The lung pathology seen in patients with coronavirus disease 2019 (COVID-19) shows marked microvascular thrombosis and haemorrhage linked to extensive alveolar and interstitial inflammation that shares features with macrophage activation syndrome (MAS). We have termed the lung-restricted vascular immunopathology associated with COVID-19 as diffuse pulmonary intravascular coagulopathy, which in its early stages is distinct from disseminated intravascular coagulation. Increased circulating D-dimer concentrations (reflecting pulmonary vascular bed thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations (reflecting emergent ventricular stress induced by pulmonary hypertension) in the face of normal fibrinogen and platelet levels are key early features of severe pulmonary intravascular coagulopathy related to COVID-19. Extensive immunothrombosis over a wide pulmonary vascular territory without confirmation of COVID-19 viraemia in early disease best explains the adverse impact of male sex, hypertension, obesity, and diabetes on the prognosis of patients with COVID-19. The immune mechanism underlying diffuse alveolar and pulmonary interstitial inflammation in COVID-19 involves a MAS-like state that triggers extensive immunothrombosis, which might unmask subclinical cardiovascular disease and is distinct from the MAS and disseminated intravascular coagulation that is more familiar to rheumatologists.
The severity of systemic inflammation in response to human coronavirus family members has features reminiscent of a cytokine storm or macrophage activation syndrome (MAS), also known as secondary haemophagocytic lymphohistocytosis (sHLH).
A key feature of sHLH or MAS is haemophagocytosis and an acute consumptive coagulopathy, leading to disseminated intravascular coagulation. Disseminated intravascular coagulation has also been reported in COVID-19 pneumonia, but usually as a pre-terminal event.
In SARS, this process might involve phagocytosis of extravascular red blood cells consequent to severe lung microvascular damage, microhaemorrhage with physiological haemophagocytosis of extravascular red blood cells, or possibly very advanced disease with frank MAS-like pathology and disseminated intravascular coagulation (figure 1). The hypercytokinaemia characteristic of sHLH or MAS is often associated with extremely high serum ferritin concentrations (≥10 000–100 000 ng/mL), whereas in patients with COVID-19, serum ferritin concentrations are typically in the 500–3000 ng/mL range, at least early in the disease course. Another clear distinguishing feature of sHLH or MAS is liver function derangement, which can contribute to coagulopathy secondary to loss of liver synthetic function and is not typically seen in patients with COVID-19 (figure 1).
Extensive lung infiltration by macrophages and other immune cells leading to diffuse alveolar damage has been reported in SARS pneumonia, with similar findings emerging in patients with COVID-19 pneumonia.
The extensive nature of viral infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in diffuse lung inflammation that involves the large juxtaposed pulmonary vascular network.
The diffuse, slowly evolving COVID-19 pneumonia has similarities to a MAS-like syndrome with regard to both clinical and laboratory features. These clinical findings suggest that an initial pulmonary intravascular coagulopathy occurs in patients with COVID-19 pneumonia that is distinct from disseminated intravascular coagulation.
Herein, we propose a model for the pathophysiology of this pulmonary intravascular coagulopathy and describe how extensive coronavirus infection and age-related changes in immunity, combined with diffuse pulmonary immunothrombosis, explain the cardiovascular mortality in these patients (table 1).
Table 1Differences and similarities between DIC and PIC
DIC linked to HLH or MAS
PIC linked to COVID-19
Pulmonary involvement (%)
Mainly lung (occasional CNS and peripheral thrombosis reported; related to DIC evolution?)
Active infection considerations
Yes usually for primary HLH; secondary HLH might not have driving infection
Thought to be ongoing alveolar infection
Decreased synthetic function including fibrinogen and other clotting factors; raised transaminase +++
Preservation of liver synthetic function; +/−
Normal or low
Immune cell cytopenia
No but lymphopenia is a feature of COVID-19 in general
+ (skeletal and cardiac origin)
+ (worse prognosis)
++ with high levels associated with worse outcome
Generalised to marrow, liver, and other sites detectable in >80%
Occasional intrapulmonary and regional lymph node haemophagocytosis reported
DIC secondary to MAS
PIC might evolve into DIC; PIC might occur without MAS
Coagulation and immunology markers
Elevated prothrombin time or activated partial thromboplastin time
+ or normal
Normal or slight increase
Fibrin degradation products or D-dimer
Present (+), usually present (++), frequently present (+++), or absent (−) clinical features, laboratory parameters, and coagulation and immunology markers. DIC=disseminated intravascular coagulation. HLH=haemophagocytic lymphohistiocytosis. MAS=macrophage activation syndrome. PIC=pulmonary intravascular coagulopathy. COVID-19=coronavirus disease 2019.
Pulmonary vascular pathology patterns in SARS and COVID-19
Acute respiratory infections are associated with a high risk of cardiovascular-related death, especially in the weeks immediately after infection, and particularly in older patients and those with pre-existing cardiovascular disease. Severity of pneumonia in these patients is linked to an increased risk of death.
indicating that vascular thrombosis triggered by infection, rather than the infection itself, could be key (figure 2).
Coronavirus family members show tropism for angiotensin-converting enzyme 2 (ACE2) on type II pneumocytes. This tropism, along with the close anatomical juxtaposition of type II pneumocytes and the pulmonary vascular network, and a severe multifaceted inflammatory reaction, is likely to drive the generalised pulmonary hypercoagulable state seen in patients with COVID-19 (figure 2).
Single-cell sequencing analysis has recently shown that most pulmonary gene expression is confined to a small population of type II pneumocytes, and ACE2 is largely absent from endothelial cells and alveolar macrophages.
From a clinical perspective, the diffuse alveolar changes (determined by CT scan) seen in patients with COVID-19 are distinct from bronchopneumonia and show how SARS-CoV-2 interfaces with a large area of the pulmonary microvasculature. This finding probably explains the propensity for diffuse pathology in patients with COVID-19 pneumonia. In these patients, extensive air space changes on CT are associated with a worse prognosis compared with patients not showing these changes.
These findings suggest that ACE2 downregulation could aggravate inflammation over a wide alveolar capillary network. It was subsequently shown that injecting the SARS spike protein led to similar lung pathology in mice, probably due to internalisation of the ACE2 receptor and subsequent inhibition of ACE2-mediated generation of the immunoregulatory angiotensin (1–7) peptide, which signals via the MAS1 receptor.
Theoretically, a similar mechanism could increase the proclivity towards immunothrombosis in humans. In humans, the Middle East respiratory syndrome coronavirus (MERS-CoV) principally uses the dipeptidyl peptidase 4 (DPP4) receptor, which is not restricted to type II pneumocytes; nonetheless, this virus results in clinical features and pathology similar to SARS-CoV and SARS-CoV-2, including a high mortality rate.
Analogous to ACE2, in some experimental systems the DPP4 receptor might negatively regulate lymphocyte function, which could indicate a shared coronavirus-specific mechanism that contributes to pulmonary intravascular coagulopathy (panel).
Initial post-mortem reports from three patients with SARS indicated not only diffuse alveolar damage and small pulmonary vessel thrombosis and haemorrhage, but also a more generalised small vessel thrombosis.
A study of pathological specimens from 20 patients with SARS showed the presence of not only diffuse alveolar damage, but also fibrin thrombi, small vessel occlusion, and pulmonary infarction in upwards of 80% of cases.
A review of aggregated SARS pathology reports showed evidence for vessel wall oedema, inflammatory cell infiltration into the walls of the pulmonary microvasculature, marked haemorrhagic necrosis, and vessel microthrombi mostly confined to the lung and pulmonary tissue infarction, in the context of septal inflammation and diffuse alveolar damage.
Some data have emerged from patients with COVID-19 pneumonia that show a similar pulmonary vascular picture with blood vessel wall oedema, modest vessel wall immune cell infiltration, hyaline thrombosis, haemorrhagic change, and infarction.
Insufficient evidence for coronavirus myocarditis or coronary vasculitis
Myocarditis might occur after severe respiratory viral pneumonia. Although this outcome is relatively rare, it is well documented, especially in younger women following influenza infection (table 2). Understandably, increased cardiac enzymes in patients with COVID-19 has been taken to potentially represent myocarditis or cardiac vasculitis associated with viral infection. In SARS-CoV infection, however, most evidence points away from cardiac involvement.
Cardiac injury in >60% with avian influenza H7N9 infection suggesting that cardiac disease linked to infection; also linked to history of cardiovascular disease, but not male sex or diabetes (myocarditis is well documented with influenza)
A role for the ACE2 receptor in cardiovascular biology predates the link between pulmonary pathology and COVID-19 pneumonia. Genetic deletion of ACE2 in rodents was associated with ventricular contractility defects, but there was no evidence of cardiomyopathy or fibrosis.
The link between ACE2 downregulation in lung tissue (either in genetically manipulated mice or mice treated with SARS spike protein) and increased inflammation suggests a relatively simple model, in which coronavirus infection of ACE2-expressing cardiomyocytes or cardiac endothelium might trigger a similar inflammatory pathology. In the most comprehensive study of cardiac involvement in patients who died from SARS, viral RNA was detectable in a third of post-mortem cardiac tissues and was associated with both decreased ACE2 expression and increased macrophage infiltration.
Overall autopsy reports, including those emerging in COVID-19, vary from showing no clinically significant pathology or infiltrating macrophages, and some reports of occasional infiltrating CD4 T cells.
The cardiac pathology in COVID-19 pneumonia needs evaluation in view of known cardiovascular comorbidities, including hypertension and pulmonary intravascular coagulopathy, as well as the MAS-like state with associated hypoxaemia and secondary pulmonary artery hypertension. The hypercytokinaemia that is part of the MAS-like state could modify ACE2 expression independently of viraemia. One key cytokine characteristic of MAS-like pathology, interferon-γ, has been shown to downregulate ACE2 expression on an epithelial cell line; however, this finding has not been reported for heart cells.
Therefore, reported changes in the heart tissue, including endothelium, could represent a cytokine and hypoxia effect rather than direct viral infection.
Laboratory data indicate early pulmonary intravascular coagulopathy
The key early laboratory observations in patients with COVID-19 pneumonia include elevated plasma D-dimer concentrations in conjunction with elevated cardiac markers, including brain natriuretic peptide, creatine kinase, and troponin T.
reported that 117 (68%) of 172 patients presenting with COVID-19 had increased activation of coagulation, as indicated by elevated D-dimer concentrations at presentation (>0·5 ug/mL). Importantly, D-dimer concentrations above 1 μg/mL were associated with an 18 times increased odds ratio for fatal outcome.
However, despite this increase in D-dimers, patients with COVID-19 do not typically develop overt systemic disseminated intravascular coagulation. In rare cases of COVID-19 in which overt disseminated intravascular coagulation does develop, it tends to be restricted to late-stage disease. This finding is reflected in the consistent observation that platelet counts and fibrinogen concentration are not substantially reduced in patients with COVID-19, despite marked increases in D-dimer concentrations.
Fibrinogen generally remains elevated in these patients, consistent with an ongoing acute phase response.
Extensive pulmonary inflammation and thrombosis in COVID-19 pathology
Severe COVID-19 sepsis is associated with a marked MAS-type picture, and increased inflammatory markers and ferritin concentrations that undoubtedly result in local activation of pulmonary vasculature endothelial cells. For example, interleukin (IL)-1, IL-6, and tumor necrosis factor have all been shown to trigger acute endothelial cell activation.
Given the crucial roles played by endothelial cells in maintaining normal haemostasis, regulating fibrinolysis, and determining vessel wall permeability, local endothelial cell dysfunction in the pulmonary microvasculature is likely to play an important role in the thromboinflammatory processes that ultimately result in COVID-19 vasculopathy, ventilation perfusion mismatch, and a clinical phenotype of refractory ARDS.
Additionally, the MAS-like picture associated with COVID-19 pneumonia will trigger expression of active tissue factor, both on endothelial cells and on activated infiltrating macrophages and neutrophils.
The net effect will be local presentation of blood-borne tissue factor within the lungs, which will further amplify activation of the coagulation cascade. Importantly, endothelial cell disruption, tissue factor expression, and activation of the coagulation cascade will all be progressively exacerbated by development of local hypoxia,
establishing a deleterious positive thromboinflammatory feedback loop within the small vessels of the lungs with thrombosis and haemorrhage (figure 3). Beyond the coagulopathic changes occurring within the pulmonary vasculature, a study of bronchoalveolar lavage showed that both severe pneumonia and ARDS are associated with enhanced thrombin generation and fibrin deposition within the bronchoalveolar system.
The biological mechanisms responsible for the extremely elevated plasma D-dimer concentrations in patients with severe COVID-19, together with the marked variations observed between individuals, are unclear. Nonetheless, these data clearly suggest hyperactive fibrinolysis with increased plasmin generation. Collectively, these findings have led to the suggestion that elevated plasmin (and plasminogen) concentrations might represent a risk factor for COVID-19 susceptibility.
Other factors, including mechanical ventilation in patients progressing to ARDS, might contribute to this picture. The role of vascular microthrombi formation, or immunothrombosis, in containment of bacterial infection and spread is well established, but its role in viral infection is not so well known.
The role of positive pressure ventilation as a factor driving release of viral nucleic acids and proteins across damaged alveolar endothelial cell barriers is another factor that needs consideration as a potential iatrogenic contributor to immunothrombosis and poor outcomes.
Experimental SARS models have shown that normal aged primates have a similar degree of viral replication as younger primates, but that aged primates have more pulmonary damage and lower activation of type 1 interferon responsive gene pathways.
At the molecular level, aged primates showed exacerbated innate immune responses associated with NF-kB pathway activation, such as elevated IL-8 and expression of tissue factor, which activates the extrinsic clotting pathway protein.
Viral or age-related impairment in type 1 interferon production appears to be associated with a second wave of inflammatory cytokine production and tissue factor expression that might substantially contribute to pulmonary intravascular coagulopathy.
Implications of pulmonary intravascular coagulopathy
The role of anticoagulation in the setting of COVID-19 pulmonary intravascular coagulopathy is of considerable interest. Expert recommendations for the use of anticoagulants have already been published, reflecting the recognition of clotting dysregulation.
However, some data are available, mostly derived from prospective cohort studies. In a study of nearly 450 patients with COVID-19, low molecular weight heparin (mostly used in prophylactic doses rather than therapeutic doses) did not confer an overall survival advantage.
However, the regimen was associated with improved survival in the group with a high sepsis-induced coagulopathy score and in patients with D-dimer concentrations that were more than six times the upper limit of normal.
The role and timing of anticoagulation in this extensive virus-related immunothrombosis, especially where pulmonary haemorrhaging occurs, needs careful consideration. In disseminated intravascular coagulation, thrombosis and bleeding might occur simultaneously, and the same scenario also appears to arise in pulmonary intravascular coagulopathy (figure 3).
Given the MAS-like pathology of COVID-19 pneumonia, the question arises whether anticytokine therapy will ameliorate the diffuse immunothrombosis process associated with severe cases. In the translational setting, the use of the IL-1β blocker canakinumab is associated with a decreased risk of all-cause cardiovascular mortality,
Unlike in low grade arterial inflammation in the absence of overt infection, it is still unclear whether severe COVID-19-associated MAS with pulmonary intravascular coagulopathy will be successfully targeted with these strategies; ongoing viral infection might represent a major hurdle in this context.
The most crucial question for optimal therapeutic strategies is whether the emergent early activation of coagulopathy and fibrinolysis in patients with COVID-19 pneumonia is purely due to an appropriate immune response to the virus, or whether there is a degree of excessive inflammation that could be targeted to help prevent progression of pulmonary intravascular coagulopathy. The potential survival advantage of drugs pioneered to treat inflammatory and hyperinflammatory states needs to be viewed from the perspective of severe diffuse pulmonary immunothrombosis. The combination of immunomodulatory and anticoagulant strategies in patients with high D-dimer concentrations and evidence of myocardial stress warrants especially close attention. The use of Janus kinase (JAK) pathway inhibition needs careful scrutiny given the association between JAK inhibitors and thromboembolic disease.
Some bleeding complications outside of the lung have been described in patients with COVID-19; this response is perhaps unsurprising in the few cases of pulmonary intravascular coagulopathy that progress to systemic disseminated intravascular coagulation. Reports of acute necrotising encephalopathy, which is associated with haemorrhage, are also emerging.
Given that ACE2 is expressed on endothelial cells, the notion of thrombosis outside either pulmonary or disseminated intravascular coagulopathy needs further consideration.
This pulmonary intravascular coagulopathy model has implications for understanding cardiovascular mortality in the COVID-19 pandemic. This model shifts the focus away from COVID-19-related myocarditis or coronary vascular involvement, with cardiac injury secondary to viral infection of myocytes or endothelial cells expressing ACE2, and towards a scenario of multisite pulmonary vascular thrombosis with progressive myocardial ischaemia. The immunothrombotic pathology that evolves over several days in some patients with COVID-19 pneumonia is likely to manifest in individuals with underlying cardiovascular risk factors such as obesity, hypertension, and type 2 diabetes, and pathology will be compounded by the cardiac ischaemia that accompanies development of ARDS. Cardiovascular mortality is higher in men than in women aged 30–64 years in many different populations.
The COVID-19 pandemic, characterised by profound immunological changes that constitute a pulmonary MAS-like picture, is revealing a large burden of subclinical cardiovascular disease among patients predisposed to disease, by slowly triggering an extensive pulmonary immunothrombosis. Our model offers a different and robust alternative to the proposed effects of medications on ACE2 expression with resulting increased viral infectivity.
It is also important to determine the degree to which COVID-19-mediated diffuse alveolar damage with development of ARDS in the absence of coagulopathy might also contribute to outcomes, because emerging post-mortem reports do not report this pathology in all cases.
Diffuse pulmonary intravascular coagulopathy is not unique to the MAS-like pattern of inflammation. Diffuse alveolar infection, activation of innate immune mechanisms, dysregulation of ACE2 protein expression, and marked adaptive antiviral immune responses could contribute to extensive pulmonary immunothrombosis without a clinically evident MAS (panel). Will this translate into differential effectiveness, if any, of immunosuppressive therapy between the MAS-like subgroup of patients and individuals without MAS? Ultimately, the tropism of COVID-19 for type II pneumocytes, along with evidence for extensive microvascular thrombosis during a global pandemic in patients without natural immunity, suggests an explanation for the increased cardiovascular mortality that has been recognised for some time in other settings of respiratory infection. We believe that this pulmonary intravascular coagulopathy, or pulmonary immunovascular coagulopathy, is the best explanation for the COVID-19 pneumonia risk factors for poor survival (eg, cardiovascular disease) in the present scenario, in which little evidence exists for systemic viraemia early in the COVID-19 disease course.