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.

ISTH guidelines for antithrombotic treatment in COVID-19.

Antithrombotic agents reduce risk of thromboembolism in severely ill patients. Patients with coronavirus disease 2019 (COVID-19) may realize additional benefits from heparins. Optimal dosing and timing of these treatments and benefits of other antithrombotic agents remain unclear. In October 2021, ISTH assembled an international panel of content experts, patient representatives, and a methodologist to develop recommendations on anticoagulants and antiplatelet agents for patients with COVID-19 in different clinical settings. We used the American College of Cardiology Foundation/American Heart Association methodology to assess level of evidence (LOE) and class of recommendation (COR). Only recommendations with LOE A or B were included. Panelists agreed on 12 recommendations: three for non-hospitalized, five for non-critically ill hospitalized, three for critically ill hospitalized, and one for post-discharge patients. Two recommendations were based on high-quality evidence, the remainder on moderate-quality evidence. Among non-critically ill patients hospitalized for COVID-19, the panel gave a strong recommendation (a) for use of prophylactic dose of low molecular weight heparin or unfractionated heparin (LMWH/UFH) (COR 1); (b) for select patients in this group, use of therapeutic dose LMWH/UFH in preference to prophylactic dose (COR 1); but (c) against the addition of an antiplatelet agent (COR 3). Weak recommendations favored (a) sulodexide in non-hospitalized patients, (b) adding an antiplatelet agent to prophylactic LMWH/UFH in select critically ill, and (c) prophylactic rivaroxaban for select patients after discharge (all COR 2b). Recommendations in this guideline are based on high-/moderate-quality evidence available through March 2022. Focused updates will incorporate future evidence supporting changes to these recommendations.

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.

Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations.

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.

Vaccine-induced immune thrombotic thrombocytopenia and patients with cancer.

Vaccines to combat SARS-CoV-2 infection and the COVID-19 pandemic were quickly developed due to significant and combined efforts by the scientific community, government agencies, and private sector pharmaceutical and biotechnology companies. Following vaccine development, which took less than a year to accomplish, randomized placebo controlled clinical trials enrolled almost 100,000 people, demonstrating efficacy and no major safety signals. Vaccination programs were started, but shortly thereafter a small number of patients with a constellation of findings including thrombosis in unusual locations, thrombocytopenia, elevated D-dimer and often low fibrinogen led another intense and concentrated scientific effort to understand this syndrome. It was recognized that this occurred within a short time following administration of adenoviral vector SARS-CoV-2 vaccines. Critical to the rapid understanding of this syndrome was prompt communication among clinicians and scientists and exchange of knowledge. Now known as vaccine-induced immune thrombotic thrombocytopenia syndrome (VITT), progress has been made in understanding the pathophysiology of the syndrome, with the development of diagnostic criteria, and most importantly therapeutic strategies needed to effectively treat this rare complication of adenoviral vector vaccination. This review will focus on the current understanding of the pathophysiology of VITT, the findings that affected patients present with, and the rational for therapies, including for patients with cancer, as prompt recognition, diagnosis, and treatment of this syndrome has resulted in a dramatic decrease in associated mortality.

Thrombosis and thrombocytopenia in COVID-19 and after COVID-19 vaccination.

Thrombosis that occurs in coronavirus disease 19 (COVID-19) is a serious complication and a critical aspect of pathogenesis in the disease progression. Although thrombocytopenia is uncommon in the initial presentation, it may also reflect disease severity due to the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to activate platelets. This occurs directly through the spike protein-angiotensin converting enzyme 2 (ACE2) interaction and indirectly by coagulation and inflammation activation. Dysregulation in both innate and adaptive immune systems is another critical factor that causes thrombosis and thrombocytopenia in COVID-19. Vaccination is the most potent and effective tool to mitigate COVID-19; however, rare side effects, namely vaccine-induced immune thrombotic thrombocytopenia (VITT)/thrombosis with thrombocytopenia syndrome (TTS) can occur following adenovirus-vectored vaccine administration. VITT/TTS is rare, and thrombocytopenia can be the clue to detect this serious complication. It is important to consider that thrombocytopenia and/or thromboembolism are not events limited to post-vaccination with vectored vaccine, but are also seen rarely after vaccination with other vaccines. Various conditions mimic VITT/TTS, and it is vital to achieving the correct diagnosis at an earlier stage. Antiplatelet factor 4 (PF4) antibody detection by the enzyme-linked immunosorbent assay (ELISA) is used for diagnosing VITT/TTS. However, false-positive rates also occur in vaccinated people, who do not show any thrombosis or thrombocytopenia. Vaccinated people with messenger RNA vaccine can show positive but low density and non-functional in terms of platelet aggregation, it is vital to check the optical density. If anti-PF4 ELISA is not available, discriminating other conditions such as antiphospholipid syndrome, thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura, systemic lupus erythematosus, and hemophagocytic syndrome/hemophagocytic lymphohistiocytosis is critical when the patients show thrombosis with thrombocytopenia after COVID-19 vaccination.

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.

Recognizing Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia is an unexpected consequence of the coronavirus disease 2019 pandemic era. We reviewed the pathogenesis, clinical presentation, diagnosis, and treatment of this rare side effect. DATA SOURCES: Online search of published medical literature through PubMed, Scopus, Web of Science, and Google Scholar using the terms "COVID-19," "vaccine," "thrombosis" was performed. STUDY SELECTION: Articles were chosen for inclusion based on their relevance to coronavirus disease 2019, vaccine, and thrombosis. DATA SYNTHESIS: Vaccine-induced immune thrombotic thrombocytopenia manifests most often as unusual thromboses (cerebral venous sinus thrombosis, splanchnic vein thrombosis) but sometimes also "usual" thromboses (arterial stroke, pulmonary embolism, deep-vein thrombosis), with oftentimes severe thrombocytopenia, that becomes clinically evident 5-30 days after adenovirus-vectored coronavirus disease 2019 vaccine administration. Most patients have disseminated intravascular coagulation. These features are the result of vaccine-triggered formation of anti-platelet factor 4 immunoglobulin G that activate platelets, clinically mimicking autoimmune heparin-induced thrombocytopenia. Early recognition based on thrombosis (sometimes, hemorrhage), thrombocytopenia, and d-dimer elevation within the day 5-30 postvaccine "window" is important given treatment with high-dose IV immunoglobulin plus nonheparin anticoagulation. CONCLUSIONS: Vaccine-induced immune thrombotic thrombocytopenia is a serious complication of vaccination that is not feasible to anticipate or prevent. When the patient presents with sustained headache, neurologic symptoms/signs, abdominal pain, dyspnea, or limb pain/swelling beginning 5-30 days post vaccination, platelet count and d-dimer must be measured, and imaging for thrombosis performed. Confirmation of vaccine-induced immune thrombotic thrombocytopenia diagnosis should be ordered (platelet factor 4/polyanion enzyme-linked immunosorbent assay; platelet factor 4-enhanced platelet activation testing) as treatment is initiated (nonheparin anticoagulation, IV immunoglobulin).

The roles of platelets in COVID-19-associated coagulopathy and vaccine-induced immune thrombotic thrombocytopenia.

In coronavirus disease 2019 (COVID-19), multiple thromboinflammatory events contribute to the pathophysiology, including coagulation system activation, suppressed fibrinolysis, vascular endothelial cell injury, and prothrombotic alterations in immune cells such as macrophages and neutrophils. Although thrombocytopenia is not an initial presentation as an infectious coagulopathy, recent studies have demonstrated the vital role of platelets in COVID-19-associated coagulopathy SARS-CoV-2 and its spike protein have been known to directly or indirectly promote release of prothrombotic and inflammatory mediators that lead to COVID-19-associated coagulopathy. Although clinical features of vaccine-induced immune thrombotic thrombocytopenia include uncommon locations of thrombosis, including cerebral venous sinus, we speculate coronavirus spike-protein-initiated prothrombotic pathways are involved in the pathogenesis of vaccine-induced immune thrombotic thrombocytopenia, as current evidence suggests that the spike protein is the promotor and other cofactors such as perturbed immune response and inflammatory reaction enhance the production of anti-platelet factor 4 antibody.

Viral-Induced Inflammatory Coagulation Disorders: Preparing for Another Epidemic.

Several viral infectious diseases have emerged or re-emerged from wildlife vectors that have generated serious threats to global health. Increased international travel and commerce increase the risk of transmission of viral or other infectious diseases. In addition, recent climate changes accelerate the potential spread of domestic disease. The coronavirus disease 2019 (COVID-19) pandemic is an important example of the worldwide spread, and the current epidemic will unlikely be the last. Viral hemorrhagic fevers, such as dengue and Lassa fevers, may also have the potential to spread worldwide with a significant impact on public health with unpredictable timing. Based on the important lessons learned from COVID-19, it would be prudent to prepare for future pandemics of life-threatening viral diseases. The key concept that connect COVID-19 and viral hemorrhagic fever is the coagulation disorder. This review focuses on the coagulopathy of acute viral infections since hypercoagulability has been a major challenge in COVID-19, but represents a different presentation compared with viral hemorrhagic fever. However, both thrombosis and hemorrhage are understood as the result of thromboinflammation due to viral infections, and the role of anticoagulation is important to consider.

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.

COVID-19: Thrombosis, thromboinflammation, and anticoagulation considerations.

Vascular endothelial injury is a hallmark of acute infection at both the microvascular and macrovascular levels. The hallmark of SARS-CoV-2 infection is the current COVID-19 clinical sequelae of the pathophysiologic responses of hypercoagulability and thromboinflammation associated with acute infection. The acute lung injury that initially occurs in COVID-19 results from vascular and endothelial damage from viral injury and pathophysiologic responses that produce the COVID-19-associated coagulopathy. Clinicians should continue to focus on the vascular endothelial injury that occurs and evaluate potential therapeutic interventions that may benefit those with new infections during the current pandemic as they may also be of benefit for future pathogens that generate similar thromboinflammatory responses. The current Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) studies are important projects that will further define our management strategies. At the time of writing this report, two mRNA vaccines are now being distributed and will hopefully have a major impact on slowing the global spread and subsequent thromboinflammatory injury we see clinically in critically ill patients.

Therapeutic strategies in patients with coagulopathy and disseminated intravascular coagulation: awareness of the phase-dependent characteristics.

INTRODUCTION: Disseminated intravascular coagulation (DIC) has long been understood as a condition where both thrombotic and hemostatic abnormalities coexist. DIC is a difficult complication for clinicians to manage as it is due to multiple underlying complications of pathophysiologic abnormalities in diverse disease states. Ongoing research continues to define the meaning of DIC, evaluate therapeutic options, and how it presents with the complex paradigm of systemic activation of coagulation. In this review we introduce the current topics regarding this difficult situation. EVIDENCE ACQUISITION: Online search of published medical literature through MEDLINE and Web of Science using the term "disseminated intravascular coagulation," "coagulopathy," "coagulation disorder," "hemostasis," "fibrinolysis," "thrombus" and "anticoagulants." EVIDENCE SYNTHESIS: Articles were chosen for inclusion based on their relevance to disseminated intravascular coagulation, coagulopathy, hemostasis and thrombosis in sepsis, COVID-19, trauma, and obstetrics. Reference lists were reviewed to identify additional relevant articles. CONCLUSIONS: DIC is recognized as a pathologically triggered and dysregulated systemic activation of coagulation in response to various noxious stimuli. DIC's phenotype and clinical manifestations can vary from prothrombotic to hemorrhagic, depending on the underlying diseases. However, the fundamental mechanisms of systemic and vascular endothelial dysfunction can be explained as different phases of the acute response, with an initial prothrombotic phase that can commonly change to hemostatic insufficiency. Thrombin is the key initiator of the pathophysiologic process along with endothelial injury and initially fibrinolysis activation followed by fibrinolysis suppression. There is no established approach for managing DIC beyond initially treating the underlying disease and replacement therapy for the management of coagulopathy. Targeting anticoagulation therapy with antithrombin concentrates and recombinant thrombomodulin for the prevention of microthrombus formation, and antifibrinolytic therapy using tranexamic acid for the coagulopathy after massive bleeding, continue to be studied as therapeutic options.

Managing thrombosis and cardiovascular complications of COVID-19: answering the questions in COVID-19-associated coagulopathy.

INTRODUCTION: The first patients with Coronavirus disease 2019 (COVID-19) emerged at the end of 2019. This novel viral infection demonstrated unique features that include prothrombotic clinical presentations. However, one year after the first occurrence, there remain many unanswered questions. We tried to address some of the important queries in this review. AREAS COVERED: We raised the following critical questions. 'Why is COVID-19 so hypercoagulable?', 'Why are most coagulation test results relatively normal?', 'Why is COVID-19-associated coagulopathy more thrombotic than most other infectious diseases?', 'Why is arterial thrombus formed frequently?', 'Is anticoagulant therapy for COVID-19 effective?', and 'Are there racial disparities in thrombosis in COVID-19?' EXPERT OPINION: There are commonalities and differences in the pathogeneses and clinical features between COVID-19 and other infectious diseases. Correct understanding will help discussing appropriate anticoagulation prophylaxis or treatment for thromboembolism.

Coagulopathy in COVID-19.

The COVID-19 pandemic has become an urgent issue in every country. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID-19. The clinical presentation of COVID-19-associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. In comparison with bacterial-sepsis-associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID-19. The mechanisms of the coagulopathy are not fully elucidated, however. It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved. Bleeding tendency is uncommon, but the incidence of thrombosis in COVID-19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain.