key: cord-0944957-ay5e43gi authors: Krishnaswamy, Sriram; Ageno, Walter; Arabi, Yaseen; Barbui, Tiziano; Cannegieter, Suzanne; Carrier, Marc; Cleuren, Audrey C.; Collins, Peter; Panicot‐Dubois, Laurence; Freedman, Jane E.; Freson, Kathleen; Hogg, Philip; James, Andra H.; Kretz, Colin A.; Lavin, Michelle; Leebeek, Frank W. G.; Li, Weikai; Maas, Coen; Machlus, Kellie; Makris, Michael; Martinelli, Ida; Medved, Leonid; Neerman‐Arbez, Marguerite; O’Donnell, James S.; O'Sullivan, Jamie; Rajpurkar, Madhvi; Schroeder, Verena; Spiegel, Paul Clinton; Stanworth, Simon J.; Green, Laura; Undas, Anetta title: Illustrated State‐of‐the‐Art Capsules of the ISTH 2020 Congress date: 2021-07-16 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12532 sha: 1de6886abf592df5ff573408c607fae704384a18 doc_id: 944957 cord_uid: ay5e43gi This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17–21, 2021. The conference, now held annually, highlighted cutting‐edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on‐line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID‐19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress. Cerebral venous sinus thrombosis conditions shown here, our data also showed vascular bed-specific EC reactivity after lipopolysaccharide-induced endotoxemia (ref 15 ). Postpartum hemorrhage (PPH) is caused by obstetric complications but may be exacerbated by impaired hemostasis. Hypofibrinogenemia is the commonest coagulopathy associated with PPH and occurs early in abruptions and amniotic fluid embolism. Depletion of other coagulation factors, thrombin generation and platelets is uncommon until large bleeds have occurred. 16 Early hypofibrinogenemia predicts progression to severe hemorrhage, however, laboratory Clauss fibrinogen is usually too slow to be clinically useful during rapid bleeding. Point-of-care viscoelastometric hemostatic assays (VHA) allow surrogate measurement of fibrinogen and predict severe outcomes. 17 A double blind RCT showed that fibrinogen >2 g/L is adequate for hemostasis during PPH. 18 An all Wales quality improvement programme involving 60,000 deliveries combined accurate measurement of blood loss with VHAs to guide early fibrinogen replacement. It was associated with reduced massive PPH (≥ 2500 ml) by 23%, decreased red cell and FFP transfusion by 22% and 58%, respectively and reduced severe anemia (Hb <80 g/L) by 33%. For references, see Carminita et al 19 More than 60 genes have already been discovered as cause of an inherited platelet disorder (IPD). 21 Many of these genes are widely expressed and are associated with broader clinical symptoms than causing solely a bleeding tendency. In this presentation examples will be discussed on how next generation sequencing has proven successful with its implementation in clinical diagnostics 22, 23 and gene discovery. 23 Still at least half of the IPD patients receive no genetic diagnosis. Ideas will be put forward on how to tackle the challenges ahead that include discoveries in the noncoding genome space and setting up improved disease models for IPD that will allow (automated) deep phenotyping. For references, see Butera and Hogg, 24 Hogg 25 Disparities in pregnanc y outcomes: Dif ferences by condition and communit y Both the maternal and fetal outcomes of pregnancy vary according to a pregnant woman's community and her condition. The most devastating outcome is the death of a month. On 2017, there were approximately 295,000 maternal deaths with dramatic differences in maternal mortality based on the region of the world, the country, and women's underlying conditions. 26 Worldwide, the leading cause of maternal death is hemorrhage. Ninety-nine percent of maternal deaths and 99% of those due to hemorrhage occur in low-or middle-income countries. Whether a hemorrhage originates from inside the uterus (80%), from laceration or incisions (20%), or from an underlying coagulopathy (less than 1%), and acute acquired coagulopathy will evolve unless the hemorrhage is not available, because besides the usual obstetric measures, blood, hemostatic medication and hematologic expertise are necessary to save mothers' lives. 27, 28 S pecif icit y of ADAMTS13 an d regulation of ADAMTS13 func tion Colin A. Kretz Pregnanc y, pos tpar tum and periods: Current challenges in the management of women with Von W illebr and disease Women are disproportionately impacted by Von Willebrand disease (VWD) due to gynaecological bleeding. Heavy menstrual bleeding (HMB) is the most frequently reported and highest scoring bleeding symptom for women with VWD yet optimal treatment strategies remain uncertain. 29 In pregnancy, there remains controversy regarding the ideal therapeutic plasma Von Willebrand factor (VWF) target at delivery. While thresholds similar to surgery are often utilized, this approach fails to account for the physiological pregnancy-induced increase in plasma Von Willebrand factor (VWF) levels, with median plasma VWF levels >200-250 IU/dl in healthy women at delivery. 30 The limitations of current approaches for women with VWD are reflected in primary postpartum haemorrhage (PPH) rates, which remain increased even when replacement therapy is used. 31 Postpartum, as plasma VWF levels return, to baseline women with VWD are at a markedly increased risk of secondary PPH following discharge. As women with VWD may be normalized to HMB, recognition of secondary PPH may be delayed or missed. In the general population Von Willebrand factor (VWF) levels rise with aging, especially above the age of 40. 32 As is shown in the figure, several mechanisms have been suggested to be responsible for this increase. This may be increased release of VWF from the endothelium, or decreased VWF clearance. Mechanisms contributing to increase of VWF are endothelial dysfunction, comorbidities (hypertension, diabetes), weight gain, atherosclerosis and inflammation. 32, 33 This age-related increase is also observed in patients with type 1 Von Willebrand disease (VWD) and may result in (near) normal levels in elderly VWD patients. 34 It is still disputed whether this rise is associated with attenuation of the bleeding tendency. Results of an observational study on bleeding symptoms over one year have shown that bleeding was not reduced in type 1 VWD patients above the age of 65 compared to those <65 years, however prospective data are still lacking. 34 • Fibrin(ogen) and its degradation products promote leukocyte transmigration and thereby inflammation by interacting with various endothelial cell receptors. • Interaction of fibrin and its degradation product E 1 fragment with the endothelial VLDL receptor (VLDLR) and VE-cadherin occurs through fibrin βN-domains. With fibrin, produced by thrombin-mediated cleavage, fibrinogen plays important roles in many physiological processes. 44, 45 Formation of a stable blood clot, containing polymerised and cross-linked fibrin, is crucial to prevent blood loss and drive wound healing upon injury. Balance between clotting and fibrinolysis is essential. Several diseases are the consequence of altered levels of fibrinogen, others are related to structural properties of the molecule. Inflammation leads to elevated circulating levels of fibrinogen and hypercoagulability, a risk factor for cardiovascular disease (CVD). The source and localisation of fibrin(ogen) also has clinical implications. Fibrin(ogen) has been associated with cancer development and progression. While fibrin(ogen) is implicated in defense against pathogens, in other settings it enhances bacterial virulence. Von W illebr and f ac tor modulates adhesion of malaria-infec ted er y throc y tes to endothelial cells Markedly elevated plasma VWF:Ag levels and VWF propeptide levels are present in children with severe Plasmodium falciparum malaria, consistent with acute endothelial cell (EC) activation and Weibel Palade body (WPB) secretion. 46 Higher VWF levels correlate with worse clinical outcomes. Pathological ultra-large (UL-) VWF multimers are also a feature of cerebral malaria. 47 In vitro studies have demonstrated that UL-VWF strings on the surface of activated EC can recruit platelets. Subsequently, the platelet-decorated UL-VWF strings can then tether malaria-infected red blood cells (IRBC) under physiological shear stress. 48 In particular, P. falciparum erythrocyte membrane protein-1 (PfEMP-1) on the IRBC interacts with platelet CD36. Collectively, these findings support the hypothesis that VWF plays role in regulating microvascular sequestration of IRBC in children with cerebral malaria. Image created with BioRender.com. For reference, see Patmore et al 49 For references, see Biss et al, 50 Carpenter et al, 51 Rajpurkar et al 52 For references, see Handrkova et al,, 53 Li et al, 54 Schroeder et al 55 What holds the A subunits together? What holds the A and B subunits together? Domains of the A subunits: AcƟvaƟon pepƟde (AP), β-sandwich, core domain, β-barrel 1, β-barrel 2 The acƟvaƟon pepƟde, and in parƟcular the sequence 8 [3] where also further references can be found Fac tor VIII s tr uc ture: D eterminant s of inhibitor development Hemophilia A is an X-linked bleeding disorder that affects 1 in 5,000 males worldwide due to a deficiency in blood coagulation factor VIII (fVIII), an essential protein for the proteolytic activation of factor X to Xa. Through the past 20 years, the structure and function of fVIII has come into focus. New atomic-level structural findings illustrate a detailed domain organization of fVIII structure, 56 novel localized and domain-scale conformational changes, the molecular nature of the fVIII/Von Willebrand factor complex, and pathogenic antibody epitopes. 57, 58 Further structural characterization of fVIII circulatory complexes will uncover the fundamental basis for its procoagulant cofactor function and may aid in next-generation bioengineering efforts to improve fVIII stability and circulatory half-life while minimizing its immunogenicity. These efforts may prove vital for both fVIII replacement and gene therapy approaches. A number of randomised trials have evaluated the risk-benefit ratio for platelet transfusion for prophylaxis and treatment of major bleeding. Trials in some settings have indicated evidence of harm with more 'liberal' use of platelets, 59 although a benefit to improve outcomes has also been found in major bleeding. 60 Our understanding of donor, storage and processing characteristics on outcomes following platelet transfusion have been inadequately investigated. 61 We need a better understanding of how platelet transfusions affect both haemostasis and inflammation in pa- Fibrin clot structure characterized by fiber diameter and pore size differs between healthy persons and patients with thromboembolic diseases. Prothrombotic fibrin clot phenotype is associated with faster formation of denser fibrin mesh, relatively resistant to lysis, as reflected by prolonged clot lysis time (CLT). Increased plasma fibrin clot density has been reported in patients with prior or acute thromboembolic events. Laurence Panicot-Dubois @chris_dubois13 Jane E. Freedman @JaneFreedmanMD Andra H. James @andrajames031 Colin A. Kretz @ColinKretz Kellie Machlus @theclotthickens Paul Clinton Spiegel @SpiegelClint Laura Green @LGreenBartsNHS Anticoagulant therapy for splanchnic vein thrombosis Effects of early mobilization on the prognosis of critically ill patients: A systematic review and metaanalysis Central venous access sites for the prevention of venous thrombosis, stenosis and infection Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials Can intermittent pneumatic compression reduce the incidence of venous thrombosis in critically ill patients: A systematic review and meta-analysis Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases Incidence of venous thromboembolism in young Swedish women and possibly preventable cases among combined oral contraceptive users Endogenous sex hormones and risk of venous thromboembolism in young women Sex difference in risk of second but not of first venous thrombosis: paradox explained American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer Successful model for guideline implementation to prevent cancer-associated thrombosis: venous thromboembolism prevention in the ambulatory cancer clinic Celltype-specific isolation of ribosome-associated mRNA from complex tissues The in vivo endothelial cell translatome is highly heterogeneous across vascular beds Management of postpartum haemorrhage: from research into practice, a narrative review of the literature and the Cardiff experience Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study Viscoelastometricguided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial DNAse-dependent but NETs-independent pathway of thrombus formation in vivo Cancer animal models in thrombosis research Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: communication from the SSC of the ISTH Strengths and limitations of high-throughput sequencing for the diagnosis of inherited bleeding and platelet disorders Whole-genome sequencing of patients with rare diseases in a national health system Fibrinogen function achieved through multiple covalent states Multiple disulphide-bonded states of native proteins: Estimate of number using probabilities of disulphide bond formation World Bank Group and the United Nations Population Division. Maternal mortality: Levels and trends Global causes of maternal death: a WHO systematic analysis Postpartum hemorrhage: when uterotonics and sutures fail Significant gynecological bleeding in women with low von Willebrand factor levels Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey Rise of levels of von Willebrand factor and factor VIII with age: role of genetic and acquired risk factors Inflammation, von Willebrand factor, and ADAMTS13. Blood Von Willebrand disease and aging: an evolving phenotype Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation Competitive tight-binding inhibition of VKORC1 underlies warfarin dosage variation and antidotal efficacy Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer The fibronectin type II domain of factor XII ensures zymogen quiescence Cold-induced urticarial autoinflammatory syndrome related to factor XII activation A mutation in the kringle domain of human factor XII that causes autoinflammation, disturbs zymogen quiescence, and accelerates activation Regulation of leukocyte-endothelium interaction by fibrinogen The fibrin-derived peptide Bβ15-42 protects the myocardium against ischemiareperfusion injury Fibrin-VLDL receptor-dependent pathway promotes leukocyte transmigration by inhibiting Src kinase Fyn and is a target for fibrin β15-42 peptide Haematologica. 2020. 45. Wolberg and Pieters. RPTH Emerging roles for hemostatic dysfunction in malaria pathogenesis A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings Von Willebrand factor and cancer; metastasis and coagulopathies Recommendations for future research in relation to pediatric pulmonary embolism: communication from the SSC of the ISTH Increasing rate of pulmonary embolism diagnosed in hospitalized children in the United States from Pulmonary embolism and in situ pulmonary artery thrombosis in paediatrics The activation peptide of coagulation factor XIII is vital for its expression and stability Identification of amino acid residues that are crucial for FXIII-A intersubunit interactions and stability Factor XIII, structure and function The 3.2 Å structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain Structure of the factor VIII C2 domain in ternary complex with 2 inhibitor antibodies reveals classical and nonclassical epitopes Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor Randomized trial of platelet-transfusion thresholds in neonates Platelet transfusions improve hemostasis and survival in a substudy of the prospective, randomized PROPPR trial The impact of platelet transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia Illustrated State-of-the-Art Capsules of the ISTH 2020