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.