Antiphospholipid syndrome may induce non-thrombus internal jugular vein stenosis - Two cases report and literature review

Background: Antiphospholipid syndrome (APS) is associated with artery or venous thrombosis. However, non-thrombus venous stenosis is rarely reported. Case presentation: This study described two young women with APS-related internal jugular vein stenosis (IJVS) and reviewed current literatures on this issue, including clinical features, diagnosis and treatment. Conclusions: IJVS is a rather rare complication of APS. This is first report of non-thrombus venous stenosis resulted from aPL mediated vessel wall damage. High titer of aPL could induce stenosis without thrombosis formation due to long-term standardized anticoagulation. Follow-up of autoantibodies are necessary to be done dynamically. Treatment for patients with IJVS of autoimmune etiology should be concomitant use of anticoagulants and steroids.


Background
Antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis in young adults with persistent laboratory evidence of high titer of antiphospholipid antibodies (aPL) [1][2][3]. However, APS induced cerebral venous damage may present various entities, such as thrombosis and non-thrombus venous stenosis. Herein, we reported two cases of APS with non-thrombus internal jugular vein stenosis (IJVS) inducing intracranial hyper-pressure. We presumed that APS might trigger autoimmune inflammatory damage, leading to edema and thickening of the venous wall, and eventually resulting in non-thrombus IJVS. However, there was no thrombus formation in IJV during long term standardized anticoagulation of these two patients. To our knowledge, this is the first report about this issue up to now. 3 We believed this report can provide an important reference for physicians.

Case 1
A 33-year-old woman complained of a history of five-year worsening blurry vision, intermittent headache on temporal regions and nocturnal bilateral tinnitus. She also reported progressive memory loss for six months on the day of presentation. There was no history of nausea and vomiting, no weakness or sensory symptoms in the face and limbs, no sphincter incontinence and loss of consciousness or seizures.
Comorbid medical issues included a 5-year history of APS (confirmed primary APS at Beijing Union Hospital) and deep vein thrombosis (DVT) in the left leg. From then on, she underwent corticosteroid for one year combined with continuously standardized anticoagulation till this admission. She denied the family history of thrombotic diseases. On physical examination, her body temperature was 37.0℃, blood pressure was 128/78mmHg, heart rate was 79 beats/minute and respiratory rate was 20 breath/minute. Her Body mass index (BMI) was 31.1. No focal neurological signs were found.
Both the platelet count (373*10^9/L) and plateletcrit (0.36%) were above the normal-cutoff levels in her baseline peripheral blood test. Protein C exceeded the normal upper limit (155%) a little. Other items related to coagulation showed no positive significance. All the results of serological tests including aPL, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA) and complements C3 and C4 were negative. The lumbar puncture opening pressure was 250 mmH 2 O with a normal cerebrospinal fluid profile. Funduscopic examination revealed bilateral optic disc edema (Frisén score = 2).

4
Color Doppler ultrasound revealed venous valve insufficiency involving bilateral common femoral veins, right deep femoral vein and left superficial femoral vein.
Transcranial Doppler (TCD) and Carotid ultrasound showed no abnormalities.
However, jugular vein ultrasound revealed a small diameter in the upper segment (J3) of the right IJV with decreased flow volume (Table 1). Contrast-enhanced magnetic resonance venography (CE-MRV) of brain and neck identified the stenosis located at left transverse sigmoid sinus junction (Figure 1

Case 2
A 32-year-old woman presented with two-week progressively aggravated pains in her head and neck accompanied by nausea and vomiting, and three-days of visual disorder (double vision) after she was recovered from pneumonitis. She once had similar symptoms two years ago. Her lumbar puncture opening pressure (LPOP) was 330 mmH 2 O at that time measured in a local hospital, and she was diagnosed as idiopathic intracranial hypertension (ICH) and underwent mannitol and corticosteroid. Her intracranial pressure (ICP) was decreased to 150 mmH 2 O at lumbar puncture follow-up before discharge. However, two weeks prior to this admission, her symptoms reappeared. Her LPOP was over 400 mmH 2 O at local hospital. Mannitol could not attenuate her symptoms.
On this admission, she presented with severe headache in a spasmodic manner, especially on the left, accompanied by persistent nausea, sometimes, vomiting undigested food. She also described the impaired vision, such as objects being blurry and doubled horizontally. Ophthalmologic examination revealed papilledema (Frisén score = 4) with small local bleeding spots. Her vital signs were as follows: body temperature, 36.5℃; blood pressure, 115/68mmHg; heart rate, 78 beats/minute; and respiratory rate, 20 breath/minute. Her BMI was 20.1.

Discussion
Our previous work demonstrated that the etiologies of IJVS included non-thrombus and non-osseous compressive entities, such as venous wall lesion [4]. It is well known that venous thrombosis is the most common complication of APS [4]. To our knowledge, this study reported non-thrombus IJVS as a complication of APS for the first time. Whereby, this report is of great significance to understand the relationship between IJVS and APS.
With regard to the pathogenesis of APS, resent studies indicated that most aPL was directly targeted at phospholipid-binding proteins [2]. Although aPL is a heterogeneous group of antibodies, anti-β2GPI antibodies play a central role in the development of APS. They recognize β2GPI on the surface of endothelial cells and immobilized platelets, then leading to cellular activation and expression of procoagulant activity [5]. Furthermore, the effect of lupus anticoagulants (LA) is also realized through β2GPI or anti-β2GPI antibodies [6,7]. Anti-β2GPI antibodies are associated with a higher risk of thrombosis than anticardiolipin (aCL) or antiprothrombin antibodies [6,7]. Other mechanisms implicate that aPL is also related to interfering with the function of coagulation factors [8][9][10] and complementmediated neutrophil activation [11,12]. In sum, the interaction between aPL and endothelial cells, coagulation cascade (primary and secondary), and inflammatory cells could result in vessel wall lesions, contributing to thrombosis and/or stenosis.
The evaluation of thrombotic risk in patients with APS was usually based on the level of plasma aPL [13], however, some patients with previously positive aPL profile would turn negative, which then became a challenge for the physicians to evaluate the thrombotic risk. Besides, Bazzan et al found that despite appropriate anticoagulant treatment, the thrombotic recurrence rate in APS has been reported as high as 7.5/100 patient-years in the first 5 years after the first thrombotic event [14]. Nevertheless, sometimes there are exceptions, such as the case-2 in this study, whose aPL levels were in a persistently moderate tilter (>40 RU/mL) but 8 without thrombotic event recurrence. Based on the clinical processes of the two cases, we speculated that this exception might be due to their long-term preventive anticoagulation. Although standardized anticoagulation successfully prevented thrombosis formation, the risk of non-thrombosis IJVS, which might result from irreversible immune damages of vascular endothelium caused by aPL, was still existed. Then, IJVS might lead to ICH.
Compared with case-1, case-2 did not receive corticosteroid for APS intervention before referred to our department. And her persistent moderate level of anti-β2GPI antibodies could cause more severe damage to the vessel wall, which might explain her symptoms recurrence and refractory high ICP.
A combination of anti-Xa inhibitor (rivaroxaban) and corticosteroid (prednisolone) was prescribed to the two patients. A previous study indicated that stenting was a promising therapeutic option for focal stenosis of IJV [4]. However, we did not perform stenting/balloon angioplasty in case 1, as her stenosis of IJV was moderate, and the risk of stenosis aggravation was lower under her stable low titer of aPL.
There is still controversy on the choice of anticoagulation. The vitamin K antagonist (VKA), most commonly warfarin, is widely used for APS-mediated thrombus [2].
Whereas, VKA has many limitations in practical use, such as its interaction with food and drug, bleeding complications and need for frequent monitoring. Moreover, aPL may affect thromboplastin reagents, tending to affect the international normalized ratio measurement. Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. However, a prospective randomized trial evaluated the efficacy of rivaroxaban (20mg/day) in high-risk APS patients (with triple aPL-positive level), which showed that rivaroxaban was associated with an increased arterial thrombotic risk of events 9 compared with warfarin (www.clinicaltrials.gov; NCT02157272) [15]. A suboptimal drug concentration may account for the thromboembolic complications during this trial. Therefore, we prescribed rivaroxaban at its relatively low dose (20mg/day) to test the optimal dose for the patient with negative aPL. Although her symptoms improved, long-term outcome still need to be followed up. Moreover, several studies have shown the benefit of immunosuppressive drugs, especially steroids. Rodriguez et al discovered that the materno-fetal prognosis could be improved by the addition of low-dose prednisolone during the first trimester of pregnancy in women with APS [16]. Cervera et al summarized the clinical approach to treat catastrophic APS as a combination of anticoagulation plus steroids plus plasma exchange or intravenous immunoglobulins [17]. Sugie et al reported one case of CVST in APS was treated successfully by the combined use of rivaroxaban and prednisolone [18]. However, to avoid deterioration of IJVS and the occurrence of new-onset venous thrombosis due to steroid-induced hypercoagulability, we administered low-dose prednisone (equivalent to 0.35mg/kg and 0.55 mg/kg in case 1 and case 2, respectively).
To sum up, these two cases reminded us that firstly, except for thrombotic events, there was non-thrombus venous stenosis resulted from aPL mediated vessel wall damage. IVJS may be a rare complication of APS, with clinical features similar to high intracranial pressure syndrome. Secondly, high titer of aPL could induce vessel wall damage despite long-term standardized anticoagulation for thrombosis prevention. Thus, follow-up of autoantibodies should be done dynamically. Thirdly, concomitant use of anticoagulants and steroids is suggested as the mainstay therapy. Long-term preventive anticoagulation might only inhibit thrombotic event and corticosteroid might attenuate aPL-mediated venous wall damage. The last but not least, the BBTI was a very useful imaging tool on confirming intravenous thrombus as well as non-thrombus stenosis induced by immune mediated inflammation. A combination of CE-MRV and BBTI may be the first option to identify non-thrombus IJVS precisely and non-invasively, although DSA is still as the golden standard to make a confirmatory diagnosis. We highly suggest future studies could shed more attention on early diagnose and treatment in patients with IJVS of autoimmune etiology.

Conclusion
IJVS is a rather rare complication of APS. This is first report of non-thrombus venous stenosis resulted from aPL mediated vessel wall damage. High titer of aPL could induce stenosis without thrombosis formation due to long-term standardized anticoagulation. Follow-up of autoantibodies are necessary to be done dynamically.
Treatment for patients with IJVS of autoimmune etiology should be concomitant use of anticoagulants and steroids.

Availability of Data and Materials
The data and materials related to these two cases are available on request to the corresponding author.