Contents lists available at ScienceDirect Thrombosis Research journal homepage: www.elsevier.com/locate/thromres Full Length Article Circulating levels of tissue factor and the risk of thrombosis associated with antiphospholipid syndrome Laís Quinteiro Tobaldini a , Fernanda Talge Arantes a , Sabrina da Silva Saraiva a , Bruna de Moraes Mazetto a , Marina Pereira Colella a , Erich Vinícius de Paula b , Joyce Annichino-Bizzachi b , Fernanda Andrade Orsi a,c, ⁎ a Hematology and Hemotherapy Center, University of Campinas, Brazil b Department of Clinical Medicine, Faculty of Medical Sciences, University of Campinas, Brazil c Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Brazil ARTICLE INFO Keywords: Thrombosis Antiphospholipid Tissue factor Coagulation Risk factor ABSTRACT The mechanisms behind the severe hypercoagulable state in antiphospholipid syndrome (APS) have not yet been fully elucidated. Knowledge on the etiology of thrombosis in APS is needed to improve treatment. We performed a case control study to evaluate the association of the levels of circulating tissue factor (TF) with thrombotic APS and unprovoked venous thromboembolism (VTE), as compared with controls without a history of thrombosis. Study participants were selected in the same geographic area. Linear regression was used to evaluate possible determinants of TF levels among controls and logistic regression was used to evaluate the association between TF, unprovoked VTE and t-APS. TF levels were grouped into three categories based on: below 50th percentile [reference], between 50-75th percentiles [second category] and 75th percentile [third category]. Two hundred and eighty participants were included in the study; 51 patients with unprovoked VTE, 111 patients with t-APS and 118 control individuals. The levels of TF were not associated with an increased risk of unprovoked VTE, as compared with controls. The adjusted odds ratio for t-APS was 2.62 (95%CI 1.03 to 6.62) with TF levels between 50-75th percentiles and 8.62 (95%CI 3.76 to 19.80) with TF levels above the 75th percentile, as compared with the reference category (below the 50th percentile). In the subgroup analysis, higher levels of TF were associated with both arterial and venous thrombosis in APS and with both primary and secondary APS. Circulating TF is associated with thrombotic complications related to APS, but not with the risk of unprovoked VTE. 1. Introduction Antiphospholipid syndrome (APS) is an rare disorder characterized by the occurrence of thrombosis or gestational complications associated with the presence of at least one antiphospholipid antibody (aPL): lupus anticoagulant (LAC), anticardiolipin (aCL) or anti-beta2glycoprotein I (aβ2GP1) [1,2]. APS can lead to a wide spectrum of thrombotic com- plications, such as venous thromboembolism (VTE), venous thrombosis in unusual sites, arterial and capillary thrombosis, which are highly susceptible to recurrence [3,4]. The mechanisms that are at the basis of the severe hypercoagulable state and thrombosis in APS have not yet been fully elucidated, but seem to differ from those observed in un- provoked VTE [5]. A mechanism that could explain the occurrence of thrombosis in APS is the overexpression of tissue factor (TF) [6]. TF is a coagulation factor encountered in endothelial cells, monocytes and in blood circu- lation [7,8]. Circulating TF comprise either soluble forms of TF or TF- bearing microparticles released from TF-producing cells [7,8]. These forms of TF encountered in blood can participate in thrombus growth and extension [9,10]. High levels of circulating TF have been associated with the risk of thrombosis in several diseases, as sepsis, diabetes, cardiovascular disease, sickle cell disease, stroke and cancer [11–14]. Despite basic research studies having demonstrated that aPL may in- crease TF expression in endothelial cells and monocytes [15–18], clinical evidence on the association between circulating TF and APS- related thrombosis (t-APS) are scarce [19,20]. The evaluation of circulating TF can provide clinical information on risk factors associated with thrombotic complications in APS. Identifying these risk factors is a critical step towards the identification of potential alternative treatments for the prevention of t-APS. https://doi.org/10.1016/j.thromres.2018.09.058 Received 24 June 2018; Received in revised form 22 September 2018; Accepted 24 September 2018 ⁎ Corresponding author at: Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas. R. Tessália Vieira de Camargo, 126. Cidade Universitária, Campinas 13083-887, Brazil. E-mail address: fernanda.orsi@unicamp.br (F.A. Orsi). Thrombosis Research 171 (2018) 114–120 Available online 25 September 2018 0049-3848/ © 2018 Published by Elsevier Ltd. T