1. What are antiphospholipid antibodies and how do you test for them?
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:
2. Is every positive antiphospholipid antibody test clinically significant?
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:
3. What is the frequency of antiphospholipid antibodies in patients who have cancer?
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).
|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%)||74/17/20||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
|Bazzan et al. (2009)||Solid tumor and hematologic malignancy||137||9 (7%)||24/-/-||LA, aCL and aβ2GPI||Not reported|
4. Is the frequency of antiphospholipid antibodies increased in patients with malignancies compared to the general population?
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.
5. What is the reason for increased frequency of antiphospholipid antibodies in patients with cancer?
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:
6. Does antiphospholipid antibody positivity increase the risk of blood clots in patients with cancer?
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.
7. Do antiphospholipid antibodies disappear after the treatment of cancer?
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.
8. Should we screen all cancer patients for antiphospholipid antibodies?
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.
9. What is the association between catastrophic antiphospholipid syndrome and cancer?
One of the most severe presentations of APS 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:
10. Should we follow antiphospholipid antibody positive patients for the development of cancer
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.