Showing papers in "Seminars in Thrombosis and Hemostasis in 2020"

COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies

Abstract: Coronavirus disease 2019 (COVID-19) may have a wide spectrum of clinical presentations, leading in some cases to a critical condition with poor long-term outcomes and residual disability requiring post-acute rehabilitation. A major concern in severe COVID-19 is represented by a concomitant prothrombotic state. However, contrasting data are available about the prevalence of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE). A detailed search on the association of COVID-19 with thromboembolic complications was conducted in the main electronic databases (PubMed, Web of Science, and Scopus) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The weighted mean prevalence (WMP) with 95% confidence interval (95% CI) was calculated with the random-effects model. Twenty studies enrolling 1,988 COVID-19 patients were included. The WMP of VTE was 31.3% (95% CI: 24.3–39.2%). The WMP of DVT was 19.8% (95% CI: 10.5–34.0%), whereas the WMP of PE was 18.9% (95% CI: 14.4–24.3%). Similar results were obtained when specifically analyzing studies on patients admitted to intensive care units and those on patients under antithrombotic prophylaxis. Regression models showed that an increasing age was associated with a higher prevalence of VTE (Z-score: 3.11, p = 0.001), DVT (Z-score: 2.33, p = 0.002), and PE (Z-score: 3.03, p = 0.002), while an increasing body mass index was associated with an increasing prevalence of PE (Z-score = 2.01, p = 0.04). Male sex did not impact the evaluated outcomes. The rate of thromboembolic complications in COVID-19 patients is definitely high. Considering the risk of fatal and disabling complications, adequate screening procedures and antithrombotic strategies should be implemented.

Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation

Abstract: Disseminated intravascular coagulation (DIC) has been recognized as a deadly complication in sepsis, and its early recognition followed by appropriate management of the underlying infection are the current management strategies. The activation of coagulation, inflammation, and other pathways are fundamental host responses against infection but also produce injury to the host. Recent advances have helped define the critical roles of thrombus formation in overcoming infection. In addition to activation of coagulation induced by pathogens, other important pathways including damage-associated molecular patterns, neutrophil extracellular traps, extracellular vesicles, and glycocalyx damage are involved in the pathogenesis of sepsis-induced DIC. The hallmark of DIC is thrombosis in the microvasculature; however, sepsis-induced DIC is a laboratory diagnosis based on coagulation test results and clinical setting. Although simplified criteria were recently introduced, DIC should be distinguished from other similar conditions such as thrombotic microangiopathy and heparin-induced thrombocytopenia. In DIC, treating the underlying cause is crucial, and additional adjunct therapies including antithrombin, thrombomodulin, and heparins may have potential benefit, but evidence supporting their use in terms of improvement of clinically relevant outcomes continues to be debated. In this review, we introduce recent findings regarding the pathophysiology, diagnosis, and treatment of sepsis-induced DIC. In addition, we also discuss future potential therapeutic approaches regarding this complex, life-threatening complication.

SARS-2 Coronavirus-Associated Hemostatic Lung Abnormality in COVID-19: Is It Pulmonary Thrombosis or Pulmonary Embolism?

Abstract: The coronavirus disease 2019 (COVID-19) pandemic has claimed several thousand lives since the first case was described in Wuhan, China, in December 2019.1 This has mainly been related to pulmonary complications presumed to be due to infection-associated inflammation and the resulting cytokine storm.2 Abnormal hemostasis was recognized early in the profile of these patients, with raised D-dimer being the most frequent abnormality in more than 70% of admitted patients with remarkably minimal changes in the remaining commonly measured hemostasis parameters (e.g., minimal prolongation of prothrombin time [PT] in some patients, and mild reduction in platelet count [almost all above 100 10/L] but with markedly raised fibrinogen levels and no schistocytes3). As may be anticipated from these laboratory findings, bleeding has not been a notable feature of this illness. In early reports, these changes were considered consistent with disseminated intravascular coagulation (DIC) or sepsis-induced coagulopathy (SIC).3,4 There is increasing recognition that the COVID-19-associated hemostasis abnormality (CAHA) may instead be resulting in localized thrombosis in the lungs, which has been reinforced by the fact that timely anticoagulation can be successful in reducing mortality of seriously unwell patients.4,5 This has led to recommendations for early intensive anticoagulation, in the absence of absolute contraindications, for all COVID-19 patients requiring hospitalization.6 Very recent postmortem reports have in fact confirmed this hypercoagulable state, with evidence of pulmonary thrombi, mostly microvascular, in all the four decedents evaluated.7 Recognizing the basis of the predominant lung pathology linked with the rapid clinical deterioration that is often unresponsive to ventilatory assistance and supportive care is critical to devising the interventions aimed at reducing mortality in these patients. Immunothrombosis and Pulmonary Microthrombi

Coronavirus Disease 2019 Coagulopathy: Disseminated Intravascular Coagulation and Thrombotic Microangiopathy-Either, Neither, or Both.

Abstract: Patients with severe coronavirus disease 2019 (COVID-19) infections manifest coagulation abnormalities that have been associated with respiratory deterioration and death.1,2 In addition, many patients with severe COVID-19 infections develop venous thromboembolism, which seems to be related to the coagulopathy.3 It has also been suggested that undiagnosed pulmonary embolism contributes to a sudden deteriorationofpulmonaryoxygenexchangethat issometimesseen in patients with COVID-19 infections.4,5 The coagulopathy associatedwith COVID-19mimics other systemic coagulopathies that are regularly seen in severe infections, such as disseminated intravascular coagulation (DIC) or thrombotic microangiopathy (TMA).6–8 However, at the same time, the clinical and laboratory characteristics of the coagulation changes in COVID-19 are distinctly different from the common presentation of these conditions.

Recommendations for Minimal Laboratory Testing Panels in Patients with COVID-19: Potential for Prognostic Monitoring.

Abstract: A new infective outbreak, which has been finally defined as coronavirus disease 2019 (COVID-19), has now taken hold all around the world.1 Although this is recognized as a viral respiratory illness causedbysevereacute respiratorysyndrome coronavirus 2 (SARS-CoV-2), the pathophysiology of the disease is far wider than respiratory, including long-term risk for adversecardiovasculardisease, thromboembolic disorders, and multiple organ failure (MOF).2 The initial clinical course of the respiratory disease can be complicated by the development of interstitial pneumonia in a considerable number of patients, evolving towardacute respiratorydistress syndrome inupto10 to15%of these,whowill then requiremechanical ventilationor intensive care.3 Increasingly recognized, however, is the potential for the development of some forms of thrombotic coagulopathies including intravascular disseminated coagulation (DIC) in a subset of patients and indeed also being prognostic for poor morbidity and mortality.4,5 Based on our understanding of the emerging literature, we aim to provide in this short commentary a simple list (►Table 1) of laboratory tests, as may be recommended for patients with COVID-19 and to potentially assist in prognosticmonitoring of such patients. The rationale for the listing is also provided and based on recent reports around clinical and laboratory features of COVID-19 affected patients.4–11 However, we recognize that such a list is time-relevant and potentially time-limited and may quickly change as new information emerges. Thus, at all times, local experts should be consulted as available and testing modified accordingly. As an example, antithrombin is noted as lower in COVID-19 cases than in controls11; however, there is no current evidence that antithrombin is differentially lower in severe cases and thus may not have clear prognostic value. As another example, the extent of thrombocytopenia does seem to be associated with the severity of disease12 and thus has been included in►Table 1. On the other hand, there is considerable interaction between platelets and viruses,13 and therefore an assessment of other platelet indices may also become relevant in the future. Thus, currently, we recommend aminimum test panel for hematology comprising (1) a complete or full blood count (CBC/FBC, representing the United States, European, United Kingdom, Australian nomenclature), (2) routine coagulation tests (prothrombin time [PT] and activated partial thromboplastin time [APTT]), (3) fibrinogen, and (4) D-dimer (optional: other associated tests such as fibrin/fibrinogen degradation products and fibrin monomers as locally available or supported). We also recommend a series of biochemistry and other tests (►Table 1), including markers for inflammation, electrolyte disturbance, liver dysfunction, and renal and cardiac damage, which would reflect the development of viral sepsis, systemic inflammatory response syndrome, and/or MOF, which are all conditions associated with an extraordinarily enhanced risk of thrombotic coagulopathies. Our recommendations in part relate to emerging evidence that intravascular coagulation, inclusive of DIC, is a feature of poor prognosis in seriously affected patients.4–11 Alsowidely recognized is worsening organ damage, even death. Our recommendations are tempered by our expertise in the area of hemostasis and biochemistry, and therefore some gaps are unavoidable. Nevertheless, several lines of evidence now attest that elevation of thrombotic biomarkers, especially D-dimer, is commonplace in patients with COVID-19,4–11 especially in thosewithmoreseveredisease.4Therefore, routinemonitoring of D-dimer and other useful tests such as PT, APTT, fibrinogen,

Platelets in Coronavirus Disease 2019.

Abstract: In December 2019, the first cases of infection with a novel human microorganism, now officially defined as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were reported in Wuhan, China.1 On April 1, 2020, as we write, more than 800,000 cases of the novel coronavirus disease 2019 (COVID-19) have been reported worldwide, with more than 40,000 COVID-19–related deaths.2 Studies have reported disturbed coagulation in COVID-19 patients, including prolonged prothrombin time,3,4 decreased antithrombin,3 and increased fibrin degradation products such as D-dimer.3–7 This implies increased risk of thromboembolic disease, as well as bleeding and, for the most serious cases, development of disseminated intravascular coagulation (DIC),which, inonecase series,was reported inasmanyas71% of nonsurvivors of COVID-19.5 This commentary explores the potential role of platelets in COVID-19, including the link between thrombocytopenia and disease severity and the considerations for the potential role for platelet function and/or platelet activation testing in COVID-19 patients.

Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection.

Abstract: A growing body of clinical evidence shows that vascular leakage leads to pulmonary edema in coronavirus disease 2019 (COVID-19) patients. Coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) use membrane ectopeptidases to invade cells, most notably dipeptidyl peptidase 4 (DPP4; https://www.uniprot.org/uniprot/P27487), aminopeptidase N (APN; https://www.uniprot.org/uniprot/P15144), and angiotensin-converting enzyme 2 (ACE2; https://www.uniprot.org/uniprot/Q9BYF1).[1] It is important to distinguish this latter protein from ACE, which is the main target for conventional blood pressure lowering drugs: ACE inhibitors do not inhibit ACE2.[2] As a result of virus entry, these membrane ectopeptidases are internalized and their activity becomes downregulated. The common denominator between these membrane ectopeptidases is their enzyme specificity: they degrade peptide hormones, for instance, angiotensin II. For SARS-CoV-2 (as well as SARS-CoV), ACE2 is the predominant target for cellular uptake in vivo.[3] It is present on lung alveolar epithelial cells, enterocytes of the small intestine, endothelial cells, and arterial smooth muscle cells.[4] In an acid aspiration lung injury mouse model, ACE2 knockout (KO) worsened the resulting edema.[5] This was accompanied by increased angiotensin II levels[6] and was prevented by angiotensin II receptor KO, leading to the conclusion that the lack of ACE2-mediated angiotensin II degradation was responsible for the observed increase pulmonary vascular permeability. The same observations were made when downregulating ACE2 with the spike protein of the SARS CoV prior to acid aspiration.[6] Yet, the authors did not measure renin in these studies. This is crucial since normally angiotensin II rises result in rapid renin suppression,[7] thereby normalizing its levels. Moreover, ACE2 is just one of many angiotensin-degrading enzymes (angiotensinases). In full accordance with this concept, Gurley et al did not find increased angiotensin II levels after ACE2 KO.[8] Hence, whether the ACE2 KO dependent permeability changes are entirely due to ACE2-mediated angiotensin II degradation remains uncertain. ACE2 has multiple other substrates. Among these are the kinins, which are also degraded by DPP4.[9] We and others believe that this deserves attention, as it offers an alternative view, and forms a basis on which novel therapeutic opportunities might be proposed.[10]

Coronavirus Disease 2019, Prothrombotic Factors, and Venous Thromboembolism.

Abstract: Coronavirus disease 2019 (COVID-19) is causing devastating morbidity and mortality worldwide. Several studies have shown that the severely ill patients have high or very high Ddimer values, and a hypercoagulable state has been described with, insomecases,developmentofdisseminatedintravascular coagulation (DIC). A few reports have indicated that there seems to be a higher incidence of venous thromboembolism than expected in otherwise severely ill patients. In this article, we will discuss the prothrombotic changes observed and to what extent they are specific for COVID-19. The incidence of thromboembolic events will be comparedwith those reported in sepsis and severe influenza A H1N1. The emphasis is on venous events, which have been the most frequently reported events. Finally, the intensity of pharmacological prophylaxis against venous thromboembolism will be discussed. The pandemic of COVID-19 is affecting almost every country in the world, with the number of cases tested and found infected exceeding two million, with an overall mortality of approximately 7% at the time of writing.1 There are preliminary reports from China on venous thromboembolism based on a relatively small number of patients.2,3 Subsequently, European physicians have reported a higher incidence of thromboembolic events, mainly venous, in patients with COVID-19 pneumonia in the intensive care unit (ICU).4Another manifestation of hypercoagulability is DIC, which was not reported in other than the occasional case in the largest published cohorts.5–7 On the other hand, abnormalities in the coagulation tests, meeting previously defined criteria for DIC, were observed during the terminal days in 71% of nonsurvivors in another cohort from Wuhan, China.8 These preliminary findings generate several questions, some which are as follows:

A Champion of Host Defense: A Generic Large-Scale Cause for Platelet Dysfunction and Depletion in Infection

Abstract: Thrombocytopenia is commonly associated with sepsis and infections, which in turn are characterized by a profound immune reaction to the invading pathogen. Platelets are one of the cellular entities that exert considerable immune, antibacterial, and antiviral actions, and are therefore active participants in the host response. Platelets are sensitive to surrounding inflammatory stimuli and contribute to the immune response by multiple mechanisms, including endowing the endothelium with a proinflammatory phenotype, enhancing and amplifying leukocyte recruitment and inflammation, promoting the effector functions of immune cells, and ensuring an optimal adaptive immune response. During infection, pathogens and their products influence the platelet response and can even be toxic. However, platelets are able to sense and engage bacteria and viruses to assist in their removal and destruction. Platelets greatly contribute to host defense by multiple mechanisms, including forming immune complexes and aggregates, shedding their granular content, and internalizing pathogens and subsequently being marked for removal. These processes, and the nature of platelet function in general, cause the platelet to be irreversibly consumed in the execution of its duty. An exaggerated systemic inflammatory response to infection can drive platelet dysfunction, where platelets are inappropriately activated and face immunological destruction. While thrombocytopenia may arise by condition-specific mechanisms that cause an imbalance between platelet production and removal, this review evaluates a generic large-scale mechanism for platelet depletion as a repercussion of its involvement at the nexus of responses to infection.

Coronavirus Disease 2019: The Role of the Fibrinolytic System from Transmission to Organ Injury and Sequelae.

Abstract: An initial cluster of severe viral pneumoniawas discovered in early December 2019 in Wuhan, China. It was found to be caused by a newly identified coronavirus, later named by the World Health Organization and the Coronavirus Study Group of the International Committee as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease as coronavirus disease 2019 (COVID-19).1–4 The disease rapidly spread globally and was then declared as a pandemic. The most notable characteristic of SARS-CoV-2 is its high infectivity. As a result,much attention has been paid to itsmode of transmission. The major route of infection is the binding of the spike protein of the virus to its natural receptor angiotensin-converting enzyme (ACE 2) on the surface of the host cells.2 ACE2 is present in tissues and is particularly abundantly expressed in the lung in the alveolar (type II) cells. This is clinically correlated as the lung is the major organ affected by the viral infection, leading to acute respiratory failure and acute respiratory distress syndrome (ARDS). Many aspects of COVID-19 are similar to those seen in the SARS and in the Middle East respiratory syndrome (MERS),5,6 including ACE2 being the receptor for the virus.7 Impaired fibrinolysis was observed in post-SARS complications.8,9 Impairedfibrinolysis10,11 is present in pneumonia and acute lung injuries; accordingly, this commentary is devoted to reviewing evidence for possible involvement of the fibrinolytic system in transmission, pulmonary complications, and sequelae of COVID-19. Several possible drug targets that alter the activity of components of the fibrinolytic system are also discussed.

Immune Thrombocytopenia in Adults: Modern Approaches to Diagnosis and Treatment.

Abstract: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20,000 people. Patients typically present with clinically benign mucocutaneous bleeding, but morbid internal bleeding can occur. Diagnosis remains clinical, possible only after ruling out other causes of thrombocytopenia through history and laboratory testing. Many adult patients do not require treatment. For those requiring intervention, initial treatment of adult ITP is with corticosteroids, intravenous immunoglobulin, or intravenous anti-RhD immune globulin. These agents are rapid-acting but do not result in durable remissions in most patients. No corticosteroid has demonstrated superiority to others for ITP treatment. Subsequent treatment of adult ITP is typically with thrombopoietin receptor agonists (TPO-RAs; romiplostim or eltrombopag), rituximab, or splenectomy. TPO-RAs are newer agents that offer an excellent response rate but may require prolonged treatment. The choice between subsequent treatments involves consideration of operative risk, risk of asplenia, drug side-effects, quality-of-life issues, and financial costs. Given the efficacy of medical therapies and the rate of spontaneous remission in the first year after diagnosis, splenectomy is frequently deferred in modern ITP treatment algorithms. Fostamatinib (a tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration) and several older immunosuppressive agents (azathioprine, cyclophosphamide, cyclosporine, danazol, dapsone, mycophenolate mofetil, and the Vinca alkaloids) may be useful in patients with disease unresponsive to standard therapies or in specific clinical circumstances. This comprehensive review explores diagnostic considerations and surveys new and old treatment options for adults with ITP.

Bleeding and Bleeding Risk in COVID-19.

Abstract: Coronavirus disease 2019 (COVID-19) is a new, emerging medical challenge worldwide, with those affected showing a variety of clinical presentations, ranging fromasymptomatic or mild conditions to critical illness. Patients affected by the causative virus—severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—usually experience cough, fever, dyspnea, myalgia, less frequently gastrointestinal (GI) manifestations and, rarely, neurological complications. Coagulopathy is common among those afflicted and appears to be one of the most significant adverse prognostic signs.1,2 Coagulopathy results from concomitant activation of coagulation and fibrinolytic systems,most likely due to a severe proinflammatory state (i.e., the so-called cytokine storm) and/or by viral sepsis that sometimes leads to consumption of coagulation factors and decreased platelet count, resulting in thrombohemorrhagic events.3 In this process, plasmin breaks down fibrin present in plasma and the bronchoalveolar lavage fluid, as well as potentially other organs, and leading to excess D-dimer/fibrin (ogen)degradationproduct (FDP) formation. Thismayalso lead to reduction in platelet count and increased risk for hemorrhage.4 In a systematic review of 6,892 patients and metaanalysis of 3,496 patients, platelets were low in 22.9% and D-dimer was high in 34.8%; D-dimer was associated with a severe clinical course with an odds ratio (OR) of 4.03, and low platelets with an OR of 1.78.5 Disseminated intravascular coagulation (DIC) in COVID-19 is accompanied by a significant decrease of fibrinogen, and a marked increase of FDP and D-dimer, which are characteristics of DIC with hyperfibrinolysis, whereas the DIC caused by infection is accompanied by plasminogen activator inhibitor-1 release and suppression of fibrinolysis. Administration of antiproteasesmay prove beneficial.6 Elevated D-dimer, and FDP, often mildly prolonged prothrombin time and mildly decreased platelet counts were also reported as common findings by Tang et al, more common and more profound in severely affected patients.2 Fibrinogen levels are sometimes lowered, but may instead be elevated, while activated partial thromboplastin time is sometimes prolonged, butmay insteadbeshortened,with thesepotentially suggestive of acute phase events.2,6 Although hypercoagulability and thrombotic events are common in COVID-19, bleeding may occur at any time during the course of disease. Several factors make patients with COVID-19 prone to bleeding, including thrombocytopenia, hyperfibrinolytic state, consumption of coagulation factors, and thromboprophylaxis administration of anticoagulants. A proposed cytokine storm, prolonged tissue hypoxia, and direct invasion of affected tissues are other possible causes.2,7,8 Although thrombosis is relatively well studied in COVID-19, bleeding and bleeding risk appear to be the forgotten side of this story, most probably due to the lessfatal consequences; however, hemorrhagic diatheses represents a significant morbidity and potential cause of death in COVID-19 in at least in a subset of patients.7,8

Hematology Laboratory Abnormalities in Patients with Coronavirus Disease 2019 (COVID-19).

Abstract: Over the past few months, Coronavirus Disease 2019 (COVID-19) has spread across much of the world leading to a pandemic. Many infected individuals do not experience signs or symptoms, or experience only mild symptoms, whilst a subset experience severe disease, which is often fatal. A number of laboratory tests have been found to be abnormal in hospitalized patients, and some studies suggest some of these tests can predict an unfavorable outcome. These include markers of acute phase reaction (elevated C-reactive protein, erythrocyte sedimentation rate, white blood cell count, fibrinogen, procalcitonin, factor VIII, von Willebrand factor), signs of tissue injury (elevated lactic dehydrogenase, alanine aminotransferase, cardiac troponins), changes in hemostasis and coagulation (elevated D-dimer, prolonged prothrombin time, decreased platelets, decreased antithrombin, elevated factor VIII and von Willebrand factor), and decreased lymphocytes. Additional studies are needed to confirm the most ideal panel of tests, and to confirm the efficiency of laboratory tests to predict clinical outcome, as well as the ideal anticoagulation management.

Temporal Changes in Fibrinolysis following Injury.

Abstract: Trauma patients present to the emergency department with a spectrum of fibrinolytic activity. This wide variance in fibrinolysis activity is a complex multifactorial process impacted by the degree of hemorrhagic shock and the amount of tissue injury the individual sustains. The fibrinolytic activity of the trauma patient at presentation to the hospital has prognostic and therapeutic implications. Those patients with high fibrinolytic activity (hyperfibrinolysis) are at risk of mortality from hemorrhage, whereas those patients with low fibrinolytic activity (shutdown or hypofibrinolysis) are at an increased risk of delayed mortality from traumatic brain injury or organ failure. These phenotypes of fibrinolysis acutely following injury change with resuscitation, and the majority of trauma patients will transition to a fibrinolytic resistant state several hours after injury. The mechanism for this near-global transition to this acquired fibrinolysis appears to be related to the generation of plasminogen activator inhibitor-1 in the liver. Those patients who do not recover from this fibrinolytic state 24 hours after injury have a poor prognosis. The purpose of this article is to review the different states of fibrinolytic activity following injury and how they change over time following resuscitation and in the intensive care unit.

The Evolution of Blood Transfusion in the Trauma Patient: Whole Blood Has Come Full Circle.

Abstract: Whole blood transfusion in the United States dates back to the Civil War, and it was widely used in all major conflicts since World War I. To understand our current civilian transfusion practices and to anticipate future changes in trauma resuscitation, it is important to understand the series of decisions that led trauma surgeons away from whole blood resuscitation and toward component therapy. In this review, we examine the historical basis for blood transfusion in trauma and examine the recent literature and future directions pertaining to blood product resuscitation in hemorrhaging patients.

Diagnosis and Treatment of Trauma-Induced Coagulopathy by Viscoelastography.

Abstract: This article explores the application of viscoelastic tests (VETs) in trauma-induced coagulopathy and trauma resuscitation. We describe the advantages of VETs over conventional coagulation tests in the trauma setting and refer to previous disciplines in which VET use has reduced blood product utilization, guided prohemostatic agents, and improved clinical outcomes such as the mortality of critically bleeding patients. We describe different VETs and provide guidance for blood component therapy and prohemostatic therapy based on specific VET parameters. Because the two most commonly used VET systems, rotational thromboelastometry and thromboelastography, use different activators and have different terminologies, this practical narrative review will directly compare and contrast these two VETs to help the clinician easily interpret either and use the interpretation to determine hemostatic integrity in the bleeding trauma patient. Finally, we anticipate the future of new viscoelastic technologies that can be used in this setting.

Thrombin Generation and Cirrhosis: State of the Art and Perspectives

Abstract: Epidemiological and laboratory studies performed in the last decades have changed our understanding of coagulopathy in cirrhosis, from a condition at increased risk of hemorrhagic events to one at higher thrombotic risk. However, it is not clear whether the decrease in factors that promote (except factor [F] VIII) versus inhibit coagulation in patients with cirrhosis results in a rebalanced state or in a hypercoagulable phenotype. This issue can be partially addressed using thrombin generation assays (TGA), which unlike routine clotting tests (prothrombin time or activated partial thromboplastin time) are sensitive to both procoagulant factors and coagulation inhibitors. However, many preanalytical issues and variable analytical methodologies used in TGAs complicate data analysis and interlaboratory comparisons. The introduction of TGAs in which activators of the protein C pathway (particularly soluble forms of thrombomodulin [TM]) are added has allowed detection of a reduced anticoagulant effect of TM or even a hypercoagulable phenotype as judged by endogenous thrombin potential. However, inter- and intra-assay variability may be greater with this TGA variant compared with "standard" TGAs. TGAs also allowed identifying main determinants of the hypercoagulability phenotype in the presence of TM: acquired antithrombin and protein C deficiencies, and elevated FVIII levels. The aim of this narrative review is to summarize the preanalytical and methodological variables of TGAs and also the findings of the main studies that have evaluated TGAs in patients with cirrhosis. The review also provides some propositions for future studies and outlines some perspectives on the potential implementation of this promising tool in clinical practice for the study of coagulation in patients with cirrhosis.

Drug-Induced Thrombocytopenia: Mechanisms and Laboratory Diagnostics

Abstract: Thrombocytopenia is a condition characterized by a decreased number of platelets in peripheral blood, which can be caused by a myriad of both congenital and acquired disorders. Drug-induced thrombocytopenia (DIT) deserves a special focus since its cumulative incidence can be as high as 10 cases per million population per year, with a prevalence of approximately 25% in critically ill patients. This condition is usually suspected following identification of an acute and severe decrease in platelet count, with values usually

Patients with Congenital Bleeding Disorders Appear to be Less Severely Affected by SARS-CoV-2: Is Inherited Hypocoagulability Overcoming Acquired Hypercoagulability of Coronavirus Disease 2019 (COVID-19)?

Abstract: 1Department of Hematology and Blood Transfusion, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran 2Anesthesiology Department & Anesthesiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 3 Iranian Comprehensive Hemophilia Care Center, Tehran, Iran 4Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran 5Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran 6Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran

Maintaining Hemostasis and Preventing Thrombosis in Coronavirus Disease 2019 (COVID-19): Part II

Abstract: Welcome to another issue of Seminars in Thrombosis and Hemostasis (STH). This issue is published under the “banner” of “Maintaining Hemostasis and Preventing Thrombosis in Coronavirus Disease 2019 (COVID-19),” this being the first such issue (or “Part I”). COVID-19 is caused by severe acute respiratory syndromecoronavirus2 (SARS-CoV-2). Believed to originate from Wuhan City in China, with the first reported case in December 2019, at the time of writing, therewere over 26 million cases reported worldwide, and nearly 900,000 attributable deaths.1 From a smattering of reports in the scientific literature in late 2019 (n1⁄4 228), there is now over 51,000 publications ascribed to COVID-19 in PubMed, including over 5,000 reviews. Given this enormous explosion of information, it is virtually impossible to keep up with the literature on COVID-19. Also given this plethora of information, one wonders if there is much point adding yet more information into the pile? Once COVID-19 exploded into our collective minds, the editorial team of STH gave serious thought to this question. One situation that was clear to us was that given the great interest and initial thirst for knowledge, all journalsbecame interested inpublishingonCOVID-19 and, indeed, some articles have been fast tracked to publication that have since been retracted, even by high impact factor journals. The STH board decided that, yes, STH needed to publish on COVID-19, but no, we did not want to publish just anything on COVID-19, and so we actually took a fairly resistant stance initially to acceptance of COVID-19 articles, just because theymentioned COVID-19. Primarily, STH did not want topublishmisinformation, oradditional “metoo”articles (e.g., reviews similar to those that had already been published elsewhere). Itwas felt thatwehavea smart Editorial Board. The Board has kept abreast of the literature, even for COVID-19, despite that being a tough task. Hence, our initial approach to COVID-19, asnoted in this issueof STH,was tocanvass fromthe STH Editorial Board, a series of commentaries around various aspects of COVID-19, although given the journal scope, obviously related primarily to thrombosis and hemostasis. The guest editors of this issue series also started the ball rolling for STH by preparing a commentary that we published some time ago, on laboratory tests that might be recommended for routine assessment of COVID-19 patients,2 and which we could then use as a kind of template to guide further commentaries. We wanted these contributions to reflect a range of topics, butbeof highquality.Wealsoneeded toname the issue series.Weknewearlyon,and thisbecamethenabsolutelyclear frompostmortem studies that despite the diseasemanifesting initially as a respiratory disease, thrombosis is a hallmark of most (if not all) severe/critical COVID-19 cases. Hence, the issue name “Maintaining Hemostasis and Preventing Thrombosis in Coronavirus Disease 2019 (COVID-19)” was coined, which we hope will become a kind of mantra to us all. ►Fig. 1 gives a kind of overview of COVID-19 from our perspective. The issue starts with themes around thrombosis, given this is a major feature in patients with severe COVID-19. The first contribution is from Di Minno et al, who provide an updated meta-analysis of literature studies around COVID19 and venous thromboembolism (VTE),3 thus providing the backdrop to a major theme of this series. COVID-19 presents with a wide spectrum of clinical presentations, leading in some cases to a critical care respiratory condition with poor long-term outcomes and residual chronic disability. A major concern in severe COVID-19 is represented by the concomitant prothrombotic state. However, contrasting data are available about the prevalence of VTE, including deep vein thrombosis (DVT) and/or pulmonary embolism (PE). The authors performed a detailed search on the association of COVID-19 with thromboembolic complications in the main

Fibrinogen Supplementation and Its Indications

Abstract: Adequate plasma levels of fibrinogen are essential for clot formation, and in severe bleeding, fibrinogen reaches a critically low plasma concentration earlier than other coagulation factors. Although the critical minimum concentration of fibrinogen to maintain hemostasis is a matter of debate, many patients with coagulopathic bleeding require fibrinogen supplementation. Among the treatment options for fibrinogen supplementation, fibrinogen concentrate may be viewed by some as preferable to fresh frozen plasma or cryoprecipitate. The authors review major studies that have assessed fibrinogen treatment in trauma, cardiac surgery, end-stage liver disease, postpartum hemorrhage, and pediatric patients. Some but not all randomized controlled trials have shown that fibrinogen concentrate can be beneficial in these settings. The use of fibrinogen as part of coagulation factor concentrate based therapy guided by point-of-care viscoelastic coagulation monitoring (ROTEM [rotational thromboelastometry] or TEG [thromboelastography]) appears promising. In addition to reducing patients' exposure to allogeneic blood products, this strategy may reduce the risk of complications such as transfusion-associated circulatory overload, transfusion-related acute lung injury, and thromboembolic adverse events. Randomized controlled trials are challenging to perform in patients with critical bleeding, and more evidence is needed in this setting. However, current scientific rationale and clinical data support fibrinogen repletion in patients with ongoing bleeding and confirmed fibrinogen deficiency.

Pulmonary Megakaryocytes in Coronavirus Disease 2019 (COVID-19): Roles in Thrombi and Fibrosis

Abstract: Este es el reporte de situación COVID-19 Colombia No 130 - 27 de agosto de 2020

Hormonal Contraceptives and the Risk of Venous Thrombosis.

Abstract: The risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE), the androgenic progestogens are better able to counteract the EE-induced stimulation of liver proteins and hence are associated with a twofold decreased risk of VT compared with non- or antiandrogenic progestogens, which exert limited counteraction of EE. Because EE is responsible for the increased risk, novel estrogens such as estradiol were developed and seem to have a lower risk of VT than EE. Besides COCs, there are other methods of hormonal contraceptives, such as progestogen-only contraceptives, which do not increase VT risk, except for injectables. Other nonoral contraceptives are combined vaginal rings and patches. There is insufficient evidence regarding the risk of VT associated with these two methods compared with COCs. The increased risk associated with COCs is more pronounced in women with inherited thrombophilia. In these women, the progestogen levonorgestrel seems to be associated with the lowest risk of VT. Currently, there are no studies that have investigated the risk of VT in women who switch COCs. We hypothesize that switching COCs, even when switching from a high- to a low-risk COC, increases the risk of VT. Finally, risk prediction models in women who use COCs are lacking. Since there is a large number of VT cases associated with COC use, it is important to identify women at risk of VT and advise them on alternative contraception methods.

Hemostatic Management of Extracorporeal Circuits Including Cardiopulmonary Bypass and Extracorporeal Membrane Oxygenation

Abstract: Cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO) cause hemostatic derangements that can predispose patients to both bleeding and thrombotic complications. Often, patients present for urgent surgery while taking medications including antiplatelet agents, vitamin K antagonists, and direct oral anticoagulants, which must be recognized, monitored, and managed. During extracorporeal circulation, appropriate anticoagulation, most commonly with heparin, is required to maintain blood flow and avoid thrombotic complications. However, anticoagulation and other effects of extracorporeal circuits can also have an undesired consequence of bleeding. Extracorporeal circulation leads to coagulopathy that may require therapy with blood products such as platelets, cryoprecipitate, and plasma in case a patient bleeds. Platelet dysfunction related to exposure to a foreign circuit is a primary concern, as is the development of acquired von Willebrand syndrome, which frequently remains undetected on routine testing. Hemorrhagic complications in ECMO, such as intracranial hemorrhage, pulmonary hemorrhage, and hemithorax, can occur. Hemostatic agents including antifibrinolytics, desmopressin, fibrinogen concentrates, and other factor concentrates may be needed to achieve hemostasis in these often-challenging patients. Managing bleeding on extracorporeal support requires careful monitoring and a thoughtful approach.

Ultrasound Microbubbles for Diagnosis and Treatment of Cardiovascular Diseases.

Abstract: Ultrasound (US) imaging of heart and major arteries and veins is among the most frequently used diagnostic techniques applied in humans. Conventional cardiovascular US sessions include anatomical B-mode and functional M-, pulsed-wave- and Doppler mode, which have their limitations in both precise cardiac chambers' delineation and small vessel imaging. The introduction of contrast-enhanced US, employing microbubble suspensions as contrast agent, has enabled a better delineation of heart chambers, the visualization of myocardial microvasculature, and the atherosclerotic plaque neovascularization. Moreover, specific disease-related molecular tracers have been developed by modifying the microbubbles with targeting ligands directed to biological markers exposed to the luminal side of the blood vessels. Microbubble functionalization has enabled in vivo molecular US imaging of various stages of atherosclerosis, from plaque initiation to plaque vulnerability, and neointima formation following revascularization procedures. Furthermore, oscillating microbubbles have been used to mechanically dissolve thrombus material and may act as carriers of drugs and nucleic acids that are released locally by US pulses. This review article summarizes recent advances in functional and molecular US images and discusses therapeutic applications of microbubbles. The addressed topics include an overview on microbubble formats, microbubble detection methods, molecular targets of cardiovascular diseases, and the use of microbubbles for thrombolysis and drug delivery.

Circulating Plasminogen Concentration at Admission in Patients with Coronavirus Disease 2019 (COVID-19)

Abstract: Este es el reporte de situación COVID-19 Colombia No 135 - 03 de septiembre de 2020

Anti-Factor Xa-Based Anticoagulation during Extracorporeal Membrane Oxygenation: Potential Problems and Possible Solutions.

Abstract: Choices for monitoring of unfractionated heparin (UFH) anticoagulation in extracorporeal membrane oxygenation (ECMO) patients include activated clotting time, activated partial thromboplastin time, reaction times of viscoelastic tests, and anti-factor Xa activity (between 0.3 and 0.7 IU/mL). Recent studies propose the anti-factor Xa to be the gold standard for monitoring UFH anticoagulation in ECMO. However, many extraneous factors combined question the utility of anti-factor Xa as the sole method of monitoring of UFH effects in ECMO. Anti-factor Xa is a chromogenic assay, which may be biased by the frequently elevated values of bilirubin and free hemoglobin in ECMO patients. The test may alternatively underestimate UFH effects in cases of low antithrombin values. More importantly, the anti-factor Xa assay is a plasma-based test which does not take into account the role of platelets and fibrinogen in forming a stable clot. Thrombocytopenia and platelet dysfunction are common features in ECMO patients, and underestimating their role may lead to over-anticoagulation, should only anti-factor Xa guiding be used to adjust the UFH dose. Conversely, fibrinogen is an acute phase protein, and some patients may experience high levels of fibrinogen during the ECMO course. In this case, an UFH monitoring based on anti-factor Xa is insensitive to this condition, although it may potentially be associated with thrombotic complications. Finally, the generally suggested range of 0.3 to 0.7 IU/mL is a somewhat arbitrary estimate, based on the desired range for treating and preventing thrombotic events in non-ECMO patients. In conclusion, anti-factor Xa may offer useful information on the real effects of UFH only when combined with a whole blood test capable of assessing the relative contribution of platelets and fibrinogen to clot formation.

International Council for Standardization in Haematology Recommendations for Hemostasis Critical Values, Tests, and Reporting

Abstract: This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH), the aim of which is to provide hemostasis-related guidance documents for clinical laboratories. The current ICSH document was developed by an ad hoc committee, comprising an international collection of both clinical and laboratory experts. The purpose of this ICSH document is to provide laboratory guidance for (1) identifying hemostasis (coagulation) tests that have potential patient risk based on analysis, test result, and patient presentations, (2) critical result thresholds, (3) acceptable reporting and documenting mechanisms, and (4) developing laboratory policies. The basis for these recommendations was derived from published data, expert opinion, and good laboratory practice. The committee realizes that regional and local regulations, institutional stakeholders (e.g., physicians, laboratory personnel, hospital managers), and patient types (e.g., adults, pediatric, surgical) will be additional confounders for a given laboratory in generating a critical test list, critical value thresholds, and policy. Nevertheless, we expect this guidance document will be helpful as a framework for local practice.

Changes in Coagulation following Brain Injury.

Abstract: Traumatic brain injury (TBI) is a worldwide public health concern due to increasing mortality, affecting around 10 million patients per year. A wide variety of clinical presentations are a function of the magnitude of injury and the anatomical perturbation of the brain parenchyma, supporting structures, and cerebral vasculature, with subsequent alteration of the blood–brain barrier. These disturbances correspond with the evolution of intracerebral hemorrhage and clinical outcomes. The associated hemostatic alterations associated with TBI are caused by the disruption of the delicate balance between bleeding and thrombosis formation, which can exacerbate initial injury. TBI-associated coagulopathy is a function of a cross-talk between coagulation and inflammation, with varying influences on the immunomodulation and regulation of coagulation that occur on platelets and the endothelium of injured TBI patients. In addition to the severity of initial injury, the following factors modulate the hemocoagulative response to TBI: time from the onset of injury to treatment, age, gender, catecholamine secretion, platelet dysfunction, endotheliopathy, premorbid anticoagulation, fibrinolysis, tissue factor, and activated protein C contribution. All these entities are intertwined and influence the pathologic evolution of TBI. These factors have implications for therapeutic options such as the choice of blood components for transfusion and hemostatic agents such as tranexamic acid. Monitoring hemostatic changes of TBI patients requires an understanding of these interactions between immunology and coagulation, which can be discerned by point-of-care viscoelastic testing with specific limitations. This review considers the implications of these interrelated influences on the evaluation of coagulopathy in TBI.

Coronavirus (COVID-19), Coagulation, and Exercise: Interactions That May Influence Health Outcomes

Abstract: The proinflammatory cytokine storm associated with coronavirus disease 2019 (COVID-19) negatively affects the hematological system, leading to coagulation activation and endothelial dysfunction and thereby increasing the risk of venous and arterial thrombosis. Coagulopathy has been reported as associated with mortality in people with COVID-19 and is partially reflected by enhanced D-dimer levels. Poor vascular health, which is associated with the cardiometabolic health conditions frequently reported in people with severer forms of COVID-19, might exacerbate the risk of coagulopathy and mortality. Sedentary lifestyles might also contribute to the development of coagulopathy, and physical activity participation has been inherently lowered due to at-home regulations established to slow the spread of this highly infectious disease. It is possible that COVID-19, coagulation, and reduced physical activity may contribute to generate a “perfect storm,” where each fuels the other and potentially increases mortality risk. Several pharmaceutical agents are being explored to treat COVID-19, but potential negative consequences are associated with their use. Exercise is known to mitigate many of the identified side effects from the pharmaceutical agents being trialled but has not yet been considered as part of management for COVID-19. From the limited available evidence in people with cardiometabolic health conditions, low- to moderate-intensity exercise might have the potential to positively influence biochemical markers of coagulopathy, whereas high-intensity exercise is likely to increase thrombotic risk. Therefore, low- to moderate-intensity exercise could be an adjuvant therapy for people with mild-to-moderate COVID-19 and reduce the risk of developing severe symptoms of illness that are associated with enhanced mortality.