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Competing Interests: D.J.A. received funding from Bayer PLC to setup the multicenter database of CA-COVID-19 study as an investigator-initiated funding (P87339) and received research grant from Leo Pharma. M.L. received consultation and speaker fees from AstraZeneca, Sobi, LEO Pharma, Takeda, and Pfizer. Others have no conflict of interest to declare.

Hemorrhage remains a major complication of anticoagulants, with bleeding leading to serious and even life-threatening outcomes in rare settings. Currently available anticoagulants target either multiple coagulation factors or specifically coagulation factor (F) Xa or thrombin; however, inhibiting these pathways universally impairs hemostasis. Bleeding complications are especially salient in the medically complex population who benefit from medical devices. Extracorporeal devices-such as extracorporeal membrane oxygenation, hemodialysis, and cardiac bypass-require anticoagulation for optimal use. Nonetheless, bleeding complications are common, and with certain devices, highly morbid. Likewise, pharmacologic prophylaxis to prevent thrombosis is not commonly used with many medical devices like central venous catheters due to high rates of bleeding. The contact pathway members FXI, FXII, and prekallikrein serve as a nexus, connecting biomaterial surface-mediated thrombin generation and inflammation, and may represent safe, druggable targets to improve medical device hemocompatibility and thrombogenicity. Recent in vivo and clinical data suggest that selectively targeting the contact pathway of coagulation through the inhibition of FXI and FXII can reduce the incidence of medical device-associated thrombotic events, and potentially systemic inflammation, without impairing hemostasis. In the following review, we will outline the current in vivo and clinical data encompassing the mechanism of action of drugs targeting the contact pathway. This new class of inhibitors has the potential to herald a new era of effective and low-risk anticoagulation for the management of patients requiring the use of medical devices., Competing Interests: J.J.S reports receiving consulting fees from Aronora Inc. The remaining authors have nothing to disclose., (Thieme. All rights reserved.)

Persistence of serum antiphospholipid antibodies (aPL) is associated with a high thrombotic risk, both arterial and venous, and with pregnancy complications. Due to the potential morbidity and mortality associated with the presence of aPL, identifying and recognizing risk factors for the development of aPL and thrombosis in aPL carriers may help to prevent and reduce the burden of disease. Multiple elements are involved in the pathomechanism of aPL development and aPL-related thrombosis such as genetics, malignancy, and infections. This review will address the role of both well-known risk factors and their evolution, and of emerging risk factors, including COVID-19, in the development of aPL and thrombosis in aPL carriers., Competing Interests: None declared., (Thieme. All rights reserved.)

Khorana score (KS) is an established risk assessment model for predicting cancer-associated thrombosis. However, it ignores several risk factors and has poor predictability in some cancer types. Machine learning (ML) is a novel technique used for the diagnosis and prognosis of several diseases, including cancer-associated thrombosis, when trained on specific diagnostic modalities. Consolidating the literature on the use of ML for the prediction of cancer-associated thrombosis is necessary to understand its diagnostic and prognostic abilities relative to KS. This systematic review aims to evaluate the current use and performance of ML algorithms to predict thrombosis in cancer patients. This study was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Databases Medline, EMBASE, Cochrane, and ClinicalTrials.gov, were searched from inception to September 15, 2023, for studies evaluating the use of ML models for the prediction of thrombosis in cancer patients. Search terms "machine learning," "artificial intelligence," "thrombosis," and "cancer" were used. Studies that examined adult cancer patients using any ML model were included. Two independent reviewers conducted study selection and data extraction. Three hundred citations were screened, of which 29 studies underwent a full-text review, and ultimately, 8 studies with 22,893 patients were included. Sample sizes ranged from 348 to 16,407 patients. Thrombosis was characterized as venous thromboembolism ( n  = 6) or peripherally inserted central catheter thrombosis ( n  = 2). The types of cancer included breast, gastric, colorectal, bladder, lung, esophageal, pancreatic, biliary, prostate, ovarian, genitourinary, head-neck, and sarcoma. All studies reported outcomes on the ML's predictive capacity. The extreme gradient boosting appears to be the best-performing model, and several models outperform KS in their respective datasets., Competing Interests: None declared., (Thieme. All rights reserved.)

Dual antiplatelet therapy (DAPT) is standard treatment for endoluminal stent insertion, and complete resistance to DAPT is rare. A case of in-stent thrombosis occurring 3 hours after stent-assisted coiling of internal carotid artery aneurysm is presented despite compliance with DAPT. Platelet function tests (PFTs) revealed complete clopidogrel and prasugrel resistance., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht‐Sponsor der Veranstaltung): nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background:  Coronavirus disease 2019 (COVID-19) and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers., Methods:  We used two-sample Mendelian randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR-Egger regression and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. All the results were examined by false discovery rate (FDR) with the Benjamin and Hochberg method for this correction to minimize false positives. We used R language for the analysis., Results:  All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (odds ratio [OR] = 0.639, 95% confidence interval [CI]: 0.435-0.938) and IL-1R1 (OR = 0.603, 95% CI = 0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 and increased C-C motif chemokine 3. Hospitalized COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had higher mean platelet volume (MPV) and lower platelet count. These changes in TFPI, tPA, IL-1R1, MPV, and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis., Conclusion:  TFPI, IL-1R, and seven other indicators provide causal clues of the pathogenesis of COVID-19 and thrombosis. This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background:  Patients with a mechanical heart valve (MHV) require oral anticoagulation. Poor anticoagulation control is thought to be associated with adverse outcomes, but data are limited., Objective:  To assess the risks of clinical outcomes in patients with a MHV and poor anticoagulation control on warfarin., Methods:  We conducted a retrospective study of consecutive patients undergoing MHV implantation at a tertiary care center (2010-2019). Primary outcome was a composite of ischemic stroke, systemic embolism, or prosthetic valve thrombosis. Major bleeding and death were key secondary outcomes. We constructed multivariable regression models to assess the association between time in therapeutic range (TTR) on warfarin beyond 90 days after surgery with outcomes., Results:  We included 671 patients with a MHV (80.6% in aortic, 14.6% in mitral position; mean age 61 years, 30.3% female). Median follow-up was 4.9 years, mean TTR was 62.5% (14.5% TTR <40%, 24.6% TTR 40-60%, and 61.0% TTR >60%). Overall rates of the primary outcome, major bleeding, and death were 0.73, 1.41, and 1.44 per 100 patient-years. Corresponding rates for patients with TTR <40% were 1.31, 2.77, and 3.22 per 100 patient-years. In adjusted analyses, every 10% decrement in TTR was associated with a 31% increase in hazard for the primary outcome (hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.13-1.52), 34% increase in major bleeding (HR: 1.34, 95% CI: 1.17-1.52), and 32% increase in death (HR: 1.32, 95% CI: 1.11-1.57)., Conclusion:  In contemporary patients with a MHV, poor anticoagulation control on warfarin was associated with increased risks of thrombotic events, bleeding, and death., Competing Interests: I.J. has received consultancy fees from AstraZeneca, Novo Nordisk, and Boehringer Ingelheim and is supported by unrestricted research grants from Stockholm County Council, Swedish Heart-Lung Foundation, AstraZeneca, and Swedish Society of Cardiology. J.W.E. has received honoraria and/or research support from Anthos, AZ, Bayer, BI, BMS, DSI, Idorsia, Janssen, Merck, and Pfizer. M.R. has received honoraria support in the past from Bayer, BI, and Pfizer. S.S. has received research funding from Octapharma and honoraria from Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Sanofi. S.J.C. has received honoraria or research grants from Bayer, BMS, Pfizer, AstraZeneca, Javelin, Daiichi Sankyo. The remaining authors have no conflicting interests to report., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background:  We conducted a prespecified meta-analysis of two randomized, placebo-controlled trials of rivaroxaban 10 mg daily in prehospital patients with acute coronavirus disease 2019 (COVID-19). Individually, the trials had limited power to detect a treatment effect due to recruitment stopping ahead of plan., Material and Methods:  The statistical analysis plan for the meta-analysis was finalized before unblinding of PREVENT-HD, the larger of the two trials. Pooled risk ratios and pooled risk differences along with the two-sided 95% confidence intervals were calculated using random-effect models., Results:  Rivaroxaban did not reduce the occurrence of either the primary prespecified endpoint, a composite of symptomatic arterial and venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, all-cause hospitalization, and all-cause mortality (risk difference: 0.0044; 95% confidence interval: -0.0263, 0.0175; p  = 0.69 for pooled risk difference) or the secondary endpoint of all-cause hospitalization ( p  = 0.76). Although thrombotic events were infrequent, pooled analysis did reveal that rivaroxaban reduced arterial and venous thrombotic events (placebo 6 events, rivaroxaban 0 events; pooled risk difference: -0.0068; 95% confidence interval: -0.0132, -0.0006; p  = 0.03). In the pooled studies, only one major bleeding event was observed in a rivaroxaban-allocated patient with no critical site or fatal bleeding events., Conclusion:  Although this meta-analysis does not support antithrombotic prophylaxis with rivaroxaban in a broad prehospital population with acute COVID-19, the prevention of arterial and venous thrombotic events among rivaroxaban-allocated patients is consistent with the known thromboprophylactic effect of the drug in medically ill patients., Competing Interests: J.H. and M.P.B. receive salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from: Agios Pharmaceuticals, Inc., Alexion Pharma Godo Kaisha, Amgen Inc., Anthos Therapeutics, Inc., ARCA Biopharma, Inc., AstraZeneca Pharma India, AstraZeneca Pharmaceuticals LP, AstraZeneca UK Ltd, AstraZeneca, Produtos Farmaceuticos, Lda, Atentiv, LLC, Bayer, Bayer (Proprietary) Limited, Bayer Aktiengesellschaft, Bayer Pharma AG, Beth Israel Deaconess Medical Center, Better Therapeutics, Bionest Partners Inc., Boston Clinical Research Institute, LLC, Bristol-Myers Squibb, CellResearch Corporation Pte Ltd, Cleerly, Inc., Colorado Department of Public Health and Environment, Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc., EPG Communication Holdings Ltd, Esperion Therapeutics, Inc., Faraday Pharmaceuticals, Inc., HeartFlow Inc., Hummingbird Bioscience PTE. Ltd., Insmed, Ionis Pharmaceuticals, IQVIA Inc., Janssen Pharmaceuticals, Inc., Janssen Research & Development, LLC, Janssen Scientific Affairs LLC, Lexicon Pharmaceuticals, Inc., LSG Corporation, MedImmune Limited, Medpace, Inc., Medscape, Merck Sharp & Dohme Corp., Northwell Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Osiris Therapeutics, Inc., Pfizer, PPD Development, L.P., Prothena Biosciences Limited, Regeneron, Regents of the University of Colorado, Sanifit Therapeutics S.A., Sanofi, Silence Therapeutics PLC, Stanford University, Stealth BioTherapeutics Inc., The Brigham & Women's Hospital, Inc., Thrombosis Research Institute, UCD iC42 Laboratory, University of Colorado Denver, University of Pittsburgh, VarmX, WraSer, LLC. J.H. also reports owning AstraZeneca stock. A.C.S. has received research support from Boehringer Ingelheim, Janssen and AstraZeneca and consulting fees from Janssen, Bristol-Meyer Squibb/Pfizer Alliance, Sanofi, Alexion, Boehringer Ingelheim, Bayer, Roche Diagnostics, AstraZeneca. G.P. has received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen and Boston Scientific Corporation, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific Corporation, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. M.W.D. reports no potential conflict of interest. S.W., C.L., and E.S.B. were employees of Janssen Research and Development during the conduct of PREVENT-HD. M.P.B. receives support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project) and also reports stock in Medtronic and Pfizer., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Competing Interests: None declared.

Ischemic limb injury can be broadly classified into arterial (absent pulses) and venous/microvascular (detectable pulses); the latter can be divided into two overlapping disorders-venous limb gangrene (VLG) and symmetrical peripheral gangrene (SPG). Both VLG and SPG feature predominant acral (distal) extremity ischemic necrosis, although in some instances, concomitant nonacral ischemia/skin necrosis occurs. Historically, for coagulopathic disorders with prominent nonacral ischemic necrosis, clinician-scientists implicated depletion of natural anticoagulants, especially involving the protein C (PC) system. This historical review traces the recognition of natural anticoagulant depletion as a key feature of nonacral ischemic syndromes, such as classic warfarin-induced skin necrosis, neonatal purpura fulminans (PF), and meningococcemia-associated PF. However, only after several decades was it recognized that natural anticoagulant depletion is also a key feature of predominantly acral ischemic microthrombosis syndromes-VLG and SPG-even when accompanying nonacral thrombosis is not present. These acquired acral limb ischemic syndromes typically involve the triad of (a) disseminated intravascular coagulation, (b) natural anticoagulant depletion, and (c) a localizing explanation for microthrombosis occurring in one or more limbs, either deep vein thrombosis (helping to explain VLG) or circulatory shock (helping to explain SPG). In most cases of VLG or SPG there are one or more events that exacerbate natural anticoagulant depletion, such as warfarin therapy (e.g., warfarin-associated VLG complicating heparin-induced thrombocytopenia or cancer hypercoagulability) or acute ischemic hepatitis ("shock liver") as a proximate factor predisposing to severe depletion of hepatically synthesized natural anticoagulants (PC, antithrombin) in the setting of circulatory shock., Competing Interests: T.E.W. has received lecture honoraria from Werfen (Instrumentation Laboratory), and royalties from Informa (Taylor & Francis) and UptoDate (Wolters Kluwer); has provided consulting services to Arbor Pharmaceuticals, Octapharma, Paradigm Pharmaceuticals, and Veralox Therapeutics; has received research funding from Werfen (Instrumentation Laboratory); has provided expert witness testimony relating to HIT and non-HIT thrombocytopenic and coagulopathic disorders., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Soon after the outbreak of coronavirus disease 2019 (COVID-19), unexplained sustained fatigue, cognitive disturbance, and muscle ache/weakness were reported in patients who had recovered from acute COVID-19 infection. This abnormal condition has been recognized as "long COVID (postacute sequelae of COVID-19 [PASC])" with a prevalence estimated to be from 10 to 20% of convalescent patients. Although the pathophysiology of PASC has been studied, the exact mechanism remains obscure. Microclots in circulation can represent one of the possible causes of PASC. Although hypercoagulability and thrombosis are critical mechanisms of acute COVID-19, recent studies have reported that thromboinflammation continues in some patients, even after the virus has cleared. Viral spike proteins and RNA can be detected months after patients have recovered, findings that may be responsible for persistent thromboinflammation and the development of microclots. Despite this theory, long-term results of anticoagulation, antiplatelet therapy, and vascular endothelial protection are inconsistent, and could not always show beneficial treatment effects. In summary, PASC reflects a heterogeneous condition, and microclots cannot explain all the presenting symptoms. After clarification of the pathomechanisms of each symptom, a symptom- or biomarker-based stratified approach should be considered for future studies., Competing Interests: T.I. has participated in advisory boards of Japan Blood Products Organization, Toray Medical, and Asahi Kasei Pharmaceuticals and received a research grant from JIMRO. J.M.C. received personal fees from Bristol Myers Squibb, Pfizer, Abbott, Alnylam, Anthos, Roche, and Sanofi; research funding to the institution from CSL Behring. J.H.L. serves on the Steering Committees for Merck, Octapharma, and Werfen., (Thieme. All rights reserved.)

Background: East Asians (EAs), compared to white Caucasians (W), have a lower risk of ischemic heart disease and a higher risk of bleeding with antithrombotic medications. The underlying mechanisms are incompletely understood., Objectives: We sought to compare thrombotic profiles of EA and W patients with myocardial infarction (MI) and relate these to cardiovascular outcomes., Methods: In a prospective study in the United Kingdom and Korea, blood samples from patients ( n  = 515) with ST- or non-ST-elevation MI (STEMI and NSTEMI) were assessed using the Global Thrombosis Test, measuring thrombotic occlusion (OT) and endogenous fibrinolysis (lysis time [LT]). Patients were followed for 1 year for major adverse cardiovascular events (MACE) and bleeding., Results: EA patients showed reduced OT (longer OT) compared to W (646 seconds [470-818] vs. 436 seconds [320-580], p  < 0.001), with similar LT. In STEMI, OT (588 seconds [440-759] vs. 361 seconds [274-462], p  < 0.001) and LT (1,854 seconds [1,389-2,729] vs. 1,338 seconds [1,104-1,788], p  < 0.001) were longer in EA than W. In NSTEMI, OT was longer (OT: 734 seconds [541-866] vs. 580 seconds [474-712], p  < 0.001) and LT shorter (1519 seconds [1,058-2,508] vs. 1,898 seconds [1,614-2,806], p  = 0.004) in EA than W patients. MACE was more frequent in W than EA (6.3 vs. 1.9%, p  = 0.014) and bleeding infrequent. While OT was unrelated, LT was a strong independent predictor of MACE event after adjustment for risk factors (hazard ratio: 3.70, 95% confidence interval: 1.43-9.57, p  = 0.007), predominantly in W patients, and more so in STEMI than NSTEMI patients., Conclusion: EA patients exhibit different global thrombotic profiles to W, associated with a lower rate of cardiovascular events., Competing Interests: D.A.G. has received institutional grants from Bayer Plc, AstraZeneca, Werfen, Medtronic, and Alpha MD and honoraria for lectures from AstraZeneca and Boehringer Ingelheim. All other authors have no disclosures to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Introduction:  Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a highly prothrombotic reaction to COVID-19 (coronavirus disease 2019) adenoviral vector vaccines. Its distinct bleeding and thrombotic patterns compared with other platelet consumptive disorders remain unclear., Methods:  We performed a systematic review of the literature (PubMed and Embase) up to July 31, 2022, including case reports and case series providing nonaggregate data of VITT patients. Accurate VITT diagnosis required fulfillment of the following criteria: (1) endorsement by the authors, (2) consistent vaccine type and timing, (3) presence of thrombocytopenia and thrombosis, (4) detection of anti-platelet factor 4 antibodies. Data are presented as frequencies with 95% confidence intervals (CIs) calculated with the exact binomial method., Results:  We retrieved 143 eligible studies, describing 366 patients. Of 647 thrombotic events, 53% (95% CI: 49-56) were venous thromboses at unusual sites and 30% (95% CI: 27-34) were cerebral venous sinus thromboses (CVSTs). The ratio of venous-to-arterial events was 4.1. Thromboses in most sites were associated with at least another thrombotic event, with the exception of CVST and CNS arterial thrombosis (isolated in 49 and 39% of cases, respectively). Bleeding occurred in 36% (95% CI: 31-41) of patients; 68% (95% CI: 59-75) of bleeding events were intracranial hemorrhages (ICHs). Overall mortality was 24% (95% CI: 19-29), and 77% (95% CI: 58-90) in patients with isolated CVST complicated by ICH., Conclusion:  VITT displays a venous-to-arterial thrombosis ratio comparable to heparin-induced thrombocytopenia. However, VITT is characterized by a higher prevalence of CVST and ICH, which contribute to the increased bleeding frequency and mortality., Competing Interests: None declared., (Thieme. All rights reserved.)

Background:  Recently, the mechanism of thrombogenesis has taken a new direction with the involvement of neutrophil extracellular traps (NETs). However, little is known about the relationship between NETs and thrombogenesis in atrial fibrillation (AF)., Objective:  Our study aimed to evaluate NETs in AF patients and their potential association with thrombogenesis. In addition, we studied the effect of NETs on thrombogenesis in rat models., Methods:  A total of 125 AF patients and 172 controls were studied. Spontaneous echo contrast (SEC) was examined using transesophageal echocardiography to assess the prothrombotic state. We used rapid atrial pacing (RAP) rat models to study NETs' formation and their effects on thrombogenesis. The levels of NETs were analyzed by flow cytometry. To deeply understand the regulatory mechanism of NET formation, the transcriptional characteristics of the left atrial appendage (LAA) tissue from RAP rats were analyzed., Results:  We found that NETs were increased significantly in AF patients and positively correlated with SEC grades. And inserting the NET level could significantly enhance the predictivity of CHA 2 DS 2 -VASc scores for the AF prothrombotic state. In the RAP models, we observed that NET levels increased significantly in the LAA and promoted thrombosis. Meanwhile, we found that these changes could be suppressed by the NET formation inhibitor. Transcriptomic analysis of the LAA tissue from RAP rats suggested that RAP might stimulate the NET formation by promoting the expression of inflammatory cytokine and adhesion genes., Conclusion:  NETs may constitute useful thrombogenesis risk markers in AF patients and provide a potential therapeutic strategy for AF management., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: None declared.

Cancer-associated thrombosis (CT), especially venous thromboembolism (VTE), is a common occurrence with several factors contributing to a wide diversity in thrombosis risk. The association between ABO blood groups and the risk for CT has been examined in various studies, with non-O blood type associated with an increased thrombosis risk; however, these studies have reported varying results with recognized limitations. ABO blood groups are known to be implicated in hemostasis, in an association mediated through von Willebrand factor (VWF). In this narrative review, we aim to summarize the current knowledge surrounding the role of ABO blood groups in VTE, with a particular focus on the role of VWF and other contributing risk factors on VTE occurrence. We found evidence from literature for the impact of ABO blood groups in determining the risk of VTE in healthy populations, with a limited number of studies examining this effect in cancer patients. Additionally, research on the impact of ABO on different cancer types lacks rigor, particularly in regard to other risk factors. Overall, most studies showed strong association of increased risk of VTE amongst cancer patients with non-O blood groups and increased VWF levels. This association was weaker in a few studies. Further research is needed before a solid conclusion can be made about the ABO or ABO-VWF-mediated hypercoagulability and VTE risk in various cancers. These studies will help determine if ABO typing can be an added biomarker to improve VTE risk assessment models in cancer patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Cancer is associated with a high risk of venous thromboembolism (VTE) and its recurrence. There is evidence that the prothrombotic fibrin clot phenotype, involving the formation of denser and stiffer clots relatively resistant to lysis, occurs in cancer patients, which is in part related to enhanced inflammation, oxidative stress, and coagulation activation, along with the release of neutrophil extracellular traps, indicating that fibrin-related mechanisms might contribute to cancer-associated thrombosis (CAT). Multiple myeloma and its therapy have been most widely explored in terms of altered fibrin characteristics, but prothrombotic fibrin clot features have also been reported in patients with active solid cancer, including lung cancer and gastrointestinal cancer. Patient-related factors such as advanced age, smoking, and comorbidities might also affect fibrin clot characteristics and the risk of CAT. Prothrombotic fibrin clot features have been shown to predict the detection of cancer in patients following VTE during follow-up. Cancer-specific therapies and anticoagulation can favorably modify the phenotype of a fibrin clot, which may alter the course of CAT. It is unclear whether the fibrin clot phenotype might help identify patients with CAT who are more likely to experience recurrent events. This narrative review summarizes the current knowledge on the role of fibrin clot structure and function in cancer patients in the context of CAT., Competing Interests: None declared., (Thieme. All rights reserved.)

CD36 (also known as platelet glycoprotein IV) is expressed by a variety of different cell entities, where it possesses functions as a signaling receptor, but additionally acts as a transporter for long-chain fatty acids. This dual function of CD36 has been investigated for its relevance in immune and nonimmune cells. Although CD36 was first identified on platelets, the understanding of the role of CD36 in platelet biology remained scarce for decades. In the past few years, several discoveries have shed a new light on the CD36 signaling activity in platelets. Notably, CD36 has been recognized as a sensor for oxidized low-density lipoproteins in the circulation that mitigates the threshold for platelet activation under conditions of dyslipidemia. Thus, platelet CD36 transduces atherogenic lipid stress into an increased risk for thrombosis, myocardial infarction, and stroke. The underlying pathways that are affected by CD36 are the inhibition of cyclic nucleotide signaling pathways and simultaneously the induction of activatory signaling events. Furthermore, thrombospondin-1 secreted by activated platelets binds to CD36 and furthers paracrine platelet activation. CD36 also serves as a binding hub for different coagulation factors and, thus, contributes to the plasmatic coagulation cascade. This review provides a comprehensive overview of the recent findings on platelet CD36 and presents CD36 as a relevant target for the prevention of thrombotic events for dyslipidemic individuals with an elevated risk for thrombosis., Competing Interests: None declared., (Thieme. All rights reserved.)

Venous and arterial thromboembolism are major complications of myeloproliferative neoplasms (MPNs), comprising polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Global hemostasis assays, including thrombin generation assay (TGA), rotational thromboelastometry (ROTEM), and thromboelastography (TEG), have been proposed as biomarkers to assess the hypercoagulability and thrombotic risk stratification in MPNs. We performed a systematic literature review on the parameters of TGA, ROTEM, and TEG and their association with thrombotic events and treatment strategies in MPNs. Thirty-two studies (all cross-sectional) were included, which collectively enrolled 1,062 controls and 1,608 MPN patients. Among the 13 studies that reported arterial or venous thrombosis, the overall thrombosis rate was 13.8% with 6 splanchnic thromboses reported. Out of the 27 TGA studies, there was substantial heterogeneity in plasma preparation and trigger reagents employed in laboratory assays. There was a trend toward increased peak height among all MPN cohorts versus controls and higher endogenous thrombin potential (ETP) between ET patients versus controls. There was an overall trend toward lower ETP between PV and PMF patients versus. controls. There were no substantial differences in ETP between JAK2-positive versus JAK2-negative MPNs, prior history versus negative history of thrombotic events, and among different treatment strategies. Of the three ROTEM studies, there was a trend toward higher maximum clot firmness and shorter clot formation times for all MPNs versus controls. The three TEG studies had mixed results. We conclude that the ability of parameters from global hemostasis assays to predict for hypercoagulability events in MPN patients is inconsistent and inconclusive. Further prospective longitudinal studies are needed to validate these biomarker tools so that thrombotic potential could be utilized as a primary endpoint of such studies., Competing Interests: C.M.K. participated in clinical research trials sponsored by Incyte; and also participated in advisory boards with both Incyte and PharmaEssentia.All other authors have nothing to disclose., (Thieme. All rights reserved.)

Extracorporeal membrane oxygenation (ECMO) is a life-support technique used to treat cardiac and pulmonary failure, including severe cases of COVID-19 (coronavirus disease 2019) involving acute respiratory distress syndrome. Blood clot formation in the circuit is one of the most common complications in ECMO, having potentially harmful and even fatal consequences. It is therefore essential to regularly monitor for clots within the circuit and take appropriate measures to prevent or treat them. A review of the various methods used by hospital units for detecting blood clots is presented. The benefits and limitations of each method are discussed, specifically concerning detecting blood clots in the oxygenator, as it is concluded that this is the most critical and challenging ECMO component to assess. We investigate the feasibility of solutions proposed in the surrounding literature and explore two areas that hold promise for future research: the analysis of small-scale pressure fluctuations in the circuit, and real-time imaging of the oxygenator. It is concluded that the current methods of detecting blood clots cannot reliably predict clot volume, and their inability to predict clot location puts patients at risk of thromboembolism. It is posited that a more in-depth analysis of pressure readings using machine learning could better provide this information, and that purpose-built imaging could allow for accurate, real-time clotting analysis in ECMO components., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: None declared.

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., Competing Interests: None declared., (Thieme. All rights reserved.)

Patients with thrombotic antiphospholipid syndrome (APS) require long-term anticoagulation due to the high-thrombotic recurrence risk. Vitamin K antagonists (VKA) have been traditionally considered the standard of care in thrombotic APS. Nevertheless, the risk of recurrence persists with VKA. There are publications considering different intensities of anticoagulation with VKA; however, the standard-intensity anticoagulation (international normalized ratio between 2.0 and 3.0) is the most recommended. Furthermore, there is no consensus on the role of antiplatelet treatment in thrombotic APS. Nonvitamin K antagonist oral anticoagulants (NOACs) have emerged as an alternative to VKA for many indications. There are, however, discrepancies regarding the management with NOACs in thrombotic APS. In this review, we update the different clinical trials with NOACs in venous, arterial, and microvascular thrombosis and suggest how these patients should be managed in agreement with the expert panels. Although scarce data are published regarding the current role of NOACs in thrombotic APS, the clinical trials failed to demonstrate noninferiority of NOACs compared with VKA, especially in patients with triple antiphospholipid antibodies positivity and/or arterial thrombosis. Single or double antiphospholipid positivity should be analyzed on a case-by-case basis. In addition, we focus on different areas of uncertainty that still remain in thrombotic APS and NOACs. To summarize, emerging clinical trials are needed to provide robust data on the management of thrombotic APS., Competing Interests: None declared., (Thieme. All rights reserved.)

Low fibrinolytic activity has been associated with pathologic thrombosis and multiple-organ failure. Low fibrinolytic activity has two commonly associated terms, hypofibrinolysis and fibrinolysis shutdown. Hypofibrinolysis is a chronic state of lack of ability to generate an appropriate fibrinolytic response when anticipated. Fibrinolysis shutdown is the shutdown of fibrinolysis after systemic activation of the fibrinolytic system. There has been interchanging of these terms to describe critically ill patients in multiple settings. This is problematic in understanding the pathophysiology of disease processes related to these conditions. There is also a lack of research on the cellular mediators of these processes. The purpose of this article is to review the on and off mechanisms of fibrinolysis in the context of low fibrinolytic states to define the importance in differentiating hypofibrinolysis from fibrinolysis shutdown. In many clinical scenarios, the etiology of a low fibrinolytic state cannot be determined due to ambiguity if a preceding fibrinolytic activation event occurred. In this scenario, the term "low fibrinolytic activity" or "fibrinolysis resistance" is a more appropriate descriptor, rather than using assumptive of hypofibrinolysis and fibrinolysis shutdown, particularly in the acute setting of infection, injury, and surgery., Competing Interests: H.B.M. has patents pending in fibrinolysis diagnostics and has received research support from Haemonetics and Instrumentation Laboratories., (Thieme. All rights reserved.)

Assisted reproductive techniques (ART) allow infertile couples to conceive. Use of hormones to obtain a controlled ovarian stimulation and an adequate growth of the endometrium preparatory for embryo implantation are not riskless. Among others, thrombotic events can occur during the ovulation induction or pregnancy following ART. As the number of women approaching ART to conceive is steadily increasing, the issue of thrombotic risk in this setting is relevant. Data on the weight of each risk factor and on potential benefit of thromboprophylaxis are largely lacking. In this review, we discuss risk of venous thromboembolism during pregnancy following ART, with a focus on general (i.e.: age, body mass index, thrombophilia, bed rest, transfusions) and ART-specific (i.e., polycystic ovarian syndrome, ovarian hyperstimulation syndrome) risk factors. We also attempt to provide some suggestions to guide clinical practice, based on available data and studies performed outside ART., Competing Interests: None declared., (Thieme. All rights reserved.)

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., Competing Interests: D.J.A. received funding from Bayer plc to setup the multicenter database of the study as an investigator-initiated funding and received research grant from Leo Pharma. C.P. has no conflict of interest to declare., (Thieme. All rights reserved.)

Introduction:  Vascular complications are severe complications of pediatric kidney transplantation (KT). We aimed to investigate whether a complex bench surgery (BS) affects the outcomes., Methods:  All pediatric KT performed at the University Hospital of Padua from 2015 to 2019 were analyzed, comparing those in which a standard BS was possible to those that necessitated a complex BS. The rates of vascular complications, patients' outcome, and graft survival were compared in the two groups., Results:  Eighty KTs were performed in 78 patients with a median age of 11 years (interquartile range [IQR] 4.3-14) and a median body weight of 24 kg (IQR 13-37). Thirty-nine donor kidneys (49%) needed a complex BS due to anomalies of renal veins in 12 (31%) and renal arteries in 16 (41%). The remaining 11 grafts (28%) underwent an elongation of the vein. There was no difference in the rate of primary graft non function ( p  = 0.97), delayed graft function ( p  = 0.72), and overall survival ( p  = 0.27). The rates of vascular complications, bleedings, and venous graft thrombosis were similar ( p  = 0.51, p  = 0.59, p  = 0.78, respectively). No arterial thrombosis or stenosis was reported., Conclusion:  Complex BS did not compromise survival of the graft and did not put the allograft at risk of vascular complications, such as bleedings or thrombosis., Competing Interests: None declared., (Thieme. All rights reserved.)

Viscoelastic testing (VET) in liver transplantation (LT) has been used since its origin, in combination with standard laboratory testing (SLT). There are only a few, small, randomized controlled trials that demonstrated a reduction in transfusion rates using VET to guide coagulation management. Retrospective analyses contrasting VET to SLT have demonstrated mixed results, with a recent concern for overtreatment and the increase in postoperative thrombotic events. An oversight of many studies evaluating VET in LT is a single protocol that does not address the different phases of surgery, in addition to pre- and postoperative management. Furthermore, the coagulation spectrum of patients entering and exiting the operating room is diverse, as these patients can have varying anatomic and physiologic risk factors for thrombosis. A single transfusion strategy for all is short sighted. VET in combination with SLT creates the opportunity for personalized resuscitation in surgery which can address the many challenges in LT where patients are at a paradoxical risk for both life-threatening bleeding and clotting. With emerging data on the role of rebalanced coagulation in cirrhosis and hypercoagulability following LT, there are numerous potential roles in VET management of LT that have been unaddressed., Competing Interests: H.B.M. reports grants from Haemonetics, other from Instrument laboratories, and other from HemoSonics, outside the submitted work., (Thieme. All rights reserved.)

It is well established that the risk of venous thromboembolism is high in coronavirus disease 19 (COVID-19). The frequency of arterial thromboembolic events (ATEs) in hospitalized patients with COVID-19 is unclear, as is the magnitude of these events in comparison with other infections. We searched MEDLINE from February 2020 to February 2022 for prospective or retrospective cohort studies and randomized clinical trials that reported the number of acute myocardial infarction (AMI), acute ischemic stroke (AIS), acute limb ischemia (ALI), or other ATE as defined by the original authors in hospitalized patients with COVID-19. The pooled frequencies were calculated through meta-analysis using random effects model with logit transformation and presented with relative 95% prediction intervals (95% PI). We retrieved a total of 4,547 studies, 36 of which (28 retrospective cohorts, five prospective cohorts and three randomized trials) were finally included in our analysis. The resulting cohort counted 100,949 patients, 2,641 (2.6%) of whom experienced ATE. The pooled ATE frequency was 2.0% (95% PI, 0.4-9.6%). The pooled ATE frequency for AMI, AIS, ALI, and other ATE was 0.8% (95% PI, 0.1-8.1%), 0.9% (95% PI, 0.3-2.9%), 0.2% (95% PI, 0.0-4.2%), and 0.5% (95% PI, 0.1-3.0%), respectively. In comparison with the ATE incidence reported in three studies on non-COVID viral pneumonia, we did not detect a significant difference from the results in our analysis. In conclusion, we found a non-negligible proportion of ATE in patients hospitalized for COVID-19. Our results are similar to those found in hospitalized patients with influenza or with non-COVID viral pneumonia., Competing Interests: M.C. has nothing to disclose. S.S. reports grants and personal fees from Boehringer Ingelheim, grants from Octapharma, personal fees from Bayer, personal fees from Bristol-Myers Squibb, personal fees from Daiichi-Sankyo, personal fees from Pfizer, personal fees from Sanofi, personal fees from Alexion, outside the submitted work., (Thieme. All rights reserved.)

Competing Interests: None declared.

Thrombophilia leads to an increased risk of venous thromboembolism. Widely accepted risk factors for thrombophilia comprise deficiencies of protein C, protein S, and antithrombin, as well as the factor V "Leiden" mutation, the prothrombin G20210A mutation, dysfibrinogenemia, and, albeit less conclusive, increased levels of factor VIII. Besides these established markers of thrombophilia, risk factors of unclear significance have been described in the literature. These inherited risk factors include deficiencies or loss-of-activity of the activity of ADAMTS13, heparin cofactor II, plasminogen, tissue factor pathway inhibitor (TFPI), thrombomodulin, protein Z (PZ), as well as PZ-dependent protease inhibitor. On the other hand, thrombophilia has been linked to the gain-of-activity, or elevated levels, of α2-antiplasmin, angiotensin-converting enzyme, coagulation factors IX (FIX) and XI (FXI), fibrinogen, homocysteine, lipoprotein(a), plasminogen activator inhibitor-1 (PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI). With respect to the molecular interactions that may influence the thrombotic risk, more complex mechanisms have been described for endothelial protein C receptor (EPCR) and factor XIII (FXIII) Val34Leu. With focus on the risk for venous thrombosis, the present review aims to give an overview on the current knowledge on the significance of the aforementioned markers for thrombophilia screening. According to the current knowledge, there appears to be weak evidence for a potential impact of EPCR, FIX, FXI, FXIII Val34Leu, fibrinogen, homocysteine, PAI-1, PZ, TAFI, and TFPI on the thrombotic risk., Competing Interests: None declared., (Thieme. All rights reserved.)

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is associated with high risk of venous and arterial thrombosis. Thrombotic complications, especially pulmonary embolism, lead to increased all-cause mortality in both intensive care unit and noncritically ill patients. Damage and activation of vascular endothelium, platelet activation, followed by thrombotic and fibrinolytic imbalance as well as hypercoagulability are the key pathomechanisms in immunothrombosis leading to a significant increase in thromboembolism in coronavirus disease 2019 (COVID-19) compared with other acute illnesses. In this review article, we discuss the incidence and prognosis, diagnosis, prevention, and treatment of venous thromboembolism in patients with COVID-19 disease, based on clinical experience and research available to date., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Formation of intravenous catheter-related thrombosis leads to central venous stenosis in patients requiring renal replacement therapy or chemotherapy infusion, yet the triggers or mechanisms remain unclear, especially in patients without symptoms of infection. In this study, we found that neutrophil extracellular traps (NETs) could be detected in the fibrin sheaths from dialysis patients without clinical manifestations of infection. Confocal microscopy revealed bacteria imbedded in NETs in the fibrin sheaths. Thirty-nine of 50 (78%) fibrin sheath specimens contained bacteria detectable by 16S ribosomal RNA genome typing with a predominance of Staphylococcus aureus (69%). In rat models, transient bacteremia of S. aureus induced NETs in enlarged fibrin sheaths, and treatment with DNase I alone significantly reduced both NET and fibrin sheath formation surrounding the catheter. Therefore, transient bacteremia could be a silent trigger that induces NET-related immunothrombosis enhancing catheter-related central venous stenosis., Competing Interests: None declared., (Thieme. All rights reserved.)

COVID-19 has been associated with the hypercoagulable state in the literature. Patients who are admitted to the hospital with severe COVID-19 may have some thrombotic complications. These patients have a high risk for venous and arterial thrombosis of large and small vessels. Here, a 42-year-old female with celiac artery thrombosis and splenic infarction after a history of mild COVID-19 was presented., Competing Interests: The author declares that he has no conflict of interest., (Thieme. All rights reserved.)

Competing Interests: None declared.

Background: Arterial and venous thromboses associated with the coronavirus disease 2019 (COVID-19) have been well described. These events are caused by a hypercoagulable state due to endotheliopathy and infection-driven coagulopathy. There has been an ever-increasing number of documented cases of aortic thrombosis (AoT) in COVID-19 patients. We conducted a systematic review of current scientific literature to identify and consolidate evidence of AoT in COVID-19 patients., Methods: A systematic review of literature was conducted between March 15, 2020, and May 1, 2021, on PubMed and Cochrane databases. Additionally, a case from our facility was included., Results: A total of 38 studies (12 case series and 26 case reports) and a case from our facility describing AoT in 56 COVID-19 patients were included. Patients were aged 64.8 ± 10.5 years, were predominantly male (75%), and had several comorbidities. AoT was symptomatic in 82,14% of patients; however, when D dimers were reported, they were significantly elevated even in otherwise asymptomatic patients. Most patients had no previous history of aortic disease. Thrombosis was described in all parts of the aorta, with several cases reporting multiple locations. The median reported time until development of AoT was 10 days. Peripheral thrombosis occurred in 73.21% of cases, most commonly causing lower limb ischemia. Mortality rate was 30.4%., Conclusions: AoT can occur with no clinical symptoms or as a primary symptom in otherwise asymptomatic COVID-19 patients. D dimers are a highly sensitive diagnostic tool. Diagnosis of this condition prior to development of complications could be instrumental in saving many lives., Competing Interests: None declared., (Thieme. All rights reserved.)

Active malignancy increases the risk of developing venous thromboembolism (VTE) by four- to seven-fold. The risk of VTE, including deep vein thrombosis and pulmonary embolism, in patients with cancer varies based on several clinical factors, such as cancer stage and age. However, race and ethnicity are also associated with increased VTE risk. Black (African American) patients with cancer have a higher risk of developing VTE than White patients, while Asian/Pacific Islanders have a lower risk. Studies on cancer-associated thrombosis demonstrate a need to advance our understanding of both the biologic and sociologic underpinnings of the observed differences according to race. Addressing the causes of these disparities can better health outcomes for historically underserved patient populations., Competing Interests: None declared., (Thieme. All rights reserved.)

Patients supported with extracorporeal membrane oxygenation (ECMO) experience a very high frequency of bleeding and ischaemic complications, including stroke and systemic embolism. These patients require systemic anticoagulation, mainly with unfractionated heparin (UFH) to prevent clotting of the circuit and reduce the risk of arterial or venous thrombosis. Monitoring of UFH can be very challenging. While most centres routinely monitor the activated clotting time and activated partial thromboplastin time (aPTT) to assess UFH, measurement of anti-factor Xa (anti-Xa) level best correlates with heparin dose, and appears to be predictive of circuit thrombosis, although aPTT may be a better predictor of bleeding. Although monitoring of prothrombin time, platelet count and fibrinogen is routinely undertaken to assess haemostasis, there is no clear guidance available regarding the optimal test.Additional tests, including antithrombin level and thromboelastography, can be used for risk stratification of patients to try and predict the risks of thrombosis and bleeding. Each has their specific role, strengths and limitations. Increased thrombin generation may have a role in predicting thrombosis. Acquired von Willebrand syndrome is frequent with ECMO, contributing to bleeding risk and can be detected by assessing the von Willebrand factor activity-to-antigen ratio, while the platelet function analyser can be used in urgent situations to detect this, with a high negative predictive value. Tests of platelet aggregation can aid in the prediction of bleeding.To personalise management, a selection of complementary tests to collectively assess heparin-effect, coagulation, platelet function and platelet aggregation is proposed, to optimise clinical outcomes in these high-risk patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Mechanical thrombectomy (MT) is a highly efficient treatment in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, in a relevant proportion of LVO, no sufficient recanalization can be achieved. The composition of cerebral thrombi is highly heterogeneous and may constitute a relevant factor for insufficient reperfusion. We hypothesized that circulating cytokines and growth factors involved in thromboinflammation and platelet activation may be associated with reperfusion status and thrombus composition in patients undergoing MT. An according biomarker panel was measured in plasma specimens taken prior to MT and at a 7-day follow-up. The reperfusion status was categorized into sufficient or insufficient. The composition of retrieved thrombi was histologically analyzed. Differences of baseline biomarker concentrations between insufficient and sufficient reperfusions were highest for interferon (IFN)-γ, epidermal growth factor, platelet-derived growth factor (PDGF)-AB/BB, and IFN-γ-induced protein 10 (IP-10/CXCL10). After applying correction for multiple comparisons and logistic regression analysis adjusting for stroke etiology, intravenous thrombolysis, and vascular risk factors, PDGF-AB/BB was identified as an independent predictor of reperfusion status (odds ratio: 0.403; 95% confidence interval: 0.199-0.819). Histological analysis revealed that the majority of thrombi had a mixed composition. In conclusion, this study provides the first evidence that cytokines and growth factors are potential effectors in patients undergoing MT for the treatment of acute ischemic stroke., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Portal vein thrombosis (PVT) is a rare but severe entity that can cause clinically significant sequela such as worsening portal hypertension or mesenteric ischemia. Those cases refractory to medical management may be referred for endovascular intervention. Several technical considerations have been described in the literature, but a cohesive comparison of these multiple techniques is lacking., Methods: The purpose of this article is to review the diagnosis and endovascular management of PVT, including areas in which further research is warranted., Results: Cases of PVT can be readily diagnosed using ultrasound, computed tomography, or magnetic resonance imaging. Treatment often begins with systemic anticoagulation and endovascular interventions may be used in selected cases. Determining the optimal approach to accessing the portal venous system depends on the underlying disease and chronicity of the thrombus and the degree of occlusion. Once access to the portal venous system is established, catheter-directed therapy may be performed to achieve recanalization., Conclusion: Despite the heterogeneity in patient presentation, cases of PVT can be readily diagnosed across several imaging modalities. Strategizing interventional approaches involves evaluation of the underlying disease and the chronicity of the thrombus., Key Points: · This review will enable interventionalists to establish a framework for treating portal vein thrombosis by identifying patient risk factors and thrombus characteristics that determine patient management.. · The unique risks and benefits for transhepatic, transsplenic, and transmesenteric approaches for establishing portal venous access will be discussed.. · Advantages and complications of thrombolysis, thrombectomy, and transjugular intrahepatic portosystemic shunt creation for treating portal vein thrombosis will be reviewed in detail based on our extensive institutional experience.., Citation Format: · Ju C, Li X, Gadani S et al. Portal Vein Thrombosis: Diagnosis and Endovascular Management. Fortschr Röntgenstr 2022; 194: 169 - 180., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Several viral infectious diseases have emerged or re-emerged from wildlife vectors that have generated serious threats to global health. Increased international travel and commerce increase the risk of transmission of viral or other infectious diseases. In addition, recent climate changes accelerate the potential spread of domestic disease. The coronavirus disease 2019 (COVID-19) pandemic is an important example of the worldwide spread, and the current epidemic will unlikely be the last. Viral hemorrhagic fevers, such as dengue and Lassa fevers, may also have the potential to spread worldwide with a significant impact on public health with unpredictable timing. Based on the important lessons learned from COVID-19, it would be prudent to prepare for future pandemics of life-threatening viral diseases. The key concept that connect COVID-19 and viral hemorrhagic fever is the coagulation disorder. This review focuses on the coagulopathy of acute viral infections since hypercoagulability has been a major challenge in COVID-19, but represents a different presentation compared with viral hemorrhagic fever. However, both thrombosis and hemorrhage are understood as the result of thromboinflammation due to viral infections, and the role of anticoagulation is important to consider., Competing Interests: T.I. has received a research grant from Japan Blood Products Organization and JIMRO. J.H.L. serves on the Steering Committees for Boehringer-Ingelheim, CSL Behring, Instrumentation Laboratories, Octapharma, and Leading Biosciences. M.L. has received grants and has participated in advisory boards of Novo Nordisk, Eli Lilly, Asahi Kasei Pharmaceuticals America, and Johnson & Johnson. The other authors state that they have no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown., Methods: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding., Results: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p  = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24)., Conclusion: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up., Competing Interests: Dr. Parikh reports being on the Advisory Board for Abbott, Boston Scientific, Medtronic, CSI, Philips, Janssen; research grants: Abbott, Boston Scientific, Surmodics, TriReme Medical, Shockwave Medical; and receiving consulting fees from Terumo and Abiomed. Dr. Gupta received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C. Martin Law Firm for work related to the Cook inferior vena cava filter litigation. Dr. Gupta holds equity in a health care telecardiology startup, Heartbeat Health, Inc. and received consulting fees from Edwards LifeSciences. Dr. Madhavan has received support from an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). Dr. Sethi reports honoraria from Janssen and Chiesi and research grant support from the American Heart Association. Dr. Piazza has received research grant support to Brigham and Women's Hospital from EKOS, a BTG International Group company, Bayer, the Bristol Myers Squibb/Pfizer Alliance, Portola, and Janssen. He has received consulting fees from Amgen, Pfizer, Boston Scientific Corporation, and Thrombolex. Dr. Kirtane reports institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, and ReCor Medical. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for speaking engagements and/or consulting. Personal: travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr. Van Tassell received research support from Novartis, Swedish Orphan Biovitrum, Olatec Therapeutics, and Serpin Pharma. He is a consultant of R-Pharm, Serpin Pharma. Dr. Stone has received speaker or other honoraria from Cook, Terumo, and Orchestra Biomed; served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, Cardiomech; and has received equity or options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. Dr. Lip reports consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are received personally. Dr. Krumholz reports personal fees from UnitedHealth, personal fees from IBM Watson Health, personal fees from Element Science, personal fees from Aetna, personal fees from Facebook, personal fees from Siegfried & Jensen Law Firm, personal fees from Arnold & Porter Law Firm, personal fees from Ben C. Martin Law Firm, personal fees from National Center for Cardiovascular Diseases, Beijing, ownership of HugoHealth, ownership of Refactor Health, contracts from the Centers for Medicare & Medicaid Services, grants from Medtronic and the Food and Drug Administration, grants from Medtronic and Johnson and Johnson, grants from Shenzhen Center for Health Information, and is a Venture Partner at FPrime, outside the submitted work. Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. All other authors report no relevant Enoxaparin was provided through Alborz Darou, Pooyesh Darou, and Caspian Pharmaceuticals companies, and atorvastatin and matching placebo were provided by Sobhan Darou. None of these companies were study sponsors and they had no other role and will not have a role in the design, conduct, analysis, or interpretation of the ongoing results or the decision to submit the resultant manuscript(s)., (Thieme. All rights reserved.)

Background: Accumulating evidence indicates toward an association between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis., Objectives: We investigated the hypothesis that the procoagulatory state in COVID-19 patients is associated with impaired fibrinolysis system., Methods: Altogether, 29 COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in this descriptive study. Whole blood samples were investigated by thromboelastography to assess coagulation and fibrinolysis. Additionally, standard routine coagulation testing and immunoassays for factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and α2-antiplasmin (A2AP) were performed., Results: A significantly increased lysis resistance and a significantly longer time of lysis after adding tissue plasminogen activator were observed in blood samples from ICU COVID-19 patients compared with healthy controls (maximal lysis: 3.25 ± 0.56 vs. 6.20 ± 0.89%, p  = 0.0127; lysis time: 365.7 ± 44.6 vs. 193.2 ± 16.3 seconds, p  = 0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92 ± 0.91 vs. 1.28 ± 0.33 U/mL, p  = 0.001). A positive correlation between the activity of PAI-1 and lysis time of the formed clot ( r  = 0.70, p  = 0.0006) was observed., Conclusion: Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Thromboelastography could offer a tool to investigate the contribution of the fibrinolytic status to the procoagulatory condition in COVID-19., Competing Interests: None declared., (Thieme. All rights reserved.)

Cancer is associated with an increased incidence of both venous thromboembolism (VTE) and arterial thrombosis (cardiovascular events and ischemic stroke). Cancer-associated arterial thrombotic events are less well studied than VTE, but increasingly recognized, particularly in specific malignancies and in association with specific anticancer therapies. The pathogenesis of arterial thrombotic events in cancer is complex and involves generation of tumor-associated procoagulant factors and a variety of alterations in platelet function as well as in the coagulation and fibrinolytic systems, and endothelial injury and dysfunction, that combine to produce hypercoagulability. The multifactorial interaction between this prothrombotic state, the individual cardiovascular risk, advanced age and presence of comorbidities, and the specific neoplasm characteristics and therapy, may induce the vascular events. Recent studies based on population databases and prospective or retrospective analyses with prolonged follow-up highlight that cancer patients experience an increased (approximately 1.5-2-fold) risk of both cerebrovascular and cardiovascular events compared with noncancer individuals, which peaks in the time period of the diagnosis of cancer but may persist for years. Beyond the type of cancer, the risk reflects the tumor burden, being higher in advanced stages and metastatic cancers. The occurrence of arterial thromboembolic events is also associated with increased overall mortality. We here present an update of the pathophysiology, risk factors, clinical evidence, and treatment considerations on cancer-associated arterial thrombosis, in the light of the need for specific multidisciplinary prevention and surveillance strategies in this setting, in the frame of cardio-oncology approaches., Competing Interests: None declared., (Thieme. All rights reserved.)

In 2019 first reports about a new human coronavirus emerged, which causes common cold symptoms as well as acute respiratory distress syndrome. The virus was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe thrombotic events including deep vein thrombosis, pulmonary embolism, and microthrombi emerged as additional symptoms. Heart failure, myocardial infarction, myocarditis, and stroke have also been observed. As main mediator of thrombus formation, platelets became one of the key aspects in SARS-CoV-2 research. Platelets may also directly interact with SARS-CoV-2 and have been shown to carry the SARS-CoV-2 virus. Platelets can also facilitate the virus uptake by secretion of the subtilisin-like proprotein convertase furin. Cleavage of the SARS-CoV-2 spike protein by furin enhances binding capabilities and virus entry into various cell types. In COVID-19 patients, platelet count differs between mild and serious infections. Patients with mild symptoms have a slightly increased platelet count, whereas thrombocytopenia is a hallmark of severe COVID-19 infections. Low platelet count can be attributed to platelet apoptosis and the incorporation of platelets into microthrombi (peripheral consumption) and severe thrombotic events. The observed excessive formation of thrombi is due to hyperactivation of platelets caused by the infection. Various factors have been suggested in the activation of platelets in COVID-19, such as hypoxia, vessel damage, inflammatory factors, NETosis, SARS-CoV-2 interaction, autoimmune reactions, and autocrine activation. COVID-19 does alter chemokine and cytokine plasma concentrations. Platelet chemokine profiles are altered in COVID-19 and contribute to the described chemokine storms observed in severely ill COVID-19 patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)