FormalPara Key Summary Points

Protein S deficiency is a predisposing factor for venous thromboembolism, but its role in recurrent arterial ischemic stroke remains uncertain.

Vitamin K antagonists (VKA) have many limitations in recurrent arterial ischemic stroke, and some studies have shown that VKA may transiently suppress the activity of protein C or S and exert paradoxical thrombotic effects in thrombophilia.

Direct oral anticoagulants (DOACs) have fewer limitations, and studies have shown that they do not suppress the activity of protein C or S. However, they are not well studied in recurrent arterial ischemic stroke due to thrombophilia such as protein S deficiency.

In this study, we report that rivaroxaban can be an effective option for secondary prevention of recurrent arterial ischemic stroke due to protein S deficiency.

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Introduction

Protein S deficiency is a thrombophilia associated with an increased risk of thromboembolism [1]. Its role as a predisposing factor for venous thromboembolism is well established; however, its role in arterial thrombosis, such as arterial ischemic stroke, remains uncertain [2].

Oral anticoagulant treatment with vitamin K antagonist (VKA) drugs is used to treat and prevent thromboembolic events caused by thrombophilia. Although VKA drugs are effective in preventing thrombotic events, their efficiency in routine clinical practice is limited. Given these limitations, direct oral anticoagulants (DOACs) are more useful for the treatment and prevention of thromboembolic events [3, 4]. However, their efficacy in the prevention of thrombosis in patients with protein S deficiency has not been established. In particular, the effect of DOACs on arterial ischemic stroke in patients with a protein S deficiency is not well studied [5, 6].

In this article we present a patient with a first diagnosis of protein S deficiency and recurrent ischemic stroke who was treated effectively with rivaroxaban.

Case Presentation

A 50-year-old male Iranian patient with a history of recurrent acute neurologic deficit in the past 18 months, including previous stroke 3 months earlier, was admitted to our emergency department in January 2020. Our patient had no symptoms such as migraine headaches, cognitive deterioration, seizure, vision problems, or psychiatric problems. In clinical neurologic examination, he showed acute-onset dysarthria, right-sided hemiparesis and hemihypoesthesia. Other neurologic examinations showed no pathologic findings, and he had no evidence of venous thrombosis. His past medical history indicated a previous hospitalization for ischemic stroke. He had no vascular risk factors (diabetes mellitus, hypertension or smoking). He had been taking aspirin 80 mg/day and rosuvastatin 20 mg/day for the past 2 months.

Brain MRI with diffusion-weighted imaging revealed an acute infarction in the left internal capsule and left corona radiata (Fig. 1). In addition, there was confluent bilateral white matter (T2) hyperintensity in both cerebral hemispheres as well as the pontine area (Fig. 2). There was no evidence of venous thrombosis or micro-bleeding on brain MRI. Brain and cervical MRA did not detect any significant arterial stenosis. Findings of transthoracic echocardiography and duplex ultrasonography were normal. Routine ECG examination showed normal sinus rhythm without abnormal changes. Applying a transesophageal echocardiography (TEE), we found no cardioembolic condition. There were no episodes of atrial fibrillation in 48-h ECG monitoring. There was no minor-risk embolic source identified in our evaluation. His routine blood test, vasculitis screening profile and blood complement levels were normal (Table 1). The patient was monitored in the hospital for 5 days.

Fig. 1
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Brain MRI with diffusion-weighted imaging showed an acute infarction in the left internal capsule and left corona radiata

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Fig. 2
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Hyperintensities in both cerebral hemispheres as well as the pontine area

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Table 1 Lab data
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Complementary workup investigations for thrombophilia revealed reduced protein S activity (18%), which was confirmed in a repeated test after 4 weeks. He had not been receiving any medication with possible effects on protein S activity. All his first relatives were tested for protein S deficiency, and none showed positive results. There were also no ischemic or thrombotic complications in his family members.

Because of recurrent ischemic stroke with confirmed protein S deficiency, we started a secondary prophylactic treatment with rivaroxaban 20 mg/day. The patient was followed for the next 12 months at an outpatient clinic. During this period, he was seen every month, and at each visit new neurological symptoms and drug side effects were evaluated. No thrombotic complications or new neurologic deficits occurred. The treatment was well tolerated by our patient, without any complications including hemorrhagic events.

The patients provided informed consent and consent for publication, and the Ethics Committee of the School of Medicine, Isfahan University of Medical Sciences, approved this study. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.

Discussion

Protein S Deficiency and Recurrent Ischemic Stroke

Protein S, a cofactor for activated protein C (APC), is a vitamin K-dependent glycoprotein. APC deactivates procoagulant factors Va and VIIIa and consequently reduces thrombin production and enhances fibrinolysis. This leads to the inhibition of prothrombin activation. Thus, thrombophilia associated with protein S deficiency is a predisposing factor for deep vein thrombosis and pulmonary embolism [7]. Current evidence about its role in arterial thrombosis, such as arterial ischemic stroke, is conflicting. Some case reports have described patients with arterial thrombosis in the setting of protein S deficiency [1, 8, 9]. On the other hand, in a cohort of 3052 healthy men aged 49–64, a reduced free protein S level was not associated with an increased risk of stroke [10]. Similarly, another study of 94 adults admitted for acute cerebral infarction and 94 hospitalized control subjects showed no difference in the prevalence of patients with free protein S deficiency between the two groups [11]. However, in a recent systematic review and meta-analysis by Chiasakul et al., the authors concluded that protein S deficiency was associated with the risk of arterial ischemic stroke in younger adults [12]. The pathophysiologic pathway of arterial ischemic stroke in protein S deficiency remains unclear [13].

Why We Used Rivaroxaban to Treat This Patient

There is no specific treatment for patients with protein S deficiency. The use of anticoagulant therapy, however, is suggested for treatment and prevention of thromboembolic events in these patients [12]. In prior studies, VKA (e.g. warfarin) were used to treat and prevent thromboembolic events in patients with a protein S deficiency. Necessary frequent blood tests due to narrow therapeutic index, increased risk of bleeding, various drug and food interactions, and genetic variability in drug metabolism limit the effectiveness in routine administration of these drugs. In this regard, DOACs may be more favorable drugs in clinical practice [3, 4]. Although controlled studies on administration of DOACs for preventing thrombotic events in patients with protein S deficiency are lacking, observational studies have shown that DOACs can be administered safely and effectively for treating patients with thrombophilia [5, 6].

Some studies have shown that VKA may transiently suppress the activity of protein C or S, which may promote thrombosis formation in thrombophilia [14, 15]. Ameku et al. recently reported a patient with protein S deficiency and recurrent venous thromboembolism (VTE) under treatment with warfarin who was effectively treated with rivaroxaban [15]. A study of 57 patients with acute VTE showed that edoxaban may have more therapeutic benefit than warfarin in VTE patients with or without pulmonary embolism, as it preserves protein C and protein S levels [16]. Another recently published case report showed that apixaban may be an alternative treatment to VKA for the secondary prevention of ischemic stroke in a patient with protein S deficiency [17]. Several studies have reported on the use of rivaroxaban for secondary prevention in patients with myocardial infarction and recurrent ischemic stroke. Previous studies have concluded that rivaroxaban is safe and effective for secondary prevention in patients with myocardial infarction and recurrent ischemic stroke. Rivaroxaban competitively inhibits factor Xa, and unlike indirect factor Xa inhibitors, rivaroxaban inhibits both free and clot-bound factor Xa, as well as prothrombinase activity, thereby prolonging clotting time [12, 18, 19]. Hence, treatment with DOAC may be more beneficial than VKA in preventing thromboembolic complications of protein S deficiency.

Conclusion

In this report we used rivaroxaban 20 mg/day as secondary prevention for recurrent acute ischemic stroke caused by protein S deficiency. Our patient with a history of recurrent ischemic stroke (three times in the previous 18 months) experienced no acute ischemic stroke or other thromboembolic events during 12 months of follow-up. However, additional controlled studies are needed to evaluate the effectiveness and other aspects of rivaroxaban treatment in recurrent ischemic stroke due to protein S deficiency.