Thrombo-inflammation in COVID-19
The SARS-COV-2 virus invades endothelial cells leading to microvascular inflammation, which in turn, triggers an intense prothrombotic state, termed thrombo-inflammation. The levels of coagulation factors, including fibrinogen and factor VIII, are often elevated in COVID-19. Circulating thrombotic microparticles and hyperviscosity also contribute to the prothrombotic state. The prothrombotic state in COVID-19 appears to be distinctly different from disseminated intravascular coagulation (DIC). Thrombocytopenia and low levels of fibrinogen are typically present in DIC; however, the prothrombotic state in COVID-19 is usually characterized by normal platelet counts and high fibrinogen levels. Other features of COVID-19-induced coagulopathy include normal prothrombin and partial thromboplastin times and elevated levels of D-dimer.
Autopsy studies of thrombotic phenomena
The SARS-CoV-2 virus gains entry into the lung through the ACE-2 receptors. Several autopsy studies confirm inflammation and hypercoagulability in patients who died of COVID-19. Diffuse alveolar damage and severe endothelial injury were seen in an autopsy study of seven patients. The presence of intracellular virus with disruption of cell membranes was also observed. Extensive capillary microthrombi in the alveoli along with widespread angiogenesis was also noted.1 In a study of 21 patients who died of COVID-19, pulmonary embolism, alveolar hemorrhage, and vasculitis were observed. Pulmonary thrombotic microangiopathy was another common finding.2 In another post-mortem study of 12 consecutive deaths due to COVID-19, deep vein thrombosis (DVT) was observed in seven patients. Pulmonary embolism was considered to be the direct cause of death in four of these patients. Diffuse alveolar damage was a common feature.3
There are several reports of arterial thrombosis in severe COVID-19. The incidence of thrombotic events in patients with severe COVID-19 was evaluated in a large cohort study.4 Among 3334 patients studied, a thrombotic event occurred in 553 (16%); 365 (11.1%) were arterial, including ischemic stroke, myocardial infarction, and systemic thromboembolism. Among important risk factors were increasing age, male gender, coronary artery disease, previous myocardial infarction, and high D-dimer levels. The all-cause mortality was significantly higher among patients who experienced thrombotic events. There are several other reports of ischemic stroke associated with COVID-19.5,6
These studies establish the high incidence of complications related to inflammation-triggered thrombogenesis among patients who die of COVID-19. The anticoagulation strategy appears to be highly variable in clinical practice, ranging from a standard thromboprophylaxis dose to full therapeutic anticoagulation; however, the optimal anticoagulation strategy remains unclear.7 Several recent clinical studies have attempted to identify the optimal dose of anticoagulation in hospitalized patients with COVID-19.
Enhanced thromboprophylaxis: do we have evidence?
Helms et al. observed 64 clinically important thrombotic complications among a cohort of 150 patients from four ICUs in France. The most commonly observed complication was pulmonary embolism (16.7%). Thrombotic complications occurred in these patients in spite of DVT prophylaxis or a therapeutic anticoagulation dose. The authors suggested a higher than usual thromboprophylaxis dose in COVID-19 patients.5 Considering the high incidence of thrombotic complications, several expert panels recommended a higher than usual dose of thromboprophylaxis among patients with severe COVID-19.8 Enhanced thromboprophylaxis that may be considered among critically ill COVID-19 patients include therapeutic or intermediate-dose anticoagulation.
A multi-centric, retrospective cohort study from 28 European ICUs evaluated the use of enhanced anticoagulation strategies and assessed its impact on ICU mortality and the incidence of hemorrhagic complications.9 Among 852 patients studied, enhanced thromboprophylaxis, based on local protocols, was administered in 274 (32.2%) patients. The majority of these patients received enoxaparin 40-80 mg twice daily. Thromboembolic occurred in 146 (17.1%) patients, including 78 (9.2%) with pulmonary embolism. A propensity score analysis was performed with each patient who received enhanced thromboprophylaxis matched with a control. The use of enhanced thromboprophylaxis was associated with significantly lower ICU mortality. Enhanced thromboprophylaxis did not result in a higher incidence of hemorrhagic complications, including “critical” hemorrhage.
Randomized controlled trials
In a randomized controlled trial from Iran, intermediate vs. standard DVT prophylaxis dose was compared among adult ICU patients admitted with COVID-19.10 Enoxaparin 40 mg daily was administered as the standard DVT prophylaxis dose and compared with an intermediate dose of 1mg/kg/d. The primary outcome was a composite of arterial or venous thrombosis, requirement for extracorporeal membrane oxygenation or the 30-d all-cause mortality. There was no significant difference in the primary outcome between the standard and intermediate-dose arms; [126/286 (44.1%) vs. 126/276 (4.7%), odds ratio: 1.06, CI: 0.76–1.48; p = 0.7]. Besides, there was no significant difference in the 30-d call-cause mortality, incidence of venous thrombosis, and ventilator-free days between the two groups. Major bleeding events were uncommon but numerically higher in the intermediate dose group. Severe thrombocytopenia was observed only in patients who received an intermediate dose (2.2%). This study points to the relative lack of efficacy of an intermediate compared to a standard dose of anticoagulation in preventing thrombotic complications among critically ill patients with COVID-19.
Three multinational adaptive platform trials (REMAP-CAP, ACTIV-4a, and ATTACC) combined to a single multiplatform randomized controlled trial to evaluate the efficacy of therapeutic anticoagulation compared with standard-dose thromboprophylaxis in adult patients hospitalized with COVID-19.11 The study population was stratified a prioriinto critically ill patients requiring organ support in the ICU, and moderately ill patients, who were hospitalized but did not require ICU level of care initially.
Severe COVID-19 was defined as the requirement for respiratory or cardiovascular support in the ICU, including the use of high-flow nasal cannula at more than 20 l/min, invasive or non-invasive ventilation, vasopressors, inotropes, or extracorporeal support. Patients were admitted to the ICU for a maximum duration of 72 hours. The choice of therapeutic anticoagulation and standard thromboprophylaxis regime was according to local protocol. At the time of interim analysis, the organ support-free days was comparable between groups; the median organ support-free days was 3 days (IQR: –1,16) in the therapeutic anticoagulation groups vs. 5 days (IQR: -1,16) in the standard thromboprophylaxis group (a score of –1 was assigned to hospital mortality). Enrolment was ceased at this stage as the pre-defined criteria for futility based on posterior probability was met. This study suggested an 89% probability of therapeutic anticoagulation being inferior to standard pharmacological thromboprophylaxis. Major thrombotic events were non-significantly lower with therapeutic anticoagulation; however, the secondary efficacy outcome of major thrombotic events or mortality was similar between the two groups. Major bleeding events were not significantly different between groups. This multiplatform randomized controlled trial does not support the routine use of therapeutic anticoagulation in patients with severe COVID-19 admitted to the ICU, requiring respiratory or cardiovascular support.
In the same study, contrasting results were observed in moderately ill patients who did not initially require organ support or ICU level of care. After enrolment of 1772 patients, an interim analysis revealed that therapeutic anticoagulation resulted in an increase in the number of organ support-free days regardless of D-dimer levels. The incidence of major bleeding was less than 2% with therapeutic anticoagulation; a “positive effect” was also noted in morbidity and mortality. These results are not peer-reviewed and in the pre-publication stage.12
- A prothrombotic state triggered by an acute inflammatory response is seen in severe COVID-19. Endothelial dysfunction and microthrombi formation occur in the lungs.
- Venous and arterial thrombosis may occur; there are several reports of stroke, acute myocardial infarction, and limb ischemia in severe COVID-19.
- Considering the relatively high incidence of thrombotic complications, the efficacy of enhanced anticoagulant dosing has evoked interest. Intermediate and therapeutic dose anticoagulation is variably used by clinicians.
- Observational studies with enhanced dose thromboprophylaxis have revealed conflicting results; two randomized controlled studies suggest a lack of benefit from the routine use of an intermediate or therapeutic dose of anticoagulation in patients admitted to the ICU with severe COVID-19.
- The question of whether commencement of enhanced anticoagulation at an earlier stage of disease may prevent organ dysfunction and improve outcomes remains unanswered and needs further evaluation.
- If acute worsening occurs with a high clinical suspicion of a thrombotic event, but cannot be proven, empirical therapeutic anticoagulation may need to be considered.
1. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-128. doi:10.1056/NEJMoa2015432
2. Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology. 2020;77(2):198-209. doi:10.1111/his.14134
3. 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. 2020;173(4):268-277. doi:10.7326/M20-2003
4. Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System. JAMA. 2020;324(8):799-801. doi:10.1001/jama.2020.13372
5. 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. 2020;46(6):1089-1098. doi:10.1007/s00134-020-06062-x
6. 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;191:145-147. doi:10.1016/j.thromres.2020.04.013
7. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. doi:10.1111/jth.14817
8. 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. Journal of Thrombosis and Haemostasis. 2020;18(8):1859-1865. doi:https://doi.org/10.1111/jth.14929
9. Lavinio A. Safety profile of enhanced thromboprophylaxis strategies for critically ill COVID-19 patients during the first wave of the pandemic: observational report from 28 European intensive care units. Published online 2021:10.
10. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.JAMA. Published online March 18, 2021. doi:10.1001/jama.2021.4152
11. Zarychanski R. Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report. medRxiv. Published online January 1, 2021:2021.03.10.21252749. doi:10.1101/2021.03.10.21252749
12. Al-Samkari H. Finding the Optimal Thromboprophylaxis Dose in Patients With COVID-19. JAMA. 2021;325(16):1613-1615. doi:10.1001/jama.2021.4295