Covid-19 and thrombosis: the view from the Middle East

Hughes Syndrome (Antiphospholipid Syndrome) and COVID-19: Is there an association?

Georges El Hasbani, Ali Taher, Ali Jawad, and Imad Uthman

Beirut, Lebanon

What is the epidemiology of blood clots (thromboembolism) in COVID-19?

The 2019 novel coronavirus (COVID-19) is believed to have originated in Wuhan, Hubei Province, China in December 2019. As a result of the global involvement, the World Health Organization (WHO) declared COVID-19 a global health emergency1. Early emerging reports illustrated an association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 and abnormal coagulation parameters in blood tests including prolonged prothrombin time (PT) and activated partial thrombin time (aPTT)2–4.

Around 25% of severe COVID-19 patients not on routine anticoagulation developed thrombotic events5. Despite routine anticoagulation, 20% of patients developed thrombosis, of whom 13% were symptomatic6.  Additionally, a high prevalence (14.7%) of asymptomatic deep venous thrombosis (DVT) has been recorded in a cohort of COVID-19 patients admitted to non-intensive care units (non-ICU)7. However, most of these studies were performed at one medical center which is a major limitation.

Among ICU patients in Dutch hospitals, the cumulative incidence of thrombosis in the veins was 27% and that of arterial thrombotic events was 3.7%, even though standard and intermediate low-molecular-weight heparin (LMWH) anticoagulation was applied8.  Similar observations have been reported in ICU patients in France and Italy9,10. Interestingly, thrombotic events has been associated with poorer prognosis3. For example, pulmonary embolism (PE) has been found to be a major mortality contributor11.

Although arising evidence hints at the association of COVID-19 with thrombosis in ICU and non-ICU patients, the real risk of a patient with COVID-19 developing clotting complications is still unknown and requires much larger studies.

How can thrombosis be prevented?

The high burden of thrombotic events in COVID-19 patients sheds light on the blood thinning regimen that such patients must undergo. The American Society of Hematology (ASH) recommends an escalated dose anticoagulation for ICU patients compared to the standard dose for ward patients12. Low molecular weight heparin (LMWH), unfractionated heparin (UFH), and fondaparinux are among the options to be used12. The International Society on Thrombosis and Haemostasis (ISTH) recommendations relied on expert opinion to determine the anticoagulation regimens for admitted COVID-19 patients13. Guidelines were stratified according to whether patients are admitted to ICU or non-ICU settings and whether contraindications to anticoagulants exist or not13.

Could COVID-19 related thrombosis be due to Hughes’ Syndrome?

An initial report from China found elevated antiphospholipid antibodies (aPL) among 3 COVID-19 patients presenting with stroke14. However, this case series reported antibodies that are not used in the criteria of diagnosis of antiphospholipid syndrome (APS)15, specifically IgA anticardiolipin antibodies (aCL) and IgA anti-Beta-2 glycoprotein 1 (aB2GPI). In addition, these three patients had major risk factors for developing strokes including a history of cardiovascular disease. Subsequently, numerous studies tried to explain the role of aPL in COVID-19 related thrombotic events. The way aPL was assessed in these studies was challenged however16,17. Moreover, certain antibodies have a significant association with inflammatory conditions which might explain the positive tests18. In addition, the majority of these studies assessed aPL at one time point and did not perform a repeat test at least 12 weeks apart which is necessary for the diagnosis of APS. In one study19, a repeat testing was done after 4 weeks. Interestingly, a major proportion of patients who tested initially positive turned out negative on the second test, with a certain proportion of these patients developing thrombotic complications, which suggests that thrombosis in COVID-19 patients is secondary to other coagulation defects.

Conclusion

The probability of COVID-19 patients developing thrombosis is still unknown. Because ICU patients are more prone to develop thrombotic complications, anticoagulation guidelines have given special attention to these patients. Antiphospholipid antibodies (aPL) have been proposed to play a possible role in inducing thrombosis among COVID-19 patients. Despite multiple studies finding elevated aPL titers among COVID-19 patients with arterial or venous thrombotic events, it is still premature to conclude that patients with antiphospholipid syndrome (APS) are more prone to develop thrombotic complications if infection with coronavirus virus occurs.

References

  1. Giwa A, Desai A. Novel coronavirus COVID-19: an overview for emergency clinicians. Emerg Med Pract. 2020;22(2 Suppl 2):1-21.
  2. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7
  3. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost JTH. 2020;18(4):844-847. doi:10.1111/jth.14768
  4. Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994
  5. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost JTH. Published online April 9, 2020. doi:10.1111/jth.14830
  6. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost JTH. Published online May 5, 2020. doi:10.1111/jth.14888
  7. Demelo-Rodríguez P, Cervilla-Muñoz E, Ordieres-Ortega L, et al. Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels. Thromb Res. 2020;192:23-26. doi:10.1016/j.thromres.2020.05.018
  8. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. Published online April 10, 2020. doi:10.1016/j.thromres.2020.04.013
  9. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. Published online May 4, 2020. doi:10.1007/s00134-020-06062-x
  10. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi:10.1016/j.thromres.2020.04.024
  11. Wichmann D, Sperhake J-P, Lütgehetmann M, et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann Intern Med. Published online May 6, 2020. doi:10.7326/M20-2003
  12. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040. doi:10.1182/blood.2020006000
  13. 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. n/a(n/a). doi:10.1111/jth.14929
  14. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020;0(0):null. doi:10.1056/NEJMc2007575
  15. Connell NT, Battinelli EM, Connors JM. Coagulopathy of COVID-19 and antiphospholipid antibodies. J Thromb Haemost. n/a(n/a). doi:10.1111/jth.14893
  16. Tang N. Response to “Lupus anticoagulant is frequent in patients with Covid-19.” J Thromb Haemost JTH. Published online May 7, 2020. doi:10.1111/jth.14890
  17. Mehta S, Bhandari S, Mehta S. Cautious Interpretation of Antiphospholipid Antibodies in COVID-19. Clin Chim Acta. 2020;509. doi:10.1016/j.cca.2020.06.024
  18. Sidelmann JJ, SjØland JA, Gram J, et al. Lupus anticoagulant is significantly associated with inflammatory reactions in patients with suspected deep vein thrombosis. Scand J Clin Lab Invest. 2007;67(3):270-279. doi:10.1080/00365510601038992
  19. Devreese KMJ, Linskens EA, Benoit D, Peperstraete H. Antiphospholipid antibodies in patients with COVID-19: a relevant observation? J Thromb Haemost. n/a(n/a). doi:10.1111/jth.14994

Antiphospholipid antibodies in patients with COVID-19: are they relevant to thrombosis? 

Professor Katrien M.J. Devreese, Professor of Hameatology and Coagulation, Department of Laboratory Medicine, Ghent University Hospital, Belgium

Many communications worldwide have reported that hospitalized, critically ill patients with coronavirus disease 2019 (COVID-19), frequently develop laboratory abnormalities compatible with a status of hypercoagulability (excess blood coagulation) and clinically a high rate of thromboembolic (clotting) events. 

There are at least two separate pathologic coagulation processes that are important in development of clinical manifestations in COVID-19. In the microcirculation of the lung and potentially other organs, there is local direct vascular and lining cell (endothelial) injury producing microvascular clots. In the systemic circulation, due to hypercoagulability there is also the potential for large vessel thrombosis. Venous thrombosis and pulmonary thromboembolism are common complications in COVID-19. Also, the prevalence of arterial thrombosis is high and besides increased fibrinogen and platelet activation, involvement of antiphospholipid antibodies (aPL) has been suggested as part of the Antiphospholipid (Hughes’ Syndrome). Investigators tested for aPL in these patients because of the hypercoagulable state, that is also observed in antiphospholipid syndrome (APS) with one of the major clinical symptoms being thrombosis either venous, arterial or small vessels thrombosis. Recently, reports have been published on aPL in COVID-19 patients.

The information on aPL in SARS-CoV-2 patients that is available so far is interesting, because some studies have detected apL in these patients, but the data are often incomplete. Attributing thrombosis to APS in these patients is difficult because aPL are often produced transiently in patients with critical illness, some drugs and various infections but do not often cause thrombosis and are not usually of clinical significance. Re-testing at three months is essential and was originally meant to avoid over-diagnosis of APS patients that were not persistently positive. In the classification criteria for APS lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-beta2-glycoprotein I antibodies (aβ2GPI) IgG or IgM are included as laboratory criteria, if persistently present at 3 months. However, in some studies of severe COVID-19 patients only one point of measurement was obtained without the required confirmation after three months. 

The presence of these apL antibodies may rarely lead to thrombosis (clotting) events in some conditions apart from primary APS but there are many other potential causes for thrombosis in critically ill patients. Some studies demonstrated that aPL, with properties similar to those found in patients with APS, can be induced by immunization with β2GPI-like PL-binding viral and bacterial products. However, it is not certain that these aPL antibodies are able to cause clotting and the clinical significance remains unknown. Infectious agents are triggers for the formation of aPL and molecular mimicry between structures of bacteria or viruses and β2GPI-derived amino acid sequences are thought to contribute to the formation of autoantibodies. In more recent publications on aPL in COVID-19, patients initially positive for aPL were retested and showed negative on the second occasion, illustrating that in COVID-19 patients most of the aPL are transient and therefore unlikely to be significant. 

To investigate the role of aPL in SARS-CoV-2 patients, it is important to measure all aPL, including LAC, aCL and aβ2GPI antibodies, the latter with their isotype and titre (level). The information on aCL and aβ2GPI has been lacking in the first published reports meaning the true level of patient risk is unclear. In previously reported covid cohorts a high incidence of LAC was illustrated, and a correlation with thrombosis was suggested. However, it is unclear whether all these patients were prophylactically anticoagulated and this would potentially affect the result. Patients were mainly single LAC positive, and only few patients were triple positive (LAC, aCL and aβ2GPI positive), known as a high-risk profile. In some of the published reports there is concern on the methods used. One of the major drawbacks in LAC testing, performed with PL-dependent coagulation tests, is the interference of C-reactive protein (CRP) and anticoagulant therapy, resulting in a false positive LAC. Interference with CRP is a concern, since most of these critically ill patients have raised levels of CRP. Therefore, repeat testing at distance from the infection may help exclude false positive LAC but this has often not been done. 

In the majority of published studies there is no information on LAC (or other aPL) positivity before COVID-19 infection as these tests are not routinely done. Previous pre-covid APS studies illustrated that in asymptomatic carriers the number of clotting events was much lower in double and single apL positives compared to triple positives. Double positive (LAC negative) patients were at lower risk than triple positive patients, and single positive patients are less likely to develop APS related clinical symptoms. Even if we assume that all patients testing positive for LAC during COVID-19 infection were asymptomatic carriers, they are less likely to develop aPL related thrombosis since triple positive COVID-19 patients were very rare.

Today, it is too premature to conclude there is a contribution of aPL to thrombosis in COVID-19 patients. The presence of aPL should be interpreted with appropriate reservations and we should be conscious that many variables can affect test results, especially for LAC. Also, we have to follow up of the first measurements and retest after three months, to evaluate the persistence of the positive aPL in these patients. 

References

Based on the presentation given during the ISTH-SSC conference in July 2020 and publication of Katrien M.J. Devreese et al. Antiphospholipid antibodies in patients with COVID-19: a relevant observation? J Thromb Haemost 2020; 18: 2191-2201, DOI: 10.1111/jth.14994