During the ICTHIC webinar “Clinical insights in CAT to include COVID‐19“, Dr. Vincent Labbé gave a talk on COVID-19 and microvascular thrombosis/inflammation effects. Here, we report the highlights of his presentation.
You can find Dr. Labbé’s presentation and the full webinar here.
SARS-CoV-2 and endotheliitis
SARS-CoV-2 infects the host using the angiotensin-converting enzyme 2 (ACE2) receptor, expressed in several organs, including the lungs, heart, kidneys, and intestines. In addition, ACE2 receptors are expressed by endothelial cells .
A study based on post-mortem analyses of a series of patients with COVID-19 demonstrated the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death .
The electron microscopy analysis of a transplanted kidney revealed viral inclusion structures in endothelial cells. In addition, the histological analyses showed an accumulation of inflammatory cells associated with endothelium and apoptotic bodies in the heart, the small bowel, and the lung. In addition, an accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested .
These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with the presence of viral bodies) and the host inflammatory response . In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19 .
SARS-CoV-2 and ACE2
In a healthy condition, ACE2 converts angiotensin II to angiotensin 1–7, which stimulates endothelial cells to produce nitric oxide (NO). NO helps the vessels to vasodilate and suppresses platelet aggregation. In COVID-19, SARS-CoV-2 occupies ACE2, and the angiotensin II level increases, which results in vasoconstriction and decreased blood flow. Von Willebrand factor stored in the Weibel Palade body is released into the circulation, promoting clot formation .
At least two separate pathologic coagulation processes appear to be important in producing clinical manifestations in critically ill COVID-19 patients :
- A local direct vascular and endothelial injury in the microcirculation of the lung and potentially other organs, producing microvascular clot formation and angiopathy ;
- Large vessel thrombosis and major thromboembolic in the systemic circulation, due to hypercoagulability with hyperfibrinogenemia .
COVID-19 vs influenza
A recent study examined the morphologic and molecular features of lungs obtained during autopsy from patients who died from COVID-19 compared with those from patients who died from influenza and age-matched, uninfected control lungs .
Patients who died from COVID-19-associated or influenza-associated respiratory failure shared a common morphologic pattern of diffuse alveolar damage with perivascular T-cell infiltration .
But the lungs from patients with COVID-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes .
Histologic analysis of pulmonary vessels in patients with COVID-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were nine times as prevalent in patients with COVID-19 as in patients with influenza (p<0.001). In addition, in lungs from patients with COVID-19, the amount of new vessel growth (predominantly through a mechanism of intussusceptive angiogenesis) was 2.7-times as high as that in the lungs from patients with influenza (p<0.001) .
As mentioned above, in the systemic circulation, due to hypercoagulability with hyperfibrinogenemia, there is also the potential for large vessel thrombosis, and major thromboembolic sequelae, including pulmonary embolism, reported in 20–30% of intensive care unit (ICU) patients .
Recently, several institutions have released guidance statements to prevent microvascular and macrovascular thrombotic events with dose-escalating anticoagulation, including low-dose prophylactic, high-dose prophylactic, and therapeutic anticoagulation [6-8]. However, no randomized trials have validated this approach.
Low-dose prophylactic, high-dose prophylactic, and therapeutic anticoagulation
Early in the COVID-19 pandemic, the lead investigators of three international adaptive platform trials harmonized their protocol to study the effect of therapeutic dose anticoagulation in patients hospitalized for COVID-19. The result was one integrated, multiplatform, randomized clinical trial aimed to accelerate the generation of evidence and maximize the external validity of the results .
The open-label, adaptive, multiplatform, controlled trial enrolled patients hospitalized with COVID-19 . The investigators hypothesized that the benefits and risks of therapeutic-dose anticoagulation would vary according to disease severity. As such, the design prospectively stratified patients according to whether they had severe disease (ICU-level care or critically ill) or moderate disease (hospitalized but noncritically ill) at enrollment .
Thromboprophylaxis in patients with severe COVID-19
A report shows the results of analyses involving patients with severe COVID-19 .
Critically ill patients were defined as patients with COVID-19 that led to the receipt of ICU-level respiratory or cardiovascular organ support (oxygen through a high-flow nasal cannula, noninvasive or invasive mechanical ventilation, extracorporeal life support, vasopressors, or inotropes) in an ICU .
Patients were randomly assigned to receive therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin or to receive usual-care pharmacologic thromboprophylaxis in an open-label fashion .
Therapeutic-dose anticoagulation was administered according to local site protocols to treat acute venous thromboembolism for up to 14 days or until recovery (defined as either hospital discharge or discontinuation of supplemental oxygen for at least 24 hours). According to local practice, usual-care thromboprophylaxis was administered at a dose and duration determined by the treating clinician, including either standard low-dose thromboprophylaxis or enhanced intermediate-dose thromboprophylaxis .
The primary outcome, organ support-free days, was evaluated on an ordinal scale indicating the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived hospital discharge; patients who died in the hospital by day 90 were assigned a value of -1 .
Prespecified secondary outcomes included survival to hospital discharge, major thrombotic events or death (a composite of myocardial infarction, pulmonary embolism, ischemic stroke, systemic arterial embolism, or in-hospital death), and any thrombotic events (major thrombotic events or deep vein thrombosis) or death .
Safety outcomes included major bleeding during the treatment period, as defined by the International Society of Thrombosis and Hemostasis for nonsurgical patients , and laboratory-confirmed heparin-induced thrombocytopenia.
The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation .
The therapeutic dose anticoagulation did not increase the probability of survival to hospital discharge or the number of days free of cardiovascular or respiratory organ support. It also had a 95% probability of being inferior to usual care pharmacologic thromboprophylaxis .
There was an 89% probability that therapeutic-dose anticoagulation led to a lower probability of survival to hospital discharge than usual-care thromboprophylaxis. Bleeding complications were infrequent in both intervention groups. These results refute the hypothesis that routine therapeutic dose anticoagulation benefits critically ill patients with COVID-19 .
In summary, in critically ill patients with COVID-19, an initial strategy of therapeutic dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis .
Thromboprophylaxis in patients with moderate COVID-19
A second report describes the results of the analyses involving patients with moderate COVID-19 .
Moderate disease severity was defined as hospitalization for COVID-19 without the need for ICU-level care. Patients admitted to an ICU, but without receiving qualifying, organ support was considered moderately ill .
Patients were randomly assigned to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis .
The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived hospital discharge .
This outcome was evaluated using a Bayesian statistical model for all patients and according to the baseline D-dimer level .
In noncritically ill patients hospitalized with COVID-19, therapeutic dose anticoagulation with heparin (most commonly, low-molecular-weight heparin) increased the probability of survival until hospital discharge with a reduced need for ICU-level organ support at 21 days compared with usual-care thromboprophylaxis .
Therapeutic-dose anticoagulation was beneficial regardless of the patient’s baseline D-dimer level. Major bleeding occurred more frequently in the anticoagulation group (1.9% vs 0.9%) .
Based on these findings, for every 1,000 hospitalized patients with moderate disease, an initial strategy of therapeutic dose anticoagulation, compared with usual-care thromboprophylaxis, would be anticipated to result in the survival of 40 additional patients until hospital discharge without organ support at the expense of seven additional major bleeding events .
Absolute treatment benefits were more apparent in the high D-dimer cohort than in the low D-dimer cohort .
Thromboprophylaxis in unselected patients with COVID-19 admitted to the ICU
Another study evaluated the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the ICU .
The primary efficacy outcome was a composite of adjudicated acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality within 30 days of enrollment .
The prespecified safety outcomes included major bleeding and severe thrombocytopenia (platelet count <20 × 103/µL). Clinically relevant nonmajor bleeding was defined as clinically significant bleeding that warranted attention from medical personnel but did not fulfill the criteria for major bleeding. Mild thrombocytopenia (platelet count <100 × 103/µL) and moderate thrombocytopenia (platelet count <50 × 103/µL) were also assessed as post hoc safety outcomes .
In this multicenter randomized clinical trial of patients with COVID-19 admitted to the ICU, intermediate-dose compared with standard-dose prophylactic anticoagulation did not improve the primary composite efficacy outcome or its major components, including all-cause mortality and venous thromboembolism (VTE) .
The results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19.
Although bleeding events were rare, both major and clinically relevant nonmajor, bleeding events were nonsignificantly more frequent with intermediate-dose anticoagulation, and noninferiority for major bleeding was not demonstrated. Furthermore, severe thrombocytopenia was observed only in patients assigned to receive intermediate-dose prophylactic anticoagulation .
In critically ill COVID-19 patients, at least two separate pathologic coagulation processes appear to be important in producing clinical manifestations:
- A local direct vascular and endothelial injury in the microcirculation of the lung and potentially other organs, producing microvascular clot formation and angiopathy;
- Large vessel thrombosis and major thromboembolic in the systemic circulation, due to hypercoagulability with hyperfibrinogenemia.
In critically ill patients with COVID-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis.
In noncritically ill patients hospitalized with COVID-19, therapeutic-dose anticoagulation with heparin increased the probability of survival until hospital discharge with a reduced need for ICU-level organ support at 21 days compared with usual-care thromboprophylaxis.
Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days.
- Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605-2610.
- Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-1418.
- Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care. 2020;24(1):360.
- Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med. 2020;48(9):1358-1364.
- 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.
- REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, et al. therapeutic anticoagulation with heparin in critically ill patients with COVID-19. N Engl J Med. 2021;385(9):777-789.
- ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, et al. therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med. 2021;385(9):790-802.
- Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in nonsurgical patients. J Thromb Haemost. 2005;3(4):692-694.
- 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. 2021;325(16):1620-1630.