Top 10 Series: Antiphospholipid Syndrome and Coronavirus Disease 2019 (COVID-19)

Top 10 points patients should know about the association between antiphospholipid antibodies and COVID-19

  1. What is antiphospholipid syndrome (APS)?
  2. What is COVID-19?
  3. Is there an association between COVID-19 and blood clots?
  4. What are the overlapping clinical features of COVID-19 and APS?
  5. Is there an association between COVID-19 and antiphospholipid antibodies?
  6. Is there increased risk of severe symptoms in COVID-19 patients with newly positive antiphospholipid antibody tests?
  7. Is there increased risk of severe COVID-19 symptoms in patients with history of APS or positive antiphospholipid antibodies?
  8. Should COVID-19 patients with newly positive antiphospholipid antibodies get follow-up testing for antiphospholipid antibodies?
  9. Should COVID-19 patients with positive antiphospholipid antibodies be on blood thinner treatments?
  10. What precautions should APS patients take to prevent COVID-19?

1. What is antiphospholipid syndrome (APS)?

Antiphospholipid syndrome (APS) is a systemic autoimmune condition, in which individuals make antibodies that target their own body cells. These antibodies, known as antiphospholipid antibodies (aPL), cause blood clots, miscarriages, and other complications such as low platelet counts. A diagnosis of APS requires both clinical symptoms and positive antibodies. A person may test positive for aPL without any clinical symptoms but may not develop APS.

A severe manifestation of APS is called catastrophic antiphospholipid syndrome (CAPS), which can develop in less than 1% of APS patients. Catastrophic antiphospholipid syndrome occurs when multiple blood clots form rapidly over the course of days, usually associated with microcirculation involvement, and cause damage to multiple organs in the body, commonly the brain, lungs, and kidneys.

2. What is COVID-19?

Coronavirus disease 2019 (COVID-19) is a systemic infectious disease caused by a strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It caused a worldwide pandemic that began with its initial outbreak in Wuhan, China in December 2019. Individuals with the disease can have no symptoms, or they may develop symptoms ranging from mild cough to severe respiratory disease that requires breathing support from a ventilator. Common symptoms include fever, cough, shortness of breath and muscle/joint pain. Other potential symptoms include diarrhea and loss of taste or smell.

3. Is there an association between COVID-19 and blood clots?

Emerging evidence suggests COVID-19 is associated with blood clots. Based on reviews of the medical literature, hospitalized patients with COVID-19 have higher than expected frequency of vein clots (for example, deep vein thrombosis), and lung vessel clots (pulmonary embolism). Other clots in small blood vessels (these clots are known as "microthrombi") have also been found in COVID-19 patients. (See below for details.)

4. What are the overlapping clinical features of COVID-19 and APS?

COVID-19 was initially thought to be primarily a respiratory infection. However, published studies, including autopsy reports of COVID-19 patients, suggest that the disease may cause other symptoms due to inflammation and damage of the lining of small vessels. This leads to small blood clots (microthrombi) in various organs. Similarly, in APS, blood clots are formed when the aPL bind to the vessel walls, causing inflammation and subsequent blood clots. Microthrombi affecting multiple organs can develop in APS, and are part of the CAPS spectrum as discussed above.

5. Is there an association between COVID-19 and antiphospholipid antibodies?

The mechanism of blood clot formation in patients with COVID-19 remains yet to be fully elucidated. COVID-19 infection results in a systemic inflammatory response causing molecules, including cytokines, to act on certain white blood cells (monocytes/macrophages) and the lining of blood vessels (endothelial cells), leading to clot formation, loss of blood flow, and eventual organ damage.

Several studies have examined aPL as contributing factors in patients who are seriously ill from COVID-19 and requiring admission to the intensive care unit. Lupus anticoagulant (LA) – one of the main aPL tests – is occasionally positive in these critically ill patients with COVID-19. However, these results are difficult to interpret as the LA test may be affected by inflammation due to COVID-19 or be falsely positive by routine use of blood thinners in the hospital. The other two main tests that detect aPL – anticardiolipin (aCL) and anti-Beta-2-glycoprotein-I (aβ2GPI) antibodies – are less likely to be clinically significantly positive in this group of severely ill COVID-19 patients.

Thus, the positive aPL tests observed in COVID-19 patients may be falsely positive among those patients experiencing systemic inflammation or be transiently positive due to COVID-19 infection. This is the case when false positives for aPL have been observed in patients who had other infections (such as hepatitis B and C, HIV and syphilis). Studies that can demonstrate whether positive aPL tests remain persistently positive in COVID-19 patients will help us better understand what associations there may be between COVID-19 and aPL.

6. Is there increased risk of severe symptoms in COVID-19 patients with newly positive antiphospholipid antibody tests?

There is mixed evidence for whether a newly positive aPL result may be associated with increased risk of clots in COVID-19 patients. In one study from Belgium of critically ill COVID-19 patients, aPL were observed but did not appear to increase the risk of clotting complications. On the other hand, another study from the US suggests that test results showing a new, positive aPL are in fact associated with increased clots. Further studies are needed to understand the role of aPL in COVID-19, and whether their emergence during a COVID-19 infection worsens a patient’s prognosis.

7. Is there increased risk of severe COVID-19 symptoms in patients with history of APS or positive antiphospholipid antibodies?

Risk of severe COVID-19 appears to be related to age and comorbidities such as high blood pressure, obesity and diabetes (among others). Studies are still investigating whether COVID-19 risk or severity is related to rheumatic diseases. In patients with rheumatologic conditions, the use of systemic glucocorticoid medications (steroids, such as prednisone) has been associated with higher risk for hospitalization for COVID-19. For this reason, it is recommended that patients use the lowest possible dose of steroids to control rheumatic disease. To our knowledge, no studies have been published which focus on the risk of severe COVID-19 symptoms in patients with a history of APS or positive aPL tests.

Compared to general population, persistently aPL-positive patients are at a higher risk for blood clots during hospitalization. Thus, in case of COVID-19-related hospitalization, it is important for persistently aPL-positive patients (independent of their history of blood clots) to discuss the blood clot prevention strategies with their physicians.

8. Should COVID-19 patients with newly positive antiphospholipid antibodies get follow-up testing for antiphospholipid antibodies?

Low levels of aPL, which can occur during infections, are usually transient (temporary). Very limited published data support the transient nature of these antibodies, as some COVID-19 patients with positive aPL were tested negative at one month. To help guide medical decision making, patients should get retested for aPL after 12 weeks if the initial set of aPL tests was positive.

9. Should COVID-19 patients with positive antiphospholipid antibodies be on blood thinner treatments?

As discussed above, there is mixed data on the association between new aPL positivity in COVID-19 patients and clotting risk. However, hospitalized COVID-19 patients have an increased frequency of blood clots and should be at least on preventive-dose blood thinners. The role of continued blood thinners after hospital discharge is still under investigation, though it is generally recommended in patients with high risk for clotting. The benefit of blood thinners in non-hospitalized COVID-19 patients is uncertain.

10. What precautions should APS patients take to prevent COVID-19?

Patients with APS should follow all standard precautions including social distancing, wearing masks when outside of the home, frequent hand washing, and avoiding contact with sick individuals.

At this time, there are no specific treatments recommended for COVID-19 precaution in patients with APS. Recommendations may be provided on a case-by-case basis by physicians.

References

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  2. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. J Am Coll Cardiol. 2020.
  3. Bowles L, Platton S, Yartey N, et al. Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19. N Engl J Med. 2020;383(3):288-290.
  4. Devreese KMJ, Linskens EA, Benoit D, Peperstraete H. Antiphospholipid antibodies in patients with COVID-19: A relevant observation?. J Thromb Haemost. 2020.
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  8. Marietta M, Coluccio V, Luppi M. COVID-19, coagulopathy and venous thromboembolism: more questions than answers. Intern Emerg Med. 2020;
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  10. Mikuls TR, Johnson SR, Fraenkel L, et al. American College of Rheumatology Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic: Version 2. Arthritis Rheumatol. 2020;
  11. Mondal R, Lahiri D, Deb S, et al. COVID-19: Are we dealing with a multisystem vasculopathy in disguise of a viral infection?. J Thromb Thrombolysis. 2020.
  12. Reyes gil M, Barouqa M, Szymanski J, Gonzalez-lugo JD, Rahman S, Billett HH. Assessment of Lupus Anticoagulant Positivity in Patients With Coronavirus Disease 2019 (COVID-19). JAMA Netw Open. 2020;3(8):e2017539.
  13. Schmidt-tanguy A, Voswinkel J, Henrion D, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927-9.
  14. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859-1865.
  15. Terpos E, Ntanasis-stathopoulos I, Elalamy I, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020;95(7):834-847.
  16. Virginie Siguret, Sebastian Voicu, Marie Neuwirth, Maxime Delrue, Etienne Gayat, Alain Stépanian, and Bruno Mégarbane. Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients? Thromb Res. 2020 Nov; 195: 74–76. Published online 2020 Jul 8. doi: 10.1016/j.thromres.2020.07.016.

Authors

Xin Wang, MD
Resident Physician, Department of Internal Medicine, NewYork–Presbyterian Hospital, Weill Cornell Medicine

Elena Gkrouzman, MD, MS
Assistant Professor, University of Massachusetts Medical School

Image - Photo of Medha Barbhaiya, MD, MPH
Medha Barbhaiya, MD, MPH

Assistant Attending Physician, Hospital for Special Surgery
Assistant Professor of Medicine, Weill Cornell Medical College

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

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