Elsevier

Autoimmunity Reviews

Volume 10, Issue 4, February 2011, Pages 222-227
Autoimmunity Reviews

Review
Solid cancer, antiphospholipid antibodies, and venous thromboembolism

https://doi.org/10.1016/j.autrev.2010.10.006Get rights and content

Abstract

The pathogenic role of antiphospholipid antibodies (aPL) in the development of venous thromboembolism (VTE) in patients with malignancies has not been established. From May 2006 to April 2008, 258 consecutive patients with solid-organ malignancies who developed VTE (VTE+) were recruited. A group of 142 patients matched for age, sex and tumor type cancer patients without VTE (VTE−) and an age-and-sex matched group of 258 healthy subjects were also included. A second blood sample was taken in positive aPL patients at least 12 weeks later. Twenty-one (8.1%) VTE+ patients, 2 (1.4%) VTE− patients (p = 0.006) and 2 (0.8%) healthy subjects (p < 0.001) were positive for aPL. Persistent aPL positivity was observed in only 4 out of 15 available VTE+ patients. No differences in demographic characteristics, clinical pattern and outcome were observed in VTE+ patients according to aPL status. The low prevalence and transience of aPL positivity in patients with solid-organ malignancies with VTE argues against a pathogenic role in the development of thrombosis in this setting. The published evidence of the relationship between cancer, aPL, and thrombosis is reviewed.

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

  • Cancer is a leading cause of venous thromboembolism. Biomarkers that permit to identify cancer patients at particular risk of thrombosis are needed.

  • The low prevalence and transience of antiphospholipid antibodies in patients with cancer-related venous thrombosis argues against a pathogenic role in this setting.

  • 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.

References (37)

  • A. Tincani et al.

    Antiphospholipid antibodies and malignancies

    Autoimmun Rev

    (2010)
  • E. De Meis et al.

    Lung adenocarcinoma and antiphospholipid antibodies

    Autoimmu Rev

    (2009)
  • T. Bombeli et al.

    Apoptotic vascular endotelial cells become procoagulant

    Blood

    (1997)
  • A.Y.Y. Lee et al.

    Venous thromboembolism and cancer: risks and outcomes

    Circulation

    (2003)
  • S. Sallah et al.

    Plasma coagulation markers in patients with solid tumors and venous thromboembolic disease receiving oral anticoagulation therapy

    Clin Cancer Res

    (2004)
  • M.B. Streiff

    Diagnosis and initial treatment of venous thromboembolism in patients with cancer

    J Clin Oncol

    (2009)
  • M. Biggioggero et al.

    The geoepidemiology of the antiphospholipid antibody syndrome

    Autoimmun Rev

    (2010)
  • H. Zinger et al.

    Common infectious agents prevalence in antiphospholipid syndrome

    Lupus

    (2009)
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