| Original Full Text | Thrombosis Research 239 (2024) 109040Available online 22 May 20240049-3848/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Pulmonary embolism versus pulmonary vasculitis in Hughes-Stovin syndrome: Characteristic computed tomography pulmonary angiographic findings and diagnostic and therapeutic implications. HSS International Study Group Yasser Emad a,*, Yasser Ragab b, Harrison W. Farber c, Doruk Erkan d, Ossama Ibrahim e, Michael Kindermann f, Jasna Tekavec-Trkanjec g, Balakrishnan Jayakrishnan h, Nashwa El- Shaarawy i, Melek Kechida j, Pablo Young k, Sonia Pankl k, Marianna Fabi l, Parag Bawaskar m, Issam Kably n, Sergio Ghirardo o, Faten Frikha p, Alaa Abou-Zeid q, Maged Hassan r, Cal Robinson s, Mohamed H. Abdelbary t, Leticia Tornes u, Jason Margolesky u, Bhupen Barman v, Sami Bennji w, Manoj Kumar Agarwala x, Khalid Alhusseiny y, Taoufik Amezyane z, Rafael S. Silva aa, Vitor Cruz ab, Bruno Niemeyer ac, Khalfan Al-Zeedy k, Hamdan Al-Jahdali ad, Natalia Jaramillo ae, Serkan Demirkan af, Aurelien Guffroy ag,ah, Jung Tae Kim ai, Nikolas Ruffer aj, Samar Tharwat ak, Diletta Cozzi al, Mabrouk Abdelali am, Tubig C. Joy an, Mona Sayed ao, Juljani Sherwina an, Tamer Gheita a, Johannes J. Rasker ap a Rheumatology Department, Faculty of Medicine, Cairo University, Kasr Al-Ainy St, 11562 Cairo, Egypt b Radiology Department, Faculty of Medicine, Cairo University, Kasr Al-Ainy St, 11562 Cairo, Egypt c Tufts University School of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Boston, MA, USA d Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY 10021, USA e Morecambe Bay University Hospitals Lancaster, Lancashire, Ashton Rd, Lancaster LA1 4RP, United Kingdom f Innere Medizin III (Kardiologie/Angiologie), Universitätskliniken des Saarlandes, Kirrberger Straße, D 66421 Homburg/Saar, Germany g Department of Pulmonary medicine, Dubrava University Hospital, AvenijaGojkaŠuška 6, 10000 Zagreb, Croatia h Department of Medicine, Sultan Qaboos University Hospital, 123, Al-Khoud, Muscat, Oman i Rheumatology and Rehabilitation Department, Faculty of Medicine, Suez Canal University, Ismailia 4.5 Km the Ring Road, 41522 Ismailia, Egypt j Internal Medicine and Endocrinology Department, Fattouma Bourguiba University Hospital, University of Monastir, Rue du 1er juin 1955, Monastir 5019, Tunisia k Servicio de Clínica Médica, Hospital Británico de Buenos Aires, Perdriel 74, C1280 AEB Buenos Aires, Argentina l Pediatric Cardiology and Adult Congenital Unit, S. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy m Department of Cardiology, Topiwala National Medical College & B.Y.L Nair Charitable Hospital, Dr. A.L. Nair road, Mumbai 400008, Maharashtra, India n Department of Radiology, Section of Vascular and Interventional Radiology, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Miami, FL, USA o Clinical Department of Medical, Surgical and Health Science, University of Trieste, Piazzale Europa, 1, 34127 Trieste, TS, Italy p Department of Internal Medicine, HediChaker Hospital, 3029 Sfax, Tunisia q Public health Department, Faculty of medicine, Cairo University, Kasr Al-Ainy St, 11562 Cairo, Egypt r Chest Diseases Department, Faculty of Medicine, Alexandria University - Al kartoom square, al Azareta, Alexandria 21526, Egypt s Department of Paediatrics, Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada t Department of Radiology, Badr Hospital, Faculty of medicine, Helwan University, Egypt u University of Miami Miller School of Medicine, Department of Neurology, Miami, FL, USA v Department of General Medicine, All India Institute of Medical Sciences (AIIMS), Guwahati, India w Division of Pulmonology, Department of Medicine, Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman x Department of Cardiology, Apollo Hospitals, Jubilee Hills, Hyderabad 500096, India y Radiology department, Dr Erfan General hospital, Jeddah, Saudi Arabia z Department of Internal Medicine, Mohammed V Military Teaching Hospital, Mohammed V-Souissi University, School of Medicine, Rabat, Morocco aa Unidad de Enfermedades Respiratorias, Hospital Regional de Talca, Calle 1 Norte 1990, Talca, Chile ab Serviço de Reumatologia, Hospital das Clínicas, Faculdade de Medicina, Universidade Federal de Goiás, Goiânia, GO, Brazil ac Departamento de Radiologia, Instituto Estadual do Cérebro Paulo Niemeyer, R. do Rezende, 156 - Centro, 20231-092 Rio de Janeiro, RJ, Brazil ad Pulmonary Division, Department of Medicine, King Saud University for Health Sciences, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia * Corresponding author at: Rheumatology Department, Faculty of medicine Cairo University, Kasr A Ainy St, Cairo, Egypt. E-mail address: yasseremad68@gmail.com (Y. Emad). Contents lists available at ScienceDirect Thrombosis Research journal homepage: www.elsevier.com/locate/thromres https://doi.org/10.1016/j.thromres.2024.109040 Received 24 March 2024; Received in revised form 11 May 2024; Accepted 21 May 2024 Thrombosis Research 239 (2024) 1090402ae Cardiology Department, Hospital Puerta de HierroMajadahonda, C/Joaquin Rodrigo 3, Madrid 28222, Spain af Department of Dermatology and Venerology, Izmir KatipÇelebi University Faculty of Medicine, Karabağlar, Izmir, Turkey ag Service d'immunologieclinique et médecine interne, centre de référence des maladies auto-immunes systémiquesrares (RESO), hôpitauxuniversitaires de Strasbourg, nouvelhôpital civil, 67091 Strasbourg, France ah UFR médecine Strasbourg, université de Strasbourg, 67000 Strasbourg, France ai Department of Cardiovascular and Thoracic Surgery, Cheonan Chungmu Hospital, 8 Dagamal 3-gil Seobuk-gu, Cheonan-si, Chungcheongnam-do, Republic of Korea aj Division of Rheumatology and Systemic Inflammatory Diseases, University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany ak Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt al Department of Emergency Radiology, Careggi University Hospital, Florence, Italy am Department of Radiology, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia an Division of Pulmonary and Critical Care Medicine, Philippine Heart Center, Quezon City, Philippines ao Nursing Medical Surgical Critical Care Department, Minia University, Minia, Egypt ap Faculty of Behavioral, Management and Social Sciences, Department Psychology, Health and Technology, University of Twente, Drienerlolaan 5, 7522NB Enschede, the Netherlands A R T I C L E I N F O Keywords: Pulmonary embolism (PE) Hughes-Stovin syndrome (HSS) Pulmonary vasculitis Computed tomography pulmonary angiography (CTPA) Pulmonary artery aneurysms A B S T R A C T Background and aim: Hughes-Stovin syndrome (HSS) is a rare systemic vasculitis with widespread venous/arterial thrombosis and pulmonary vasculitis. Distinguishing between pulmonary embolism (PE) and in-situ thrombosis in the early stages of HSS is challenging. The aim of the study is to compare clinical, laboratory, and computed tomography pulmonary angiography (CTPA) characteristics in patients diagnosed with PE versus those with HSS. Methods: This retrospective study included 40 HSS patients with complete CTPA studies available, previously published by the HSS study group, and 50 patients diagnosed with PE from a single center. Demographics, clinical and laboratory findings, vascular thrombotic events, were compared between both groups. The CTPA findings were reviewed, with emphasis on the distribution, adherence to the mural wall, pulmonary infarction, ground glass opacification, and intra-alveolar hemorrhage. Pulmonary artery aneurysms (PAAs) in HSS were assessed and classified. Results: The mean age of HSS patients was 35 ± 12.3 years, in PE 58.4 ± 17 (p < 0.0001). Among PE 39(78 %) had co-morbidities, among HSS none. In contrast to PE, in HSS both major venous and arterial thrombotic events are seen.. Various patterns of PAAs were observed in the HSS group, which were entirely absent in PE. Paren-chymal hemorrhage was also more frequent in HSS compared to PE (P < 0.001). Conclusion: Major vascular thrombosis with arterial aneurysms formation are characteristic of HSS. PE typically appear loosely-adherent and mobile whereas “in-situ thrombosis” seen in HSS is tightly-adherent to the mural wall. Mural wall enhancement and PAAs are distinctive pulmonary findings in HSS. The latter findings have significant therapeutic ramifications. 1. Introduction Hughes Stovin Syndrome (HSS) was named after two British physi-cians in 1959 [1]. They described two male patients presenting with unexplained fever, weight loss, recurrent deep vein thrombosis (DVT) despite anticoagulation, and recurrent hemoptysis. Both patients died during unpredictable massive episodes of hemoptysis [1]. Currently, HSS is regarded as a systemic vasculitis characterized by widespread venous /arterial thrombosis and serious pulmonary vasculitis leading to the formation of pulmonary artery aneurysms (PAAs). This pulmonary vasculitis can affect all pulmonary artery (PA) branches. Well- established radiological and morphological signs can be visualized with computed tomography pulmonary angiography (CTPA) [2,3]. In the most recent report, the HSS International Study Group (HSSISG) created a novel CTPA reference atlas that defines the wide spectrum of pulmonary vasculitis observed in HSS [3]. Several CTPA patterns are used to classify PAAs in HSS: true stable PAAs with adherent in-situ thrombosis, stable bronchial artery aneurysms (BAAs), stable pulmonary artery pseudo-aneurysms (PAPs) and the corresponding unstable aneurysmal patterns [4–35]. These classifications were devel-oped according to lesion severity and to the associated morbidity [3]. Of note, all fatalities in HSS have been attributed to unpredictable massive hemoptysis explained by PAA(s) rupture into an adjacent bronchus [1,36–44]. Acute pulmonary embolism (PE) is a common and potentially fatal condition. CTPA imaging is critical in its early identification and treat-ment. The most prevalent cause of acute PE is lower extremity venous thromboembolism, also known as acute thrombotic PE or acute pul-monary thromboembolism. [45,46]. PE and in-situ thrombosis related to HSS are pathophysiologically separate entities. PE is caused by the embolization of a travelling thrombus from the venous periphery to the lungs, whereas in HSS, the pulmonary arterial thrombus typically evolves in-situ due to pulmonary artery mural wall vasculitis [3].In both situations, the pulmonary vascular obstruction and altered pulmonary hemodynamic will eventually lead to right ventricular strain (RVS) [2,3]. Most published HSS case reports did not include a cardiac eval-uation [4–35]. However, cardiac function assessment is recommended in patients with extensive in-situ thrombosis and CTPA evidence of RVS [3]. Our aim was to compare, demographic, clinical and laboratory findings in patients diagnosed with PE versus those with HSS and especially to compare CTPA findings between PE and HSS-related pul-monary vasculitis, to identify differentiating features to facilitate diag-nostic clarification and targeted treatment. 2. Methods 2.1. Study design The current retrospective, cross-sectional study included 50 patients with established PE, enrolled from the Dr. Erfan and Bagedo General Hospital, Jeddah, KSA. These cases were compared against a retro-spective cohort of 40 HSS cases, previously published by members of the HSSISG [4–35]. Only patients, in both groups, with complete clinical data and with complete CTPA studies available for review were included [4–35]. The study was conducted between 2022 and 2024. Inclusion criteria: The diagnosis of HSS cases was made based on the presence of typical features [2,3]. These features include a normal coagulation profile and widespread recurrent vasculo-occlusive disease, such as DVT, cerebral venous sinus thrombosis, pulmonary vasculitis, intracar-diac or arterial thrombosis, and PAAs associated with in situ thrombosis and/or BAAs. The diagnosis of PE was made in accordance to the American College of Physicians Clinical Guidelines [47]. Only patients Y. Emad et al. Thrombosis Research 239 (2024) 1090403fulfilling these criteria we included in the study Echo-Doppler studies were performed in all patients in both groups. 2.2. Ethics The study was approved by the ethical committee of the medical faculty of Monastir, Tunis. The patients had provided informed consents to participate and the study was in accordance to the 1964 Helsinki declaration. 2.3. Patient and imaging characteristics Demographics, clinical characteristics, with special emphasis on pulmonary and vascular occlusive manifestations, laboratory in-vestigations and coagulation profile as well as CTPA findings were recorded as described in the case reports. In PE patients, D-dimer (0–0.49 mg/l), procalcitonin (0–0.07 ng/ml) and pro-brain natriuretic peptide (pro-BNP)(300 pg/ml) were also examined at the time of their initial presentation. Regarding the HSS cases, all members of the HSS working group shared their complete CTPA data, which were then uploaded to a single Siemens (Syngo.via) CT workstation. The uploaded source images were interpreted in different windows such as lung and mediastinal windows in both pre- and post-contrast phases and further analyzed. In certain cases for the purpose of illustration and demon-stration, software was used to create new reconstructions from the source images, such as multi-planar reconstruction, maximum intensity projection, and three dimensional volume rendering technique in the case of unstable leaking PAAs (Figs. 1–6). 2.4. Interpretation of CTPA findings Full CTPA studies in both groups were reviewed and interpreted. The shape, distribution and laterality of the PE, adherence to the mural wall of the pulmonary artery (PA) branch and the in-situ thrombosis in the HSS were recorded. Pulmonary infarction, lung infection, pulmonary consolidation, ground glass opacification, parenchymal and/or intra- alveolar hemorrhages were noted. In HSS patients, the pattern, distri-bution of PAAs, loss of aneurysmal wall definition, perianeurysmal leaking with adjacent ground glass opacification, and bronchial inden-tation by the aneurysm were recorded. CTPA images were analyzed and classified according to the recently published CTPA Reference Atlas by the HSSISG [3]. We evaluated for the following CTPA signs in HSS patients: mural wall enhancement on post-contrast CTPA and PAAs. PAAs were classified into distinctive CTPA patterns including true stable PAAs with adherent in-situ thrombosis, BAAs, PAPs and corresponding unstable aneurysmal patterns. Radiological evaluation of the proximity and structural associations of PAAs and PAPs with adjacent bronchi is critical in determining the risk of subsequent rupture and fatal outcomes [3]. Table 1 depicts detailed CTPA definitions of each lesion. 2.5. Statistical analysis Data were collected on a standardized data collection forms and stored in an electronic database.. Statistical Package for Social Sciences (SPSS) version 25 was used. Variables were presented using descriptive statistics, including frequencies and percentages for categorical vari-ables or mean and standard deviation for continuous variables. Bivariate comparison was done using Chi-square test (categorical data) or Mann Whitney U tests (continuous data). P value 0.05 was considered statis-tically significant for all analyses. 3. Results This study included 40 patients diagnosed with HSS, with a male to female ratio of 3:1, and 50 patients with established PE with a male to female ratio of 1.2:1 (p = 0.04). The mean age at diagnoses was 35 ±12.3 years among patients with HSS compared to 58.4 ± 17 years in patients with PE (p < 0.0001). In HSS cases, mean disease duration was 55.1 ± 67.6 months prior to diagnosis and the mean age at onset was 32.2 ± 10.2 years. Presenting clinical features in the HSS group were DVT in 18 (45 %) patients, hemoptysis in 23 (57.5 %), thrombophlebitis in three (7.5 %), fever in five (12.5 %) and diplopia due to cerebral venous sinus thrombosis in two (5 %). Other detailed comparisons are presented in Table 2. Among the PE patients 39(78 %) had co- morbidities, among HSS none. For details see Table 2. The mean D-dimer (12.4 ± 9.6 mg/l), procalcitonin (5.6 ± 11.2 ng/ ml), and pro-BNP (1824 ± 3252.5 pg/ml) were elevated. Positive anti-cardiolipin (ACL) and β2-glycoprotein (anti-β2-GPI) antibodies were found in 4 (8 %) PE patients; three were in their thirties and one was 16 years old. Two (5 %) HSS patients had positive ACL. Detailed peripheral vascular complications, distribution of throm-botic events (venous and arterial) and arterial aneurysms are detailed in Table 3. Regarding CTPA findings, PAAs were only seen in HSS patients. Fig. 1. CTPA of patient with HSS showing bilateral lower lung lobar arterial filling defects with aneurysmal dilatation and marginal enhancement in sequential late arterial (a) and venous (b) phases. Y. Emad et al. Thrombosis Research 239 (2024) 1090404Table 4 compares CTPA findings between patients with PE vs. HSS, including the pattern of PAAs, PA branches involved, bronchial inden-tation, pulmonary infarction, and parenchymal hemorrhage. 4. Discussion Our study has an atypical design. We use retrospective data of pa-tients diagnosed with PE from a single center and then compare that data with those of HSS patients seen by members of the HSS study group. We only included HSS cases when complete clinical and radiological data were available. To make clear, our study is not a comparison with data from a literature review. As our HSSIgroup includes the authors of most HSS cases published world-wide during the last decade, one may consider the HSS cases included in this study as a worldwide retro-spective series of HSS patients. Distinguishing PE from in-situ thrombosis in HSS-related pulmonary vasculitis is a key diagnostic challenge, particularly in the early stages of both conditions. Accurate early diagnosis has significant therapeutic and prognostic implications. In the case of PE, anticoagulation is mandatory, whereas immunosuppressive drugs are the mainstay line of treatment in HSS-related pulmonary vasculitis and associated in-situ thrombosis to prevent pulmonary disease progression. Thus, misdiagnosis can have life-threatening consequences. Untreated in-situ thrombosis will prog-ress to the formation of PAAs. If inflammation extends extra-luminally, PAAs can become unstable and cause unpredictable, life-threatening haemoptysis. Individuals with HSS that are inappropriately treated with anticoagulation without immunomodulatory therapy are therefore at risk of severe haemoptysis. The HSSISG recommended that the decision to initiate anti-coagulation for major vascular venous/arterial thrombotic events in HSS should be made after careful interpretation of CTPA findings and the exclusion of unstable aneurysm patterns, such as unstable true or false aneurysms [2,3]. HSS and Behçet disease (BD)-related pulmonary vasculitis share identical characteristic CTPA signs [2–5,11,19,22,52]. Although, BD patients typically present with the classic triad of recur-rent oral aphthous ulcers, genital ulcers, and uveitis. When pulmonary manifestations develop after a DVT or PAAs are visible on CTPA, then discriminating BD-related pulmonary vasculitis from PE can be straightforward [48,49]. Patients with BD that have vascular thrombotic events or iridocyclitis should receive immunosuppressants based on the 2018 update of the EULAR recommendations [50]. This immunosup-pression should simultaneously improve the associated pulmonary vasculitis, except in aggressive cases with a rapidly progressive disease course [2,3]. We recommend that the radiological term “in-situ throm-bosis” should be used in a standardized manner to describe the early stages of either HSS or BD-related pulmonary vasculitis, in order to distinguish it from PE. In our study, there were significant differences between the PE and HSS patients that could help differentiate between these clinical entities at an early disease stage. The presence of PAAs are pathognomonic of HSS. We also observed that PE occurred more frequently in elderly pa-tients with other co-morbidities. However, those with systemic lupus erythematosus, antiphospholipid syndrome, and other coagulopathies are at risk for developing PE at a younger age. Positive ACL and β2-GP-I Fig. 2. (A) Magnified 3-D reconstruction of right lower lobe pulmonary artery true saccular aneurysms; (B–C), and (E) Volume render oblique magnified views showing right lower lobe pulmonary artery aneurysms (PAAs); (F): Axial image of CTPA mid thoracic level, demonstrating stable bilateral lower lobe PAAs with in- situ thrombosis; (G) Axial CTPA obtained in delayed phase to demonstrate the circumferential arterial mural enhancement of the affected lower lobe arteries bilaterally; (H): Axial CTPA obtained in delayed phase demonstrating right upper lobe pulmonary artery mural enhancement in a stable PAA with in-situ thrombus; (I): Sagittal CTPA (late phase) showing stable PAA of the lobar and segmental arteries with in-situ thrombosis in the lower lobe branches with mural enhancement; (I–L): Sagittal, coronal and axial CTPA images for patients with true bilateral pulmonary artery aneurysms with floating thrombi/emboli; (M-P): Coronal and axial CTPA images showing pulmonary hemorrhage as right lower lobe ground glass opacities around pulmonary artery aneurysms. Y. Emad et al. Thrombosis Research 239 (2024) 1090405antibodies were found in 8 % of PE patients; three in their thirties and one was 16 years old. ACL was also present in 5 % of HSS patients. DVT was the most common cause of PE (up to 85 % of cases), followed by thrombosis of the iliac, renal, and inferior vena cava. The upper limbs are rarely identified as a source of significant PE [51]. Risk factors for PE are age, a history of venous thromboembolism DVT, active malignancy, heart or respiratory failure, congenital or ac-quired coagulation disorders, hormone replacement therapy, and oral contraception [53]. In our study, most PE patients had co-morbidities such as hypertension, diabetes, dyslipidaemia, ischemic heart disease, with heart failure, malignancy, stroke, or liver cirrhosis. Death occurred in 28 % of PE patients. Co-morbidities were uncommon in HSS patients but death due to massive haemoptysis occurred in 15 %. Alveolar hemorrhage was more frequently observed among HSS cases when compared to those with PE (p < 0.001). In HSS, alveolar hemorrhage may occur due to leakage through the inflamed aneurysmal wall, which is exacerbated by anticoagulation. Pulmonary hemorrhage in PE has been attributed solely to anticoagulation therapy. In both PE and HSS patients, DVT typically occurred in lower limb veins. Both PE and HSS patients experienced widespread vascular venous thrombotic events. However, superficial thrombophlebitis was significantly more common among HSS patients. Major thrombotic events, such as inferior vena cava thrombosis, were also more common in HSS compared to PE patients. Peripheral arterial thrombosis and aneurysms were also more common among HSS patients than after PE, including aneurysms of the femoral, brachial, splenic and superior mesenteric arteries. Peripheral arterial aneurysms in HSS are indicative of the underlying systemic vasculitis, which also explains the involve-ment of both the pulmonary and bronchial circulations [2,3]. The most important finding of this study was that the CTPA findings in PE patients differ significantly from those with HSS-related pulmo-nary vasculitis. In younger patients with major venous/arterial throm-botic events and/or peripheral arterial aneurysms, without evidence of a prothrombotic disorder or significant co-morbidities, HSS-related pul-monary vasculitis should be considered. Although CTPA findings between acute PE and HSS are overlapping in the early stages of disease, there are characteristic findings which can differentiate the two conditions and accurately identify those with HSS. Approximately one-third of the HSS patients show arterial wall enhancement on CTPA (Fig. 1), which does not occur in typical PE. arterial wall enhancement may be an early sign of pulmonary vasculitis in HSS, indicating true mural wall inflammation related to the under-lying vasculitic process. Furthermore, the in-situ thrombosis that evolves locally is due to the activation of coagulation cascade and is adherent to the mural wall. This is distinct from typical PE, where the embolus appears loose in the lumen and is serpiginous. In patients with HSS where the diagnosis is initially missed, there are characteristics features of disease progression. Persistent arterial wall Fig. 3. (A–D): Coronal and axial CTPA images demonstrating a right lower lobe pulmonary artery pseudoaneurysm (PAP) with eccentric thrombus. (E) Coronal reformatted CTPA image for the same patient showing bilateral true and pseudoaneurysms. (F) Axial lung window for the same patient with a right lower lobe pulmonary pseudoaneurysm and left lower lobe true aneurysm. (G) Axial lung window CT image showing bilateral lower lobe pulmonary aneurysms. (H) and (I): Coronal and Sagittal reformatted images showing true bronchial artery aneurysms. Y. Emad et al. Thrombosis Research 239 (2024) 1090406inflammation of PA branches results in progressive mural wall injury. Over time, with exposure to the shear forces of the pulmonary circula-tion pressure, this can lead to outpouching of the wall, which is iden-tified by CTPA as a stable “true PAA” (Fig. 2F–L). “True PAAs” are histologically defined as: ‘focal dilatation of PA branch involving all three layers of the arterial wall’ [2,3]. True PAAs may progress to become unstable; loss of arterial wall definition and peri-aneurysmal parenchymal hemorrhage can occur due to acute rupture (Fig. 2M–P). Aneurysm rupture typically occurs due to missed or delayed diagnosis and suboptimal immunosuppressive treatment, but can occur earlier in rapidly progressive cases. Other patients with HSS may experience chronic extravasation of blood through an inflamed aneurysmal wall. This gradually accumulates and coalesces around the dilated arterial lumen, resulting in a pulmonary artery pseudo-aneurysm (“PAP”). PAPs are defined as a sharply demarcated contrast filled aneurysmal lesion with a variably sized marginal hypodense perianeurysmal component. This represents ‘marginal thrombosis’ entangling the sharply demar-cated contrast filled ectatic lumen with adjacent ground glass opacifi-cation or frank consolidation in the case of active hemorrhage (best visualized in a lung window; Fig. 3). This stage represents a contained rupture of the aneurysm [2,3]. Careful assessment should be made for the presence of an “air bronchogram” and its relationship to the false aneurysmal wall. Subsequent formation of a broncho-vascular fistula can lead to sudden death from massive haemoptysis. We found that air bronchograms were seen adjacent to the false wall of PAPs in 62.5 % of patients. A close and intimate relationship has been explained in an autopsy report by Kirk and Seal in 1964. [38].The authors described the histo-pathological findings of ruptured PAP in one HSS patient, which revealed a segmental disruption of the elastica of the pulmonary artery at its origin. The clot was mostly extra-luminal, with a large portion of its wall formed by an expanded “false wall” of the adjacent bronchus. The organizing thrombus was separated from the bronchial lumen by a thin layer of respiratory epithelium, and squamous metaplasia had occurred in places. Given that, in-situ thrombosis which is intra-luminal and adherent to the aneurysmal wall in true PAAs is quite different from extra luminal marginal thrombosis as seen in PAP which indicates chronic leaking through the inflamed aneurysmal wall (contained rupture). Such unmistakable pattern in HSS was first described in the literature by the HSSISG and was considered the most serious pattern because it can result in unpredictable fatal hemoptysis and should be considered for immediate stabilization by pulmonary artery coil Fig. 4. (A) Maximum intensity projection coronal CTPA image showing a floating thrombus within the main left pulmonary artery. (B) Sagittal reformatted CTPA image showing a pulmonary artery embolism as a floating thrombus/embolus. (C) Axial CTPA images for the same patient showing a saddle thrombus surrounded with contrast. (D–I) Axial CTPA images for the same patient showing a saddle thrombus surrounded with contrast in a case of acute pulmonary embolism. (J–L) Coronal and sagittal reformatted CTPA images for a case of acute bilateral pulmonary embolism demonstrated as bilateral pulmonary artery filling defects sur-rounded with contrast. (M–P) Axial and coronal reformatted CTPA images for the same patient with acute bilateral pulmonary embolism with non-adherent PE. Y. Emad et al. Thrombosis Research 239 (2024) 1090407embolization (PACE). [1–3] Another significant finding of the present study was that RVS was observed on CTPA in 30 % of HSS and 25 % PE patients. Both conditions can rapidly increase pulmonary vascular resistance, resulting in hemo-dynamic consequences. Increased pulmonary vascular resistance in HSS due to widespread in-situ thrombosis also predisposes to PAA formation. Thus, the presence of RVS on CTPA may be an indicator of disease progression. Due to the lack of vascular wall inflammation, patients with PE do not develop knobby arterial wall as seen in HSS (Fig. 6). Vascular wall inflammation also results in BAAs in 7.5 % of HSS patients but not in PE. Because of their smaller diameter, bronchial arteries can develop high resistance, low capacitance, and less distensible circulation. When pulmonary blood flow is reduced, the bronchial circulation and other collateral vessels can hypertrophy to maintain blood flow to ischemic lung areas and engage in gas exchange via systemic-pulmonary arterial anastomoses. [54]. Additionally, with reduced pulmonary blood flow, the total systemic cardiac output to the bronchial arteries may increase from 1 to 18–30 % [55]. Although the latter hemodynamic changes occur in both domains, vascular wall inflammation in HSS combined with increased bronchial artery pressures increase the risk of BAA for-mation in HSS. The study has some limitations. Ideally would have been a prospective series of PE and HSS patients from one or several centers. As that is not feasible, HSS being an extremely rare disease, our study has an atypical design. We use retrospective data of patients diagnosed with PE from a single center; the findings in our PE series appear to be comparable with those in the world literature. We compare the data of the PE series with those of all HSS patients seen by members of the HSSISG who had complete clinical and CTPA data available. Thus we consider our cases as a world-wide retrospective series of HSS patients. As HSS is a very rare disease and <100 HSS patients (in total 88 in PubMed) have been described world-wide, and complete CTPA studies are only available during last decennium, in our opinion this is the best and only feasible way to collect these data. We realise that our study design may still raise questions about appropriateness of the statistical comparisons between the two cohorts, given the inherent differences in study populations and methodologies. The strength of our study is that it is the first attempt to compare manifestations and outcomes of a large series of HSS cases with those of a representative series of PE patients, showing clear differences that have clinical consequences. Fig. 5. (A): Axial CTPA image with acute pulmonary embolism appeared as non-adherent filling defects in the right lower lobe segmental branches with evidence of acute right ventricular strain (RVS). (B–E): Axial CTPA images with acute RVS in a case of acute PE. (H) Axial lung window image with left basal triangular opacity, in keeping with pulmonary infarction secondary to acute PE. (I): Axial lung window image with right basal pleural based opacities, in keeping with small pulmonary infarction secondary to acute PE. (J): Axial lung window image with right lung middle lobe ground glass opacity, in keeping with pulmonary hemorrhage secondary to acute bilateral PE. Fig. 6. 3D reconstructed images of CTPA in different known patients with PE. (A–C) are known cases of HSS with PAAs appearing as multiple mural nubs seen at the external arterial walls. While in images (D–F) patients with acute PE showing diffuse distension of the arteries due to the presence of PE, but without external mural nubs. Y. Emad et al. Thrombosis Research 239 (2024) 10904085. Conclusions Differentiating acute PE from in-situ thrombosis seen in HSS-related pulmonary vasculitis represents a challenging diagnostic dilemma, given the overlap in clinical CTPA features in the early stages of HSS. However, there are characteristic CTPA findings, related to the under-lying pathophysiology of HSS, which can differentiate the two condi-tions and facilitate early diagnosis and treatment of HSS-related pulmonary vasculitis. We found that PE was more common in older individuals with sig-nificant co-morbidities that predispose to venous thromboembolism, whereas HSS-related pulmonary vasculitis is more common in previ-ously healthy younger individuals, with a male predominance. The presence of major venous and/or arterial thrombotic events or periph-eral arterial aneurysms with normal coagulation profiles and no asso-ciated co-morbidities should raise suspicion for HSS. On CTPA imaging, PE typically appear to be more mobile and non- adherent to the pulmonary artery mural wall, whereas in-situ throm-bosis in HSS exhibits characteristic features, including adherent thrombi and arterial wall enhancement. These CTPA features can be used to guide diagnosis and therapeutic decision-making in this patient population. 6. In summary If we see in our clinics a (young, male) patient with unexplained DVT, recurrent thrombophlebitis, with no co-morbidities and/or risk factors, and normal coagulation profile, presenting with major arterial or venous thrombotic events or peripheral arterial aneurysms, one should raise the clinical suspicion of HSS and not PE. This diagnosis HSS is confirmed when on CTPA adherent thrombus to the pulmonary mural wall is seen with mural wall enhancement in post arterial phase Table 1 Computed tomography pulmonary angiography (CTPA) definitions of arterial wall enhancement, pattern of pulmonary artery aneurysms, right ventricular strain (RVS) and intracardiac thrombosis in Hughes-Stovin syndrome (HSS) patients. Variable CTPA definition AWE Arterial wall enhancement is the earliest CTPA sign in HSS-related pulmonary vasculitis. It is frequently observed during early stages of the disease process. Arterial wall enhancement is radiologically defined as an “enhancing aneurysmal wall,” which is typically visualized in the mediastinal window in sequential arterial and venous post-contrast phases True stable PAA True stable PAA is defined as an “aneurysmal lesion (contrast filled) of the affected PA branch with a well-defined aneurysmal wall and associated with intra-aneurysmal adherent in- situ thrombosis (filling defects) without any perianeurysmal parenchymal GGO, which would be suggestive of an extra-luminal acute leak (best visualized in the lung window)” Unstable leaking true PAA Unstable PAA is defined as “aneurysmal lesion” (contrast filled) of the affected PA branch with loss of aneurysmal wall definition and perianeurysmal alveolar hemorrhage (ground- glass opacification and/or consolidation) with ‘air-bronchograms’.The latter refers to air-filled bronchi (dark) being made visible by the opacification of surrounding alveoli (gray/ white). Pulmonary artery pseudoaneurysm (PAP) A PAP is defined radiologically as “sharply demarcated contrast-filled aneurysmal lesions with a variably Sized marginal hypodense perianeurysmal component (marginal thrombosis) entangling a contrast-filled ectatic lumen.” The lesion is not associated with adjacent ground glass opacification or frank consolidation, distinguishing it from leaking PAA or PAP. Air bronchograms (air-filled bronchi/ bronchiole) can be associated within the hypodense component (marginal thrombosis). Unstable Pulmonary artery pseudoaneurysm (PAP) Unstable PAP is defined radiologically as “sharply demarcated contrast-filled aneurysmal lesions with a variably sized marginal hypodense perianeurysmal component (marginal thrombosis), entangling the sharply demarcated contrast-filled ectatic lumen plus adjacent GGO or frank consolidation due to active hemorrhage from the leaking ectatic lumen.” The air bronchogram (air-filled bronchi/bronchiole) can be associated within the hypodense component. RVS RVS is defined radiologically by CTPA as “interventricular septal flattening or paradoxical interventricular septal bowing towards the left ventricle, which occurs secondary to the altered pulmonary hemodynamic in the context of pulmonary hypertension.” In addition, RVS is characterized by a right ventricle size that exceeds that of the left ventricle. Intracardiac thrombosis Intracardiac thrombosis is defined by CTPA as a low attenuation non-enhancing filling defect in the involved cardiac chamber(s). PAA; Pulmonary artery aneurysm; PAP; Pulmonary artery pseudoaneurysm; CTPA: Computed tomography pulmonary angiography; GGO: ground-glass opacification; RVS: right ventricular strain. Table 2 Demographic, disease manifestations, laboratory findings and co-morbidities in the pulmonary thromboembolism (PE) and Hughes-Stovin syndrome (HSS) patients. Variables HSS (n = 40) PE (n = 50) p Age (years) 35 ± 12.3 58.4 ± 17 <0.0001 Gender (M/F) 30:10 (3:1) 27:23 (1.2:1) 0.037 Disease duration (months) 55.1 ± 67.6 27.9 ± 24 0.0096 Age at onset (years) 32.2 ± 10.2 56.3 ± 16.8 <0.0001 Smoking 0(0) 16(32) NA Fever 26(65) 14(28) 0.000072 Cough 37(92.5) 20(40) <0.0001 Dyspnea 34(85) 16(32) <0.0001 Chest pain 6(15) 14(28) 0.13 Hemoptysis (ml/24 h) 36(90) 13(26) <0.0001 Mild (< 20 ml/24 h) 12(30) 13(26) 0.67 Moderate (20–600 ml/24 h) 14(35) 0(0) NA Massive (> 600 ml/24 h) 10 (25) 0(0) NA Superficial thrombophlebitis 21(52.5) 5(10) <0.0001 DVT 34(85) 42(84) 0.89 Intra cardiac thrombosis 8(20) 1(2) 0.004 ESR (mm/1st h) 52.8 ± 25.8 48.5 ± 24.4 0.43 CRP (mg/dl) 18.9 ± 19.6 9.3 ± 9 0.006 HB (gm/dl) 11.1 ± 1.8 11 ± 1.9 0.81 WBCs (1010/L) 8.7 ± 4.2 8.8 ± 4 0.88 Platelet count (103/μL) 333.5 ± 105.6 263.1 ± 106.7 Abnormal coagulation panel 3(6) 5(10) 0.67 aCL autoantibodies 2(5) 4(8) 0.57 Factor V Leiden mutation 1(2.5) 1(2) 0.87 Beta-2 glycoprotein 0(0) 4(8) NA Comorbidities 0(0) 39(78) NA Hypertension 0(0) 38(76) NA Diabetes 0(0) 21(42) NA IHD with heart failure 0(0) 17(34) NA SLE/APS 2(5) 4(8) 0.57 Cardiac anomalies 0(0) 1(2) NA Pulmonary metastasis 0(0) 6(12) NA CVA 0(0) 7(14) NA Dyslipidemia 0(0) 26(54) NA Liver cirrhosis 0(0) 2(4) NA Fatal outcome 6(15) 14(28) 0.14 Data are either Mean ± SD or n (%);HSS: Hughes-Stovin syndrome; aCL: anti-cardiolipin antibodies; ESR: Erythrocyte Sedimentation Rate; CRP: C-reactive protein; HB: Hemoglobin; WBCs: White Blood Cells; CVA: cerebral vascular accident; SLE/APS: Systemic Lupus Erythematosus/Antiphospholipid Syn-drome; IHD: Ischemic heart disease; Anti-TNF: Anti-tumor necrosis factor; IQR: Inter Quartile Range; NA = Not Applicable. Y. Emad et al. Thrombosis Research 239 (2024) 1090409persisting in the venous phase, Abbreviations ACL anticardiolipin BAAs bronchial artery aneurysms, CTPA computed tomography pulmonary angiography DVT deep vein thrombosis EULAR European Alliance of Associations for Rheumatology Hughes-Stovin syndrome (HSS) HSSISG HSS International Study Group PA pulmonary artery PAAs Pulmonary artery aneurysms PAPs pulmonary artery pseudo-aneurysms PE pulmonary embolism RVS right ventricular strain SPSS Statistical Package for Social Sciences Ethics The authors attest they are in compliance with human studies com-mittees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Yasser Ragab: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. Harrison W. Farber: Writing – review & editing, Writing – original draft, Meth-odology, Investigation, Conceptualization. Doruk Erkan: Writing – re-view & editing, Writing – original draft, Methodology, Investigation, Conceptualization. Ossama Ibrahim: Writing – review & editing, Writing – original draft, Methodology, Investigation, Conceptualization. Michael Kindermann: Writing – review & editing, Writing – original draft, Methodology, Investigation, Conceptualization. Jasna Tekavec- Trkanjec: Writing – review & editing, Writing – original draft, Investi-gation, Conceptualization. Balakrishnan Jayakrishnan: Writing – re-view & editing, Writing – original draft, Investigation, Conceptualization. Nashwa El-Shaarawy: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Melek Kechida: Writing – review & editing, Writing – original draft, Investi-gation, Conceptualization. Pablo Young: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Sonia Pankl: Writing – original draft, Investigation, Conceptualization. Marianna Fabi: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Parag Bawaskar: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Issam Kably: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Sergio Ghirardo: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Faten Frikha: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Alaa Abou-Zeid: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation. Maged Hassan: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Cal Robinson: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Mohamed H. Abdelbary: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Leticia Tornes: Writing – re-view & editing, Writing – original draft, Investigation, Conceptualiza-tion. Jason Margolesky: Writing – review & editing, Writing – original Table 3 Vasculoocculisve findings and peripheral arterial aneurysms in pulmonary thromboembolism (PE) and Hughes-Stovin syndrome (HSS) patients. Variables HSS (n = 40) PE (n = 50) p CVST 3(7.5) 0(0) NA Intra-cardiac Thrombosis 8(20) 1(2) 0.004 Right ventricle 4(10) 1(2) 0.09 Right atrium 4(10) 0(0) NA Venous thrombosis DVT (unilateral vs. bilateral) 26:8 (3.3:1) 40:2 (20:1) 0.72 Inferior vena cava 10 (25) 2 (4) 0.003 Internal jugular vein 2 (5) 0 (0) NA Common femoral vein 14(35) 25(50) 0.15 Iliac vein 13 (32.5) 8 (16) 0.065 Popliteal vein 17 (42.5) 34 (68) <0.001 Superficial femoral vein 2 (5) 30 (60) Anterior tibial veins 6 (15) 24 (48) 0.0009 Posterior tibial veins 7 (17.5) 32 (64) <0.001 Peroneal vein 0 (0) 9 (18) NA Soleal vein 0 (0) 3 (6) NA Saphenous vein 0 (0) 7 (14) NA Arterial thrombosis Aortic artery 2 (5) 1 (2) 0.43 Common iliac artery 2 (5) 1 (2) 0.43 Anterior tibial artery 1 (2.5) 1 (2) 0.87 Posterior tibial artery 1 (2.5) 1 (2) 0.87 Superior mesenteric artery 1 (2.5) 0 (0) NA Femoral artery 1(2.5) 1 (2) 0.87 Brachial artery 2 (5) 0 (0) NA Splenic artery 1 (2.5) 0 (0) NA Popliteal artery 1 (2.5) 1 (2) 0.87 Peripheral arterial aneurysms Celiac artery 1 (2.5) 0 (0) NA Femoral artery 1 (2.5) 0 (0) NA Brachial artery 1 (2.5) 0 (0) NA Splenic artery 1 (2.5) 0 (0) NA Aortic artery 1 (2.5) 1 (2) 0.87 Superior mesenteric artery 1 (2.5) 0 (0) NA CVST: cerebral venous sinus thrombosis; DVT: deep vein thrombosis; NA = Not Applicable. Table 4 Computed tomography pulmonary angiography (CTPA) findings in pulmonary thromboenbolism (PE) and Hughes-Stovin syndrome (HSS) patients. Variables HSS (n = 40) PE (n = 50) p AWE 13(32.5) 0(0) NA Pulmonary artery aneurysms 40(100) 0(0) NA Stable true PAAs 15(37.5) 0(0) NA Unstable true PAAs 9(22.5) 0(0) NA BAAs 3(7.5) 0(0) NA Unilateral vs. Bilateral 4/36 10/40 0.19 PA branches involved Main 19(47.5) 30(60) 0.24 Lobar 34(85) 49(98) Segmental 27 (67.5) 39(78) 0.28 Subsegmental 10 (25) 13(26) 0.92 Air bronchogram in the vicinity of PAAs 25(62.5) 0(0) NA Pulmonary infarction 13(32.5) 14(28) 0.64 Pleural effusion 3(32.5 %) 14(28) 0.01 Parenchymal hemorrhage 25(62.5) 3(6 %) <0.001 Main PA diameter (mm) 2.91 ± 0.56 2.47 ± 0.7 0.002 CTPA /RVS 15(30) 10(25) 0.6 PACE 6(15) 0(0) NA PA: Pulmonary artery;PAAs: pulmonary artery aneurysms; BAAs: bronchial ar-tery aneurysm; PA: pulmonary artery; CTPA: computed tomography pulmonary angiography; RVS: right ventricular strain; PACE: pulmonary artery coil embolization. Y. Emad et al. Thrombosis Research 239 (2024) 10904010draft, Methodology, Investigation, Conceptualization. Bhupen Barman: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Sami Bennji: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Manoj Kumar Agar-wala: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Khalid Alhusseiny: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Taoufik Amezyane: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Rafael S. Silva: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Vitor Cruz: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Bruno Niemeyer: Writing – review & editing. Khalfan Al-Zeedy: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Hamdan Al-Jahdali: Writing – re-view & editing. Natalia Jaramillo: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Serkan Demirkan: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Aurelien Guffroy: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Jung Tae Kim: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Nikolas Ruffer: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Samar Tharwat: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Conceptualization. Diletta Cozzi: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Conceptualization. Mab-rouk Abdelali: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Conceptualization. Tubig C. Joy: Writing – review & editing, Writing – original draft, Conceptualization. Mona Sayed: Writing – review & editing, Writing – original draft, Conceptualization. Juljani Sherwina: Writing – review & editing, Writing – original draft, Conceptualization. Tamer Gheita: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Johannes J. Rasker: Writing – review & editing, Writing – original draft, Supervi-sion, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Declaration of competing interest The authors declare no conflict of interest regarding this study. Acknowledgements We thank the patients for their willingness to participate in this study. References [1] J.P. Hughes, P.G. Stovin, Segmental pulmonary artery aneurysms with peripheral venous thrombosis, Br. J. Dis. Chest 53 (1959) 19–27, https://doi.org/10.1016/ s0007-0971(59)80106-6. 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