Showing papers in "Seminars in Thrombosis and Hemostasis in 2023"

COVID-19 Vaccine-Associated Immune Thrombosis and Thrombocytopenia (VITT): Diagnostic Discrepancies and Global Implications

Abstract: Abstract Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported in association with the coronavirus disease 2019 preventative adenovirus vector-based vaccines ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson) in hundreds of recipients across the globe. VITT is characterized by thrombosis, typically at unusual sites, low fibrinogen, and elevated plasma D-dimer, generally manifesting between 4 and 28 days following vaccination. Detection of anti-platelet factor antibodies using an enzyme-linked immunosorbent assay (ELISA) is often confirmatory. Although several similar principles subside in most diagnostic criteria for VITT, the presentation of a positive ELISA assay, use of expert hematology and neurology opinion, and exclusion of possible VITT cases outside the “standard” 4 to 28-day timeframe have contributed a lack of global standardization for defining VITT. Accordingly, the global and regional incidence of VITT differs according to the diagnostic pathway and case definition used. This has influenced the public perception of VITT's severity and the decision to use adenovirus vector-based vaccines for limiting severe acute respiratory syndrome coronavirus 2 infection. We hereby delineate the recognized pathogenic mechanisms, global incidence, discrepancies in diagnostic criteria, recommended treatments, and global implications to vaccine hesitancy from this coagulopathy.

Mechanisms of Thrombosis in Heparin-Induced Thrombocytopenia and Vaccine-Induced Immune Thrombotic Thrombocytopenia

Abstract: Abstract Heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT) are rare, iatrogenic immune-mediated conditions with high rates of thrombosis-related morbidity and mortality. HIT is a long-recognized reaction to the administration of the common parenterally administered anticoagulant heparin (or its derivatives), while VITT is a new, distinct syndrome occurring in response to adenovirus-based vaccines against coronavirus disease 2019 and potentially other types of vaccines. A feature of both HIT and VITT is paradoxical thrombosis despite a characteristic low platelet count, mediated by the presence of platelet-activating antibodies to platelet factor 4. Several additional factors have also been suggested to contribute to clot formation in HIT and/or VITT, including monocytes, tissue factor, microparticles, endothelium, the formation of neutrophil extracellular traps, complement, procoagulant platelets, and vaccine components. In this review, we discuss the literature to date regarding mechanisms contributing to thrombosis in both HIT and VITT and explore the pathophysiological similarities and differences between the two conditions.

Increased Platelet Activation demonstrated by Elevated CD36 and P-Selectin Expression in 1-Year Post-Recovered COVID-19 Patients

Abstract: Samuel Sherng Young Wang, MD1 Keefe Chee, PhD2 Shiun Woei Wong, MRCP3,4,5 Guat Bee Tan, MSc6,7 Hong Ang, BSc6 Bernard PuiLam Leung, PhD4,8,9 Chuen Wen Tan, FRCPath10 Kollengode Ramanathan, FCCP4,11 Rinkoo Dalan, FRCP3,4,12 Christine Cheung, PhD3,13 David Chien Lye, FRCP3,4,14,15 Barnaby Edward Young, MRCP3,4,14,15 Eng Soo Yap, FRCPath4,16 Yew Woon Chia, FRCP3,4,5 Bingwen Eugene Fan, MRCP1,2,3,4 and The COVID-19 Clotting and Bleeding Investigators

Maintaining Hemostasis and Preventing Thrombosis in Coronavirus Disease 2019 (COVID-19)—Part IV

Abstract: Welcome to another issue of Seminars in Thrombosis and Hemostasis (STH), published under the “banner” of “Maintaining hemostasis and preventing thrombosis in coronavirus disease 2019 (COVID-19),” this being Part IV, or the fourth such volume. The first three issues were, respectively, published in 2020,[1] 2021,[2] and 2022,[3] and proved very popular with the STH readership. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Believed to originate from Wuhan City in China, with the first reported case in November 2019, at the time of writing, there were over 630 million cases reported worldwide and over 6.5 million attributable deaths, thus including it among the 10 most deadly pandemics throughout recent human history.[4]

Prognostic Impact of the International Society on Thrombosis and Hemostasis Disseminated Intravascular Coagulation Score in Sepsis: A Systematic Review

Abstract: Abstract The International Society on Thrombosis and Haemostasis (ISTH) diagnostic criteria for disseminated intravascular coagulation (DIC) are widely used for DIC diagnosis. However, the prognostic value of the score may vary between different patient populations and settings. This systematic review investigated the association between the ISTH DIC score and mortality in sepsis patients. A literature search was conducted in PubMed and Embase. Inclusion criteria were studies including adult and pediatric patients hospitalized with sepsis, using any sepsis definition, and investigating the association between mortality and the ISTH DIC score. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. In total, 42 studies were included. A positive association between the ISTH DIC score and mortality was consistently reported, with odds ratios of death in DIC versus non-DIC patients ranging from 1.125 (95% confidence interval [CI]: 0.838–1.511) to 21.008 (95% CI: 1.408–313.405) in adults and from 1.378 (95% CI: 1.004–1.893) to 2.99 (95% CI: 0.54–16.6) in pediatric populations. However, the DIC score only had a low-moderate positive predictive value for mortality, as area under receiver-operator characteristics ranged from 0.602 (95% CI: 0.575–0.630) to 0.815 (95% CI: 0.676–0.954) in adults. Of note, only few studies adjusted for potential confounders such as age, gender, and comorbidity. The ISTH DIC score is consistently associated with sepsis-related mortality but is not a strong positive predictor for mortality. Nevertheless, the score may still have a prognostic value and its use in sepsis is encouraged.

Evolution of Antiphospholipid Syndrome

Abstract: Abstract Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disease characterized by thrombosis and/or pregnancy complications caused by antiphospholipid antibodies (aPL). The history of APS can be traced back to observations made during screening programs for syphilis conducted in the mid-20th century, with identification of patients with the so-called biological false-positive serological reactions for syphilis. Initial observation linking aPL with recurrent miscarriages was first reported more than 40 years ago. Since then, our understanding of the pathogenesis and management of APS has evolved markedly. Although APS is an autoimmune disease, anticoagulation mainly with vitamin K antagonists (VKAs) rather than immunomodulation, is the treatment of choice for thrombotic APS. Direct acting oral anticoagulants are inferior to VKAs, especially those with triple-positive APS and arterial thrombosis. Inflammation, complement activation, and thrombosis in the placenta may contribute to pathogenesis of obstetric APS. Heparin, mainly low-molecular-weight heparin, and low-dose aspirin represent the treatments of choice for women with obstetric complications. Increasingly, immunomodulatory agents such as hydroxychloroquine for thrombotic and obstetric APS are being used, especially in patients who are refractory to present standard treatment.

Clinical Studies with Anticoagulants that Have Changed Clinical Practice

Abstract: Abstract Anticoagulant therapy is the cornerstone of treatment and prevention of arterial and venous thromboembolism. Taking a historical perspective, starting in the 1960s, and progressing through to 2022, we discuss key clinical trials of anticoagulants that have changed clinical practice, and examine obstacles encountered in bringing these anticoagulants to the clinic. The design of some of the early studies that shaped clinical practice was poor by current standards, but their results were influential because nothing better was available. Both heparin and vitamin K antagonists had been in clinical use for several decades before well-designed trials in the 1980s optimized their dosing and enhanced their safety and efficacy. Low-molecular-weight heparin then replaced unfractionated heparin because it had a more predictable dose–response and a longer half-life, thereby allowing it to be used conveniently in out-of-hospital settings. More recently, direct oral anticoagulants became the oral anticoagulants of choice for most indications because they were shown to be at least as safe and effective as vitamin K antagonists when used in fixed doses without the need for laboratory monitoring. The design of the trials that led to the approval of the direct oral anticoagulants was excellent, but further studies are required to optimize their dosing in selected patients who were underrepresented in these trials.

The Post–Venous Thromboembolism Functional Status Scale: From Call to Action to Application in Research, Extension to COVID-19 Patients, and Its Use in Clinical Practice

Abstract: Abstract A broad spectrum of long-term sequelae may be present in venous thromboembolism (VTE) survivors, affecting their quality of life and functioning. To monitor recovery and improve the prognosis of patients with persistent functional limitations, the development of a new outcome measure that could better capture the consequences of VTE was an unmet need. Starting as a call to action, the Post-VTE Functional Status (PVFS) scale was developed to meet this need. The PVFS scale is an easy-to-use clinical tool to measure and quantify functional outcomes after VTE by focusing on key aspects of daily life. As the scale was considered useful in coronavirus disease 2019 (COVID-19) patients as well, the Post-COVID-19 Functional Status (PCFS) scale was introduced early in the pandemic after slight adaptation. The scale has been well incorporated into both the VTE and COVID-19 research communities, contributing to the shift of focus toward patient-relevant functional outcomes. Psychometric properties have been evaluated, mainly for the PCFS scale but recently also for the PVFS scale, including validation studies of translations, showing adequate validity and reliability. In addition to serving as outcome measure in studies, guidelines and position papers recommend using the PVFS and PCFS scale in clinical practice. As broad use of the PVFS and PCFS scale in clinical practice is valuable to capture what matters most to patients, widespread implementation is a crucial next step. In this review, we discuss the development of the PVFS scale and introduction in VTE and COVID-19 care, the incorporation of the scale in research, and its application in clinical practice.

Causal Associations Between Cardiovascular Risk Factors and Venous Thromboembolism

Abstract: Abstract Objective The aim of the study is to assess the causal effects of cardiovascular risk factors on venous thromboembolism (VTE) and its subtypes including deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods A summary-level Mendelian randomization (MR) analysis was performed by extracting data from public and large-scale genome-wide association studies for cardiovascular risk factors (hypertension, systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, triglycerides, high-density lipoprotein [HDL], low-density lipoprotein [LDL], type 2 diabetes, fasting glucose, body mass index [BMI], smoking, alcohol, and physical activity), VTE, DVT, and PE to identify genetic instruments. Results BMI (per standard deviation [SD] increase; odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.25–1.54; p = 8.02 × 10 −10 ) could increase the VTE risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98–0.99; p = 0.0005) could decrease the VTE risk. For DVT, BMI (per SD increase; OR: 1.48; 95% CI: 1.28–1.72; p = 1.53 × 10 −7 ) could increase the risk, whereas physical activity (per SD increase; OR: 0.05; 95% CI: 0.01–0.33; p = 0.0020) could decrease the risk. For PE, BMI (per SD increase; OR: 1.29; 95% CI: 1.12–1.49; p = 0.0005) could increase the risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98–1.00; p = 0.0032) could decrease the risk. Suggestive evidence between smoking and higher risks of VTE and DVT was also observed. Conclusion Our study supports that BMI is a causal risk factor for VTE, DVT, and PE. SBP is a protective factor for VTE and PE. Physical activity is a protective factor for DVT. However, the effects of other cardiovascular risk factors are not identified.

The Use of Bypassing Treatment Strategies in Hemophilia and Their Effect on Laboratory Testing

Abstract: Abstract Factor VIII and IX inhibitors in congenital hemophilia A and B, respectively, neutralize the infused coagulation factor concentrate rendering them ineffective. Bypassing agents (BPAs) that circumvent the block imposed by the inhibitors are used for the prevention and management of bleeding. Activated prothrombin complex concentrate was the original BPA, recombinant activated factor VII was then introduced, and more recently nonfactor agents that target the procoagulant and anticoagulant systems have been developed and are in clinical use (e.g., emicizumab, a bispecific antibody for hemophilia A). Other BPAs are in clinical trials (e.g., fitusiran targets antithrombin, concizumab and marstacimab target tissue factor pathway inhibitor, and SerpinPC targets activated protein C). The BPAs have a varied effect on coagulation assays, and as more patients are exposed to these agents, it is important to be aware of the effects. Herein, we present an overview of the effect of BPAs on routine and specialized coagulation assays including thrombin generation and viscoelastic assays.

Increased Levels of Inflammatory and Endothelial Biomarkers in Blood of Long COVID Patients Point to Thrombotic Endothelialitis

Abstract: Abstract The prevailing hypotheses for the persistent symptoms of Long COVID have been narrowed down to immune dysregulation and autoantibodies, widespread organ damage, viral persistence, and fibrinaloid microclots (entrapping numerous inflammatory molecules) together with platelet hyperactivation. Here we demonstrate significantly increased concentrations of von Willebrand factor (VWF), platelet factor 4 (PF4), serum amyloid A (SAA), α-2 antiplasmin (α-2AP), endothelial-leukocyte adhesion molecule 1 (E-selectin), and platelet endothelial cell adhesion molecule (PECAM-1) in the soluble part of the blood. It was noteworthy that the mean level of α-2 antiplasmin exceeded the upper limit of the laboratory reference range in Long COVID patients, and the other 5 were significantly elevated in Long COVID patients as compared to the controls. This is alarming if we take into consideration that a significant amount of the total burden of these inflammatory molecules has previously been shown to be entrapped inside fibrinolysis-resistant microclots (thus decreasing the apparent level of the soluble molecules). We conclude that presence of microclotting, together with relatively high levels of six biomarkers known to be key drivers of endothelial and clotting pathology, points to thrombotic endothelialitis as a key pathological process in Long COVID.

Drug–Drug Interactions in the Treatment of Cancer-Associated Venous Thromboembolism with Direct Oral Anticoagulants

Abstract: Abstract Venous thromboembolism (VTE) is a frequent complication of cancer, and management of cancer-associated thrombosis (CAT) is challenging due to increased risks of bleeding and recurrent VTE. Recent trials have shown an acceptable efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of CAT compared to low-molecular weight heparin. Although DOACs provide an effective and convenient treatment option in CAT, the need to assess the risk of drug–drug interactions (DDI) with antineoplastic therapies poses a barrier to their use in clinical practice. With the aim of supporting the assessment of CAT patients for treatment with DOAC, this review provides a comprehensive overview of the compatibility of antineoplastic therapies with the individual DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban). Using several data sources, we characterized 100 widely used antineoplastic agents with regard to their effect on p-glycoprotein and cytochrome P450, both important in the transport and elimination of DOACs. This enabled us to evaluate 400 “DOAC-antineoplastic agent”-pairs regarding their likelihood to interact (unlikely, potential, or likely), ultimately leading to clinical recommendations on the appropriateness of concomitant use for each pair. A potential or likely DDI was identified for 12% of the evaluated pairs. For nearly all antineoplastic agents, at least one DOAC was considered compatible.

Evolution of Hemostasis Testing: A Personal Reflection Covering over 40 Years of History *

Abstract: Abstract There is no certainty in change, other than change is certain. As Seminars in Thrombosis and Hemostasis celebrates 50 years of publication, I felt it appropriate to reflect on my own 40-year plus scientific career. My career in the thrombosis and hemostasis field did not start until 1987, but the subsequent 35 years reflected a period of significant change in associated disease diagnostics. I started in the Westmead Hospital “coagulation laboratory” when staff were still performing manual clotting tests, using stopwatches, pipettes, test tubes, and a water bath, which we transported to the hospital outpatient department to run our weekly warfarin clinic. Several hemostasis instruments have come and gone, including the Coag-A-Mate X2, the ACL-300R, the MDA-180, the BCS XP, and several StaR Evolution analyzers. Some instruments remain, including the PFA-100, PFA-200, the AggRAM, the CS-5100, an AcuStar, a Hydrasys gel system, and two ACL-TOP 750s. We still have a water bath, but this is primarily used to defrost frozen samples, and manual clotting tests are only used to teach visiting medical students. We have migrated across several methodologies in the 45-year history of the local laboratory. Laurel gel rockets, used for several assays in the 1980s, were replaced with enzyme-linked immunosorbent assay assays and most assays were eventually placed on automated instruments. Radio-isotopic assays, used in the 1980s, were replaced by an alternate safer method or else abandoned. Test numbers have increased markedly over time. The approximately 31,000 hemostasis assays performed at the Westmead-based laboratory in 1983 had become approximately 200,000 in 2022, a sixfold increase. Some 90,000 prothrombin times and activated partial thromboplastic times are now performed at this laboratory per year. Thrombophilia assays were added to the test repertoires over time, as were the tests to measure several anticoagulant drugs, most recently the direct oral anticoagulants. I hope my personal history, reflecting on the changes in hemostasis testing over my career to date in the field, is found to be of interest to the readership, and I hope they forgive any inaccuracies I have introduced in this reflection of the past.

Sex-Related Differences in Patients Characteristics, Risk Factors, and Symptomatology in Older Adults with Pulmonary Embolism: Findings from the SERIOUS-PE Study

Abstract: Abstract Sex-specific factors are implicated in pulmonary embolism (PE) presentation in young patients, as indicated by increased risk in pregnancy. Whether sex differences exist in PE presentation, comorbidities, and symptomatology in older adults, the age group in which most PEs occur, remains unknown. We identified older adults (aged ≥65 years) with PE in a large international PE registry replete with information about relevant clinical characteristics (RIETE registry, 2001–2021). To provide national data from the United States, we assessed sex differences in clinical characteristics and risk factors of Medicare beneficiaries with PE (2001–2019). The majority of older adults with PE in RIETE (19,294/33,462, 57.7%) and in the Medicare database (551,492/948,823, 58.7%) were women. Compared with men, women with PE less frequently had atherosclerotic diseases, lung disease, cancer, or unprovoked PE, but more frequently had varicose veins, depression, prolonged immobility, or history of hormonal therapy ( p < 0.001 for all). Women less often presented with chest pain (37.3 vs. 40.6%) or hemoptysis (2.4 vs. 5.6%) but more often with dyspnea (84.6 vs. 80.9%) ( p < 0.001 for all). Measures of clot burden, PE risk stratification, and use of imaging modalities were comparable between women and men. PE is more common in elderly women than in men. Cancer and cardiovascular disease are more common in men, whereas transient provoking factors including trauma, immobility, or hormone therapy are more common in elderly women with PE. Whether such differences correlate with disparities in treatment or differences in short- or long-term clinical outcomes warrants further investigation.

The Future of Laboratory-Developed Tests in Hemostasis Laboratories

Abstract: Abstract Laboratory-developed tests (LDTs) are widely used in clinical hemostasis laboratories. The extent to which LDTs are regulated varies greatly around the world, and proposed changes to regulations have raised concerns about the future of LDTs in clinical laboratories. It is increasingly difficult to justify the use of an LDT where a commercially available method with regulatory approval is available. Conversely, where there is no suitable test with regulatory approval and there is a compelling clinical need, using an LDT outweighs the risk associated with not performing the test. We argue that LDTs are still required in specialist clinical laboratories to fulfill unmet clinical needs, and in lower middle-income countries where they are a vital resource.

Hemostasis in the Pregnant Woman, the Placenta, the Fetus, and the Newborn Infant

Abstract: Abstract The hemostasis system is composed of procoagulant, anticoagulant, and fibrinolytic proteins that interact with endothelial and blood cells and with each other in a complex system of checks and balances to maintain blood flow while preventing both hemorrhage and thrombosis. Pregnancy is a unique physiological state in which biological alterations predispose both mother and fetus to both bleeding and clotting. The placenta is a vascular interface for maternal and fetal blood exchange which predisposes the mother to hemorrhage. Maternal hemostasis presents a compensatory hypercoagulability including elevated factor VIII, von Willebrand factor, fibrinogen and thrombin generation, decreased thrombin regulation with resistance to activated protein C and decreased free protein S, and decreased fibrinolysis with increased plasminogen activator inhibitors. The placental vascular surface is of fetal trophoblastic origin that derives many characteristics of endothelium but differs in that tissue factor is constitutively expressed. Ontogeny of fetal hemostasis is characteristic. Platelets, von Willebrand factor, factor VIII, and fibrinogen are expressed and mature early in gestation, while vitamin K–dependent and contact factors exhibit delayed development. The fetal hemostatic system has a decreased capacity to generate or regulate thrombin, resulting in a fragile balance with little capacity to compensate under stress conditions, particularly in the infant born prematurely. Dysfunction of the maternal/placental/fetal unit gives rise to gestational disorders including preeclampsia, fetal growth restriction, placental abruption, and premature delivery. Knowledge of normal hemostasis levels and function are critical to evaluate bleeding or clotting syndromes in the pregnant woman and her fetus or newborn infant.

Assessment of Hemostatic Profile in Neonates with Intrauterine Growth Restriction: A Systematic Review of Literature

Abstract: Abstract Intrauterine growth restriction (IUGR) affects nearly 10 to 15% of pregnancies and is responsible for many short- and long-term adverse consequences, including hemostatic derangement. Both thrombotic and hemorrhagic events are described in the perinatal period in these neonates. The aim of this study was to systematically review the literature on the laboratory studies used to evaluate the hemostatic system of the IUGR small for gestational age neonate. We reviewed the current literature via PubMed and Scopus until September 2022. Following our inclusion/exclusion criteria, we finally included 60 studies in our review. Thrombocytopenia, characterized as hyporegenerative and a kinetic upshot of reduced platelet production due to in utero chronic hypoxia, was the main finding of most studies focusing on growth-restricted neonates, in most cases is mild and usually resolves spontaneously with the first 2 weeks of life. In regard to coagulation, growth-restricted newborns present with prolonged standard coagulation tests. Data regarding coagulation factors, fibrinolytic system, and anticoagulant proteins are scarce and conflicting, mainly due to confounding factors. As thromboelastography/rotational thromboelastometry (TEG/ROTEM) provides a more precise evaluation of the in vivo coagulation process compared with standard coagulation tests, its use in transfusion guidance is fundamental. Only one study regarding TEG/ROTEM was retrieved from this population, where no difference in ROTEM parameters compared with appropriate for gestational age neonates was found. Despite the laboratory aberrations, no correlation could be achieved with clinical manifestations of bleeding or thrombosis in the studies included. More studies are needed to assess hemostasis in IUGR neonates and guide targeted therapeutic interventions.

Laboratory Evaluation of Antithrombin, Protein C, and Protein S

Abstract: Abstract Thrombophilia is a complex disease process, clinically manifesting in various forms of venous thromboembolism. Although both genetic and acquired (or environmental) risks factors have been reported, the presence of a genetic defect (antithrombin [AT], protein C [PC], protein S [PS]) is considered three of the major contributing factors of thrombophilia. The presence of each of these risk factors can be established by clinical laboratory analysis; however, the clinical provider and laboratory personnel must understand the testing limitations and shortcomings associated with the assays for these factors to be able to ensure an accurate diagnosis. This article will describe the major pre-analytical, analytical, and post-analytical issues associated with the various types of assays and discuss evidence-based algorithms for analyzing AT, PC, and PS in plasma.

2023 Eberhard F. Mammen Award Announcements: Part I-Most Popular Articles.

Abstract: Welcome to the latest of our Eberhard F. Mammen award announcements. As noted in previous editorials ([Table 1]), Thieme, the publisher of Seminars in Thrombosis and Hemostasis (STH), has created the “Eberhard F. Mammen Excellence in Thrombosis and Hemostasis Awards” in honor of Eberhard Mammen ([Fig. 1]), and in recognition of his contribution to this field and to the journal that he both founded and steered for over three decades. These awards began in 2009, under two categories, “Most Popular Article Awards” and “Young Investigator Awards.” Accordingly, 2023 represents 15 years of award presentations ([Table 1]). Current details and conditions of the award can be summarized as:

NETosis in Acute Thrombotic Disorders

Abstract: Abstract The release of extracellular traps by neutrophils (NETs) represents a novel active mechanism of cell death that has been recently implicated in the pathogenesis of thrombotic disorders. The aim of this study was to investigate the generation of NETs in different groups of patients with acute thrombotic events (ATEs) and to establish whether NETs markers can predict the risk of new cardiovascular events. We performed a case–control study of patients with ATE, including acute coronary syndrome ( n = 60), cerebrovascular accident ( n = 50), and venous thromboembolism ( n = 55). Control subjects ( n = 70) were identified among patients admitted for acute chest pain and in which a diagnosis of ATE was excluded. Serum levels of NET markers and neutrophil activation, such as myeloperoxidase (MPO)-DNA complexes, neutrophil gelatinase-associated lipocalin, polymorphonuclear neutrophil elastase, lactoferrin, and MPO, were measured in each patient. We found that circulating levels of MPO-DNA complexes were significantly increased in patients with ATE ( p < 0.001) compared with controls and that this association remained significant even after fully adjustment for traditional risk factors ( p = 0.001). A receiver operating characteristics analysis of circulating MPO-DNA complexes in discriminating between controls and patients with ATE showed a significant area under the curve of 0.76 (95% confidence interval: 0.69–0.82). After a median follow-up of 40.7 (± 13.8) months, 24 out of the 165 patients with ATE presented a new cardiovascular event and 18 patients died. None of the markers under investigation influenced survival or the incidence of new cardiovascular events. In conclusion, we found that increase of markers of NETosis can be observed in acute thrombotic conditions, occurring both on the arterial and venous site. Nevertheless, the level of neutrophil markers measured during the ATE is not predictive of future risk of mortality and cardiovascular events.

A Brief History of Hemostasis and Thrombosis at the Mayo Clinic

Abstract: Abstract Coagulation is a crucial biological mechanism in human bodies to prevent blood loss. Abnormal coagulation can cause bleeding diathesis or thrombosis, common pathologic conditions in our clinical practice. Many individuals and organizations have dedicated their efforts in the past decades to understanding the biological and pathological mechanisms of coagulation and developing laboratory testing tools and treatment options to help patients with bleeding or thrombotic conditions. Since 1926, the Mayo Clinic coagulation group has made significant contributions to the clinical and laboratory practice, basic and translational research on various hemostatic and thrombotic disorders, and the education and collaboration to share and advance our knowledge in coagulation through a highly integrated team and practice model. We would like to use this review to share our history and inspire medical professionals and trainees to join the efforts to advance our understanding of coagulation pathophysiology and improve our care for patients with coagulation disorders.

Platelet Parameters as Biomarkers for Thrombosis Risk in Cancer: A Systematic Review and Meta-analysis

Abstract: Abstract Cancer-associated thrombosis (CAT) is a major cause of both morbidity and mortality in cancer patients. Platelet count has been investigated as a predictor of CAT in various settings while knowledge on platelet activation parameters is sparse. This report provides a systematic review and meta-analysis on available literature on associations between platelet count and/or function and arterial and venous thrombosis in adult cancer patients. The review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. PubMed and Embase were searched up to March 2022. The National Heart, Lung, and Blood Institute's tools were used for quality assessment. In total, 100 studies were included which investigated the association between CAT and platelet count ( n = 90), platelet indices ( n = 19), and platelet function/activation markers ( n = 13) in patients with solid cancers ( n = 61), hematological cancers ( n = 17), or mixed cancer types ( n = 22). Eighty-one studies had venous thrombosis as their outcome measure, while 4 had arterial thrombosis and 15 studies had both. We found significantly elevated odds ratio of 1.50 (95% confidence interval: 1.19–1.88) for thrombosis with higher platelet counts. We saw a tendency toward an association between markers of platelet activation in forms of mean platelet volume and soluble P selectin and both arterial and venous thrombosis. Only one study investigated dynamic platelet function using flow cytometry. In conclusion, platelet count is associated with CAT across different cancer types and settings. Platelet function or activation marker analysis may be valuable in assisting thrombosis risk assessment in cancer patients but is sparsely investigated so far.

Novel Insights into Heterozygous Factor XIII Deficiency

Abstract: Abstract The prevalence and clinical significance of heterozygous factor XIII (FXIII) deficiency has long been debated, with controversial reports emerging since 1988. In the absence of large epidemiologic studies, but based on a few studies, a prevalence of 1 per 1,000 to 5,000 is estimated. In southeastern Iran, a hotspot area for the disorder, a study of more than 3,500 individuals found an incidence of 3.5%. Between 1988 and 2023, a total of 308 individuals were found with heterozygous FXIII deficiency, of which molecular, laboratory, and clinical presentations were available for 207 individuals. A total of 49 variants were found in the F13A gene, most of which were missense (61.2%), followed by nonsense (12.2%) and small deletions (12.2%), most occurring in the catalytic domain (52.1%) of the FXIII-A protein and most frequently in exon 4 (17%) of the F13A gene. This pattern is relatively similar to homozygous (severe) FXIII deficiency. In general, heterozygous FXIII deficiency is an asymptomatic condition without spontaneous bleeding tendency, but it can lead to hemorrhagic complications in hemostatic challenges such as trauma, surgery, childbirth, and pregnancy. Postoperative bleeding, postpartum hemorrhage, and miscarriage are the most common clinical manifestations, while impaired wound healing has been rarely reported. Although some of these clinical manifestations can also be observed in the general population, they are more common in heterozygous FXIII deficiency. While studies of heterozygous FXIII deficiency conducted over the past 35 years have shed light on some of the ambiguities of this condition, further studies on a large number of heterozygotes are needed to answer the major questions related to heterozygous FXIII deficiency.

Applications of Viscoelastic Testing in Breast Cancer Patients: A Systematic Review Focusing on Hypercoagulability and Free Flap Thrombosis

Abstract: Abstract Viscoelastic testing is a clinically available method to assess hypercoagulability. This systematic review aims to provide a comprehensive overview of the existing literature and the potential use of such testing in patients with breast cancer. A systematic literature search for studies investigating the application of viscoelastic testing for patients with breast cancer was conducted. Studies were included as long as they were original, peer-reviewed, and in the English language. Studies were excluded if they were review articles, did not include breast cancer patients, or if the full text was unavailable. This review identified 10 articles that met the inclusion criteria. Two of the studies utilized rotational thromboelastometry, and an additional four studies used thromboelastography, to assess hypercoagulability in patients with breast cancer. Three of the identified articles discussed the use of thromboelastometry in free flap breast reconstruction for patients with breast cancer. One study was a retrospective chart review looking at thromboelastography and microsurgical breast reconstruction. Current literature regarding the application of viscoelastic testing in breast cancer and free flap breast reconstruction is limited, with no randomized trials thus far. However, some studies suggest that there may be potential utility in viscoelastic testing to assess risk for thromboembolism in breast cancer patients, and future research in this area is warranted.

The History of Factor XIII Deficiency

Abstract: Abstract Despite the early discovery of factor XIII (FXIII) in 1944, the diagnosis of FXIII deficiency was not made until 1960, after all the other coagulation factor deficiencies, most likely due to the normality of routine coagulation testing in FXIII deficiency. Although the first case was detected by the clot solubility test and this test has long since been used to detect FXIII deficiency, the test is no longer recommended by experts. Over the past 60 years, knowledge about FXIII deficiency has expanded considerably, between 1992, when the first variant was identified, and 2022, 197 mutations have been reported. Almost all missense mutations have a similar effect on FXIII, leading to instability and faster degradation of mutant FXIII protein. Therapeutic options have evolved from historical fresh frozen plasma (FFP), old plasma, whole blood, and cryoprecipitate, to plasma-derived and recombinant FXIII concentrates, respectively available since 1993 and 2012. These concentrate products were respectively approved by the Food and Drug Administration in 2011 and 2013. This historical review covers various aspects of FXIII related disorders, including the discovery of the FXIII, associated disorders, molecular basis, diagnosis, and treatment of FXIII deficiency.

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

Abstract: Abstract Coagulation factor XI (FXI) has increasingly been shown to play an integral role in several physiologic and pathological processes. FXI is among several zymogens within the blood coagulation cascade that are activated by proteolytic cleavage, with FXI converting to the active serine protease form (FXIa). The evolutionary origins of FXI trace back to duplication of the gene that transcribes plasma prekallikrein, a key factor in the plasma kallikrein–kinin system, before further genetic divergence led to FXI playing a unique role in blood coagulation. While FXIa is canonically known for activating the intrinsic pathway of coagulation by catalyzing the conversion of FIX into FIXa, it is promiscuous in nature and has been shown to contribute to thrombin generation independent of FIX. In addition to its role in the intrinsic pathway of coagulation, FXI also interacts with platelets, endothelial cells, and mediates the inflammatory response through activation of FXII and cleavage of high-molecular-weight kininogen to generate bradykinin. In this manuscript, we critically review the current body of knowledge surrounding how FXI navigates the interplay of hemostasis, inflammatory processes, and the immune response and highlight future avenues for research. As FXI continues to be clinically explored as a druggable therapeutic target, understanding how this coagulation factor fits into physiological and disease mechanisms becomes increasingly important.

Hematohidrosis in 15th Century Renaissance Art and a Review of Modern Literature

Abstract: Hematohidrosis, or hematidrosis, is a rare medical condition characterized by blood oozing from the intact skin in the absence of a bleeding problem. 1 Prior to modern-day medical literature, these phenomena had been captured in Renaissance and also present-day artwork. While the purpose of medical literature is to aid healthcare professionals and patients in the better understanding and treatment of dis-ease, a signi fi cant proportion of Renaissance art commis-sioned by the church depicted scenes from the Bible, for the purposes of a visual depiction of key events to promote teachings of the faith

Laboratory Diagnostics for Thrombosis and Hemostasis Testing—Part 2

Abstract: Welcome to a second themed issue of Seminars inThrombosis and Hemostasis dedicated to laboratory diagnostics. In this issue, we will present several state-of-the art reviews highlighting hemostasis/thrombosis testing aspects relevant to a spectrum of bleeding and thrombotic disorders and treatments. The issue begins with a contribution by Adcock et al summarizing the performance of mixing studies to further evaluate the etiology of prolonged clotting times and differentiate factor de fi ciencies from factor inhibitors, inhibitor anticoagulants, and lupus anticoagulants. 1 Due to technical and interpretive non-standardization, combined with patient variables, there is no single approach to mixing studies that will correctly classify all cases as a de fi ciency or an inhibitor. Because mixing study results are often used as an early test to help determine what additional specialized testing is needed, it is vitally important to understand the pre-analytical, analytical, and post-analytical variables that affect the testing, including when the result patterns may be misleading. This review is an excellent summary of the variables that must be considered with each situation. The second manuscript, by Saadalla and colleagues, provides an informative review of traditional and partially automated von Willebrand factor multimeric analysis, and the role of multimers in discriminating different subtypes of von Willebrand disease (VWD). 2 The review includes discussion of VWD subtypes, underlying pathophysiology, and abnormalities of triplet or quintuplet structure that can be seen on multimer gels. The third contribution, authored by Keiji Nogami, describes clot waveform analysis (CWA), an information analysis method that is available on certain coagulation laboratory instruments. 3 The method decon-structs the coagulation pathway of the

Why Does Rivaroxaban Not Work in Severe Mitral Stenosis?

Abstract: Mitral stenosis is not a rare disease. Rheumatic fever is the principal cause of mitral stenosis. Anulus calci fi cation and congenital heart disease are recognized as other causes of mitral stenosis. 1 In developed countries, the prevalence is approximately0.6 in 1,000 in the United States, but it is much higher in developing nations: 21 cases per 1,000 in Asia, 15 cases per 1,000 in Africa, and 17 cases per 1,000 in South America. 2 Atrial fi brillation occurs in approximately 32% of symptomatic patients, thus decreasing cardiac output and exercise capacity, and greatly increasing the risk of thromboembolism. 3 Oral anticoagulationis thereforemandatory in these patients. Although direct oral anticoagulants (DOACs) have been found to be noninferior or superior versus vitamin K antagonists (VKAs; e.g., warfarin) in preventing cardi-oembolism in patients with atrial fi brillation, 4 patients with atrial fi brillation and rheumatic heart disease were not enrolled in earlier trials, thus excluding this pathological condition from approved indications. 5 Since ensuring ade-quate anticoagulation with laboratory monitoring while using VKAs may be dif fi cult in developing countries, DOACs have the potential to improve the extension of oral anticoagulation without the need of any laboratory control. The commitment to plan a superiority trial (DOAC vs. VKA) came in 2016