, while clopidogrel is a P2Y12 receptor antagonist [25]. For patients with VAD, there may be little clinically justified rationale for testing genetic resistance to acetylsalicylic acid, as there are currently no viable alternatives. In contrast, testing for genetic resistance to clopidogrel is highly significant. If resistance is identified, the dose of clopidogrel should be increased or it should be replaced with another P2Y12 receptor antagonist. Convincing evidence exists linking the CYP2C19 genotype to clinical outcomes in patients with ischemic stroke. Results from a large meta-analysis demonstrated that carriers of the CYP2C19 loss-of-function allele undergoing DAPT with clopidogrel for transient ischemic attack have a significantly higher risk of stroke, and stroke patients have a higher risk of recurrent stroke, compared to non-carriers [26].

Prasugrel and ticagrelor are P2Y12 receptor antagonists that serve as alternatives to clopidogrel [27]. Unlike clopidogrel, prasugrel and ticagrelor have a significantly lower prevalence of genetic resistance in the population; it is described in 3–15% of patients for prasugrel and 0–3% for ticagrelor [27]. This is due to differences in the metabolism of these antiplatelet agents [28]. Therefore, in cases of VAD with confirmed genetic resistance to clopidogrel, prasugrel or ticagrelor should be considered as alternative P2Y12 antagonists.

Some authors suggest that for patients with a heterozygous genotype for rs4244285 in the CYP2C19 gene (leading to a non-functional enzyme) combined with a heterozygous genotype for rs12248560, doubling the clopidogrel dose to 150 mg daily may overcome resistance [29]. However, in our view and that of other leading experts, this strategy is unlikely to successfully overcome genetic resistance and may expose patients with VAD to the risk of delayed stroke [30]. The presented clinical case demonstrates the safety and efficacy of a treatment strategy for VAD that involved continuing antiplatelet therapy with the substitution of clopidogrel for prasugrel.

This clinical case of a patient who developed a delayed ischemic stroke following VAD highlights the issue of genetic resistance to antiplatelet agents in this patient population. The occurrence of a delayed ischemic stroke in the context of VAD warrants consideration for testing genetic resistance to antiplatelet agents and subsequent potential modification of the treatment regimen. Further research is necessary to establish criteria for initiating diagnostics for genetic resistance to antiplatelet agents and to develop an effective protocol for adjusting antiplatelet therapy in patients with VAD.