The nature of venous thromboembolism (VTE) in COVID-19 patients is complex, and treatment strategies regarding drug type and dosing continue to evolve, writes Sanjum Sethi. In this context, Sethi concludes that a multidisciplinary approach to treatment, in the form of pulmonary embolism response teams (PERTs), is necessary.
Infection with SARS-CoV-2 leading to COVID-19 illness was declared a worldwide pandemic by the World Health Organisation (WHO) in March 2020.1 Early reports from Wuhan, China suggested an increased prevalence of VTE in this patient population.2 These reports were then confirmed with subsequent reports from France, The Netherlands, and the USA,3–5 all early locations of excess COVID-19 cases.
While these observations remained consistent across different hospital systems, many questions lingered. Was there truly an excess of VTE in this patient population relative to other critically-ill patients? What is the mechanism of the thrombosis? How should we treat patients to prevent thrombotic events? As our collective scientific experience has grown over the last several months, we have accrued data to answer some of the above questions, but many questions still require further inquiry.
COVID-19 and thromboinflammation
An initial report out of The Netherlands found a nearly 30% incidence of thrombotic events in 184 COVID-19 intensive care unit (ICU) patients.3 All patients had received prophylactic anticoagulation. Subsequently, Poissy and colleagues compared 107 COVID-19 patients admitted to the ICU versus both influenza ICU patients and general ICU admitted during a similar time period the year before.4 The rates of pulmonary embolism (PE) were much higher in the COVID-19 group (20% vs. 7%), generating further evidence of the association between COVID-19 and VTE.
While epidemiologic studies have quantified the number of COVID-19 patients that are diagnosed with VTE, mechanistic studies suggest multiple potential avenues that may lead to VTE in this population. Patients are critically ill and sedentary. They have higher levels of circulating biomarkers suggesting inflammation, including D-Dimer, fibrinogen, and Factor VIII.6–7 Furthermore, in vitro studies suggest excessive platelet and neutrophil activation.8 One autopsy study of 12 patients demonstrated severe endothelial injury/dysfunction with alveolar capillary microthrombi nine times more prevalent as compared to patients with influenza.9 In total, these findings suggest both a component of micro and macro vascular thrombosis associated with this virus.
Given the complexities of VTE in this patient population, pulmonary embolism response teams (PERTs) can be an important resource in clinical care. PERTs are multidisciplinary collaborations involving varying specialties, depending on the institution, but may include haematology, cardiology, interventional radiology, vascular medicine, emergency medicine, pulmonary, cardiothoracic surgery, critical care, and more.10
This multidisciplinary approach allows for issues specific to COVID-19 VTE patients to be factored into the decision-making process. At our institution, we saw a three-fold increase in the number of consults relative to the same period in 2019 (Figure 1).11 Patients with COVID-19 and suspected to have VTE tended to be more likely to necessitate ventilator support and less likely have a confirmatory imaging study performed. Furthermore, invasive treatment was less commonly offered and systemic thrombolysis was more often utilised. This finding is likely reflective of concerns to limit staff exposure and preserve personal protective equipment, particularly in the early stages of the pandemic.
As multidisciplinary PERTs can aid in treatment decisions for COVID-19 patients, consensus agreement has emerged regarding therapeutic anticoagulation as the standard of care for confirmed VTE cases with an emphasis on low molecular weight heparin to reduce provider exposure.12,13 However, the degree of anticoagulation for COVID-19 patients without documented VTE remains controversial. Centres have advocated varying risk stratification models including D-Dimer, invasive ventilation, and ICU stay, as well as varying dosing regimens, including full dose, intermediate dose, and prophylactic dose. A retrospective analysis from Nadkarni and colleagues suggests that anticoagulation for hospitalised COVID-19 reduced mechanical ventilation and death.14
These findings have spurred multiple randomised controlled trials testing varying drug and dosing regimens. The majority of active trials have chosen heparin-based regimens using full dose versus prophylactic dose. At our centre, we have initiated a cluster randomised trial (IMPROVE-COVID) examining prophylactic heparin (or LMWH) versus intermediate dose heparin (or LMWH) (Figure 2).15 This pragmatic trial was designed during the first wave of the pandemic as a way to determine a plausible answer with a relatively small sample size. We continue to enrol in this study and look forward to sharing the results in the future.
COVID-19 illness appears to be associated with an increased propensity for VTE, likely due to underlying thromboinflammation. We advocate for a multidisciplinary approach to target treatments in a patient-specific fashion, especially as strategies regarding drug type and dosing continue to evolve.
- Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020 May 12;75(18):2352–2371.
- Cui S, Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020;18:1421–1424.
- Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020 Jul;191:145–147.
- Poissy J, Goutay J, Caplan M, Lille ICU haemostasis COVID-19 group. Pulmonary embolism in COVID-19 patients: Awareness of an increased prevalence. Circulation 2020;142:184–186.
- Piazza G, Campia U, Hurwitz S, et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol 2020 Nov 3;76(18):2060–
- Piazza G, Morrow DA. Diagnosis, management, and pathophysiology of arterial and venous thrombosis in COVID-19. JAMA 2020 Nov 23.
- Zhang Y, Cao W, Jiang W, et al. Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients.J Thromb Thrombolysis 2020;50(3):580–
- Nicolai L, Leunig A, Brambs S, et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation 2020;142(12):1176–
- Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N Engl J Med 2020;383(2):120–
- Rosovsky R, Zhao K, Sista A, et al. Pulmonary embolism response teams: Purpose, evidence for efficacy, and future research directions. Res Pract Thromb Haemost 2019;3(3):315–
- Finn M, Sethi SS, et al. PERT Consortium Meeting 2020.
- Bikdeli B, Madhavan MV, Gupta A, et al. Pharmacological agents targeting thromboinflammation in COVID-19: Review and implications for future research. Thromb Haemost 2020;120(7):1004– doi:10.1055/s-0040-1713152.
- Rosovsky RP, Grodzin C, Channick R, et al. Diagnosis and treatment of pulmonary embolism during the coronavirus disease 2019 pandemic: A position paper from the National PERT Consortium [published online ahead of print, 2020 Aug 27]. Chest 2020;158(6):2590–
- Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol 2020;76(16):1815– doi:10.1016/j.jacc.2020.08.041.
- Intermediate or prophylactic-dose anticoagulation for venous or arterial thromboembolism in severe COVID-19 (IMPROVE). https://clinicaltrials.gov/ct2/show/NCT04367831.
Sanjum S Sethi is an assistant professor of Medicine at Columbia University Irving Medical Center in New York, USA.