Anti-coagulation in COVID-19 patients: More questions than answers?
Coagulation dysfunction constitutes a part of the sepsis pathophysiology. (1) Targeting such dysfunction had been previously investigated with the aim to improve sepsis outcome (e.g. Activated Protein C). (2) Critically-ill patients are also at increased risk of thrombo-embolism due to other reasons (e.g. Immobility, dehydration, intravascular catheters, etc).
Recently, there have been increased concerns about hypercoagulability in COVID-19 patients; and D-Dimer became a part of the laboratory work-up in many centres.
Klok et al conducted an observational study of 184 COVID-19 ICU patients in three Dutch hospitals to investigate the incidence of thrombotic complications. (3) Patients were generally overweight (Mean 87 Kg) and 2.7% had active cancer. They were treated with prophylactic anticoagulation (9.2% on therapeutic anticoagulation and 38% had a coagulation abnormality). The median follow-up was 7 days (IQR: 1-13 days).
31 patients developed thromboembolism (25 CTPA confirmed PE, 1 DVT, 2 catheter related thrombus and 3 ischemic stroke). No myocardial infarction nor systemic arterial embolism were observed. The cumulative incidence (number of events adjusted for the at-risk period for each patient) was high at 31%. Diagnostic tests were undertaken based on clinical suspicion, and as such the authors hypothesised that the true incidence may be even higher.
The cumulative incidence graph shows that the thrombotic complications reach a plateau at day-10 after ICU admission. Age and coagulopathy (spontaneously prolonged PT > 3 sec and aPTT > 5 sec) were risk factors as per regression analysis.
The study represents an important step and can impact the management. This is not the first work highlighting hypercoagulability in COVID-19. Zhang et al also documented three cases with thrombosis and positive antiphospholipid antibodies. (4) However, the work done by Klok et al did not explore the underlying mechanism. The complexity of the coagulation system means different drugs can target different molecules or pathways. The radiologically evident thrombosis can also be the tip of an iceberg, which includes microcirculatory thrombosis (e.g. Pulmonary microthrombi).
An understanding of such points can form the base for RCTs to weigh the benefits versus the risks of excessive anticoagulation. Thanks to the current public and political interest in COVID-19, cost issues can be overcome. Large-scale multicentric studies can also recruit in a relatively short period due to the high disease prevalence.
For patients with (multi-)organ failure, a well applied supportive care is as important as a potential antiviral treatment.
Finally, the study may be another proof of the importance of point of care testing like Thrombo-elastography, Critical Care Echocardiography and venous Doppler as a robust tool in the unstable ICU patients.
STUDY STRENGTHS & LIMITATIONS
- The article answers an important research question.
- Short and concise.
- Theory generating.
- Observational study with a small sample size. Larger observational trials and RCT are needed before translation into clinical practice, to weigh benefit versus risk.
- The article did not investigate the underlying coagulation dysfunctional mechanism. Such a point is fundamental to guide both testing and treatment.
- Short follow-up period means the incidence may be underestimated.
TAKE HOME MESSAGE
Klok et al work showed a high incidence of thrombosis in COVID-19 patients pending further exploration of the underlying mechanism and the best intervention. Till such a higher quality of evidence appears, observational studies and expert opinion can serve as the base of any change in the management.
This article review was prepared and submitted by Dr Ashraf Roshdy, Whipps Cross University Hospital – Barts Health NHS Trust, London, United Kingdom, on behalf of the ESICM Journal Review Club.
Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S et al. Drotrecogin alfa (activated) in adults with septic shock.N Engl J Med. 2012 May 31;366(22):2055-64. doi: 10.1056/NEJMoa1202290
F.A.Klok, M.J.H.A.Kruip, N.J.M.vanderMeer et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Thrombosis Research(2020), https://doi.org/10.1016/j.thromres.2020.04.013
Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 8. doi: 10.1056/NEJMc200757