Over the past few months, overwhelming evidence has accumulated suggesting the dysregulation of the coagulation pathways in COVID patients stemming from the altered immune and inflammatory response towards SARS-CoV2.
Observed coagulation abnormalities have multi-faceted pathogenesis. The most likely suspect is microvascular dysfunction secondary to cytokine storm-like state, tipping the balance towards thrombosis. Direct vascular injury is also likely with evidence of endothelial viral inclusions in some cases.
-Pulmonary Intravascular Thrombosis
Evidence suggests that starking discrepancy exists between hypoxemia onset and respiratory failure in COVID patients, with the former occurring fairly early in the disease course, pointing to the fact that it's not classic ARDS-like pathology that is responsible for the marked deterioration in the pulmonary gas exchange process. It is appropriately explained by the diffuse thrombosis affecting the pulmonary vasculature. In fact, it's so prominent that a whole new entity called "Pulmonary Intravascular Thrombosis" has been proposed as the framework for explaining this phenomenon.
Pulmonary Intravascular Thrombosis could be considered as lying along the spectrum of classic DIC with few important dissimilarities. It is usually localized to the pulmonary vascular bed at least initially and doesn't feature hypofibrinogenemia, consistent with the acute phase response driving continued fibrinogen production. D-dimers levels, however, are significantly elevated suggesting thrombus formation and ongoing hyperfibrinolysis.
-Pathogenesis
ACE2 is expressed in huge numbers on the alveolar epithelial cells, especially type 2 cells and also pulmonary endothelial cells. Hence, in contrast to patchy involvement classically seen in bronchopneumonia, in COVID, extensive involvement of the alveolo-capillary network is seen. This, in turn, results in florid interstitial inflammation resulting in efflux and activation of macrophages in the alveoli. It is so rampant that it has been likened to Macrophage Activation Syndrome (MAS) or sHLH like state. Activated epithelial cells and macrophages then orchestrate the cytokine storm leading to microvascular dysfunction and widespread thrombosis in the juxtaposed capillary network. Enhanced tissue factor and thrombin expression, coupled simultaneously with the reduced levels of PAI-1 drives thrombosis. Hypoxemia due to V/Q mismatch further exacerbates this process.
Levels of ACE2 in alveoli initially decrease as the virus particles are internalized. ACE2, by virtue of its ability to convert AngII to anti-inflammatory Ang1-7 peptide, keeps excessive inflammation in check. Hence, reduced ACE2 expression compounds the thrombotic propensity in the vascular bed. Direct involvement of endothelial cells by virus leading to endothelitis/vasculitis has also been suggested, although endothelial activation due to inflammatory cytokines seems more likely.
Reduced type 1 interferon signaling pathways are another intriguing possibility contributing to hyperinflammation. The role of positive pressure ventilation in forcing the viral particles and cytokines in vasculature also merits consideration.
- Skin manifestations
A variety of skin manifestations ranging from pseudo-chilblains to livedoid lesions have been described in COVID patients. While some of the lesions, like acral vesicles and pustules, confer to the pattern of viral exanthem, livedoid lesions suggest the possibility of vascular injury. These vasculopathy eruptions are known as "toevids", appearing as violaceous plaque-like eruptions over toes. Upon molecular testing, such patients often are negative, suggesting that they have probably cleared the infection and vascular injury is perhaps immune-mediated.
Interestingly, papular gloves and socks syndrome, occasionally seen in association with viral infections, especially Parvovirus, bears substantial similarity to certain COVID lesions, both clinically and histologically, with some reports even documenting evidence of leukocytoclastic vasculitis in the former.
-Clinical Relevance
Significant elevations in pulmonary pressures due to diffuse thrombosis strains the right ventricle causing hemodynamic dysfunction. Elevated D-dimer, pro- BNP, and troponin levels have been proven to be poor prognostic markers consistently across various studies. The development of an overt DIC-like state certainly portends a dismal prognosis.
Troponinemia in COVID can be attributed to severe right ventricular strain in the setting of pulmonary embolism and/or Pulmonary Intravascular Thrombosis. Some evidence also exists regarding the possibility of myocarditis, however, without classic lymphocytic infiltration characteristic of viral myocarditis.
To summarize, the intricate interplay of diffuse pulmonary intravascular thrombosis and MAS-like state drives the severe and often fatal pulmonary microvascular dysfunction in COVID.
SARS-CoV2 infection--> diffuse alveolar damage--> interstitial inflammation--> MAS like state--> massive activation of macrophages--> local inflammatory cytokine milieu--> Microvascular dysfunction--> Pulmonary Intravascular Thrombosis
-Kirtan Patolia
Reference:
1.) https://doi.org/10.1016/S2665-9913(20)30121-1
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30121-1/fulltext
2.) https://doi.org/10.1111/bjd.19163
https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.19163
Observed coagulation abnormalities have multi-faceted pathogenesis. The most likely suspect is microvascular dysfunction secondary to cytokine storm-like state, tipping the balance towards thrombosis. Direct vascular injury is also likely with evidence of endothelial viral inclusions in some cases.
-Pulmonary Intravascular Thrombosis
Evidence suggests that starking discrepancy exists between hypoxemia onset and respiratory failure in COVID patients, with the former occurring fairly early in the disease course, pointing to the fact that it's not classic ARDS-like pathology that is responsible for the marked deterioration in the pulmonary gas exchange process. It is appropriately explained by the diffuse thrombosis affecting the pulmonary vasculature. In fact, it's so prominent that a whole new entity called "Pulmonary Intravascular Thrombosis" has been proposed as the framework for explaining this phenomenon.
Pulmonary Intravascular Thrombosis could be considered as lying along the spectrum of classic DIC with few important dissimilarities. It is usually localized to the pulmonary vascular bed at least initially and doesn't feature hypofibrinogenemia, consistent with the acute phase response driving continued fibrinogen production. D-dimers levels, however, are significantly elevated suggesting thrombus formation and ongoing hyperfibrinolysis.
-Pathogenesis
ACE2 is expressed in huge numbers on the alveolar epithelial cells, especially type 2 cells and also pulmonary endothelial cells. Hence, in contrast to patchy involvement classically seen in bronchopneumonia, in COVID, extensive involvement of the alveolo-capillary network is seen. This, in turn, results in florid interstitial inflammation resulting in efflux and activation of macrophages in the alveoli. It is so rampant that it has been likened to Macrophage Activation Syndrome (MAS) or sHLH like state. Activated epithelial cells and macrophages then orchestrate the cytokine storm leading to microvascular dysfunction and widespread thrombosis in the juxtaposed capillary network. Enhanced tissue factor and thrombin expression, coupled simultaneously with the reduced levels of PAI-1 drives thrombosis. Hypoxemia due to V/Q mismatch further exacerbates this process.
Levels of ACE2 in alveoli initially decrease as the virus particles are internalized. ACE2, by virtue of its ability to convert AngII to anti-inflammatory Ang1-7 peptide, keeps excessive inflammation in check. Hence, reduced ACE2 expression compounds the thrombotic propensity in the vascular bed. Direct involvement of endothelial cells by virus leading to endothelitis/vasculitis has also been suggested, although endothelial activation due to inflammatory cytokines seems more likely.
Reduced type 1 interferon signaling pathways are another intriguing possibility contributing to hyperinflammation. The role of positive pressure ventilation in forcing the viral particles and cytokines in vasculature also merits consideration.
- Skin manifestations
A variety of skin manifestations ranging from pseudo-chilblains to livedoid lesions have been described in COVID patients. While some of the lesions, like acral vesicles and pustules, confer to the pattern of viral exanthem, livedoid lesions suggest the possibility of vascular injury. These vasculopathy eruptions are known as "toevids", appearing as violaceous plaque-like eruptions over toes. Upon molecular testing, such patients often are negative, suggesting that they have probably cleared the infection and vascular injury is perhaps immune-mediated.
Interestingly, papular gloves and socks syndrome, occasionally seen in association with viral infections, especially Parvovirus, bears substantial similarity to certain COVID lesions, both clinically and histologically, with some reports even documenting evidence of leukocytoclastic vasculitis in the former.
-Clinical Relevance
Significant elevations in pulmonary pressures due to diffuse thrombosis strains the right ventricle causing hemodynamic dysfunction. Elevated D-dimer, pro- BNP, and troponin levels have been proven to be poor prognostic markers consistently across various studies. The development of an overt DIC-like state certainly portends a dismal prognosis.
Troponinemia in COVID can be attributed to severe right ventricular strain in the setting of pulmonary embolism and/or Pulmonary Intravascular Thrombosis. Some evidence also exists regarding the possibility of myocarditis, however, without classic lymphocytic infiltration characteristic of viral myocarditis.
To summarize, the intricate interplay of diffuse pulmonary intravascular thrombosis and MAS-like state drives the severe and often fatal pulmonary microvascular dysfunction in COVID.
SARS-CoV2 infection--> diffuse alveolar damage--> interstitial inflammation--> MAS like state--> massive activation of macrophages--> local inflammatory cytokine milieu--> Microvascular dysfunction--> Pulmonary Intravascular Thrombosis
-Kirtan Patolia
Reference:
1.) https://doi.org/10.1016/S2665-9913(20)30121-1
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30121-1/fulltext
2.) https://doi.org/10.1111/bjd.19163
https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.19163
Precise. To the point. Accurate. Amazing work brother
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