Biomarkers of Hypercoagulability in COVID-19.

This issue focuses on the pathophysiology of coronavirus disease 2019 (COVID-19) [...].

Thrombotic Mechanism Involving Platelet Activation, Hypercoagulability and Hypofibrinolysis in Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) has spread, with thrombotic complications being increasingly frequently reported. Although thrombosis is frequently complicated in septic patients, there are some differences in the thrombosis noted with COVID-19 and that noted with bacterial infections. The incidence (6-26%) of thrombosis varied among reports in patients with COVID-19; the incidences of venous thromboembolism and acute arterial thrombosis were 4.8-21.0% and 0.7-3.7%, respectively. Although disseminated intravascular coagulation (DIC) is frequently associated with bacterial infections, a few cases of DIC have been reported in association with COVID-19. Fibrin-related markers, such as D-dimer levels, are extremely high in bacterial infections, whereas soluble C-type lectin-like receptor 2 (sCLEC-2) levels are high in COVID-19, suggesting that hypercoagulable and hyperfibrinolytic states are predominant in bacterial infections, whereas hypercoagulable and hypofibrinolytic states with platelet activation are predominant in COVID-19. Marked platelet activation, hypercoagulability and hypofibrinolytic states may cause thrombosis in patients with COVID-19.

Plasma Soluble Fibrin Is Useful for the Diagnosis of Thrombotic Diseases.

BACKGROUND: Soluble fibrin (SF) is a form of fibrinogen that is activated by thrombin and is considered to be useful for the diagnosis of the prethrombotic state or thrombosis. METHODS: Plasma levels of fibrin-related markers (FRMs), such as SF, D-dimer, fibrinogen, and fibrin degradation prioduct (FDP) levels in critically ill patients, were examined for the diagnosis of disseminated intravascular coagulation (DIC), venous thromboembolism (VTE), peripheral arterial thromboembolism (PATE), acute myocardial infarction (AMI), and acute cerebral infarction (ACI). RESULTS: FRMs showed the usefulness in diagnosing DIC and VTE and the cutoff values of D-dimer, FDP, and SF for DIC were 7.2-7.8 µg/mL, 10.0 µg/mL, and 9.5 µg/mL, respectively. The cutoff values of D-dimer and FDP for VTE were similar to the 97.5th percentile values of healthy volunteers, while the cutoff value of SF was 6.9 µg/mL. In AMI and ACI, the cutoff values of D-dimer and FDP were lower than the 97.5 percentile values of healthy volunteers. A receiver operating characteristic analysis for all thrombosis cases showed that an adequate cutoff value in only SF among FRMs was higher than the confidence interval of healthy volunteers. Only SF had high sensitivity for thrombosis, as the FDP/SF ratio was markedly low for ACI, AMI and VTE. CONCLUSIONS: FRMs, especially D-dimer and FDP, were useful for diagnosing thrombosis with hyperfibrinolysis (e.g., DIC). As SF showed high sensitivity for predominantly thrombotic diseases, including arterial thrombosis, such as ACI and AMI, a high SF value suggests the possibility of an association with thrombosis. Finally, SF is the most useful marker for raising suspicion of an association with thrombosis, especially arterial thrombosis.

Platelet Activation and Thrombosis in COVID-19.

Although thrombosis frequently occurs in infectious diseases, the coagulopathy associated with COVID-19 has unique characteristics. Compared with bacterial sepsis, COVID-19-associated coagulopathy presents with minimal changes in platelet counts, normal prothrombin times, and increased D-dimer and fibrinogen levels. These differences can be explained by the distinct pathophysiology of the thromboinflammatory responses. In sepsis-induced coagulopathy, leukocytes are primarily responsible for the coagulopathy by expressing tissue factor, releasing neutrophil extracellular traps, multiple procoagulant substances, and systemic endothelial injury that is often associated with vasoplegia and shock. In COVID-19-associated coagulopathy, platelet activation is a major driver of inflammation/thrombogenesis and von Willebrand factor and platelet factor 4 are deeply involved in the pathogenesis. Although the initial responses are localized to the lung, they can spread systemically if the disease is severe. Since the platelets play major roles, arterial thrombosis is not uncommon in COVID-19. Despite platelet activation, platelet count is usually normal at presentation, but sensitive biomarkers including von Willebrand factor activity, soluble P-selectin, and soluble C-type lectin-like receptor-2 are elevated, and they increase as the disease progresses. Although the role of antiplatelet therapy is still unproven, current studies are ongoing to determine its potential effects.

Elevated Plasma Soluble C-Type Lectin-like Receptor 2 Is Associated with the Worsening of Coronavirus Disease 2019.

Although thrombosis in coronavirus disease 2019 (COVID-19) infection has attracted attention, the mechanism underlying its development remains unclear. The relationship between platelet activation and the severity of COVID-19 infection was compared with that involving other infections. Plasma soluble C-type lectin-like receptor 2 (sCLEC-2) levels were measured in 46 patients with COVID-19 infection and in 127 patients with other infections. The plasma sCLEC-2 levels in patients with COVID-19 infection {median (25th, 75th percentile), 489 (355, 668) ng/L} were significantly higher (p < 0.001) in comparison to patients suffering from other pneumonia {276 (183, 459) ng/L}, and the plasma sCLEC-2 levels of COVID-19 patients with severe {641 (406, 781) ng/L} or critical illness {776 (627, 860) ng/L} were significantly higher (p < 0.01, respectively) in comparison to those with mild illness {375 (278, 484) ng/L}. The ratio of the sCLEC-2 levels to platelets in COVID-19 patients with critical illness of infection was significantly higher (p < 0.01, p < 0.001 and p < 0.05, respectively) in comparison to COVID-19 patients with mild, moderate or severe illness. Plasma sCLEC-2 levels were significantly higher in patients with COVID-19 infection than in those with other infections, suggesting that platelet activation is triggered and facilitated by COVID-19 infection.

Evaluation of Biomarkers of Severity in Patients with COVID-19 Infection.

OBJECT: Although many Japanese patients infected with coronavirus disease 2019 (COVID-19) only experience mild symptoms, in some cases a patient's condition deteriorates, resulting in a poor outcome. This study examines the behavior of biomarkers in patients with mild to severe COVID-19. METHODS: The disease severity of 152 COVID-19 patients was classified into mild, moderate I, moderate II, and severe, and the behavior of laboratory biomarkers was examined across these four disease stages. RESULTS: The median age and male/female ratio increased with severity. The mortality rate was 12.5% in both moderate II and severe stages. Underlying diseases, which were not observed in 45% of mild stage patients, increased with severity. An ROC analysis showed that C-reactive protein (CRP), ferritin, procalcitonin (PCT), hemoglobin (Hb) A1c, albumin, and lactate dehydrogenase (LDH) levels were significantly useful for the differential diagnosis of mild/moderate I stage and moderate II/severe stage. In the severe stage, Hb levels, coagulation time, total protein, and albumin were significantly different on the day of worsening from those observed on the day of admission. The frequency of hemostatic biomarker abnormalities was high in the severe disease stage. CONCLUSION: The evaluation of severity is valuable, as the mortality rate was high in the moderate II and severe stages. The levels of CRP, ferritin, PCT, albumin, and LDH were useful markers of severity, and hemostatic abnormalities were frequently observed in patients in the severe disease stage.

Roles of Coagulation Abnormalities and Microthrombosis in Sepsis: Pathophysiology, Diagnosis, and Treatment.

The diagnostic criteria of overt disseminated intravascular coagulation (DIC) were established by the International Society on Thrombosis and Haemostasis (ISTH) in 2001. Since then, DIC has long been associated with adverse outcomes. However, recent advances in sepsis shed light on the role of coagulation disorders in the progression of sepsis. Currently, inflammation and coagulation are recognized as the two drivers that promote organ dysfunction in sepsis and septic shock. The ISTH has published new diagnostic criteria for improved management, namely sepsis-induced coagulopathy (SIC), in 2017. SIC is a pragmatic scoring system composed of platelet count, prothrombin time, and organ dysfunction score to detect the early-stage of sepsis-associated DIC. Since overt DIC represents an uncompensated coagulation disorder, a two-step approach using SIC and overt DIC criteria is a novel strategy to evaluate the severity and manage this challenging complication. Although there is no globally agreed on anticoagulant therapy for DIC, the Japanese Surviving Sepsis Campaign Guidelines 2020 recommend using antithrombin and recombinant thrombomodulin for sepsis associated DIC. Since research in this area has been previously reported, an international collaborative study is necessary to develop future diagnostic tools and treatment strategies.

Ethnic differences in thromboprophylaxis for COVID-19 patients: should they be considered?

Thromboembolic events contribute to morbidity and mortality in coronavirus disease 2019 (COVID-19). As a result, thromboprophylaxis using low-molecular-weight heparin (LMWH) is universally recommended for hospitalized patients based on multiple guidelines. However, ethnic differences with respect to thrombogenicity have been reported and the incidence of thromboembolic events is considered to be lower in the Asian population. Despite the importance of thromboprophylaxis, bleeding is also a side effect that should be considered. We examine the data relating to potential ethnic differences in thrombosis and bleeding in COVID-19. Although sufficient data is not yet available, current evidence does not oppose routine anticoagulant use and thromboprophylaxis using a standard dose of LMWH for admitted patients regardless of ethnicity based on our review.