ReviewSolid cancer, antiphospholipid antibodies, and venous thromboembolism☆
Introduction
Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is the main manifestation of the hypercoagulable state associated with cancer and a leading cause of morbidity and mortality in patients with malignancies [1]. Various predisposing factors for VTE coexist in these patients: surgery, hospital admissions, immobilization, use of central catheters, chemotherapy, use of recombinant erythropoietins and new molecular targeted therapies such as anti-angiogenic agents. In addition, even in the absence of manifest thrombosis, patients with cancer commonly have plasma markers of clotting activation, including thrombin–antithrombin complex, prothrombin fragments 1 and 2 and D-dimer, showing that continuous fibrin formation and removal occurs during malignancy processes [2], [3]. The search for biomarkers capable of identifying cancer patients with a specific risk of VTE might help to indicate primary thromboprophylaxis and optimize anticoagulant therapy for established VTE [4], [5].
The relationship between cancer and autoimmunity is well known. Some autoimmune diseases, such as Sjögren's syndrome, rheumatoid arthritis and SLE have been associated with the development of lymphoproliferative syndromes [6]. Of note, patients with dermatomyositis have a greater risk of developing solid-organ malignancies than the general population. In these patients, cancer can precede, parallel or follow myositis diagnosis [7]. In addition, a pleyade of autoantibodies have been found in patients with non-hematological malignancies [8]. Occasionally, autoantibodies will be responsible for autoimmune manifestations in patients with neoplasms. Paraneoplastic retinopathy is a paraneoplastic syndrome associated with anti-retinal autoantibodies and, therefore, mediated by an autoimmune mechanism. It can occur in patients with lung, breast, colon, prostate cancer, and melanoma [9].
The mechanisms of generation of autoantibodies in patients with cancer are not completely known. They seem to be secondary to the abnormal expression of self-antigens by tumor cells and the inflammatory microenvironment present in the neoplasm tissue [10]. This intratumoral inflammatory context through stimulation apoptosis and leading the exposition of autoantigens may play a key role in the induction of autoimmune disease-associated autoantibodies in cancer patients.
The antiphospholipid syndrome (APS) is the most frequently acquired autoimmune prothrombotic condition, characterized by arterial and/or venous thromboses and pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL) including lupus anticoagulant (LAC), anticardiolipin antibodies (aCL) and/or antiβ2glycoprotein I (aβ2GPI) antibodies [11]. About half of patients with APS have primary APS while the remaining cases are associated with systemic autoimmune diseases, mainly systemic lupus erythematosus. In addition, aPL have occasionally been detected in healthy individuals [12] and patients with chronic diseases and infections [13], [14] although they are rarely associated with thrombotic events.
There are various reports on the association between aPL and cancer [15], [16], [17], [18], although evidence on the relationship between aPL status and the risk of thromboembolic events in cancer patients is contradictory [19], [20], [21], [22]. It is unclear whether aPL antibody positivity has a pathogenic role in the development of thromboses or whether, in contrast, these antibodies are an epiphenomenon in cancer patients [23].
The aim of this study was to determine the prevalence and isotypes of aPL in a cohort of patients with cancer and newly-diagnosed VTE. In addition, we described the clinical characteristics and outcomes of cancer patients with positive aPL. Two age–sex matched groups of cancer patients without thrombotic events and healthy subjects, respectively, were recruited as controls. Furthermore, the literature regarding the relationship between solid cancer, aPL, and thrombosis was reviewed.
Section snippets
Study population
From May 2006 to April 2008 a prospective observational study consecutively enrolling adult patients with solid tumors and newly-diagnosed VTE (VTE+) was carried out in the Medical Oncology Department of the Hospital Clinic of Barcelona, a tertiary teaching hospital with a reference population of ≥ 500,000. All patients included in the study had histologically-confirmed solid tumors and were eligible if they had either active cancer (locoregional or metastatic) or developed VTE while receiving
Results
A total of 248 VTE+ patients and 156 VTE− patients were initially enrolled. During the follow-up, 10 VTE-patients developed VTE and were included in the VTE+ group. Four VTE− patients were excluded from the analysis due to arterial thrombosis. Therefore, 258 VTE+ patients (144 males and 114 females), 142 VTE− patients (81 males and 61 females) and 258 healthy subjects (144 males and 114 females) were included in the final analysis. Demographic and clinical characteristics of patients and
Discussion and review of the literature
The present study provides in depth information on the prevalence of aPL in a large cohort of consecutive cancer patients who developed VTE. The results show that the prevalence of aPL was higher in VTE+ patients than in VTE− patients and healthy subjects. However, the overall prevalence of aPL in our series of VTE+ patients was relatively low (less than 10%). In addition, aPL positivity persisted in only 4 VTE+ patients suggesting that aPL may play only a anecdotal pathogenic role in
Conclusions
The current study indicates that there are two independent scenarios with regard to aPL in cancer patients. On the one hand, cancer and APS can coexist in sporadic cases while, on the other hand, some cancer patients with or without VTE may show aPL positivity, which is mostly transitory. The results strongly indicate that aPL are not pathogenic for the development of VTE commonly observed in patients with solid malignancies. Consequently, routine aPL screening in cancer patients seems to be of
Take-home messages
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Cancer is a leading cause of venous thromboembolism. Biomarkers that permit to identify cancer patients at particular risk of thrombosis are needed.
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The low prevalence and transience of antiphospholipid antibodies in patients with cancer-related venous thrombosis argues against a pathogenic role in this setting.
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Routine antiphospholipid antibodies screening in cancer patients is of little clinical utility in identifying cancer patients at risk for VTE.
Funding source
This study was supported in part by Grant FIS PI070387 from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain. The funds were used to finance laboratory studies.
Conflict of interest
All the authors state that they have no conflicts of interest to declare.
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2021, Revista Colombiana de ReumatologiaCitation Excerpt :Several reasons have been submitted to explain the increased risk of thrombosis in cancer patients. For instance, blood flow stasis due to vascular invasion, immobilization, up-regulation of thrombophilic substances by both, tumor and endothelial cells, chemotherapy and central venous devices have been suggested as conditions that could account for the increased frequency of thrombosis in these patients.11,12 Clinically, catastrophic APS usually affects the kidneys (74% of cases), followed by the brain (56%), the lungs (55%), the heart (53%) and the skin (45%).2
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2020, Blood AdvancesCitation Excerpt :The highest pooled prevalence rate was 31% (22% to 41%) in patients with GU cancer. Ten studies reported the isotype distribution of aCL antibodies in patients with solid tumors, and 3 included healthy controls.19,24-26,29,41-43,48,50 IgM was the most frequent isotype (87/601; 14.5%) compared with IgA (9/106; 8.5%) and IgG (41/532; 7.7%).
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The preliminary results of this study were presented at the 2008 Annual European Congress of Rheumatology (EULAR). Ann. Rheum. Dis. 2008; 67 (Suppl. II), (abstract 250).