Lupus Anticoagulant in Patients with Covid-19 | NEJM - nejm.org - nejm.org

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To the Editor

In their letter to the editor, Bowles et al. (July 16 issue)¹ report on a study in which 20% of the patients with Covid-19 had a prolonged activated partial-thromboplastin time (aPTT), and in 31 of 34 patients, evidence of lupus anticoagulant was detected by means of plasma-based laboratory methods. These findings provide support for a phenomenon described by Wenzel et al., who found evidence of lupus anticoagulant in 52% of critically ill patients (before the Covid-19 pandemic).²

Causes of a prolonged aPTT include intrinsic-factor deficiency and the presence of an inhibitor such as lupus anticoagulant or C-reactive protein. Although both inhibitory mechanisms are possible in patients with thrombosis, C-reactive protein may contribute to a considerable proportion of positive results. In the study conducted by Bowles et al., the C-reactive protein level was at least 100 mg per liter in 27 patients, and a study by van Rossum et al. showed that aPTT may be prolonged by C-reactive protein itself through a phospholipid-dependent mechanism.³ This effect appears to be mitigated by kaolin-based reagents. The clotting time as measured with the use of dilute Russell’s viper-venom time (DRVVT) has not consistently been shown to be prolonged by C-reactive protein,^3,4 although this prolongation is plausible and worthy of further study with different reagents. As Bowles and colleagues conclude, the use of anticoagulation in patients with Covid-19 who have abnormal coagulation remains valuable in clinical practice for the prevention and treatment of venous thrombosis.

Richard Gooding, M.B., Ch.B.
Bethan Myers, F.R.C.Path.
Styliani Salta, M.D.
University Hospitals of Leicester, Leicester, United Kingdom
[email protected]

No potential conflict of interest relevant to this letter was reported.

This letter was published on October 23, 2020, at NEJM.org.

1. 1. Bowles L, Platton S, Yartey N, et al. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med 2020;383:288-290.

2. 2. Wenzel C, Stoiser B, Locker GJ, et al. Frequent development of lupus anticoagulants in critically ill patients treated under intensive care conditions. Crit Care Med 2002;30:763-770.

3. 3. van Rossum AP, Vlasveld LT, van den Hoven LJM, de Wit CWM, Castel A. False prolongation of the activated partial thromboplastin time (aPTT) in inflammatory patients: interference of C-reactive protein. Br J Haematol 2012;157:394-395.

4. 4. Schouwers SME, Delanghe JR, Devreese KMJ. Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results? Thromb Res 2010;125:102-104.

Response

The authors reply: With regard to the effect of C-reactive protein, as measured with the use of Stago PTT-LA reagent, normal plasma spiked with C-reactive protein at levels higher than 86 mg per liter is associated with a prolonged aPTT, but as measured with the use of DRVVT, C-reactive protein at levels up to 288 mg per liter does not have an effect on aPTT.¹ In our study, according to International Society on Thrombosis and Haemostasis (ISTH) criteria for lupus anticoagulant positivity,² 18 patients were positive for lupus anticoagulant by both DRVVT and aPTT, 7 were positive by DRVVT alone, and 6 were positive by aPTT alone. Of the 25 samples that were positive for lupus anticoagulant by DRVVT, 14 (56%) had a C-reactive protein level below 288 mg per liter, and of the 6 samples that were positive for lupus anticoagulant by aPTT alone, 2 (33%) had a C-reactive protein level below 86 mg per liter.

In studies involving patients with Covid-19, the incidence of lupus anticoagulant positivity by DRVVT was increased both in patients with thrombosis (with adjustment for the C-reactive protein level)³ and in those without thrombosis.⁴ The results of these studies that meet ISTH criteria for lupus anticoagulant positivity suggest that the presence of lupus anticoagulant is real and not an artifact. Whether the presence of lupus anticoagulant is transient or persistent — or clinically relevant — remains to be seen.

Sean Platton, M.Sc.
Louise Bowles, M.B., B.S.
K. John Pasi, M.B., Ch.B., Ph.D.
Royal London Hospital, London, United Kingdom
[email protected]

Since publication of their letter, the authors report no further potential conflict of interest.

This letter was published on October 23, 2020, at NEJM.org.

1. 1. Schouwers SME, Delanghe JR, Devreese KMJ. Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results? Thromb Res 2010;125:102-104.

2. 2. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009;7:1737-1740.

3. 3. 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-e2017539.

4. 4. Siguret V, Voicu S, Neuwirth M, et al. Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients? Thromb Res 2020;195:74-76.

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Lupus Anticoagulant in Patients with Covid-19 | NEJM - nejm.org - nejm.org

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