Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Lupus Anticoagulant and Anticardiolipin Antibody IgG are Associated with Increased Atherosclerosis at the Suprainguinal Elastic and Infrainguinal Muscular Arteries in the Abdomen and Lower Extremities

Lupus Anticoagulant and Anticardiolipin Antibody IgG are Associated with Increased... Purpose: Whether antiphospholipid antibodies (aPLs) cause atherosclerosis in certain arteries with specific compo - sitions and locations remains unknown. We investigated the relationship between aPLs and their association with locations of atherosclerosis in the arteries of the abdomen and lower extremities. Methods: Of 2273 patients, 697 who underwent computed tomography angiography of the abdomen and lower extremities and aPL evaluation were included. Atherosclerosis distribution score (ADS) was employed to quantify atherosclerosis severity. Multiple linear regression analysis was performed using the ADS of the suprainguinal elastic and infrainguinal muscular arteries as dependent variables and all aPLs, conventional risk factors of atherosclerosis, and coagulation-related factors as independent variables. Results: In the suprainguinal elastic and infrainguinal muscular arteries, common risk factors for higher ADS were age, smoking, hypertension, higher glycated hemoglobin, male sex, decreased protein S, and increased homocyst- eine. Lupus anticoagulant (LA) and increased triglyceride level in the suprainguinal elastic arteries and anticardiolipin antibody (aCL) immunoglobulin (Ig)G, longer alcohol consumption duration, and increased fibrinogen level in the infrainguinal muscular arteries were also risk factors for higher ADS. Conclusion: LA and aCL IgG were associated with atherosclerosis in the suprainguinal elastic and infrainguinal mus- cular arteries, respectively. aPLs could predict the location of atherosclerosis. Keywords: Lupus anticoagulant, Anticardiolipin IgG antibody, Suprainguinal elastic arteries, Infrainguinal muscular arteries, Atherosclerosis 1 Introduction Antiphospholipid antibodies (aPLs), which are sub- stances that cause antiphospholipid syndrome (APS), have been reported to be closely related to the devel- opment of atherosclerosis [1, 2]. However, it remains *Correspondence: jparkvk@gmail.com unknown whether each aPL causes atherosclerosis in cer- Department of Surgery, Haeundae Paik Hospital, College of Medicine, Inje tain arteries with specific compositions and locations. In University, 875, Haeundae-ro, Haeundae-gu, Busan 48108, Republic of Korea this study, we investigated the association between aPLs Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Park and Yi Artery Research and specific locations of atherosclerosis in the arteries of quantified by a standardized enzyme-linked immuno - the abdomen and lower extremities. sorbent assay (ELISA); and (3) the anti-β GP1 IgG/IgM To avoid confounding factors for aPLs, a multivariate isotype was present in serum or plasma with a titer > the study, including all aPLs, conventional atherosclerosis 99th-percentile level, quantified by a standardized ELISA risk factors, and coagulation-related factors, was per- according to recommended procedures. Hypertension formed. Additionally, to directly evaluate atherosclerosis was defined as being on antihypertensive medication severity, images of whole arteries, except for the splanch- or having a systolic blood pressure of ≥ 140  mmHg or a nic arteries, taken by computed tomography (CT) angi- diastolic blood pressure of ≥ 90  mmHg. Medical history ography of the abdomen and lower extremities were taking was performed for the days of alcohol consump- analyzed. The arteries of the abdomen and lower extrem - tion and pregnancy-related morbidities. Days of alcohol ities were divided into the suprainguinal elastic and consumption were calculated using the following equa- infrainguinal muscular arteries according to their com- tion: average number of days of alcohol consumption positions and locations [3]. The atherosclerosis distribu - per month × 12  months × number of years of alcohol tion score (ADS) was defined as an objective numerical consumption. In women, pregnancy-related morbidity value to quantify atherosclerosis severity and to study the for premature fetal death at or beyond the 10th week, relationship between the location of atherosclerosis and premature birth of neonates before the 34th week, and aPLs. unexplained consecutive spontaneous abortions before the 10th week of gestation were investigated for obstet- 2 Materials and Methods ric APS diagnosis [1]. As previously reported, indications 2.1 Participants for aPL testing could be classified as justified, potentially From March 2010 to February 2021, 2273 patients were justified, and not adequately justified [7]. However, there treated at the Division of Vascular Surgery in our hospi- is no current consensus on the indication for aPL test- tal. For the 2273 patients, we retrospectively analyzed the ing. In this study, the aPL test was performed for patients imaging study, blood tests, and medical history taking. with coagulation abnormalities, vascular thrombosis, symptoms and signs of autoimmune diseases, pregnancy- 2.2 C linical and Hematologic Factors related morbidity, and those who chose to be tested. The imaging study consisted of CT angiography of the abdomen and lower extremities or ultrasonography (US) 2.3 Elastic and Muscular Arteries of the Abdomen of the lower extremity veins. This study was performed and Lower Extremities using the results of the first blood test at the Division Elastic arteries are located near the heart and composed of Vascular Surgery in our hospital, and the blood tests of more elastic tissue in the tunica media than muscu- consisted of conventional atherosclerosis risk factors, lar arteries, while muscular arteries are located periph- coagulation-related factors, and aPLs. The conventional erally and made up of more smooth muscle cells in the atherosclerosis risk factors were age, body mass index tunica media than the elastic arteries [3]. We classified 2 2 [BMI; body weight (kg)/height (m )], smoking.pack.year the abdominal and lower extremity arteries, excluding (cigarette packs smoked per day × years as a smoker), the splanchnic arteries, into the suprainguinal elastic and hypertension, glycated hemoglobin (HbA1c), total cho- infrainguinal muscular arteries bordered by the inguinal lesterol, high-density lipoprotein (HDL) cholesterol, low- ligament. density lipoprotein (LDL) cholesterol, triglyceride, and homocysteine. 2.4 Inclusion Criteria and Characteristics of Participants Coagulation-related factors were protein C/S, Individuals who underwent both CT angiography of the antithrombin III, fibrinogen, and factor VIII. The aPLs abdomen and lower extremities and aPL testing were included lupus anticoagulant (LA), anticardiolipin included in the study. Those without any of these meas - antibody (aCL) immunoglobulin (Ig)G/IgM, and anti- urements were excluded. Of the 2273 patients, 697 (303 β glycoprotein (GP)1 IgG/IgM. The laboratory criteria men, 394 women) were enrolled in this study. Of these for determining positive aPLs were as follows [1, 4–6]: 697 participants, 617 (262 men, 355 women) also under- (1) LA present in plasma was detected according to the went US of the lower extremity veins to diagnose venous guidelines of the International Society on Thrombosis thrombus or reflux, 82 had arterial diseases requiring and Hemostasis (Scientific Subcommittee on LAs/phos - surgical treatment or endovascular intervention, 204 had pholipid-dependent antibodies); (2) the aCL IgG/IgM venous diseases, and 411 had vascular diseases that did isotype was present in serum or plasma with medium not require surgery or endovascular intervention. Of the or high titer [>40 IgG phospholipid units (GPL) or IgM 82 patients with arterial diseases, 13 underwent open vas- phospholipid units (MPL); or > the 99th-percentile level], cular surgery, 64 underwent endovascular intervention, P ark and Yi Artery Research and 5 underwent hybrid surgery consisting of open sur- suprainguinal elastic arteries, 0 to 16 in the infrainguinal gery and endovascular intervention. Of the 204 patients muscular arteries, and 0 to 23 in the total arteries of the with venous diseases, 196 underwent varicose vein sur- abdomen and lower extremities. A higher ADS indicated gery, 6 underwent excision for venous malformation, higher atherosclerosis severity (Fig. 1; Table 1). and 2 underwent sclerotherapy. Of the 411 participants with vascular diseases that did not require surgery or 2.6.2 US Acquisition endovascular intervention, 362 had atherosclerotic arte- Two US scanners were used (IU22, Philips, Bothell, rial diseases and were treated pharmacologically, 37 had WA, USA; LOGIQ E9, GE Healthcare, Wauwatosa, WI, thrombotic diseases and received anticoagulation ther- USA) with linear transducers (L9-3  MHz linear array apy, and 12 were only followed up. and L9-5  MHz linear array, respectively). During the examination, two image sets (without compression and 2.5 Blood Tests with compression of the vessels) were acquired at the Blood tests were carried out as previously described [8]. same level to evaluate the presence or absence of venous Blood sampling was performed in the morning after thrombosis (Fig. 2). overnight fasting. All measurements were performed according to the manufacturer’s instructions. Serum lev-2.7 Image Analysis els of total, HDL and LDL cholesterol, and homocysteine Both CT angiography and US data were retrospectively were measured using enzyme kits (Cholesterol Gen.2, reviewed by a radiologist who was blinded to the clini- HDL-Cholesterol Gen.4, LDL- Cholesterol Gen.3, and cal data. For controversial cases of lower-leg CT angiog- Homocysteine Enzymatic Assay, respectively; Roche raphy, both the radiologist and vascular surgeon reached Diagnostics, Mannheim, Germany). Measurements of a consensus. The presence of any degree of calcified, protein C, protein S, antithrombin III, factor VIII, and mixed, and non-calcified plaques (soft plaque) in the fibrinogen levels were performed using an analyzer arteries was reported as atherosclerosis [9]. Anatomic (CA-7000; Sysmex, Kobe, Japan). All reagents were pur- variations of below-knee arteries, including hypoplasia chased from Siemens Healthcare Diagnostics Products or aplasia, were not assigned as atherosclerosis [10]. Both GmbH (Marburg, Germany). LA was measured using pre- and post-contrast source images were compared, LA 1 screening reagent/LA 2 confirmation reagent (Dade and reconstructed images were assessed to evaluate the Behring Inc. Newark, NJ, USA). Levels of aCL IgG/IgM presence or absence of atherosclerotic plaque. Arterial were measured using ELISA with the autoimmune aCL thrombosis was also diagnosed in 23 arterial segments. IgG/IgM test kits (Bio-Rad Laboratories, Hercules, CA, Venous thrombosis was evaluated for the inferior vena USA). Serum concentrations of anti-β GP1 IgG/IgM cava, right and left common iliac, external iliac, internal were evaluated using Triturus (Grifols, Barcelona, Spain) iliac, common femoral, femoral, deep femoral, popliteal, with the REAADS anti-β GP1 IgG/IgM test kits (Corge- posterior tibial, peroneal, and anterior tibial veins, intra- nix Inc., Denver, CO, USA). muscular vein of the calf, and great and small saphenous veins. Arterial or venous thrombosis was defined as fol - 2.6 Imaging Studies lows: (1) low-attenuated complete or partial filling defect 2.6.1 CT Angiography and ADS of the vessel lumen in at least two consecutive images All examinations were performed at a single center with with or without distension of the vessel; (2) centered or two multidetector row CT systems on the axial plane cov- eccentric round filling defects (on axial images) and the ering from the diaphragm to the foot in the supine posi- “railway track” sign on sagittal images with or without tion using a 128-slice system (Definition AS + , Siemens collateral flows; and (3) intramural thrombosis of aneu - Healthineers, Forchheim, Germany) and a 64-slice sys- rysm [11, 12]. For US, venous thrombosis was evaluated tem (Discovery CT 750 HD, GE Healthcare, Waukesha, in the deep and superficial venous systems of the bilateral WI, USA). From the popliteal area to the foot, a delayed lower extremities from the inguinal to the ankle levels. image was acquired 10  s after post-contrast imaging to Venous thrombosis was defined as either a complete or minimize the possibility of delayed enhancement of the partial intra-luminal filling defect, lack of vessel compres - peripheral arteries due to the variability of the hemody- sion, and complete or partial absence of the Doppler sig- namic status of each participant. Axial images were auto- nal regardless of the chronicity of the lesion [13]. matically reconstructed with a 5-mm thickness and no gaps. On CT angiography, all the 23 target arteries were 2.8 Statistical Analysis scored as 0 (absence of atherosclerosis) or 1 (presence Because not all the continuous variables in this study of atherosclerosis). The sum of the scores is the ADS of showed normal distribution by the Shapiro‒Wilk test, a particular participant, which ranged from 0 to 7 in the non-parametric tests were used in comparative studies. Park and Yi Artery Research Fig. 1 CT angiography for lower extremity atherosclerosis and thrombosis. A 62-year-old man with aPLs showed an ADS of 6 points in the total arteries of the abdomen and lower extremities. A Calcified atherosclerotic plaques were observed in the infrarenal abdominal aorta (arrows, point = 1) on the pre-contrast CT image. A partial thrombus was observed in the infrarenal abdominal aorta on the post-contrast CT image (arrowhead). B, C Mixed atherosclerotic plaques were observed in the bilateral common iliac arteries (arrows in B, point = 2) and bilateral internal iliac arteries (arrows in C, point = 2). D A calcified atherosclerotic plaque was observed in the left proximal femoral artery (arrow, point = 1). Abbreviations: ADS atherosclerosis distribution score, aPLs antiphospholipid antibodies, CT computed tomography The numbers of the atherosclerotic arteries between comparison of the ADS among the participants with the suprainguinal elastic and infrainguinal muscular different numbers of positive aPLs was performed arteries were compared using the Mann–Whitney U by the Kruskal–Wallis test. Finally, a multiple linear test. Nominal variables could be used in a multiple lin- regression analysis was performed, with the ADS of ear regression analysis by converting them into dummy the suprainguinal elastic and infrainguinal muscular variables [14]. Therefore, sex (man = 0, woman = 1), arteries as dependent variables and all continuous and hypertension (normal = 0, hypertension = 1), and five nominal dummy variables as independent variables. aPLs (negative = 0, positive = 1) were converted into Statistical significance was defined as p < 0.05. Statisti- dummy variables using the statistical program of this cal analyses were performed using PASW Statistics 18 study. The ADS of the APS and non-APS participants release 18.0.0 (WinWrap Basic, Polar Engineering and was compared using the Mann–Whitney U test. A Consulting, Nikiski, AK, USA). P ark and Yi Artery Research Table 1 The 23 arterial segments, ADS, and comparison of the number of atherosclerotic arteries 23 Arteries Laterality ADS absence/presence of Number of atherosclerotic arteries Mean ± SD p* atherosclerosis out of 697 participants Suprainguinal elastic arteries Abdominal aorta 0/1 499 335.57 ± 152.81 0.001 Common iliac artery Right 0/1 444 Left 0/1 411 External iliac artery Right 0/1 119 Left 0/1 122 Internal iliac artery Right 0/1 379 Left 0/1 375 Sum 0/7 Infrainguinal muscular arteries Common femoral artery Right 0/1 216 109.44 ± 50.93 Left 0/1 229 Femoral artery Right 0/1 144 Left 0/1 137 Deep femoral artery Right 0/1 67 Left 0/1 68 Popliteal artery Right 0/1 120 Left 0/1 119 Anterior tibial artery Right 0/1 98 Left 0/1 92 Tibio-peroneal trunk Right 0/1 85 Left 0/1 80 Peroneal artery Right 0/1 66 Left 0/1 57 Posterior tibial artery Right 0/1 87 Left 0/1 86 Sum 0/16 Total 0/23 ADS atherosclerosis distribution score (atherosclerosis: absence = 0, presence = 1), mean mean of the number of atherosclerotic arteries, SD standard deviation *p, Mann–Whitney U test 3 Results iliac (23/188, 12.2%), left femoral (20/188, 10.6%), left 3.1 F requency of Atherosclerosis in the Suprainguinal external iliac (17/188, 9%), right femoral (14/188, 7.4%), and Infrainguinal Arteries right common iliac (14/188, 7.4%), right external iliac The most frequent location of atherosclerosis was the (6/188, 3.2%), right internal iliac (6/188, 3.2%), left pop- abdominal aorta (499/697, 71.6%), followed by the right liteal (6/188, 3.2%), left internal iliac (4/188, 2.1%), right common iliac (444/697, 63.7%) and left common iliac popliteal (4/188, 2.1%), right common femoral (2/188, (411/697, 59%) arteries. The number of atherosclerotic 1%), left common femoral (2/188, 1%) arteries, and the arteries in the suprainguinal elastic arteries was sig- right tibioperoneal trunk (1/188, 0.5%). In the veins, nificantly higher than that in the infrainguinal muscular thrombotic lesions were most frequently observed in arteries (p = 0.001, Table 1). the right popliteal vein (11/64, 17.2%), followed by the left femoral (10/64, 15.6%), right femoral (7/64, 10.9%), 3.2 Vascular Thrombosis left popliteal (7/64, 10.9%), left common femoral (4/64, A total of 252 vascular thrombotic lesions, consist- 6.3%), right external iliac (3/64, 4.7%), left external ing of 188 arterial (188/252, 74.6%) and 64 venous iliac (3/64, 4.7%), left soleus (3/64, 4.7%), right pero- (64/252, 25.4%) thrombotic lesions, were observed in neal (3/64, 4.7%), left peroneal (3/64, 4.7%), left poste- 136 patients (136/697, 19.5%). In the arteries, throm- rior tibial (3/64, 4.7%), right common iliac (2/64, 3.1%), botic lesions were most frequently observed in the right common femoral (2/64, 3.1%), right internal iliac aorta (69/188, 36.7%), followed by the left common (1/64, 1.6%), and left great saphenous vein (1/64, 1.6%). Park and Yi Artery Research Fig. 2 CT angiography and US findings of arterial thrombosis in a 65-year-old man with aPLs. A A near-complete intra-luminal filling defect was observed in the left proximal FA on CT angiography. On US, B an echogenic filling defect was observed in the left proximal FA on gray-scale image without compression and C with compression by probe. D No color signal was observed in the left proximal FA on color Doppler image. Abbreviations: aPLs antiphospholipid antibodies, CFV common femoral vein, CT computed tomography, DFA deep femoral artery, FA femoral artery, US ultrasonography 3.3 Pregnancy‑Related Morbidity 3.4 Comparison of ADS Between APS and Non‑APS Of the 697 participants, 142 (142/697, 20.4%) showed Participants positive aPLs in the initial tests. Of these 142 par- Of the 79 participants (40 men, 39 women) who fulfilled ticipants, 79 (40 men and 39 women) underwent the the required diagnostic tests for APS, 13 patients (16.5%, required diagnostic studies for APS, including reexami- 13/79) were diagnosed with APS. All of them were men. nations of aPLs at least 12 weeks apart, radiologic stud- APS patients had significantly higher ADS than the non- ies, and clinical history taking [1]. Of the 39 women, 20 APS participants in both the suprainguinal elastic and showed pregnancy-related morbidity. Specifically, one infrainguinal muscular arteries (p = 0.012 and 0.005, woman experienced unexplained fetal death after the respectively; Table 2). 10th week of gestation twice. Six women experienced premature births of morphologically normal neonates 3.5 Comparison of ADS Among the Participants before the 34th week of gestation. Thirteen women with Different Numbers of Positive aPLs experienced three or more unexplained consecutive Of the five aPLs, the maximal number of positivity was spontaneous abortions before the 10th week of gesta- three. ADS showed a tendency to increase as the num- tion. However, none of the 20 women showed repeated ber of positive aPLs increased in the suprainguinal elastic positivity for aPLs, tested at least 12 weeks apart. Thus, and infrainguinal muscular arteries. However, there was there was no female patient with obstetric APS. no significant difference in ADS among the participants P ark and Yi Artery Research Table 2 Comparison of the ADS between 13 APS patients and Table 4 List of continuous variables, including conventional risk 66 non-APS participants factors of atherosclerosis and coagulation-related factors Arteries APS (number) Mean ± SD of ADS p* Variables Number of Mean ± SD participants Suprainguinal elastic Presence (13) 5.31 ± 1.93 0.012 arteries Age (years) 697 65.25 ± 12.61 Absence (66) 3.58 ± 2.47 BMI 697 24.95 ± 3.90 Infrainguinal muscular Presence (13) 6.23 ± 4.85 0.005 Smoking.pack.year 697 14.85 ± 26.08 arteries Days of alcohol consumption 697 3013.94 ± 5222.92 Absence (66) 3.27 ± 4.92 HbA1c (%) 694 5.91 ± 1.02 ADS atherosclerosis distribution score, APS antiphospholipid syndrome, SD Total cholesterol (mg/dL) 697 183.51 ± 40.74 standard deviation HDL cholesterol (mg/dL) 696 49.47 ± 14.00 *p, Mann‒Whitney U test LDL cholesterol (mg/dL) 696 107.25 ± 33.23 Triglyceride (mg/dL) 696 151.71 ± 108.50 with 0, 1, 2, and 3 positive aPLs in the suprainguinal elas- Homocysteine (μmol/L) 695 10.32 ± 5.61 tic and infrainguinal muscular arteries (p = 0.193 and Protein C (%) 690 104.82 ± 25.10 0.211, respectively; Table 3). Protein S (%) 689 80.55 ± 21.93 Antithrombin III (%) 691 95.15 ± 15.01 3.6 R isk Factors for Higher ADS in the Suprainguinal Fibrinogen (mg/dL) 688 288.69 ± 90.76 Elastic and Infrainguinal Muscular Arteries Factor VIII (%) 691 121.26 ± 27.82 Tables  4 and 5 show the continuous and nominal vari- 2 2 BMI body mass index body (weight [kg]/height [m ]); days of alcohol ables used as independent variables in the multiple lin- consumption, average number of days of alcohol consumption per 1 month × 12 months × number of years of alcohol consumption, HbA1c ear regression analysis. In the suprainguinal elastic and glycated hemoglobin, HDL high-density lipoprotein, LDL low-density infrainguinal muscular arteries of the abdomen and lipoprotein, smoking.pack.year cigarette packs smoked per day × years as a smoker; SD standard deviation lower extremities, the common significant risk factors for higher ADS were increased age, higher tobacco con- sumption, hypertension, higher HbA1c level, male sex, in which atherosclerosis occurred more frequently in decreased protein S level, and increased level of homo- the elastic arteries of the abdomen than in the muscular cysteine. Meanwhile, LA and increased level of triglyc- arteries of the lower extremities [8]. erides in the suprainguinal elastic arteries and aCL IgG, In this study, 19.5% (136/697) of the participants had longer duration of alcohol consumption, and increased vascular thrombotic lesions. While the precise mecha- fibrinogen level in the infrainguinal muscle arteries were nism of thrombosis by aPLs remains unknown, the other significant risk factors for higher ADS (Table 6). complex of plasma protein β GP1 and platelet factor 4 reportedly could activate platelets in the presence of anti- 4 Discussion β2GP1 antibodies, leading to thrombosis [15]. A previous In this study, the number of atherosclerotic arteries of study reported that a higher number of aPLs was associ- the suprainguinal elastic arteries was significantly higher ated with a higher risk of developing atherosclerosis [16]. than that of the infrainguinal muscular arteries. This In this study, 13 APS patients had a significantly higher finding is consistent with the finding in our recent study, Table 3 Comparison of the ADS among the participants with different numbers of positive aPLs Arteries Number of positive aPLs Number of participants Mean ± SD of ADS p* Suprainguinal elastic arteries 0 555 3.31 ± 2.37 0.193 1 100 3.47 ± 2.52 2 39 3.79 ± 2.22 3 3 5.67 ± 1.16 Infrainguinal muscular arteries 0 555 2.40 ± 4.12 0.211 1 100 3.00 ± 4.70 2 39 2.62 ± 3.92 3 3 6.33 ± 6.03 ADS atherosclerosis distribution score, aPLs antiphospholipid antibodies, SD standard deviation *p, Kruskal–Wallis test Park and Yi Artery Research Table 5 List of nominal variables, including conventional risk Regarding the relationship between aPLs and athero- factors of atherosclerosis and aPLs sclerosis, the currently proposed mechanism is that the plasma protein β GP1 binds to oxidized low-density lipo- Variables Category (dummy Number of variable number) participants protein (oxLDL) to form oxLDL/β GP1 complexes, which (%) enhance the development of atherosclerosis by promoting monocyte and T cell activation and accelerating their influx Sex Men (0) 303 (43.5) into macrophages via anti-β GP1-mediated phagocytosis Women (1) 394(56.5) [21–25]. In this study, aCL IgG was a significant risk fac - Hypertension No (0) 400 (57.4) tor for higher ADS in the infrainguinal muscular arteries. Yes (1) 297 (42.6) The mechanism by which aCL IgG induces atherosclerosis LA Negative (0) 678 (97.3) is not well understood. In one report, 46% of systemic lupus Positive (1) 19 (2.7) erythematosus patients had increased concentrations of aCL IgG Negative (0) 664 (95.3) aCL IgG, and there was a cross reaction between aCL IgG Positive (1) 33 (4.7) and oxLDL [26]. This finding suggested that aCL IgG might aCL IgM Negative (0) 628 (90.1) participate in the development of atherosclerosis. Contrary Positive (1) 69 (9.9) to its name, LA causes vascular thrombosis [27–29]. In this Anti-β GP1 IgG Negative (0) 693 (99.4) study, LA was a significant risk factor for higher ADS in the Positive (1) 4 (0.6) suprainguinal elastic arteries. A meta-analysis of 21 stud- Anti-β GP1 IgM Negative (0) 635 (91.1) ies comprising 6,057 aPL-positive patients revealed that all Positive (1) 62 (8.9) aPLs were related to peripheral arterial disease, and LA was aCL, anticardiolipin antibody; anti-β GP1, anti-β glycoprotein 1; aPLs, 2 2 related to critical limb ischemia and failed revasculariza- antiphospholipid antibodies; iG, immunoglobulin; LA, lupus anticoagulant tion [30]. In this study, we found that LA and aCL IgG were likely to induce atherosclerosis in the suprainguinal elastic and infrainguinal muscular arteries, respectively, suggest- ADS than the remaining 66 non-APS participants. How- ing that aPL could be used as a tool to predict the location ever, there were no significant differences in the ADS of atherosclerosis. among the participants with 0, 1, 2, or 3 aPLs. From these While aPLs have been linked to the pathogenesis of results, we hypothesized that specific aPLs might be atherosclerosis, the precise underlying mechanism of this involved in the pathogenesis of atherosclerosis. association is not completely understood. Furthermore, In our multivariate analysis, LA of the suprainguinal whether each aPL causes atherosclerosis in a specific elastic arteries and aCL IgG of the infrainguinal mus- area of the arteries remains unknown. Thus, we believe cular arteries were significant risk factors for higher that our study may be novel because it revealed a rela- ADS, along with the conventional risk factors of ath- tionship between certain aPLs and the specific locations erosclerosis, alcohol consumption, and hypercoagulable of atherosclerosis. state. Aging, smoking, hypertension, high HbA1c level, This study had some limitations. This clinical study was increased homocysteine and triglyceride levels, hyper- retrospective by nature and a single center study. How- coagulable state, and male sex are well-known conven- ever, our study was conducted with participants over a tional risk factors of atherosclerosis [17, 18]. In this study, period of 11  years under the same diagnostic principles. the decreased protein S and increased fibrinogen levels Therefore, we believe that our data were homogeneous might act as significant risk factors for higher ADS in the and reliable. hypercoagulable state. Although the relationship between alcohol consump- tion and atherosclerosis has not been well established, 5 Conclusion moderate alcohol consumption reduced the severity The severity of atherosclerosis in APS patients was signifi - of atherosclerosis and the risk of heart failure [19, 20]. cantly higher than that in non-APS individuals. In addition However, our findings showed that prolonged alcohol to the conventional risk factors for atherosclerosis, hyper- consumption increased the risk of atherosclerosis in the coagulable state, and prolonged consumption of alcohol, infrainguinal muscular arteries. Thus, we speculated that LA of the suprainguinal elastic arteries and aCL IgG of the long-term continuous, but not moderate, alcohol con- infrainguinal muscular arteries were significant risk factors sumption might enhance the development of atheroscle- for atherosclerosis. These findings suggest that aPLs could rosis in the infrainguinal muscular arteries. be utilized to predict the location of atherosclerosis. P ark and Yi Artery Research Table 6 Risk factors for higher ADS identified in a multiple linear regression analysis Model Unstandardized Standardized p* 95.0% Confidence interval for B coefficients coefficients B Beta Lower bound Upper bound Suprainguinal elastic arteries Constant −5.205 < 0.001 −6.208 −4.202 Age 0.105 0.553 < 0.001 0.095 0.115 Smoking 0.015 0.167 < 0.001 0.010 0.021 Hypertension 0.718 0.149 < 0.001 0.470 0.967 HbA1c 0.275 0.119 < 0.001 0.162 0.389 Sex −0.472 −0.098 0.001 −0.759 −0.184 Protein S −0.009 −0.081 0.001 −0.014 −0.003 Homocysteine 0.031 0.074 0.005 0.009 0.053 LA 0.975 0.067 0.005 0.294 1.657 Triglyceride 0.001 0.055 0.028 0.000 0.002 Infrainguinal muscular arteries Constant −9.273 < 0.001 −11.460 −7.087 Age 0.078 0.231 < 0.001 0.056 0.100 Smoking 0.024 0.146 < 0.001 0.011 0.036 HbA1c 0.849 0.206 < 0.001 0.599 1.099 Hypertension 1.153 0.134 < 0.001 0.613 1.692 Days of alcohol consump- 0.000 0.136 < 0.001 0.000 0.000 tion Fibrinogen 0.005 0.116 < 0.001 0.003 0.008 Homocysteine 0.070 0.093 0.004 0.022 0.117 Protein S −0.017 −0.090 0.003 −0.029 −0.006 aCL IgG 1.449 0.072 0.014 0.295 2.603 Sex −0.800 −0.094 0.017 −1.456 −0.144 The ADSs of the suprainguinal elastic and infrainguinal muscular arteries were the dependent variables. The independent variables were all the continuous and nominal variables (dummy variables) aCL anticardiolipin antibody, ADS atherosclerosis distribution score, HbA1c glycated hemoglobin, Ig immunoglobulin, LA lupus anticoagulant *p, multiple linear regression analysis Abbreviations Availability of Data and Materials aCL: Anticardiolipin antibody; ADS: Atherosclerosis distribution score; aPLs: The datasets used and/or analyzed during the current study are available from Antiphospholipid antibodies; CT: Computed tomography; ELISA: Enzyme- the corresponding author on reasonable request. linked immunosorbent assay; GP: Glycoprotein; HbA1c: Glycated hemoglobin; HDL: High-density lipoprotein; Ig: Immunoglobulin; LA: Lupus anticoagulant; Declarations LDL: Low-density lipoprotein; oxLDL: Oxidized low-density lipoprotein; US: Ultrasonography. Conflict of Interest The authors declare that they have no competing interests. Acknowledgements Not applicable. Ethical Approval and Consent to Participate This study was conducted according to the Declaration of Helsinki, and the Authors’ contribution study protocol was reviewed and approved by Institutional Review Board (IRB) J.Y. is co-first author with J.P. J.P.: conception and design, acquisition of data, of Inje University Haeundae Paik Hospital, Busan, Republic of Korea, approval analysis and interpretation of data, drafting of the manuscript, critical revision number HPIRB 2021–12-017. The need for consent was waived by the IRB of the manuscript, guarantor of integrity of the entire study. J.Y.: conception because of the minimal risk to participants. and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, guarantor of integrity of the entire study. Consent for Publication Both authors read and approved the final manuscript. Not applicable. Funding Not applicable. Park and Yi Artery Research Author details or secondary prevention: insights from the KP REACH study. J Am Heart Department of Surgery, Haeundae Paik Hospital, College of Medicine, Inje Assoc. 2021;10:e020377. University, 875, Haeundae-ro, Haeundae-gu, Busan 48108, Republic of Korea. 19. Laguzzi F, Baldassarre D, Veglia F, Strawbridge RJ, Humphries SE, Rau- Department of Radiology, Haeundae Paik Hospital, College of Medicine, Inje ramaa R, et al. Alcohol consumption in relation to carotid subclinical University, Busan, Republic of Korea. atherosclerosis and its progression: results from a European longitudinal multicentre study. Eur J Nutr. 2021;60:123–34. Received: 2 September 2022 Accepted: 27 November 2022 20. Goncalves A, Claggett B, Jhund PS, Rosamond W, Deswal A, Aguilar D, et al. Alcohol consumption and risk of heart failure: the Atherosclerosis Risk in Communities Study. Eur Heart J. 2015;36:939–45. 21. Lopez-Pedrera C, Barbarroja N, Jimenez-Gomez Y, Collantes-Estevez E, Aguirre MA, Cuadrado MJ. Oxidative stress in the pathogenesis of athero- thrombosis associated with anti-phospholipid syndrome and systemic References lupus erythematosus: new therapeutic approaches. Rheumatology 1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. (Oxford). 2016;55:2096–108. International consensus statement on an update of the classification 22. Matsuura E, Shen L, Matsunami Y, Quan N, Makarova M, Geske FJ, et al. criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. Pathophysiology of beta2-glycoprotein I in antiphospholipid syndrome. 2006;4:295–306. Lupus. 2010;19:379–84. 2. Matsuura E, Lopez LR. Autoimmune-mediated atherothrombosis. Lupus. 23. Conti F, Spinelli FR, Alessandri C, Pacelli M, Ceccarelli F, Marocchi E, 2008;17:878–87. et al. Subclinical atherosclerosis in systemic lupus erythematosus and 3. Tucker WD, Arora Y, Mahajan K. Anatomy, blood vessels. Treasure Island: antiphospholipid syndrome: focus on beta2GPI-specific T cell response. StatPearls; 2022. Arterioscler Thromb Vasc Biol. 2014;34:661–8. 4. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis 24. Matsuura E, Lopez LR. Are oxidized LDL/beta2-glycoprotein I complexes of lupus anticoagulants: an update. On behalf of the Subcommittee pathogenic antigens in autoimmune-mediated atherosclerosis? Clin Dev on Lupus Anticoagulant/Antiphospholipid Antibody of the Scien- Immunol. 2004;11:103–11. tific and Standardisation Committee of the ISTH. Thromb Haemost. 25. Matsuura E, Kobayashia K, Koikeb T, Shoenfeld Y, Khamashta MA, Hughes 1995;74:1185–90. GR. Atherogenic autoantigen: oxidized LDL complexes with beta2-glyco- 5. Tincani A, Allegri F, Sanmarco M, Cinquini M, Taglietti M, Balestrieri G, et al. protein I. Immunobiology. 2003;207:17–22. Anticardiolipin antibody assay: a methodological analysis for a better 26. Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho K, Palosuo consensus in routine determinations—a cooperative project of the T. Crossreaction between antibodies to oxidised low-density lipo- European Antiphospholipid Forum. Thromb Haemost. 2001;86:575–83. protein and to cardiolipin in systemic lupus erythematosus. Lancet. 6. Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC, Standardiza- 1993;341:923–5. tion group of the European Forum on Antiphospholipid A. Proposals for 27. Wood W Jr. PROCEEDINGS of the forty-fourth annual meeting of the the measurement of anti-beta2-glycoprotein I antibodies Standardization American Society for Clinical Investigation held in Atlantic City, N. J. May group of the European Forum on Antiphospholipid Antibodies. J Thromb 5, 1952. J Clin Invest. 1952;31:611–75. Haemost. 2004;2:1860–2. 28. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are 7. Mameli A, Barcellona D, Vannini ML, Marongiu F. High frequency of stronger risk factors for thrombosis than anticardiolipin antibodies in the inadequate test requests for antiphospholipid antibodies in daily clinical antiphospholipid syndrome: a systematic review of the literature. Blood. practice. Clin Chem Lab Med. 2011;49:695–8. 2003;101:1827–32. 8. Park JK, Jung WB, Yoon JH. Distribution pattern of atherosclerosis in the 29. Shapiro SS. The lupus anticoagulant/antiphospholipid syndrome. Annu abdomen and lower extremities and its association with clinical and Rev Med. 1996;47:533–53. hematological factors. Vasc Health Risk Manag. 2021;17:13–21. 30. Merashli M, Bucci T, Pastori D, Pignatelli P, Marottoli V, Arcaro A, et al. 9. He C, Yang JG, Li YM, Rong J, Du FZ, Yang ZG, et al. Comparison of Antiphospholipid antibodies and lower extremity peripheral artery lower extremity atherosclerosis in diabetic and non-diabetic patients disease: a systematic review and meta-analysis. Semin Arthritis Rheum. using multidetector computed tomography. BMC Cardiovasc Disord. 2020;50:1291–8. 2014;14:125. 10. Demirtas H, Degirmenci B, Celik AO, Umul A, Kara M, Aktas AR, et al. Anatomic variations of popliteal artery: evaluation with 128-section CT- angiography in 1261 lower limbs. Diagn Interv Imaging. 2016;97:635–42. 11. Cannavale A, Santoni M, Gazzetti M, Catalano C, Fanelli F. Updated clinical and radiological classification of lower limb atherosclerotic disease. Ann Vasc Surg. 2019;55:272–84. 12. Schriefl AJ, Collins MJ, Pierce DM, Holzapfel GA, Niklason LE, Humphrey JD. Remodeling of intramural thrombus and collagen in an Ang-II infusion ApoE−/− model of dissecting aortic aneurysms. Thromb Res. 2012;130:e139–46. 13. Fraser JD, Anderson DR. Deep venous thrombosis: recent advances and optimal investigation with US. Radiology. 1999;211:9–24. 14. Lunt M. Introduction to statistical modelling 2: categorical variables and Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : interactions in linear regression. Rheumatology (Oxford). 2015;54:1141–4. 15. Vlachoyiannopoulos PG, Routsias JG. A novel mechanism of thrombosis fast, convenient online submission in antiphospholipid antibody syndrome. J Autoimmun. 2010;35:248–55. thorough peer review by experienced researchers in your field 16. Di Minno MND, Emmi G, Ambrosino P, Scalera A, Tufano A, Cafaro G, et al. Subclinical atherosclerosis in asymptomatic carriers of persistent rapid publication on acceptance antiphospholipid antibodies positivity: a cross-sectional study. Int J support for research data, including large and complex data types Cardiol. 2019;274:1–6. • gold Open Access which fosters wider collaboration and increased citations 17. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, maximum visibility for your research: over 100M website views per year et al. Inter-Society Consensus for the Management of Peripheral Arterial • Disease ( TASC II). J Vasc Surg. 2007;45(Suppl S):S5-67. 18. Ambrosy AP, Yang J, Sung SH, Allen AR, Fitzpatrick JK, Rana JS, et al. At BMC, research is always in progress. Triglyceride levels and residual risk of atherosclerotic cardiovascular Learn more biomedcentral.com/submissions disease events and death in adults receiving statin therapy for primary http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Artery Research Springer Journals

Lupus Anticoagulant and Anticardiolipin Antibody IgG are Associated with Increased Atherosclerosis at the Suprainguinal Elastic and Infrainguinal Muscular Arteries in the Abdomen and Lower Extremities

Park, Jong Kwon; Yi, Jisook
Artery Research , Volume 29 (1) – Mar 1, 2023
Download PDF
10 pages

Loading next page...
 
/lp/springer-journals/lupus-anticoagulant-and-anticardiolipin-antibody-igg-are-associated-onYVnTGJmi

References (34)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2022
eISSN
1876-4401
DOI
10.1007/s44200-022-00026-w
Publisher site
See Article on Publisher Site

Abstract

Purpose: Whether antiphospholipid antibodies (aPLs) cause atherosclerosis in certain arteries with specific compo - sitions and locations remains unknown. We investigated the relationship between aPLs and their association with locations of atherosclerosis in the arteries of the abdomen and lower extremities. Methods: Of 2273 patients, 697 who underwent computed tomography angiography of the abdomen and lower extremities and aPL evaluation were included. Atherosclerosis distribution score (ADS) was employed to quantify atherosclerosis severity. Multiple linear regression analysis was performed using the ADS of the suprainguinal elastic and infrainguinal muscular arteries as dependent variables and all aPLs, conventional risk factors of atherosclerosis, and coagulation-related factors as independent variables. Results: In the suprainguinal elastic and infrainguinal muscular arteries, common risk factors for higher ADS were age, smoking, hypertension, higher glycated hemoglobin, male sex, decreased protein S, and increased homocyst- eine. Lupus anticoagulant (LA) and increased triglyceride level in the suprainguinal elastic arteries and anticardiolipin antibody (aCL) immunoglobulin (Ig)G, longer alcohol consumption duration, and increased fibrinogen level in the infrainguinal muscular arteries were also risk factors for higher ADS. Conclusion: LA and aCL IgG were associated with atherosclerosis in the suprainguinal elastic and infrainguinal mus- cular arteries, respectively. aPLs could predict the location of atherosclerosis. Keywords: Lupus anticoagulant, Anticardiolipin IgG antibody, Suprainguinal elastic arteries, Infrainguinal muscular arteries, Atherosclerosis 1 Introduction Antiphospholipid antibodies (aPLs), which are sub- stances that cause antiphospholipid syndrome (APS), have been reported to be closely related to the devel- opment of atherosclerosis [1, 2]. However, it remains *Correspondence: jparkvk@gmail.com unknown whether each aPL causes atherosclerosis in cer- Department of Surgery, Haeundae Paik Hospital, College of Medicine, Inje tain arteries with specific compositions and locations. In University, 875, Haeundae-ro, Haeundae-gu, Busan 48108, Republic of Korea this study, we investigated the association between aPLs Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Park and Yi Artery Research and specific locations of atherosclerosis in the arteries of quantified by a standardized enzyme-linked immuno - the abdomen and lower extremities. sorbent assay (ELISA); and (3) the anti-β GP1 IgG/IgM To avoid confounding factors for aPLs, a multivariate isotype was present in serum or plasma with a titer > the study, including all aPLs, conventional atherosclerosis 99th-percentile level, quantified by a standardized ELISA risk factors, and coagulation-related factors, was per- according to recommended procedures. Hypertension formed. Additionally, to directly evaluate atherosclerosis was defined as being on antihypertensive medication severity, images of whole arteries, except for the splanch- or having a systolic blood pressure of ≥ 140  mmHg or a nic arteries, taken by computed tomography (CT) angi- diastolic blood pressure of ≥ 90  mmHg. Medical history ography of the abdomen and lower extremities were taking was performed for the days of alcohol consump- analyzed. The arteries of the abdomen and lower extrem - tion and pregnancy-related morbidities. Days of alcohol ities were divided into the suprainguinal elastic and consumption were calculated using the following equa- infrainguinal muscular arteries according to their com- tion: average number of days of alcohol consumption positions and locations [3]. The atherosclerosis distribu - per month × 12  months × number of years of alcohol tion score (ADS) was defined as an objective numerical consumption. In women, pregnancy-related morbidity value to quantify atherosclerosis severity and to study the for premature fetal death at or beyond the 10th week, relationship between the location of atherosclerosis and premature birth of neonates before the 34th week, and aPLs. unexplained consecutive spontaneous abortions before the 10th week of gestation were investigated for obstet- 2 Materials and Methods ric APS diagnosis [1]. As previously reported, indications 2.1 Participants for aPL testing could be classified as justified, potentially From March 2010 to February 2021, 2273 patients were justified, and not adequately justified [7]. However, there treated at the Division of Vascular Surgery in our hospi- is no current consensus on the indication for aPL test- tal. For the 2273 patients, we retrospectively analyzed the ing. In this study, the aPL test was performed for patients imaging study, blood tests, and medical history taking. with coagulation abnormalities, vascular thrombosis, symptoms and signs of autoimmune diseases, pregnancy- 2.2 C linical and Hematologic Factors related morbidity, and those who chose to be tested. The imaging study consisted of CT angiography of the abdomen and lower extremities or ultrasonography (US) 2.3 Elastic and Muscular Arteries of the Abdomen of the lower extremity veins. This study was performed and Lower Extremities using the results of the first blood test at the Division Elastic arteries are located near the heart and composed of Vascular Surgery in our hospital, and the blood tests of more elastic tissue in the tunica media than muscu- consisted of conventional atherosclerosis risk factors, lar arteries, while muscular arteries are located periph- coagulation-related factors, and aPLs. The conventional erally and made up of more smooth muscle cells in the atherosclerosis risk factors were age, body mass index tunica media than the elastic arteries [3]. We classified 2 2 [BMI; body weight (kg)/height (m )], smoking.pack.year the abdominal and lower extremity arteries, excluding (cigarette packs smoked per day × years as a smoker), the splanchnic arteries, into the suprainguinal elastic and hypertension, glycated hemoglobin (HbA1c), total cho- infrainguinal muscular arteries bordered by the inguinal lesterol, high-density lipoprotein (HDL) cholesterol, low- ligament. density lipoprotein (LDL) cholesterol, triglyceride, and homocysteine. 2.4 Inclusion Criteria and Characteristics of Participants Coagulation-related factors were protein C/S, Individuals who underwent both CT angiography of the antithrombin III, fibrinogen, and factor VIII. The aPLs abdomen and lower extremities and aPL testing were included lupus anticoagulant (LA), anticardiolipin included in the study. Those without any of these meas - antibody (aCL) immunoglobulin (Ig)G/IgM, and anti- urements were excluded. Of the 2273 patients, 697 (303 β glycoprotein (GP)1 IgG/IgM. The laboratory criteria men, 394 women) were enrolled in this study. Of these for determining positive aPLs were as follows [1, 4–6]: 697 participants, 617 (262 men, 355 women) also under- (1) LA present in plasma was detected according to the went US of the lower extremity veins to diagnose venous guidelines of the International Society on Thrombosis thrombus or reflux, 82 had arterial diseases requiring and Hemostasis (Scientific Subcommittee on LAs/phos - surgical treatment or endovascular intervention, 204 had pholipid-dependent antibodies); (2) the aCL IgG/IgM venous diseases, and 411 had vascular diseases that did isotype was present in serum or plasma with medium not require surgery or endovascular intervention. Of the or high titer [>40 IgG phospholipid units (GPL) or IgM 82 patients with arterial diseases, 13 underwent open vas- phospholipid units (MPL); or > the 99th-percentile level], cular surgery, 64 underwent endovascular intervention, P ark and Yi Artery Research and 5 underwent hybrid surgery consisting of open sur- suprainguinal elastic arteries, 0 to 16 in the infrainguinal gery and endovascular intervention. Of the 204 patients muscular arteries, and 0 to 23 in the total arteries of the with venous diseases, 196 underwent varicose vein sur- abdomen and lower extremities. A higher ADS indicated gery, 6 underwent excision for venous malformation, higher atherosclerosis severity (Fig. 1; Table 1). and 2 underwent sclerotherapy. Of the 411 participants with vascular diseases that did not require surgery or 2.6.2 US Acquisition endovascular intervention, 362 had atherosclerotic arte- Two US scanners were used (IU22, Philips, Bothell, rial diseases and were treated pharmacologically, 37 had WA, USA; LOGIQ E9, GE Healthcare, Wauwatosa, WI, thrombotic diseases and received anticoagulation ther- USA) with linear transducers (L9-3  MHz linear array apy, and 12 were only followed up. and L9-5  MHz linear array, respectively). During the examination, two image sets (without compression and 2.5 Blood Tests with compression of the vessels) were acquired at the Blood tests were carried out as previously described [8]. same level to evaluate the presence or absence of venous Blood sampling was performed in the morning after thrombosis (Fig. 2). overnight fasting. All measurements were performed according to the manufacturer’s instructions. Serum lev-2.7 Image Analysis els of total, HDL and LDL cholesterol, and homocysteine Both CT angiography and US data were retrospectively were measured using enzyme kits (Cholesterol Gen.2, reviewed by a radiologist who was blinded to the clini- HDL-Cholesterol Gen.4, LDL- Cholesterol Gen.3, and cal data. For controversial cases of lower-leg CT angiog- Homocysteine Enzymatic Assay, respectively; Roche raphy, both the radiologist and vascular surgeon reached Diagnostics, Mannheim, Germany). Measurements of a consensus. The presence of any degree of calcified, protein C, protein S, antithrombin III, factor VIII, and mixed, and non-calcified plaques (soft plaque) in the fibrinogen levels were performed using an analyzer arteries was reported as atherosclerosis [9]. Anatomic (CA-7000; Sysmex, Kobe, Japan). All reagents were pur- variations of below-knee arteries, including hypoplasia chased from Siemens Healthcare Diagnostics Products or aplasia, were not assigned as atherosclerosis [10]. Both GmbH (Marburg, Germany). LA was measured using pre- and post-contrast source images were compared, LA 1 screening reagent/LA 2 confirmation reagent (Dade and reconstructed images were assessed to evaluate the Behring Inc. Newark, NJ, USA). Levels of aCL IgG/IgM presence or absence of atherosclerotic plaque. Arterial were measured using ELISA with the autoimmune aCL thrombosis was also diagnosed in 23 arterial segments. IgG/IgM test kits (Bio-Rad Laboratories, Hercules, CA, Venous thrombosis was evaluated for the inferior vena USA). Serum concentrations of anti-β GP1 IgG/IgM cava, right and left common iliac, external iliac, internal were evaluated using Triturus (Grifols, Barcelona, Spain) iliac, common femoral, femoral, deep femoral, popliteal, with the REAADS anti-β GP1 IgG/IgM test kits (Corge- posterior tibial, peroneal, and anterior tibial veins, intra- nix Inc., Denver, CO, USA). muscular vein of the calf, and great and small saphenous veins. Arterial or venous thrombosis was defined as fol - 2.6 Imaging Studies lows: (1) low-attenuated complete or partial filling defect 2.6.1 CT Angiography and ADS of the vessel lumen in at least two consecutive images All examinations were performed at a single center with with or without distension of the vessel; (2) centered or two multidetector row CT systems on the axial plane cov- eccentric round filling defects (on axial images) and the ering from the diaphragm to the foot in the supine posi- “railway track” sign on sagittal images with or without tion using a 128-slice system (Definition AS + , Siemens collateral flows; and (3) intramural thrombosis of aneu - Healthineers, Forchheim, Germany) and a 64-slice sys- rysm [11, 12]. For US, venous thrombosis was evaluated tem (Discovery CT 750 HD, GE Healthcare, Waukesha, in the deep and superficial venous systems of the bilateral WI, USA). From the popliteal area to the foot, a delayed lower extremities from the inguinal to the ankle levels. image was acquired 10  s after post-contrast imaging to Venous thrombosis was defined as either a complete or minimize the possibility of delayed enhancement of the partial intra-luminal filling defect, lack of vessel compres - peripheral arteries due to the variability of the hemody- sion, and complete or partial absence of the Doppler sig- namic status of each participant. Axial images were auto- nal regardless of the chronicity of the lesion [13]. matically reconstructed with a 5-mm thickness and no gaps. On CT angiography, all the 23 target arteries were 2.8 Statistical Analysis scored as 0 (absence of atherosclerosis) or 1 (presence Because not all the continuous variables in this study of atherosclerosis). The sum of the scores is the ADS of showed normal distribution by the Shapiro‒Wilk test, a particular participant, which ranged from 0 to 7 in the non-parametric tests were used in comparative studies. Park and Yi Artery Research Fig. 1 CT angiography for lower extremity atherosclerosis and thrombosis. A 62-year-old man with aPLs showed an ADS of 6 points in the total arteries of the abdomen and lower extremities. A Calcified atherosclerotic plaques were observed in the infrarenal abdominal aorta (arrows, point = 1) on the pre-contrast CT image. A partial thrombus was observed in the infrarenal abdominal aorta on the post-contrast CT image (arrowhead). B, C Mixed atherosclerotic plaques were observed in the bilateral common iliac arteries (arrows in B, point = 2) and bilateral internal iliac arteries (arrows in C, point = 2). D A calcified atherosclerotic plaque was observed in the left proximal femoral artery (arrow, point = 1). Abbreviations: ADS atherosclerosis distribution score, aPLs antiphospholipid antibodies, CT computed tomography The numbers of the atherosclerotic arteries between comparison of the ADS among the participants with the suprainguinal elastic and infrainguinal muscular different numbers of positive aPLs was performed arteries were compared using the Mann–Whitney U by the Kruskal–Wallis test. Finally, a multiple linear test. Nominal variables could be used in a multiple lin- regression analysis was performed, with the ADS of ear regression analysis by converting them into dummy the suprainguinal elastic and infrainguinal muscular variables [14]. Therefore, sex (man = 0, woman = 1), arteries as dependent variables and all continuous and hypertension (normal = 0, hypertension = 1), and five nominal dummy variables as independent variables. aPLs (negative = 0, positive = 1) were converted into Statistical significance was defined as p < 0.05. Statisti- dummy variables using the statistical program of this cal analyses were performed using PASW Statistics 18 study. The ADS of the APS and non-APS participants release 18.0.0 (WinWrap Basic, Polar Engineering and was compared using the Mann–Whitney U test. A Consulting, Nikiski, AK, USA). P ark and Yi Artery Research Table 1 The 23 arterial segments, ADS, and comparison of the number of atherosclerotic arteries 23 Arteries Laterality ADS absence/presence of Number of atherosclerotic arteries Mean ± SD p* atherosclerosis out of 697 participants Suprainguinal elastic arteries Abdominal aorta 0/1 499 335.57 ± 152.81 0.001 Common iliac artery Right 0/1 444 Left 0/1 411 External iliac artery Right 0/1 119 Left 0/1 122 Internal iliac artery Right 0/1 379 Left 0/1 375 Sum 0/7 Infrainguinal muscular arteries Common femoral artery Right 0/1 216 109.44 ± 50.93 Left 0/1 229 Femoral artery Right 0/1 144 Left 0/1 137 Deep femoral artery Right 0/1 67 Left 0/1 68 Popliteal artery Right 0/1 120 Left 0/1 119 Anterior tibial artery Right 0/1 98 Left 0/1 92 Tibio-peroneal trunk Right 0/1 85 Left 0/1 80 Peroneal artery Right 0/1 66 Left 0/1 57 Posterior tibial artery Right 0/1 87 Left 0/1 86 Sum 0/16 Total 0/23 ADS atherosclerosis distribution score (atherosclerosis: absence = 0, presence = 1), mean mean of the number of atherosclerotic arteries, SD standard deviation *p, Mann–Whitney U test 3 Results iliac (23/188, 12.2%), left femoral (20/188, 10.6%), left 3.1 F requency of Atherosclerosis in the Suprainguinal external iliac (17/188, 9%), right femoral (14/188, 7.4%), and Infrainguinal Arteries right common iliac (14/188, 7.4%), right external iliac The most frequent location of atherosclerosis was the (6/188, 3.2%), right internal iliac (6/188, 3.2%), left pop- abdominal aorta (499/697, 71.6%), followed by the right liteal (6/188, 3.2%), left internal iliac (4/188, 2.1%), right common iliac (444/697, 63.7%) and left common iliac popliteal (4/188, 2.1%), right common femoral (2/188, (411/697, 59%) arteries. The number of atherosclerotic 1%), left common femoral (2/188, 1%) arteries, and the arteries in the suprainguinal elastic arteries was sig- right tibioperoneal trunk (1/188, 0.5%). In the veins, nificantly higher than that in the infrainguinal muscular thrombotic lesions were most frequently observed in arteries (p = 0.001, Table 1). the right popliteal vein (11/64, 17.2%), followed by the left femoral (10/64, 15.6%), right femoral (7/64, 10.9%), 3.2 Vascular Thrombosis left popliteal (7/64, 10.9%), left common femoral (4/64, A total of 252 vascular thrombotic lesions, consist- 6.3%), right external iliac (3/64, 4.7%), left external ing of 188 arterial (188/252, 74.6%) and 64 venous iliac (3/64, 4.7%), left soleus (3/64, 4.7%), right pero- (64/252, 25.4%) thrombotic lesions, were observed in neal (3/64, 4.7%), left peroneal (3/64, 4.7%), left poste- 136 patients (136/697, 19.5%). In the arteries, throm- rior tibial (3/64, 4.7%), right common iliac (2/64, 3.1%), botic lesions were most frequently observed in the right common femoral (2/64, 3.1%), right internal iliac aorta (69/188, 36.7%), followed by the left common (1/64, 1.6%), and left great saphenous vein (1/64, 1.6%). Park and Yi Artery Research Fig. 2 CT angiography and US findings of arterial thrombosis in a 65-year-old man with aPLs. A A near-complete intra-luminal filling defect was observed in the left proximal FA on CT angiography. On US, B an echogenic filling defect was observed in the left proximal FA on gray-scale image without compression and C with compression by probe. D No color signal was observed in the left proximal FA on color Doppler image. Abbreviations: aPLs antiphospholipid antibodies, CFV common femoral vein, CT computed tomography, DFA deep femoral artery, FA femoral artery, US ultrasonography 3.3 Pregnancy‑Related Morbidity 3.4 Comparison of ADS Between APS and Non‑APS Of the 697 participants, 142 (142/697, 20.4%) showed Participants positive aPLs in the initial tests. Of these 142 par- Of the 79 participants (40 men, 39 women) who fulfilled ticipants, 79 (40 men and 39 women) underwent the the required diagnostic tests for APS, 13 patients (16.5%, required diagnostic studies for APS, including reexami- 13/79) were diagnosed with APS. All of them were men. nations of aPLs at least 12 weeks apart, radiologic stud- APS patients had significantly higher ADS than the non- ies, and clinical history taking [1]. Of the 39 women, 20 APS participants in both the suprainguinal elastic and showed pregnancy-related morbidity. Specifically, one infrainguinal muscular arteries (p = 0.012 and 0.005, woman experienced unexplained fetal death after the respectively; Table 2). 10th week of gestation twice. Six women experienced premature births of morphologically normal neonates 3.5 Comparison of ADS Among the Participants before the 34th week of gestation. Thirteen women with Different Numbers of Positive aPLs experienced three or more unexplained consecutive Of the five aPLs, the maximal number of positivity was spontaneous abortions before the 10th week of gesta- three. ADS showed a tendency to increase as the num- tion. However, none of the 20 women showed repeated ber of positive aPLs increased in the suprainguinal elastic positivity for aPLs, tested at least 12 weeks apart. Thus, and infrainguinal muscular arteries. However, there was there was no female patient with obstetric APS. no significant difference in ADS among the participants P ark and Yi Artery Research Table 2 Comparison of the ADS between 13 APS patients and Table 4 List of continuous variables, including conventional risk 66 non-APS participants factors of atherosclerosis and coagulation-related factors Arteries APS (number) Mean ± SD of ADS p* Variables Number of Mean ± SD participants Suprainguinal elastic Presence (13) 5.31 ± 1.93 0.012 arteries Age (years) 697 65.25 ± 12.61 Absence (66) 3.58 ± 2.47 BMI 697 24.95 ± 3.90 Infrainguinal muscular Presence (13) 6.23 ± 4.85 0.005 Smoking.pack.year 697 14.85 ± 26.08 arteries Days of alcohol consumption 697 3013.94 ± 5222.92 Absence (66) 3.27 ± 4.92 HbA1c (%) 694 5.91 ± 1.02 ADS atherosclerosis distribution score, APS antiphospholipid syndrome, SD Total cholesterol (mg/dL) 697 183.51 ± 40.74 standard deviation HDL cholesterol (mg/dL) 696 49.47 ± 14.00 *p, Mann‒Whitney U test LDL cholesterol (mg/dL) 696 107.25 ± 33.23 Triglyceride (mg/dL) 696 151.71 ± 108.50 with 0, 1, 2, and 3 positive aPLs in the suprainguinal elas- Homocysteine (μmol/L) 695 10.32 ± 5.61 tic and infrainguinal muscular arteries (p = 0.193 and Protein C (%) 690 104.82 ± 25.10 0.211, respectively; Table 3). Protein S (%) 689 80.55 ± 21.93 Antithrombin III (%) 691 95.15 ± 15.01 3.6 R isk Factors for Higher ADS in the Suprainguinal Fibrinogen (mg/dL) 688 288.69 ± 90.76 Elastic and Infrainguinal Muscular Arteries Factor VIII (%) 691 121.26 ± 27.82 Tables  4 and 5 show the continuous and nominal vari- 2 2 BMI body mass index body (weight [kg]/height [m ]); days of alcohol ables used as independent variables in the multiple lin- consumption, average number of days of alcohol consumption per 1 month × 12 months × number of years of alcohol consumption, HbA1c ear regression analysis. In the suprainguinal elastic and glycated hemoglobin, HDL high-density lipoprotein, LDL low-density infrainguinal muscular arteries of the abdomen and lipoprotein, smoking.pack.year cigarette packs smoked per day × years as a smoker; SD standard deviation lower extremities, the common significant risk factors for higher ADS were increased age, higher tobacco con- sumption, hypertension, higher HbA1c level, male sex, in which atherosclerosis occurred more frequently in decreased protein S level, and increased level of homo- the elastic arteries of the abdomen than in the muscular cysteine. Meanwhile, LA and increased level of triglyc- arteries of the lower extremities [8]. erides in the suprainguinal elastic arteries and aCL IgG, In this study, 19.5% (136/697) of the participants had longer duration of alcohol consumption, and increased vascular thrombotic lesions. While the precise mecha- fibrinogen level in the infrainguinal muscle arteries were nism of thrombosis by aPLs remains unknown, the other significant risk factors for higher ADS (Table 6). complex of plasma protein β GP1 and platelet factor 4 reportedly could activate platelets in the presence of anti- 4 Discussion β2GP1 antibodies, leading to thrombosis [15]. A previous In this study, the number of atherosclerotic arteries of study reported that a higher number of aPLs was associ- the suprainguinal elastic arteries was significantly higher ated with a higher risk of developing atherosclerosis [16]. than that of the infrainguinal muscular arteries. This In this study, 13 APS patients had a significantly higher finding is consistent with the finding in our recent study, Table 3 Comparison of the ADS among the participants with different numbers of positive aPLs Arteries Number of positive aPLs Number of participants Mean ± SD of ADS p* Suprainguinal elastic arteries 0 555 3.31 ± 2.37 0.193 1 100 3.47 ± 2.52 2 39 3.79 ± 2.22 3 3 5.67 ± 1.16 Infrainguinal muscular arteries 0 555 2.40 ± 4.12 0.211 1 100 3.00 ± 4.70 2 39 2.62 ± 3.92 3 3 6.33 ± 6.03 ADS atherosclerosis distribution score, aPLs antiphospholipid antibodies, SD standard deviation *p, Kruskal–Wallis test Park and Yi Artery Research Table 5 List of nominal variables, including conventional risk Regarding the relationship between aPLs and athero- factors of atherosclerosis and aPLs sclerosis, the currently proposed mechanism is that the plasma protein β GP1 binds to oxidized low-density lipo- Variables Category (dummy Number of variable number) participants protein (oxLDL) to form oxLDL/β GP1 complexes, which (%) enhance the development of atherosclerosis by promoting monocyte and T cell activation and accelerating their influx Sex Men (0) 303 (43.5) into macrophages via anti-β GP1-mediated phagocytosis Women (1) 394(56.5) [21–25]. In this study, aCL IgG was a significant risk fac - Hypertension No (0) 400 (57.4) tor for higher ADS in the infrainguinal muscular arteries. Yes (1) 297 (42.6) The mechanism by which aCL IgG induces atherosclerosis LA Negative (0) 678 (97.3) is not well understood. In one report, 46% of systemic lupus Positive (1) 19 (2.7) erythematosus patients had increased concentrations of aCL IgG Negative (0) 664 (95.3) aCL IgG, and there was a cross reaction between aCL IgG Positive (1) 33 (4.7) and oxLDL [26]. This finding suggested that aCL IgG might aCL IgM Negative (0) 628 (90.1) participate in the development of atherosclerosis. Contrary Positive (1) 69 (9.9) to its name, LA causes vascular thrombosis [27–29]. In this Anti-β GP1 IgG Negative (0) 693 (99.4) study, LA was a significant risk factor for higher ADS in the Positive (1) 4 (0.6) suprainguinal elastic arteries. A meta-analysis of 21 stud- Anti-β GP1 IgM Negative (0) 635 (91.1) ies comprising 6,057 aPL-positive patients revealed that all Positive (1) 62 (8.9) aPLs were related to peripheral arterial disease, and LA was aCL, anticardiolipin antibody; anti-β GP1, anti-β glycoprotein 1; aPLs, 2 2 related to critical limb ischemia and failed revasculariza- antiphospholipid antibodies; iG, immunoglobulin; LA, lupus anticoagulant tion [30]. In this study, we found that LA and aCL IgG were likely to induce atherosclerosis in the suprainguinal elastic and infrainguinal muscular arteries, respectively, suggest- ADS than the remaining 66 non-APS participants. How- ing that aPL could be used as a tool to predict the location ever, there were no significant differences in the ADS of atherosclerosis. among the participants with 0, 1, 2, or 3 aPLs. From these While aPLs have been linked to the pathogenesis of results, we hypothesized that specific aPLs might be atherosclerosis, the precise underlying mechanism of this involved in the pathogenesis of atherosclerosis. association is not completely understood. Furthermore, In our multivariate analysis, LA of the suprainguinal whether each aPL causes atherosclerosis in a specific elastic arteries and aCL IgG of the infrainguinal mus- area of the arteries remains unknown. Thus, we believe cular arteries were significant risk factors for higher that our study may be novel because it revealed a rela- ADS, along with the conventional risk factors of ath- tionship between certain aPLs and the specific locations erosclerosis, alcohol consumption, and hypercoagulable of atherosclerosis. state. Aging, smoking, hypertension, high HbA1c level, This study had some limitations. This clinical study was increased homocysteine and triglyceride levels, hyper- retrospective by nature and a single center study. How- coagulable state, and male sex are well-known conven- ever, our study was conducted with participants over a tional risk factors of atherosclerosis [17, 18]. In this study, period of 11  years under the same diagnostic principles. the decreased protein S and increased fibrinogen levels Therefore, we believe that our data were homogeneous might act as significant risk factors for higher ADS in the and reliable. hypercoagulable state. Although the relationship between alcohol consump- tion and atherosclerosis has not been well established, 5 Conclusion moderate alcohol consumption reduced the severity The severity of atherosclerosis in APS patients was signifi - of atherosclerosis and the risk of heart failure [19, 20]. cantly higher than that in non-APS individuals. In addition However, our findings showed that prolonged alcohol to the conventional risk factors for atherosclerosis, hyper- consumption increased the risk of atherosclerosis in the coagulable state, and prolonged consumption of alcohol, infrainguinal muscular arteries. Thus, we speculated that LA of the suprainguinal elastic arteries and aCL IgG of the long-term continuous, but not moderate, alcohol con- infrainguinal muscular arteries were significant risk factors sumption might enhance the development of atheroscle- for atherosclerosis. These findings suggest that aPLs could rosis in the infrainguinal muscular arteries. be utilized to predict the location of atherosclerosis. P ark and Yi Artery Research Table 6 Risk factors for higher ADS identified in a multiple linear regression analysis Model Unstandardized Standardized p* 95.0% Confidence interval for B coefficients coefficients B Beta Lower bound Upper bound Suprainguinal elastic arteries Constant −5.205 < 0.001 −6.208 −4.202 Age 0.105 0.553 < 0.001 0.095 0.115 Smoking 0.015 0.167 < 0.001 0.010 0.021 Hypertension 0.718 0.149 < 0.001 0.470 0.967 HbA1c 0.275 0.119 < 0.001 0.162 0.389 Sex −0.472 −0.098 0.001 −0.759 −0.184 Protein S −0.009 −0.081 0.001 −0.014 −0.003 Homocysteine 0.031 0.074 0.005 0.009 0.053 LA 0.975 0.067 0.005 0.294 1.657 Triglyceride 0.001 0.055 0.028 0.000 0.002 Infrainguinal muscular arteries Constant −9.273 < 0.001 −11.460 −7.087 Age 0.078 0.231 < 0.001 0.056 0.100 Smoking 0.024 0.146 < 0.001 0.011 0.036 HbA1c 0.849 0.206 < 0.001 0.599 1.099 Hypertension 1.153 0.134 < 0.001 0.613 1.692 Days of alcohol consump- 0.000 0.136 < 0.001 0.000 0.000 tion Fibrinogen 0.005 0.116 < 0.001 0.003 0.008 Homocysteine 0.070 0.093 0.004 0.022 0.117 Protein S −0.017 −0.090 0.003 −0.029 −0.006 aCL IgG 1.449 0.072 0.014 0.295 2.603 Sex −0.800 −0.094 0.017 −1.456 −0.144 The ADSs of the suprainguinal elastic and infrainguinal muscular arteries were the dependent variables. The independent variables were all the continuous and nominal variables (dummy variables) aCL anticardiolipin antibody, ADS atherosclerosis distribution score, HbA1c glycated hemoglobin, Ig immunoglobulin, LA lupus anticoagulant *p, multiple linear regression analysis Abbreviations Availability of Data and Materials aCL: Anticardiolipin antibody; ADS: Atherosclerosis distribution score; aPLs: The datasets used and/or analyzed during the current study are available from Antiphospholipid antibodies; CT: Computed tomography; ELISA: Enzyme- the corresponding author on reasonable request. linked immunosorbent assay; GP: Glycoprotein; HbA1c: Glycated hemoglobin; HDL: High-density lipoprotein; Ig: Immunoglobulin; LA: Lupus anticoagulant; Declarations LDL: Low-density lipoprotein; oxLDL: Oxidized low-density lipoprotein; US: Ultrasonography. Conflict of Interest The authors declare that they have no competing interests. Acknowledgements Not applicable. Ethical Approval and Consent to Participate This study was conducted according to the Declaration of Helsinki, and the Authors’ contribution study protocol was reviewed and approved by Institutional Review Board (IRB) J.Y. is co-first author with J.P. J.P.: conception and design, acquisition of data, of Inje University Haeundae Paik Hospital, Busan, Republic of Korea, approval analysis and interpretation of data, drafting of the manuscript, critical revision number HPIRB 2021–12-017. The need for consent was waived by the IRB of the manuscript, guarantor of integrity of the entire study. J.Y.: conception because of the minimal risk to participants. and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, guarantor of integrity of the entire study. Consent for Publication Both authors read and approved the final manuscript. Not applicable. Funding Not applicable. Park and Yi Artery Research Author details or secondary prevention: insights from the KP REACH study. J Am Heart Department of Surgery, Haeundae Paik Hospital, College of Medicine, Inje Assoc. 2021;10:e020377. University, 875, Haeundae-ro, Haeundae-gu, Busan 48108, Republic of Korea. 19. Laguzzi F, Baldassarre D, Veglia F, Strawbridge RJ, Humphries SE, Rau- Department of Radiology, Haeundae Paik Hospital, College of Medicine, Inje ramaa R, et al. Alcohol consumption in relation to carotid subclinical University, Busan, Republic of Korea. atherosclerosis and its progression: results from a European longitudinal multicentre study. Eur J Nutr. 2021;60:123–34. Received: 2 September 2022 Accepted: 27 November 2022 20. Goncalves A, Claggett B, Jhund PS, Rosamond W, Deswal A, Aguilar D, et al. Alcohol consumption and risk of heart failure: the Atherosclerosis Risk in Communities Study. Eur Heart J. 2015;36:939–45. 21. Lopez-Pedrera C, Barbarroja N, Jimenez-Gomez Y, Collantes-Estevez E, Aguirre MA, Cuadrado MJ. Oxidative stress in the pathogenesis of athero- thrombosis associated with anti-phospholipid syndrome and systemic References lupus erythematosus: new therapeutic approaches. Rheumatology 1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. (Oxford). 2016;55:2096–108. International consensus statement on an update of the classification 22. Matsuura E, Shen L, Matsunami Y, Quan N, Makarova M, Geske FJ, et al. criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. Pathophysiology of beta2-glycoprotein I in antiphospholipid syndrome. 2006;4:295–306. Lupus. 2010;19:379–84. 2. Matsuura E, Lopez LR. Autoimmune-mediated atherothrombosis. Lupus. 23. Conti F, Spinelli FR, Alessandri C, Pacelli M, Ceccarelli F, Marocchi E, 2008;17:878–87. et al. Subclinical atherosclerosis in systemic lupus erythematosus and 3. Tucker WD, Arora Y, Mahajan K. Anatomy, blood vessels. Treasure Island: antiphospholipid syndrome: focus on beta2GPI-specific T cell response. StatPearls; 2022. Arterioscler Thromb Vasc Biol. 2014;34:661–8. 4. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis 24. Matsuura E, Lopez LR. Are oxidized LDL/beta2-glycoprotein I complexes of lupus anticoagulants: an update. On behalf of the Subcommittee pathogenic antigens in autoimmune-mediated atherosclerosis? Clin Dev on Lupus Anticoagulant/Antiphospholipid Antibody of the Scien- Immunol. 2004;11:103–11. tific and Standardisation Committee of the ISTH. Thromb Haemost. 25. Matsuura E, Kobayashia K, Koikeb T, Shoenfeld Y, Khamashta MA, Hughes 1995;74:1185–90. GR. Atherogenic autoantigen: oxidized LDL complexes with beta2-glyco- 5. Tincani A, Allegri F, Sanmarco M, Cinquini M, Taglietti M, Balestrieri G, et al. protein I. Immunobiology. 2003;207:17–22. Anticardiolipin antibody assay: a methodological analysis for a better 26. Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho K, Palosuo consensus in routine determinations—a cooperative project of the T. Crossreaction between antibodies to oxidised low-density lipo- European Antiphospholipid Forum. Thromb Haemost. 2001;86:575–83. protein and to cardiolipin in systemic lupus erythematosus. Lancet. 6. Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC, Standardiza- 1993;341:923–5. tion group of the European Forum on Antiphospholipid A. Proposals for 27. Wood W Jr. PROCEEDINGS of the forty-fourth annual meeting of the the measurement of anti-beta2-glycoprotein I antibodies Standardization American Society for Clinical Investigation held in Atlantic City, N. J. May group of the European Forum on Antiphospholipid Antibodies. J Thromb 5, 1952. J Clin Invest. 1952;31:611–75. Haemost. 2004;2:1860–2. 28. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are 7. Mameli A, Barcellona D, Vannini ML, Marongiu F. High frequency of stronger risk factors for thrombosis than anticardiolipin antibodies in the inadequate test requests for antiphospholipid antibodies in daily clinical antiphospholipid syndrome: a systematic review of the literature. Blood. practice. Clin Chem Lab Med. 2011;49:695–8. 2003;101:1827–32. 8. Park JK, Jung WB, Yoon JH. Distribution pattern of atherosclerosis in the 29. Shapiro SS. The lupus anticoagulant/antiphospholipid syndrome. Annu abdomen and lower extremities and its association with clinical and Rev Med. 1996;47:533–53. hematological factors. Vasc Health Risk Manag. 2021;17:13–21. 30. Merashli M, Bucci T, Pastori D, Pignatelli P, Marottoli V, Arcaro A, et al. 9. He C, Yang JG, Li YM, Rong J, Du FZ, Yang ZG, et al. Comparison of Antiphospholipid antibodies and lower extremity peripheral artery lower extremity atherosclerosis in diabetic and non-diabetic patients disease: a systematic review and meta-analysis. Semin Arthritis Rheum. using multidetector computed tomography. BMC Cardiovasc Disord. 2020;50:1291–8. 2014;14:125. 10. Demirtas H, Degirmenci B, Celik AO, Umul A, Kara M, Aktas AR, et al. Anatomic variations of popliteal artery: evaluation with 128-section CT- angiography in 1261 lower limbs. Diagn Interv Imaging. 2016;97:635–42. 11. Cannavale A, Santoni M, Gazzetti M, Catalano C, Fanelli F. Updated clinical and radiological classification of lower limb atherosclerotic disease. Ann Vasc Surg. 2019;55:272–84. 12. Schriefl AJ, Collins MJ, Pierce DM, Holzapfel GA, Niklason LE, Humphrey JD. Remodeling of intramural thrombus and collagen in an Ang-II infusion ApoE−/− model of dissecting aortic aneurysms. Thromb Res. 2012;130:e139–46. 13. Fraser JD, Anderson DR. Deep venous thrombosis: recent advances and optimal investigation with US. Radiology. 1999;211:9–24. 14. Lunt M. Introduction to statistical modelling 2: categorical variables and Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : interactions in linear regression. Rheumatology (Oxford). 2015;54:1141–4. 15. Vlachoyiannopoulos PG, Routsias JG. A novel mechanism of thrombosis fast, convenient online submission in antiphospholipid antibody syndrome. J Autoimmun. 2010;35:248–55. thorough peer review by experienced researchers in your field 16. Di Minno MND, Emmi G, Ambrosino P, Scalera A, Tufano A, Cafaro G, et al. Subclinical atherosclerosis in asymptomatic carriers of persistent rapid publication on acceptance antiphospholipid antibodies positivity: a cross-sectional study. Int J support for research data, including large and complex data types Cardiol. 2019;274:1–6. • gold Open Access which fosters wider collaboration and increased citations 17. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, maximum visibility for your research: over 100M website views per year et al. Inter-Society Consensus for the Management of Peripheral Arterial • Disease ( TASC II). J Vasc Surg. 2007;45(Suppl S):S5-67. 18. Ambrosy AP, Yang J, Sung SH, Allen AR, Fitzpatrick JK, Rana JS, et al. At BMC, research is always in progress. Triglyceride levels and residual risk of atherosclerotic cardiovascular Learn more biomedcentral.com/submissions disease events and death in adults receiving statin therapy for primary

Journal

Artery Research – Springer Journals

Published: Mar 1, 2023

Keywords: Lupus anticoagulant; Anticardiolipin IgG antibody; Suprainguinal elastic arteries; Infrainguinal muscular arteries; Atherosclerosis

There are no references for this article.