Antiphospholipid Syndrome (APS) and Cancer – Top 10 Series

1. What are antiphospholipid antibodies and how do you test for them?
2. Is every positive antiphospholipid antibody test clinically significant?
3. What is the frequency of antiphospholipid antibodies in patients who have cancer?
4. Is the frequency of antiphospholipid antibodies increased in patients with malignancies compared to the general population?
5. What is the reason for increased frequency of antiphospholipid antibodies in patients with cancer?
6. Does antiphospholipid antibody positivity increase the risk of blood clots in patients with cancer?
7. Do antiphospholipid antibodies disappear after the treatment of cancer?
8. Should doctors screen all cancer patients for antiphospholipid antibodies?
9. What is the association between catastrophic antiphospholipid syndrome and cancer?
10. Should doctors follow antiphospholipid antibody-positive patients for the development of cancer?

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:

• Lupus anticoagulant (LA) test
• Anticardiolipin antibody (aCL) test
• Anti-β2-glycoprotein-I antibody (aβ2GPI) test

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:

• Antiphospholipid antibodies should be positive in tests conducted on two occasions at least 12 weeks apart.
• The lupus anticoagulant (LA) test is the most important aPL test.
• Anticardiolipin antibody (aCL) and aβ2GPI have several subclasses; immunoglobulin (Ig) subclass IgG and IgM levels greater than or equal to 40 units (40U) are clinically more significant than lower levels.

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).

* 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.

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:

• The immune system – as a response to tumor antigens, cancer immunotherapy, or inflammatory microenvironment created by the tumor tissue.
• Cancer cells.

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 doctors 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 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:

1. Cancer, aPL and other clinical problems such as severe infections increase the risk of blood clots in multiple organs.
2. If cancer and aPL exist together, they may have an additive effect for blood clot development.
3. When cancer and aPL exist together, it can be more challenging to make an accurate diagnosis for CAPS.

10. Should doctors 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.

Posted: 9/13/2018

Authors

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

Doruk Erkan, MD, MPH
Attending Rheumatologist, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medical College

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