Antiphospholipid antibodies (aPL) are a group of various autoantibodies produced by the immune system. The aPL are directed against different self-proteins and may cause blood clots in arteries or veins, as well as pregnancy complications. The three most common medical tests to detect aPL are:
Not every positive aPL test is clinically relevant, and not every aPL-positive patient has the same risk of aPL-related clinical problems. A “positive” aPL test result alone does not necessarily mean a person has an increased risk of developing aPL-created blood clots. In addition, aPL-positive patients who also have a cardiovascular disease risk factor (high blood pressure, elevated cholesterol, diabetes, smoking or obesity, etc.), have a higher risk of developing blood clots.
Proper interpretation of aPL laboratory results is required to accurately assess the risk of developing a blood clot in a specific patient.
When the healthcare team is interpreting the aPL test results, the following points are important to determine whether the aPL profile is clinically significant:
The frequency of positive aPL results in cancer patients varies widely because of limitations in the medical literature – not all research studies define “positive” aPL-tests as they should. In fact, the reported frequency of positive aPL results in patients who have cancer varies anywhere from 1.4% to 74%.
This dramatic range is due in part to differences in the designs of the various studies, and in part to inconsistent definitions of “aPL-positivity” within the medical literature that report those studies. The table below demonstrates some of the studies that analyzed the frequency of aPL-positivity in patients with cancer. The authors of some studies consider an aPL level of more than 20 units (>20U) to be “positive.” Others, meanwhile, consider results to be positive only when a test indicates a higher level of more than 40 units (>40U).
Study (author reference) |
Type of Cancer* | Number of Patients | Number of Patients with Blood Clots | Frequency (Percentage) of aPL Positivity (in all patients / in those with blood clots / in those without blood clots) |
Type of aPL Tested | Definitions of aCL and aβ2GPI Positivity |
Vassalo et al. (2014) | Solid tumor and hematologic malignancy | 95 | 17 (18%) | 74 / – / –** | LA, aCL and aβ2GPI | aCL and/or aβ2GPI IgG/M >40U† |
Yoon et al.(2003) | Hematologic malignancy only | 33 | 33 (100%) | 61 / 100 / – | LA, aCL and aβ2GPI | aCL and/or aβ2GPI IgG/M >20U‡ |
Zuckerman et al. (1995) | Solid tumor and hematologic malignancy | 216 | 37 (17%) | 22 / – / | aCL | aCL IgG/M >30U‡ |
Font et al. (2011) | Solid tumor only | 400 | 258 (65%) | – / 8 / 1 | LA and aCL aβ2GPI | aCL IgG/M >40U† |
Gomez-Puerta et al. (2006) | Solid tumor and hematologic malignancy | 120 | 76 (63%) | 67 / – / – | LA and aCL aβ2GPI | Not reported |
Miesbach et al. (2009) | Solid tumor and hematologic malignancy | 58 | 24 (41%) | ST: 54 / 44 / 62 HM: 42 / 33 / 6 |
LA | Not tested |
Bazzan et al. (2009) | Solid tumor and hematologic malignancy | 137 | 9 (7%) | 24 / – / – | LA, aCL and aβ2GPI | Not reported |
* Solid tumor defined as an abnormal mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas or carcinomas (breast, colon, lung, renal). Hematologic malignancy defined as cancer cells developing in blood-forming tissue, such as the bone marrow, or in the cells of the immune system. Examples of hematologic cancer are leukemia, lymphoma and plasma cell dyscrasias (multiple myeloma, Waldenstrom’s macroglobulinemia, and monoclonal gammopathy of undetermined significance [MGUS]).
– Not reported
** When aPL tests were repeated in 12 weeks in 27 aPL-positive patients, aPL remained positive in only 9 (33%) patients.
† Two positive tests 12 weeks apart.
† Unknown whether study participants were tested just once or multiple times.
A prospective study of healthy blood donors who were tested twice for aPL demonstrated, at baseline, 10% and 1% positivity for aCL and LA tests, respectively. However, less than 1% of healthy blood donors remained positive for aCL or LA one year later.
One of the studies listed in the above table (Zuckerman et al.) demonstrated that approximately 22% of cancer patients have positive aCL IgG and/or IgM (although 25% of the aCL were less than 30U), compared to 3% in the healthy controls. This study did not report whether or not patients were tested for other aPL tests as defined in Question/Answer #2). It is also unknown whether the aCL was tested on more than two occasions; thus the frequency may be overestimated. In another study (Font et al.), approximately 8% and 1% of cancer patients with or without blood clots, respectively, were positive for aPL, compared to 1% of the healthy subjects.
Based on the above reports, we can conclude that patients with cancer have higher frequency of aPL. However, there is no clinical relevance for patients with low level aPL.
The factors causing the production of aPL in patients with cancer remain mostly unknown. Several mechanisms have been suggested, including the production of aPL by:
Independent of aPL, patients with cancer are at increased risk for blood clots – approximately 4 to 5 times higher, compared to patients with no cancer (Young et al). Blood clots cause significant morbidity in cancer patients and are the second cause of death in these patients. Based on one study listed above (Zuckerman et al), 28% of aCL positive cancer patients developed blood clots – double that of the 14% of aCL-negative cancer patients who developed clots.
In summary, cancer patients with clinically significant aPL profiles may have increased risk of developing blood clots; however well-designed large-scale population studies are still needed to determine the true risk.
There are no comparison studies designed to show us whether there is a difference in aPL levels between those cancer patients who are responding to cancer treatment versus those who are not. However, based on case series, most often, low-level aPL disappears in patients who respond to treatment of their cancer.
Although aPL positivity can help with the blood clot risk prediction, currently there are no strong data to recommend aPL screening in cancer patients. However, aPL may be part of the testing in cancer patients in the context of a clinical trial or research study.
One of the most severe presentations of antiphospholipid syndrome is catastrophic antiphospholipid syndrome (CAPS). This syndrome is characterized by the rapid development of blood clots, especially in small vessels, affecting multiple organs. The analysis of 500 CAPS patients included in the international CAPS registry reported a 16% rate of cancer, mostly lymphomas and leukemia. Catastrophic APS patients with cancer are more likely to be older than those without cancer, and CAPS is usually triggered by cancer in these patients.
It is important to note that:
There are no studies evaluating whether aPL-positive patients without systemic autoimmune disease are at increased risk for cancer. There are no recommendations to follow up aPL-positive patients for the risk of developing cancer.
Posted: 9/13/2018
Damla Ernur, MD
Medical Resident, Academic Visitor, Hospital for Special Surgery
Zeynep Belce Erton
Medical Student, Academic Visitor, Hospital for Special Surgery
Maria De Sancho, MD, MSc
Associate Professor of Clinical Medicine, Weill Cornell Medicine
Abdollahi A, Omranipour R. Is Increase of Homocysteine, Anti-Cardiolipin, Anti-Phospholipid Antibodies associated with Breast Tumors? Acta Med Iran 2015; 53:681-685.
Asherson RA, Carrasco MG, Zeron MPB, et al. Antiphospholipid Antibodies and Malignancies. In: The Antiphospholipid Syndrome II: Autoimmune Thrombosis. Eds: Asherson RA, Cervera R, Piette JC. Oxford: Elsevier, 2002;p: 317-329.
Bazzan, M, Montarulli B, Vaccarino A, et al. Presence of low titre of antiphospholipid antibodies in cancer patients: A prospective study. Intern Emerg Med 2009; 4:491–495.
de Meis E, Monteiro RQ, Levy RA. Lung adenocarcinoma and antiphospholipid antibodies. Autoimmun Rev 2009; 8:529-532.
de Meis E, PinheiroVR, Zamboni MM, et al. Clotting, immune system, and venous thrombosis in lung adenocarcinoma patients: A prospective study. Cancer Investig 2009; 27:989–997.
Finazzi G. The Italian Registry of Antiphospholipid Antibodies. Haematologica 1997; 82:101-105.
Font C, Vidal L, Espinosa G, et al. Solid cancer, antiphospholipid antibodies, and venous thromboembolism. Autoimmun Rev Elsevier BV. 2011; 10:222–227.
Gómez-Puerta JA, Espinosa G, Cervera R. Antiphospholipid Antibodies: From General Concepts to Its Relation with Malignancies. Antibodies 2016; 5:18.
Gómez-Puerta JA, Cervera R, Espinosa G, et al. Antiphospholipid antibodies associated with malignancies: Clinical and pathological characteristics of 120 patients. Semin Arthritis Rheum 2006; 35:322–332.
Jude B, Goudermand J, Dolle I, et al. Lupus anticoagulant: a clinical study of 100 cases. Clin Lab Haematol 1988; 10:41-51.
Miesbach W, Scharrer I, Asherson R. Thrombotic Manifestations of the Antiphospholipid Syndrome in Patients with Malignancies. Clin Rheumatol 2006; 25:840-844.
Miesbach W, Asherson RA, Cervera R, Shoenfeld Y, et al. The catastrophic antiphospholipid syndrome and malignancies. Autoimmun Rev 2006; 6:94-97.
Mortazavizadeh MR, Sadeghmanesh R. Antiphospholipid Antibodies in Neoplastic Patients. IJCP 2009; 2:63-66.
Reinstein E, Shoenfeld Y. Antiphospholipid Syndrome and Cancer. Clinic Rev Allerg Immunol 2007; 32: 184.
Schved JF, Dupuy-Fons C, Biron C, et al. A prospective epidemiological study of the occurrence of antiphospholipid antibody: the Montpellier antiphospholipid study (MAP). Haemostasis 1994; 24:175-182.
Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid Antibodies and Malignancies. Autoimmun Rev 2010; 9:200-202.
Tincani A, Ziglioli T, Andreoli L, et al. Update on antiphospholipid antibodies: clinical significance. Int J Clin Rheumatol 2009; 4:551–560.
Vassalo J, Spector N, de Meis Eet al. Antiphospholipid antibodies in critically ill patients with cancer: a prospective cohort study. J Crit Care 2014; 29:533-538.
Yoon KH, Wong A, Shakespeare T, et al. High prevalence of antiphospholipid antibodies in Asian cancer patients with thrombosis. Lupus 2003; 12:112-116
Young A, Chapman O, Connor C, et al. Thrombosis and cancer. Nature reviews Clinical oncology 2012; 9: 437-449.
Zuckerman E, Toubi E, Golan TD, et al. Increased thromboembolic incidence in anti-cardiolipin positive patients with malignancy. Br J Cancer 1995; 72: 447-451.
Or call
+1.877.606.1555