SARS-CoV-2, responsible for the COVID-19 pandemic, causes lung inflammation that progresses to a cytokine storm in the most severe cases. The spectrum of diseases caused is very broad, with the hemostatic system frequently being compromised.
Severe lung inflammation can trigger thrombosis early in the course of the disease and there is a high incidence of venous thromboembolism (VTE) in hospitalized patients, particularly those with severe disease.
Hypercoagulability due to severe viral pneumonia is not new. This increased incidence of VTE in patients with COVID-19 is similar to that observed in patients with other epidemic coronavirus pneumonias, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). However, the risk of developing VTE due to H1N1 influenza is 18 times greater.
Patients with COVID-19 pneumonia present with coagulation abnormalities, most commonly elevated levels of fibrinogen and D-dimer, often with mild thrombocytopenia.
Elevated D-dimer has been associated with a higher mortality rate. In more severely affected patients, disseminated intravascular coagulopathy (DIC) may develop, which, unlike classic DIC due to sepsis or trauma, in Covid-19 the prolongation of clotting times is minimal, thrombocytopenia is mild, hypofibrinogemia is Rare, and laboratory results supporting hyperfibrinolysis are uncommon. COVID-19-associated coagulopathy is the term used to describe this spectrum of coagulation changes.
Here we will discuss what is known about COVID-19-associated changes in platelet counts, activation and production states; We will review the association of these platelet parameters with the outcomes of this disease. Additionally, we will examine the predominantly procoagulant changes observed during infection and their association with mortality.
| platelets |
Thrombocytopenia is detected in 5–41.7% of patients with COVID-19 (incidence varies depending on the severity of the disease) and is usually mild even in most severe cases. The rare severe thrombocytopenia is usually associated with diseases such as immune thrombocytopenic purpura.
A meta-analysis of 7,613 patients with COVID-19 revealed that the greater the severity of the disease, the lower the platelet count. Additionally, nonsurvivors had much lower platelet counts than survivors. However, not all studies can confirm the value of the number of platelets as a predictor of mortality.
The authors mention that platelets play an important role in inflammatory signaling as well as the infectious response. By combining thrombotic and immune recruitment functions, platelets may help focus hemostasis and immune responses against potential infectious agents to prevent microbial invasion. Interactions between endothelial cells, platelets and leukocytes play a fundamental role in the procoagulant effect of viral infections.
Several mechanisms of COVID-19-associated thrombocytopenia have been postulated . This could be purely consumption-related, related to endothelial damage and formation of platelet aggregates in the lung, but also marrow suppression and immune clearance are possible contributors.
Some authors showed that COVID-19 patients with thrombocytopenia had a significantly higher mean platelet volume (MPV) than COVID-19 patients with normal platelet counts. Larger platelets have greater hemostatic potential, bind more fibrinogen, and have higher levels of phosphorylation after thrombin stimulation than smaller platelets. In preliminary data from our hospital, COVID-19 patients were found to have larger MPV than non-COVID-19 critically ill patients matched by platelet count.
Cross-linked platelets are immature platelets with a high granule content, residual mRNA, and increased MPV compared to older circulating platelets. In healthy adults with normal platelet counts, the relative fraction of immature platelets (IPP), also known as cross-linked platelets, ranges between 3.3 and 8.6%. Younger platelets show higher levels of activation, therefore, more easily promote the formation of platelet aggregates.
Reticulated platelet count is positively associated with cardiovascular risk and mortality.
In our hospital there is a significant trend of elevated IPF in patients with COVID-19. These findings suggest that the disease is associated with increased production of large immature platelets. Interestingly, the increase in the number of this type of platelets even occurs under normal platelet count conditions. As immature platelets are known to be more functional, this could be another mechanism for increased clotting events.
A role for antiplatelet agents has been considered in COVID19 disease, but there is not enough evidence to support this treatment at the moment. Particularly for those patients with mild thrombocytopenia, it would even carry an increased risk of bleeding.
| Endothelium, von Willebrand factor and ABO group blood |
COVID-19 pneumonia is associated with alteration of endothelial cells, tissue factor expression, and activation of the coagulation cascade.
These responses worsen oxygenation, and local hypoxia establishes a detrimental positive thromboinflammatory feedback . Direct endothelial damage by the virus and/or endothelial activation by cytokines released during COVID-19 infection are possible mechanisms of thrombosis.
Activated or damaged endothelial cells release ultra-large molecular weight von Willebrand Factor (VWF) multimers. Ultralarge VWF multimers can spontaneously bind to platelets and cause microthrombosis. According to a study from Yale New Haven Hospital, markers of endothelial cell and platelet activation (VWF antigen, P-selectin, and soluble thrombomodulin) were significantly elevated in COVID-19 patients in the intensive care unit (ICU) compared with patients who were not in the ICU.
In a study of ABO blood group distribution in 2,173 COVID-19 patients, people in group A were more likely to have symptomatic COVID-19 disease, while people in group O were less likely to have symptomatic COVID-19 disease. However, this association is not universally identified.
This study also confirmed a protective effect in blood group O compared to other blood groups. This could be due to elevated VWF levels in non-group O individuals, which predispose to thromboembolic events.
| Coagulation |
Patients hospitalized with COVID-19 often have elevated levels of fibrinogen and D-dimer.
The marked elevation of the latter seems to reflect the activation of coagulation by viremia and cytokine storm, but superinfection and organ dysfunction are other possible causes. Temporarily increasing D-dimer levels indicate the progressive severity of the infection and can be used as a predictor that more aggressive intensive care will be needed.
Several studies demonstrated that high D-dimer values on admission were associated with increased mortality. All of these data have led the International Thrombosis and Hemostasis Association to suggest for COVID-19 coagulopathy that patients who have a 3- to 4-fold increase in D-dimers should be considered for hospital admission, even in the absence of other serious symptoms.
Viscoelastic analysis: COVID-19 is associated with a hypercoagulable profile, which primarily affects clot formation kinetics and clot strength. COVID-19 coagulopathy is somewhat similar to sepsis-induced disseminated intravascular coagulation, which typically presents with suppressed fibrinolysis. However, compared to sepsis-associated DIC, D-dimer levels are often significantly elevated in COVID-19.
Several studies recommend low-molecular-weight heparin at a prophylactic dose for all hospitalized patients with COVID-19 despite abnormal coagulation tests in the absence of active bleeding. It should be noted that therapeutic anticoagulation is associated with increased bleeding.
While bleeding is rare in the COVID-19 setting, transfusion therapy should not be instituted solely on the basis of laboratory results but should be reserved for those with active bleeding, who require an invasive procedure, or who have a high risk of hemorrhagic complications.
| Conclusions |
Currently available evidence suggests that COVID-19 coagulopathy represents a combination of localized pulmonary platelet consumption, low-grade DIC, and, variably, a thrombotic microangiopathy.
Elevated levels of VWF and soluble thrombomodulin imply activated or damaged endothelium, as seen histologically in autopsy studies. It would be anticipated that damaged endothelium would result in the release of ultralarge VWF multimers capable of interacting with platelets, leading to platelet activation, microthrombi, and consumption.
The homeostatic response to platelet consumption is increased platelet production with increased IPF. This compensatory response is robust in COVID-19 and may be disproportionate to the degree of thrombocytopenia, with MPV and FPI elevated even in COVID-19 patients with normal platelet counts.
Despite the large number of publications focusing on hemostatic changes associated with COVID-19, it should be noted that all serious infectious disorders are associated with changes in hemostasis laboratory values, as well as thrombotic and hemorrhagic events. .
Continued controlled studies are needed to guide the best treatment for patients and better elucidate the role platelets play in the pathophysiology of COVID-19.
