Transient Antiphospholipid Antibody Positivity in a Patient with Cerebral Infarction Due to Vertebral Artery Dissection: A Case Report and Literature Review

Abstract

We herein report a 60-year-old man with transient lupus anticoagulant positivity in the acute phase of cerebral infarction due to left vertebral artery dissection who experienced repeated occlusion of the affected artery despite mechanical thrombectomy and stent placement. The addition of anticoagulants prevented further cerebral infarctions. In this case, it was believed that vascular injury caused by vertebral artery dissection, combined with the presence of antiphospholipid antibodies, accelerated repeated thrombosis. Interestingly, anti-cardiolipin antibodies were detected eight months later, although all antiphospholipid antibodies were negative at the time of the first follow-up.

Introduction

Antiphospholipid syndrome (APS) is an autoimmune disorder that can cause thrombosis, including cerebral infarctions. The diagnosis of APS requires not only clinical findings, such as thrombosis or pregnancy complications, but also confirmation of antiphospholipid antibodies, such as lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2-glycoprotein I (β2-GPI) antibodies, at least twice over a span of more than 12 weeks (1). However, there have been reports of transient antiphospholipid antibody positivity during the acute phase of cerebral infarction without a definitive APS diagnosis (2-6), and the clinical significance of transiently positive antibodies remains unclear.

We herein report a case of cerebral infarction due to vertebral artery dissection with transient LA positivity and recurrent thrombosis along with a review of the literature.

Case Report

A 60-year-old man presented to a local hospital on the third day after the sudden onset of left posterior cervical pain and dizziness. Magnetic resonance imaging (MRI) of the brain showed no significant findings at that time, and the patient was kept under observation. However, he visited our hospital on day 14 because of visual impairment. He had a medical history of hypertension and type 2 diabetes but no history of smoking or a family history of cerebrovascular disease.

On admission, his height was 176.0 cm, weight was 85.0 kg, body mass index was 27.4 kg/m², body temperature was 36.9°C, pulse was 80 beats/min (regular), blood pressure was 133/82 mmHg, and respiratory rate was 17 breaths/min. A physical examination revealed no significant abnormalities. A neurological examination revealed that he was alert and well oriented, but he had left homonymous inferior quadrantanopia. No other cranial nerve abnormalities, significant limb weakness, or sensory disturbances were noted. However, limb ataxia was also observed.

Blood tests revealed a white blood cell count of 4,400 /μL, hemoglobin of 17.5 g/dL, and platelet count of 123,000 /μL, indicating mild thrombocytopenia. The HbA1c level was elevated to 7.1%, and the LDL cholesterol level was 176 mg/dL. Coagulation tests showed a PT-INR of 1.08, an APTT of 31.6 seconds, and a D-dimer 0.76 μg/mL, all within normal ranges. LA was positive (diluted Russell's viper venom test positive, mixing time 78.9 s). The aCL-IgG was 4.0 U/mL (normal ＜12.3 U/mL), and anti-β2-GPI antibody was less than 1.2 U/mL (normal ＜3.5 U/mL), both negative. Antinuclear antibody, anti-ds-DNA antibody, anti-Sm antibody, anti-SS-A antibody, and anti-SS-B antibody tests were all negative. The complement levels were within normal limits, with C3 at 132 mg/dL, C4 at 24 mg/dL, and CH50 at 54.6 CH50/mL. Both RPR and TPHA tests were negative, with levels of 0.0 RU.

Brain MRI performed at another local hospital on day 3 showed no obvious acute cerebral infarction or left vertebral artery stenosis (Fig. 1A-C). However, on day 14, when he was first seen at our hospital, brain MRI showed hyperintense lesions in the right occipital lobe and bilateral cerebellar hemispheres on diffusion-weighted imaging (Fig. 1D, E). Magnetic resonance angiography (MRA) maximum intensity projection (MIP) and original coronal source images revealed distal stenosis in the left intracranial vertebral artery (Fig. 1F, G). The outer diameter of the vessel was preserved on basiparallel anatomic scanning (BPAS) (Fig. 1H), whereas a T1 hyperintense structure was detected along the vessel wall on magnetization prepared acquisition with gradient echo (MPRAGE) (Fig. 1I). A 24-h Holter electrocardiogram showed no atrial fibrillation. Carotid artery ultrasonography on admission showed no significant stenosis in the observable cervical vessels, and both vertebral artery flows were anterograde. Chest and abdominal computed tomography (CT) revealed no findings suggestive of malignancy.

Figure 1.

Brain MRI findings. Brain MRI on day 3 showed no obvious cerebral infarction or left vertebral artery stenosis (A-C). On day 14, cerebral infarctions were observed in the right occipital lobe and in both cerebellar hemispheres (D, E). MRA MIP and original coronal source images revealed stenosis of the distal left vertebral artery (F, G, white arrows). Although the outer diameter of the vessel was preserved on basiparallel anatomic scanning (BPAS) (H, yellow arrow), the inner diameter showed a T1-high signal structure along the vessel wall on magnetization-prepared acquisition with gradient echo (MPRAGE) (I, blue arrow), suggesting intramural hematoma.

The presence of cervical pain, rapid progression of left vertebral artery stenosis, and high signal intensity on T1-weighted images, suggesting an intramural hematoma in the left vertebral artery, led to the diagnosis of acute cerebral infarction due to left vertebral artery dissection based on the proposed criteria (7). Continuous intravenous heparin infusion was initiated for secondary prevention of cerebral infarction and was switched to prasugrel on day 18. On day 25, the patient experienced sudden nausea and vomiting and became somnolent, raising the suspicion of vertebrobasilar insufficiency. Cerebral angiography revealed occlusion of the left intracranial vertebral artery (Fig. 2A), and mechanical thrombectomy and stent placement were performed (Fig. 2B, C). Aspirin was added after the stent placement. On day 26, right upper and lower limb paralysis occurred, and cerebral angiography again showed occlusion of the left vertebral artery (Fig. 2D). Another mechanical thrombectomy was performed to restore the patency (Fig. 2E). However, on returning to the ward, left upper limb paralysis occurred, and repeat angiography showed thrombus protrusion in the vessel (Fig. 2F), necessitating another mechanical thrombectomy (Fig. 2G). Given the positive LA on admission and the recurrent in-stent thrombosis, APS was suspected, and continuous intravenous heparin was restarted and later switched to warfarin. In addition, prasugrel was switched to cilostazol for a potential vascular endothelial cell prospective effect (8).

Figure 2.

Cerebral angiography. Occlusion of the left vertebral artery was observed on day 25 (A). Mechanical thrombectomy and stent placement were performed, and the left vertebral artery was patent (B). The position of the stent is indicated by (C arrows). On day 26, the vessel is occluded (D). Mechanical thrombectomy was performed to achieve reperfusion (E). On the same day, thrombus protrusion was detected in the vessel (F, arrows), and mechanical thrombectomy was performed again (G).

After the resumption of anticoagulation therapy, there was no apparent recurrence of cerebral infarction, and secondary prevention with aspirin, cilostazol, and warfarin was continued. He was transferred to another hospital on day 90 with a modified Rankin Scale score of 4. On day 106, LA, aCL-IgG (＜4.0 U/mL), and anti-β2-GPI antibodies (＜1.3 U/mL) measured were all negative, which did not meet the criteria for definite APS (1). He was later discharged from the hospital and, upon follow-up at our hospital on day 266, blood tests showed positive aCL-IgG at 15.2 U/mL, although LA and anti-β2-GPI antibodies (＜1.2 U/mL) remained negative.

The patient satisfied the clinical criteria based on the 2023 ACR/EULAR classification criteria (9); however, in terms of laboratory criteria, although transient positivity for LA was observed, aCL-IgG remained at a low titer, and the classification criteria for APS were not met at that time. Nevertheless, owing to recurrent thrombotic events and seroconversion of aCL-IgG on day 266, preventive treatment for recurrence with warfarin and aspirin was continued in accordance with the APS management protocol. Thereafter, no recurrence of cerebral infarction was reported for one year.

Discussion

Initially, APS was thought to be involved in recurrent thrombus occlusion because the LA was positive at the time of hospitalization. However, the results of the follow-up blood test on day 106 were negative, indicating that LA positivity was transient. To date, there have been six reports (including this case) of transiently positive antiphospholipid antibodies in adults with acute cerebral infarction (Table) (2-6). The median age was 48 (range, 35-61) years old, and 4 of the patients were men. Ischemic lesions were observed in the anterior and posterior circulation. Among the five previously reported cases, only one had a history of typical vascular risk factors, namely, hypertension (6). In some cases, two types of antiphospholipid antibodies were initially positive (4-6), and in cases where only one type was positive, the antibodies often became negative later (10), as was the case in this patient. While several reports have suggested transient antiphospholipid antibody positivity following infections (11), no prior infection was evident in our case. Information on antithrombotic agents was available for two of the five previously reported cases, and anticoagulants were administered in both cases (4,6). In our case, anticoagulants were added because of repeated thrombosis, and no obvious recurrence of the cerebral infarction was observed.

Table.

Clinical Characteristics of Cases with Transient Antiphospholipid Antibody Positivity in the Acute Phase of Cerebral Infarction.

Reference	Age	Sex	Underlying condition	Ischemic lesions	Prior infection	Positive antiphospholipid antibodies	Thrombocytopenia	Antithrombotic drug
(2)	35	M	Migraine	Cerebellum, occipital lobe	N/A	aCL	Normal	N/A
(3)	61	F	No notable findings	Corona radiate	Dengue virus infection	LA	70,000/µL*1	N/A
(4)	44	F	No notable findings	Occipital lobe	Bacterial pneumonia	aCL, anti-β2-GPI antibodies	83,000/µL*2	Heparin, warfarin
(5)	35	M	No notable findings	Middle cerebral artery territory	COVID-19	aCL, anti-β2-GPI antibodies	N/A	N/A
(6)	52	M	Hypertension	Corona radiata, semioval centre	COVID-19	aCL, anti-β2-GPI antibodies	N/A	Acetylsalicylic acid, low-molecular-weight heparin
Current case	60	M	Type 2 diabetes, hypertension, dyslipidemia	Brainstem, cerebellum, occipital lobe	No	LA	123,000/µL*1	Aspirin, cilostazol, warfarin

N/A: not available, LA: lupus anticoagulant, aCL: anticardiolipin antibodies, β2-GPI: β2-glycoprotein I

*1: The condition returned to normal over time.*2: Unresponsive to disseminated intravascular coagulation (DIC) treatment.

Our patient showed mild thrombocytopenia on admission that returned to normal over time. Two of the five previously reported cases also had thrombocytopenia (3,4). The association between antiphospholipid antibodies and thrombocytopenia is well-established (1), and antiphospholipid antibodies may enhance platelet activation, leading to consumptive thrombocytopenia (12). Furthermore, thrombocytopenia in patients with primary APS is thought to be a risk factor for thrombosis and complications during pregnancy (13). In our patient, only platelets were reduced among the three blood cell categories, and there was no history of drug use that could cause thrombocytopenia or findings suggesting secondary thrombocytopenia, such as systemic lupus erythematosus (SLE) or hepatic cirrhosis. Therefore, LA positivity was suggested to be related to thrombocytopenia in our patient. In the acute phase of cerebral infarction, unexplained isolated thrombocytopenia may support the suspicion of antiphospholipid antibody involvement, particularly in younger patients or in those with few atherosclerotic risk factors. Persistent elevation of antiphospholipid antibody levels is generally thought to be associated with thrombosis. However, it has also been suggested that in addition to the presence of antiphospholipid antibodies, damage to the vessel is crucial in the pathogenesis of thrombosis (14). In this case, it is thought that the combination of vascular damage caused by left vertebral artery dissection and the presence of antiphospholipid antibodies contributed to the recurrent thrombus formation at the dissection site.

Another notable feature of this case is that, despite the fact that all antiphospholipid antibodies became negative on day 106, aCL-IgG turned positive on day 266. In cases where the antiphospholipid antibody titer is low, it may be negative at follow-up (10). In addition, in SLE patients with persistently positive antiphospholipid antibodies, the antibodies reportedly turn negative after the development of thrombosis and then become positive again within five years (15). Furthermore, differences in the frequency of seroconversion and repositivity have been reported depending on the isotype of anticardiolipin antibodies, and these isotypes may also differ in their associated risk of thrombosis (16). In our patient, the titer of antiphospholipid antibodies before the development of cerebral infarction was unknown, and the specific antibody isotypes could not be evaluated. However, the antibody titer increased again over time after the event, indicating the necessity for continuous monitoring of antibody titers. In clinical settings, there are cases of repeated thrombosis that do not meet the diagnostic criteria for APS because of transient positivity or low titers of antiphospholipid antibodies (16). This phenomenon gives rise to the concept of “seronegative APS” (16). The results of the serial antibody examinations in our patient suggest that it is important to recognize that even when the first follow-up results are negative and transiently positive, antibody titers can still increase over time.

In general, warfarin is recommended for secondary prevention of cerebral infarction related to APS, and the addition of low-dose aspirin can be considered based on the risk of recurrence and bleeding in each case (17). As mentioned above, the titer of antiphospholipid antibodies may fluctuate and become positive. Therefore, even in cases where antiphospholipid antibodies are temporarily positive during the acute phase of cerebral infarction, careful consideration of antithrombotic drugs is needed.

In conclusion, we reported a case of cerebral infarction due to vertebral artery dissection that was transiently positive for LA and had repeated thrombosis. It is thought that the combination of vascular damage caused by vertebral artery dissection and the presence of antiphospholipid antibodies exacerbates thrombophilia. Our case suggests that it is important to consider the involvement of antiphospholipid antibodies in cases of repeated thrombosis despite antiplatelet therapy or in cases with unexplained thrombocytopenia in the acute phase of cerebral infarction. In addition, antiphospholipid antibodies can be detected again, even in patients who are transiently positive for these antibodies, indicating that it is crucial to monitor antibody titers over time, particularly in patients with repeated thrombosis.

The authors state that they have no Conflict of Interest (COI).