Protein S deficiency manifesting with cerebral arterial and venous thrombosis in a young female with kissing carotids phenomenon

Abstract

Background

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Majority of people with “kissing carotids”, an anatomical variation of the cervical carotid arteries showing tortuosity, kinking or coiling and coming in proximity at the midline are asymptomatic. Less than 1% of the general population have Protein S Deficiency. This report discusses a rare case of a young female with co-existent Protein S deficiency and kissing carotids, who presented with sequential thrombosis in both arterial and venous cerebral circulation systems and further discusses potential mechanisms of arterial thrombosis in Protein S deficiency and medical options for secondary stroke prophylaxis in this context.

Case presentation

A 29-year-old female presented with sudden left hemiparesis and dysarthria. Index Brain MRI revealed acute non-haemorrhagic infarcts in the right middle cerebral artery (MCA) territory. Index brain MRA of cerebral vessels revealed abrupt cut off of the right MCA M1 segment following arterial thrombosis with extracranial kissing internal carotid arteries. Interval imaging of her brain and cerebral vasculature on day 4 of admission following a convulsion revealed left transverse cerebral venous sinus thrombosis. Laboratory workup confirmed low Protein S activity of only 18% (normal 55–123). She was started on rivaroxaban for lifelong secondary arterial stroke prophylaxis.

Conclusions

This is an index sub-Saharan case report of a young female with co-existent Protein S deficiency and kissing carotids phenomenon presenting with sequential cerebral arterial and venous thromboses. Potential mechanisms of arterial thrombosis in Protein S deficiency in which case warfarin may not be a preferred singular option for secondary arterial stroke prophylaxis are discussed.

Background

The term “kissing carotids” refers to an anatomical variation of the cervical carotid arteries, showing tortuosity, kinking, or coiling that come in proximity at the midline [1]. Majority of people with kissing carotids are asymptomatic [2]. Protein S Deficiency (PSD) is a type of thrombophilia prevalent in less than 1% of the general population, that is associated with both cerebral venous and arterial thromboembolism [3]. This report discusses a rare case of a young female with co-existent Protein S deficiency and kissing carotids, who presented with sequential thrombosis in both arterial and venous cerebral circulation systems and further discusses potential mechanisms of arterial thrombosis in Protein S deficiency and medical options for secondary stroke prophylaxis in this context.

Case description

S.S evaluated a 29-year-old right handed housewife and mother of 3 with no documented chronic illnesses or medication. She was independent for all basic and instrumental activities of daily living at baseline. She had been admitted within a day of domestic trauma, with left hemiparesis and dysarthria of sudden onset. She had no associated headaches or convulsion and was otherwise constitutionally well.

On index examination, she was not in distress and was noted to have discrete non-palpable purpura over her right shoulder and left supraclavicular area and a small right plantar ulceration that was healing well. She was notably tall but with no marfanoid features. She had normal systemic vital parameters, no carotid bruits and normal cardiorespiratory and abdominopelvic examination findings. On initial neurological examination, she was noted fully conscious and of normal sensorium, with mild slurring of speech but otherwise normal language parameters. She had no left side neglect or other significant higher cortical dysfunction and had no meningism. She had a transient left homonymous hemianopia and mild loss of her left nasal labial fold but no other cranial nerve deficits. She had normal limb tone globally, moved her right upper and lower extremities normally but was unable to make any movements in her left upper and lower extremities. She had mild loss of sensation to touch and pin prick in her left side extremities. Her tendon stretch reflexes were still globally normal. She had normal limb coordination in her right side extremities but was hemiplegic to test in her left extremities. Gait testing was deferred due to her left hemiplegia.

Index CT scan of her brain revealed a hypodense lesion in the right corpus striatum and its immediate vicinity, reported to be in keeping with established infarct (Fig. A1). Subsequent index brain MRI diffusion weighted, and apparent diffusion coefficient map images confirmed acute infarcts in the right middle cerebral artery (MCA) territory (Fig. A2, A3). Initial MRA of cerebral vessels revealed evident abrupt cut off of the M1 segment of the right MCA with absent flow in its distal course and its branches suggestive of arterial thrombosis (Fig. B1). Additionally, the extracranial cervical portions of her bilateral internal carotid arteries were noted to be approximating each other close to their origin, in keeping with a “kissing carotids” morphology (Fig. B2). There was no evidence of carotid dissection on a subsequent CT Angiogram of her cerebral vessels and her MRI vessel wall imaging was suboptimal. Interval brain imaging on day 4 of admission (Brain MRI and brain MRV) for new complaints of hallucinations and a reported convulsion revealed left transverse sinus cut off suspicious for cerebral venous sinus thrombosis however with no venous infarcts (Fig.C1–C3, D1). Chest X-ray, electrocardiogram and echocardiogram were all normal.

Laboratory testing showed mildly elevated D-dimer levels but with normal full blood count, extended electrolytes, renal function, liver function, INR, APTT, C-reactive protein, ANA, p- and c-ANCA tests. HIV serology was negative. Her thrombophilia work up showed no lupus anticoagulant present and was negative for anticardiolipin IgG and Beta-2-glycoprotein IgA, IgG and IgM antibodies. She was homozygous normal for both prothrombin gene (G20210A) mutation and Factor V 1691 G > A gene mutation. She had normal antithrombin III and serum homocysteine levels. She also had normal protein C activity (90% with normal reference range 67–195) but notably deficient protein S activity (18% with normal reference range of 55–123 for non-pregnant females).

Fig. 1

(A1) Non-contrasted index Axial brain CT scan shows a hypodense lesion in the right corpus striatum nuclei (orange arrow). (A2) Diffusion weighted imaging on brain MRI shows diffusion restricting lesion (blue arrow) in the right corpus striatum nuclei and a punctate right insular lesion on axial view. (A3) Apparent Diffusion Coefficient map on brain MRI confirms the acute infarct (green arrow) in the right corpus striatum nuclei on axial view. (B1) MRA of cerebral arteries reveals proximal right middle cerebral artery cut off in its M1 region (red arrow). (B2) MRA of cerebral arteries reveals extracranial kissing carotids morphology (yellow arrow) at the origins of the internal carotid arteries bilaterally. No evidence for carotid dissection or carotid web is visualized. CTA of cerebral vessels (not shown) was done and also did not show evidence for intracranial or extracranial carotid dissection. (C1) Axial T2-FLAIR MRI of brain interval imaging reveals unchanged infarct in the right corpus striatum nuclei. (C2) Diffusion weighted imaging on interval brain MRI shows unchanged infarct (blue arrow) in the right corpus striatum nuclei on axial view. (C3) Susceptibility weighted imaging on interval brain MRI confirms the unchanged acute infarct (green arrow) in the right corpus striatum nuclei on axial view without intralesional hemorrhage. (D1) MRV of the patient’s cerebral venous circulation reveals left transverse venous sinus abrupt cut off (red arrow) suggestive of left transverse venous sinus thrombosis

Discussion

Morphological variations of the cervical carotids like kissing carotids are found in about 5% of the general population and have been reported to be more prevalent in women [2]. However, unlike in this patient, these appear to be more apparent in women over 60 years of age and are usually asymptomatic [2]. It remains controversial whether there is association between kissing carotids and cerebrovascular accidents such as stroke and transient ischemic attacks [2] and there is consideration that these malformations may not have any additive risk for stroke [4]. In keeping with this, there was no evidenced direct contribution of this patient’s kissing carotids phenomenon to her stroke etiology. Furthermore, even though most ischemic strokes following traumatic vessel injury occur before admission or within 24 h to 72 h post injury [3, 5], there was no radiological evidence for traumatic vessel injury ipsilateral to the stroke lesion of this patient and so although trauma could have accelerated her presentation, it was considered not a sufficient etiology for her clinical presentation and recurrent stroke risk.

The etiology for this patient’s clinical presentation was considered to be PSD. Protein S is a vitamin K- dependent glycoprotein that induces the inactivation of coagulation factor V through activated protein C or the activation of coagulation factor VIII, and therefore a protein S deficiency can lead to thrombotic events [6]. PSD is a type of thrombophilia prevalent in less than 1% of the general population [3]. It is described to have an increased risk of thromboembolism [7] and to not only be causative for venous hypercoagulability which was also observed in this case, but in some contexts to also be causative for cerebral arterial ischemic stroke [6, 8]. Only one in three patients with thromboembolism reports a positive family history for a hypercoagulability disorder [3] and so it may not be unusual that this patient had no known family history of PSD. Nonetheless, in very select cases, molecular testing for PROS1 gene is advisable [9, 10] but it is not readily available in our setting. It is also recommended to have confirmatory repeat protein S testing at least 4 weeks from the first laboratory indication of a deficiency [10]. This was not achieved for this case as the patient did not adhere to the planned further follow up schedule.

Although the pathophysiologic pathway and evidence for the role of PSD in arterial ischemic stroke is unclear and conflicting [7], a systematic review and meta-analysis on inherited thrombophilias and their risk for arterial ischemic stroke has reported association of PSD with a small but significant increase in the risk of arterial ischemic stroke in adults, especially in young patients like this case [8]. This was this patient’s index stroke presentation and it is interesting that a sensitivity analysis from this same systematic review and meta-analysis also showed PSD to have a strong association with a first ever stroke [7].

Several potential mechanisms may explain how inherited thrombophilias like PSD could lead to formation and progression of atherosclerotic lesions resulting in arterial ischemic stroke. These include activation of platelet, dysregulation of endothelial and vascular smooth muscle cells, and recruitment of phagocytes following unbalanced thrombin activation [8]. PSD can also potentiate progression of atherosclerotic changes by inducing the Tyro3-Axl-Mer (TAM) receptor [6]. Furthermore, following the multiple hit hypothesis, interplay of both genetic and environmental factors, is proposed to have a role in thrombosis observed in hypercoagulability disorders [3].

For this patient’s secondary arterial stroke prophylactic treatment, Rivaroxaban, a direct oral anticoagulant (DOAC) was prescribed. Unlike warfarin, the DOACs have been shown not to suppress the activity of protein C or S [7]. Warfarin on the other hand is shown to suppress the activity of coagulant factors VIII, IX, or X, and protein C or S [6]potentially resulting in paradoxical thrombotic effects in thrombophilias like PSD and that undesirably calls for additional anticoagulant cover. Even though the DOACs are not well studied in thrombophilia patients with recurrent arterial ischemic stroke, rivaroxaban can be an effective treatment option through its diverse mechanisms of action which includes inhibiting both free and clot-bound activated coagulant factor X and pro-thrombinase activity, by which it prolongs clotting time hence reducing hypercoagulability [7].

Conclusions

This is an index case in literature of a young female with co-existent Protein S deficiency and kissing carotids phenomenon, clinically presenting with thrombosis in both cerebral arterial and venous circulation systems. Potential mechanisms of arterial thrombosis in Protein S deficiency are discussed and it is noted that warfarin may not be a preferred singular option for secondary arterial stroke prophylaxis in patients with Protein S deficiency. Further studies are needed to determine the pathogenicity of hypercoagulability disorders like Protein S deficiency for arterial stroke and to guide secondary stroke prophylaxis of patients with arterial ischemic stroke in the context of hypercoagulability disorders.