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Sepsis is a common and critical condition encountered in clinical practice that can lead to multi-organ dysfunction. Sepsis-induced coagulopathy (SIC) significantly affects patient outcomes. However, the precise mechanisms remain unclear, making the identification of effective prognostic and therapeutic targets imperative. The analysis of transcriptome data from the whole blood of sepsis patients, facilitated the identification of key genes implicated in coagulation. Then we developed a prognostic model and a nomogram to predict patient survival. Consensus clustering classified sepsis patients into three subgroups for comparative analysis of immune function and immune cell infiltration. Single-cell sequencing elucidated alterations in intercellular communication between platelets and immune cells in sepsis, as well as the role of the coagulation-related gene FYN. Real-time quantitative PCR determined the mRNA levels of critical coagulation genes in septic rats' blood. Finally, administration of a FYN agonist to septic rats was observed for its effects on coagulation functions and survival. This study identified four pivotal genes—CFD, FYN, ITGAM, and VSIG4—as significant predictors of survival in patients with sepsis. Among them, CFD, FYN, and ITGAM were underexpressed, while VSIG4 was upregulated in patients with sepsis. Moreover, a nomogram that incorporates the coagulation-related genes (CoRGs) risk score with clinical features of patients accurately predicted survival probabilities. Subgroup analysis of CoRGs expression delineated three molecular sepsis subtypes, each with distinct prognoses and immune profiles. Single-cell sequencing shed light on heightened communication between platelets and monocytes, T cells, and plasmacytoid dendritic cells, alongside reduced interactions with neutrophils in sepsis. The collagen signaling pathway was found to be essential in this dynamic. FYN may affect platelet function by modulating factors such as ELF1, PTCRA, and RASGRP2. The administration of the FYN agonist can effectively improve coagulation dysfunction and survival in septic rats. The research identifies CoRGs as crucial prognostic markers for sepsis, highlighting the FYN gene's central role in coagulation disorders associated with the condition and suggesting novel therapeutic intervention strategies. [Display omitted] • Found four key genes for sepsis prognosis linked to coagulation. • Created sepsis survival nomogram combining gene scores and clinical data. • Unveiled three sepsis subtypes with unique prognoses and immune traits. • Showed potential of FYN agonist in treating sepsis-induced coagulopathy. [ABSTRACT FROM AUTHOR]

Coagulation disorders frequently complicate the clinical course of acute myeloid leukemia (AML) patients. This study examined the frequency and prognostic significance, with regards of early mortality, of the presence of overt disseminated intravascular coagulation (DIC) at AML diagnosis and its correlation with clinical and biological characteristics. A retrospective analysis of 351 newly diagnosed non-promyelocytic AML patients was conducted, utilizing the 2018 ISTH DIC-Score criteria to evaluate the presence of overt DIC at AML onset. The study cohort had a median age of 65 years with a predominance of male gender (59 %). Overt DIC was present in 21 % of cases and was associated with advanced age, comorbidities, poor performance status, hyperleukocytosis, LDH levels, NPM1 mutations, expression of CD33 and CD4, and lack of expression of CD34. With a median follow-up of 72 months (3–147 months), the 6-year overall survival (OS) was 17.4 %, with patients having overt DIC showing significantly poorer outcomes (7.2 % compared to 20.3 % of those without DIC, p < 0.001). Patients with overt DIC showed markedly high early mortality rates at 30 (42.5 % vs 8 %), 60 (49.3 % vs 16.9 %), and 120 days (64.4 % vs 25.6 %) from disease onset. In multivariate analysis overt DIC retained its independent prognostic value for early mortality. In conclusion, the prevalence and clinical relevance of DIC in non-promyelocytic AML is not negligible, underlining its potential as an unfavorable prognostic marker. In newly diagnosed patients with AML, early recognition and measure to counteract coagulation disturbances might help mitigate the elevated mortality risk associated with DIC. • Disseminated intravascular coagulation frequently complicates acute leukemias. • The 2018 ISTH DIC-Score criteria serve as a simple tool to diagnose disseminated intravascular coagulation in acute myeloid leukemia patients. • Acute myeloid leukemia patients with disseminated intravascular coagulation at presentation have a 14-fold increased risk of major bleeding. • Disseminated intravascular coagulation has independent prognostic value for early death. [ABSTRACT FROM AUTHOR]

Viscoelastic testing has been used in adult hematologic malignancies in conjunction with conventional coagulation tests (CCTs) to predict coagulopathies and tailor blood product replacement. However, there is a paucity of similar pediatric studies. Analyze and correlate leukemia-associated coagulopathy in newly diagnosed pediatric leukemia patients using CCT's and Rotational Thromboelastometry (ROTEM). Pediatric patients with newly diagnosed acute leukemia underwent testing with ROTEM and CCTs on days 0, 15 and 29 of induction chemotherapy. Sixty-two patients were enrolled. At presentation, 54.8 % of patients had platelets <50 K/μL, 73 % had prolonged PT, 1.6 % had fibrinogen <150 mg/dL. Fifteen patients (24.2 %) had WHO grade 1 bleeding and two patients (3 %) had WHO grade 4 bleeding. EXTEM/INTEM values at presentation (day 0) reflected hypocoagulability, however FIBTEM revealed hypercoagulability. Patients showed a progressive hypocoagulability in all ROTEM assays by day 15 (day 0 vs day 15, p < 0.001), with improvement by day 29 (day 15 vs day 29, p < 0.001). Day 0 ROTEM parameters were comparable to day 29. Fibrinogen strongly correlated with ROTEM at all three time points (p < 0.0001), along with platelet count with moderate correlations (p < 0.001). Fibrinogen and platelets appear to be the drivers of leukemia associated coagulopathy in the pediatric population, suggesting the utility of using CCTs and ROTEM in this population to better evaluate hemostatic function and guide blood product replacement. • Rotational Thromboelastometry (ROTEM) has been used to assess leukemia-associated coagulopathy in adult malignancies, with a paucity of similar studies in pediatric leukemia • Abnormal coagulation test (PT/aPTT) values in leukemia patients do not clearly predict the risk of bleeding • Pediatric leukemia patients had evidence of hypocoagulability during induction chemotherapy using ROTEM assays despite acquired hypofibrinogenemia and thrombocytopenia and a low bleeding risk in our cohort • Strategies adopting ROTEM as a point of care test along with conventional coagulation tests (CCTs) can better evaluate hemostatic function to guide non-erythrocyte hemostatic factor replacement in this patient population • Our study demonstrates the utility of CCTs and ROTEM in newly diagnosed pediatric leukemia patients, with fibrinogen and platelets as the main drivers of leukemia-associated coagulopathy. [ABSTRACT FROM AUTHOR]

Congenital coagulopathies have, throughout the history of medicine, been a focus of scientific study and of great interest as they constitute an alteration of one of the most important and conserved pathways of evolution. The first therapeutic strategies developed to address them were aimed at restoring the blood components lost during hemorrhage by administering whole blood or plasma. Later on, the use of cryoprecipitates was a significant breakthrough as it made it possible to decrease the volumes of blood infused. In the 1970′ and 80′, clotting factor concentrates became the treatment and, from the 1990's to the present day, recombinant factors –with increasingly longer half-lives– have taken over as the treatment of choice for certain coagulopathies in a seamless yet momentous transition from biological to biotechnological drugs. The beginning of this century, however, saw the emergence of new advanced (gene and cell) treatments, which are currently transforming the therapeutic landscape. The possibility to use cells and viruses as well as specific or bispecific antibodies as medicines is likely to spark a revolution in the world of pharmacology where therapies will be individualized and have long-term effects. Specifically, attention is nowadays focused on the development of gene editing strategies, chiefly those based on CRISPR/ Cas technology. Rare coagulopathies such as hemophilia A and B, or even ultra-rare ones such as factor V deficiency, could be among those deriving the greatest benefit from these new developments. • Hemostasis is a highly relevant and highly conserved pathway which may be disrupted by congenital coagulopathies. • Recombinant coagulation factors constituted the transition from biological to biotechnological drugs. • The effect of advanced therapies may persist longer than that of current treatments. • Advanced therapies and CRISPR/ Cas technologies are currently being developed to address rare coagulopathies. [ABSTRACT FROM AUTHOR]

Trauma induced coagulopathy (TIC) is common after severe trauma, increasing transfusion requirements and mortality among patients. TIC has several phenotypes, with primary hyperfibrinolysis being among the most lethal. We aimed to investigate the contribution of hypercoagulation, hemodilution, and fibrinolytic activation to the hyperfibrinolytic phenotype of TIC, by examining fibrin formation in a plasma-based model of TIC. We hypothesized that instabilities arising from TIC will be due primarily to increased fibrinolytic activation rather than hemodilution or tissue factor (TF) induced hypercoagulation. The influence of TF, hemodilution, fibrinogen consumption, tissue plasminogen activator (tPA), and the antifibrinolytic tranexamic acid (TXA) on plasma clot formation and structure were examined using rheometry, optical properties, and confocal microscopy. These were then compared to plasma samples from trauma patients at risk of developing TIC. Combining TF-induced clot formation, 15 % hemodilution, fibrinogen consumption, and tPA-induced fibrinolysis, the clot characteristics and hyperfibrinolysis were consistent with primary hyperfibrinolysis. TF primarily increased fibrin polymerization rates and reduced fiber length. Hemodilution decreased clot optical density but had no significant effect on mechanical clot stiffness. TPA addition induced primary clot lysis as observed mechanically and optically. TXA restored mechanical clot formation but did not restore clot structure to control levels. Patients at risk of TIC showed increased clot formation, and lysis like that of our simulated model. This simulated TIC plasma model demonstrated that fibrinolytic activation is a primary driver of instability during TIC and that clot mechanics can be restored, but clot structure remains altered with TXA treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Plasma proteins involved in coagulation and fibrinolysis are essential to hemostasis. Consequently, their circulating levels and functionality are critical in bleeding and thrombosis development. Well-established laboratory tests to assess these are available; however, said tests do not allow high multiplicity, require large volumes of plasma and are often costly. A novel technology to quantify plasma proteins is quantitative protein mass spectrometry (QPMS). Aided by stable isotope-labeled internal standards a large number of proteins can be quantified in one single analytical run requiring <30 μL of plasma. This provides an opportunity to improve insight in the etiology and prognosis of bleeding and thrombotic disorders, in which the balance between different proteins plays a crucial role. This manuscript aims to give an overview of the QPMS potential applications in thrombosis and hemostasis research (quantifying the 38 proteins assigned to coagulation and fibrinolysis by the KEGG database), but also to explore the potential and hurdles if designed for clinical practice. Advantages and limitations of QPMS are described and strategies for improved analysis are proposed, using as an example the test requirements for antithrombin. Application of this technology in the future could represent a step towards individualized patient care. • Well-established laboratory tests are available for coagulation and fibrinolysis. • Unmet clinical needs for test development exist for undiagnosed bleeding disorders and venous thrombosis risk stratification. • Quantitative targeted proteomics (QPMS) might address these needs through multiplex proteins quantitation. • Application of QPMS in the future could represent a step towards individualized patient care. [ABSTRACT FROM AUTHOR]

The activation of coagulation, inflammation and other pathways is the basic response of the host to infection in sepsis, but this response also causes damage to the host. Brain-derived extracellular vesicles (BDEVs) have been reported to cause a hypercoagulable state that can rapidly develop into consumptive coagulopathy, which is consistent with the pathophysiological process of sepsis-induced coagulopathy. However, the role of BDEVs in sepsis-induced coagulopathy remains unclear. Male Sprague-Dawley (SD) rats were used for sepsis modeling using cecal ligation puncture (CLP). Flow cytometry was used to measure the levels of circulating BDEVs. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of plasminogen activator inhibitor type 1 (PAI-1), thrombin-antithrombin (TAT), D-dimer, fibrinogen(Fib), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6. Nanoparticle tracking analysis (NTA) and Transmission electron microscopy (TEM) were used to identify BDEVs. Western blot (WB) was used to determine the expression of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), bax, bcl-2 and cleaved caspase-3. Hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were performed to detect tissue injury. Survival was monitored over the course of 168 h. We found that a large number of BDEVs were released into the circulating blood in septic rats. Moreover, we observed that BDEVs injection activated the systemic coagulation reaction and induced lung, liver and kidney inflammation and apoptosis(P <.05). Compared with BDEVs from sham-operated rats, BDEVs from septic rats exacerbated this process(P <.05). This finding suggests that inhibiting BDEVs may yield therapeutic benefits in the treatment of sepsis-induced coagulopathy. • Brain-derived extracellular vesicles were released into blood in septic rats. • Brain-derived extracellular vesicles induced coagulopathy and tissue damage. • Brain-derived microvesicles from septic rats aggravated coagulopathy and organ injury. [ABSTRACT FROM AUTHOR]

Currently, Chagas disease (CD) constitutes one of the main public health problems in Latin America. However, little is known about potential mechanisms of disease different from cardiac or digestive involvement, such as the coagulation disorders elicited by the parasite persistence in the tissues. The aim of this systematic review was to describe and characterize all the published literature that evaluated the pathophysiological aspects of coagulation disorders in CD. Searches in Medline, EMBASE, and LILACS databases (from inception to July 28th, 2020) were performed. Articles of any language reporting the levels of different coagulation factors/markers or the prevalence of abnormal levels of the mentioned molecules in patients with CD were included. Two reviewers independently selected the studies, extracted the data, and assessed the quality of evidence. Estimates were pooled using random-effects meta-analyses. Seven studies evaluating a total of 676 participants fulfilled the criteria and were included, while only six were suitable for meta-analyzing (544 participants, 52% men, mean age: 49 ± 8 years). 57.16% of the patients in the meta-analysis had a serological confirmed diagnosis of CD, while 97% of these were in the indeterminate stage of the disease. Patients in the CD group had higher levels of F 1 + 2 (SMD 5.15. 95% CI 1.92, 8.38), PAI-1 (SMD 0.46. 95% CI 0.07; 0.89), and P-selectin (SMD 1.8; 95% CI 0.13–3.47) compared to healthy controls. Furthermore, benznidazole therapy was associated with a reduction in the levels of these biomarkers after treatment. The results of the present study suggest that patients with chronic T. cruzi infection are affected by a potential hypercoagulable state irrespective of the development of cardiac or digestive disease. Furthermore, the reduction in the levels of the coagulation markers after benznidazole therapy may suggest a significant role of the parasite load in the development of these coagulation disorders. There is a scarcity of research assessing the molecular and pathophysiological mechanisms of coagulation disorders in Chagas disease. Further research is needed to assess the benefit of benznidazole therapy on this hypercoagulable state in the long-term, along with its impact on the risk of thromboembolic events in CD patients. • Chagas disease constitutes one of the leading public health problems in Latin America and the world. • The impact of Chagas Disease goes beyond the development of heart failure. • The levels of F 1 + 2, PAI-1, and P-Selectin were significantly increased in the group of patients with Chagas Disease compared to healthy subjects. • Patients with chronic T. cruzi infection may be affected by a hypercoagulable state irrespective of the presence of cardiac disease. [ABSTRACT FROM AUTHOR]

There is limited awareness of von Willebrand disease (VWD), leading to challenges in both diagnosis and defining the optimal treatment approach for these patients. Patients with VWD are typically treated on-demand, with short-term prophylaxis used during surgery. In contrast, early initiation, and long-term use of prophylaxis is the standard of care in patients with severe haemophilia and can be successfully used to prevent joint bleeding and reduce chronic arthropathy. To provide an understanding of the current evidence for the prophylactic treatment of patients with VWD and compare this to the management of patients with haemophilia. Review of published literature using a non-systematic search of PubMed and reference lists of sourced articles. The successes seen with prophylaxis in haemophilia provide the rationale for long-term prophylaxis in patients with severe forms of VWD; preventing spontaneous, excessive and sometimes life-threatening bleeding, and reducing chronic joint disease. Currently, there are a few clinical trials assessing the long-term benefits of prophylaxis in VWD, and guidelines for the optimal prophylaxis treatment approach are lacking. Greater attempts to provide comprehensive, long-term care for patients with VWD are needed but still lacking within the community. This review highlights the success of prophylaxis in haemophilia and how this knowledge might be applied and translated to patients with VWD. Lessons can be learned from the use of prophylaxis in haemophilia and prophylaxis should be considered the standard of care for a subgroup of patients with severe VWD. • A high proportion of individuals diagnosed with VWD may not be receiving treatment. • Benefits of prophylaxis in haemophilia provide the rationale for use in severe VWD. • Prophylaxis should be encouraged in VWD to reduce bleeding and improve outcomes. • The introduction of recombinant VWF concentrate may improve prophylaxis uptake. • Prophylaxis could reduce the burden of VWD and ultimately improve quality-of-life. [ABSTRACT FROM AUTHOR]

In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8–15%), 16% (13–19%) and 21% (17–25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41–0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65–1.2). Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted. • Half overall mortality in the second wave compared to first wave COVID-19 patients. • Still high incidence of thrombotic complications in second wave. • More subsegmental PE in second wave than in first wave. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Previous studies reported pulmonary embolism (PE) in severe COVID-19 patients. Aim of the study was to estimate the prevalence of symptomatic PE in COVID-19 patients and to identify the clinical, radiological or biological characteristics associated with PE. We conducted a retrospective nested case-control study in 2 French hospitals. Controls were matched in a 1:2 ratio on the basis of age, sex and center. PE patients with COVID-19 were compared to patients in whom PE was ruled out (CTPA controls) and in whom PE has not been investigated (CT controls). PE was suspected in 269 patients among 1042 COVID-19 patients, and confirmed in 59 patients (5.6%). Half of PE was diagnosed at COVID-19 diagnosis. PE patients did not differ from CT and CTPA controls for thrombosis risk factors. PE patients more often required invasive ventilation compared to CTPA controls (odds ratio (OR) 2.79; 95% confidence interval (CI) 1.33–5.84) and to CT controls (OR 8.07; 95% CI 2.70–23.82). PE patients exhibited more extensive parenchymal lesions (>50%) than CT controls (OR 3.90; 95% CI 1.54–9.94). D-dimer levels were 5.1 (95% CI 1.90–13.76) times higher in PE patients than CTPA controls. Our results suggest a PE prevalence in COVID-19 patients close to 5% in the whole population and to 20% of the clinically suspected population. PE seems to be associated with more extensive lung damage and to require more frequently invasive ventilation. • Pulmonary embolism is highly prevalent in patients with COVID-19 pneumonia. • In 1 out of 2 cases, pulmonary embolism was diagnosed on hospital admission. • COVID-19 patients admitted to ICU were at high risk for pulmonary embolism. • Pulmonary embolism was correlated with extension of COVID-19 lesions on CT scan. [ABSTRACT FROM AUTHOR]

Background: Underlying mechanisms for bleeding and impaired thrombin generation (TG) and plasma clot formation (PCF) in patients with mild to moderate bleeding disorders (MBDs) are still to be elucidated, especially in bleeding disorder of unknown cause (BDUC). The role of the natural anticoagulants activated protein C (APC) and free protein S (PS) has not yet been investigated in this patient population., Aims: To analyze antigen levels of APC and PS in patients with MBDs and BDUC and investigate associations to clinical bleeding phenotype and severity as well as and hemostatic capacity., Methods: Antigen levels of APC and free PS were measured in 262 patients from the Vienna Bleeding Biobank (VIBB), a single-center cohort study, by ELISA and compared to 61 healthy controls (HC)., Results: Antigen levels of APC were higher in MBD patients than in HC when adjusted for age, sex and BMI (median (IQR) 33.1 (20.6-52.6) and 28.6 (16.4-47.2) ng/mL). This was most pronounced in patients with BDUC (35.3 (21.7-54.3) ng/mL). No differences in PS antigen levels between patients and HC were seen overall, or according to specific diagnoses. Further, no association between APC or PS and bleeding severity or global tests of hemostasis or TG were identified, while paradoxically APC weakly correlated with shorter lag time and time to peak of PCF in BDUC., Conclusion: Our data demonstrate increased antigen levels of APC in BDUC, which might contribute to the bleeding tendency in some patients and could be a future therapeutic target in BDUC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.M. received honoraria for advisory board meetings from CSL Behring. C.A. received honoraria from Bayer, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi, and Takeda for lectures and/or participation in advisory board meetings. I.P. has received honoraria from Bayer, CSL Behring, Novo-Nordisk, Pfizer, Roche, Sobi, and Takeda for lectures and advisory board meetings. J.G. received honoraria for lectures and advisory board meetings, and research funding for the Medical University of Vienna from CSL Behring, Novartis, Amgen, and Sobi. TS, BFB and HH have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rare coagulation disorders (RCDs) are a group of diseases due to coagulation factors deficiency leading to life-long bleeding diathesis. The diagnosis of RCDs is challenging due to the limited knowledge of these disorders and the large heterogeneity of their bleeding patterns. The clinical symptoms of RCDs are extremely diverse in terms of bleeding type, site, severity, age at onset, and duration. The strength of the association between clotting factor activity level in plasma and clinical symptoms is also variable within each RCD. The clinical evaluation of RCDs starts with a detailed collection of clinical history and has been facilitated by bleeding assessment tools, however their effectiveness in diagnosing RCDs requires further investigation. The following laboratory diagnosis of RCDs involves coagulation screening tests, including activated partial thromboplastin time, prothrombin time, and thrombin time. After ruling out the presence of an inhibitor by mixing studies, in case of abnormal results, the specific deficiency is identified by performing one-stage clotting assays using the specific factor-depleted plasmas as substrate. In fibrinogen and FXIII deficiencies coagulation screening tests are not informative, therefore additional tests are needed. Global assays have been developed and are thought to aid in patient management, however, they are not well standardized yet. In addition to outlining the principles of clinical and laboratory diagnosis, this review explores molecular basis of RCDs and laboratory techniques for genetic analysis, and discusses the importance and effectiveness of quality control programs to ensure standardized laboratory results. • Rare coagulation diseases (RCDs) are inherited deficiencies of coagulation factors. • The clinical picture of RCDs is characterized by heterogeneous bleeding diathesis. • Bleeding assessment tools were developed to aid in the clinical diagnosis. • Screening clotting tests and global assays identify the specific factor deficiency. • Molecular diagnosis is based on the identification of causative genetic variants. [ABSTRACT FROM AUTHOR]

Long before the classification of vascular anomalies from the International Society for the Study of Vascular Anomalies (ISSVA) provided a framework to differentiate vascular anomalies, otherwise known as vascular birthmarks, it was recognized that patients with such lesions can present with acute life-threatening hemostatic and/or thrombotic complications, as well as chronic long-standing bleeding or thrombotic issues. Scenarios such as a rapidly growing vascular lesion with severe acute thrombocytopenia, a visceral hemorrhagic lesion, a lesion associated with repetitive and painful superficial thrombosis, and cases of unprovoked or post-procedural fatal pulmonary embolism highlight the wide spectrum of manifestations of abnormal coagulation in patients with vascular anomalies. The separation of vascular anomalies into two distinct groups, vascular tumors and vascular malformations, was followed by the characterization that their respective coagulopathies were due to either a derangement of platelets or to a disequilibrium of the patient's coagulation/fibrinolytic process. This configuration of coagulopathies will be the foundation for this two-chapter review series. In the initial review, coagulopathies where thrombocytopenia is the main feature will be characterized, whereas the second review will focus on vascular malformations that have a coagulation disorder secondary to some degree of coagulation consumption and/or fibrinolytic pathway derangement. • Patients with vascular anomalies, otherwise known as birth marks, can present with acute life-threatening hemostatic and/or thrombotic complications, as well as chronic long-standing bleeding or thrombotic issues. • The separation of vascular anomalies into two distinct groups, vascular tumors and vascular malformations, was followed by the characterization that their respective coagulopathies were due to either a derangement of platelets or to a disequilibrium of the patient's coagulation/fibrinolytic process. • Part I of this two-part review will focus on coagulopathies in children with vascular anomalies where thrombocytopenia is the main feature. [ABSTRACT FROM AUTHOR]

• Understanding of the disorders of coagulation/fibrinolysis associated with COVID-19 is lacking. • D-dimer levels have been demonstrated to be consistently elevated in the setting of COVID-19. • These D-dimer elevations are found even in the absence of VTE or systemic hyperfibrinolysis. • COVID-19 patients have depressed systemic fibrinolysis and resistance to exogenous fibrinolytics. • This paradox may be due to tissue level hyperfibrinolysis but insufficient systemic fibrinolysis. [ABSTRACT FROM AUTHOR]

We aimed to assess the relationship between procoagulant imbalance and the occurrence of variceal bleeding in patients with liver cirrhosis. We compared the results of chromogenic assay for the functional evaluation of the Protein C anticoagulant pathway (ThromboPath®), thromboelastometry and the levels of factor VII, VIII, and antithrombin in two groups of cirrhotic patients: Group 1 (n = 25) — patients with moderate or large esophageal or gastric varices, who had never experienced acute gastrointestinal bleeding and Group 2 (n = 24) — patients with a history of variceal bleeding. Despite the differences in MELD score and the results of basic laboratory tests indicating more severe cirrhosis and suggesting a greater risk of bleeding in Group 2, the results of thromboelastometry did not differ significantly between groups. The ThromboPath® test results [ThP B: 67.8 ± 13.4 versus 59.09 ± 12.4%, p = 0.023] and factor VII level [69.04 ± 24.16 vs 53.54 ± 25.06, p = 0.032] confirmed greater plasma procoagulant activity in Group 1 compared to Group 2. However, there were no statistically significant differences in thrombin generation after activation of the protein C. Plasma of patients in Group 2 was more resistant to anticoagulation with protein C compared to Group 1 (PICI%: 65.58 ± 7.24 versus 55.64 ± 13.07%, p = 0.001). The results of our study confirm the lack of influence of coagulation disorders on the occurrence of variceal bleeding. Moreover, the results of ThromboPath® assay indicate hypercoagulability in patients with a history of variceal bleeding and more severe liver cirrhosis, compared to patients who have never bled. • Procoagulant imbalance can be easily detected in liver cirrhosis. • The hypercoagulability in liver cirrhosis does not prevent variceal bleeding. • ROTEM shows no association between variceal bleeding and coagulopathy in cirrhosis. [ABSTRACT FROM AUTHOR]

Association of acute myocardial infarction (AMI) and acquired haemophilia A (AHA) is extremely rare, and very difficult to treat, if the patient then presents several serious comorbidities and must undergo an urgent major surgery, the correct choice of haemostatic therapy is essential to avoid potentially life-threatening adverse events for the patient. The recombinant porcine FVIII (rpFVIII) is considered, together with the bypassing agents, as first-line therapy for the AHA, but compared to these it presents a reduced thromboembolic risk which makes it safer in patients who already present at the onset of haemorrhagic event an underlying cardiovascular disease. Haemorrhagic and thrombotic events are always to be taken into consideration in the case of surgery, but in the case of patients with concomitant acquired haemophilia the risk of having serious bleeding has further increase. Today there have been no reports of surgeries carried out under Obizur® coverage. We are reporting the successful case of an elderly critical patient with acquired haemophilia A and concomitant myocardial infarction, treated with rpFVIII and in which an urgent major surgery under coverage of this dug was performed for the first time. • rpFVIII (Obizur®) is recognized as first-line therapy for AHA, together to bypassing agents, but its use is not so widespread • no cases of thrombosis due to rpFVII have been reported in the literature, unlike what happened for the bypassing agents • on these basis, rpFVIII can therefore be considered the best choice especially in elderly patients with severe comorbidities • surgery is an event with a high risk of bleeding, especially if the patient has a pre-existing coagulation disorder • ours is the first report in which an urgent major surgery under rpFVIII coverage was performed [ABSTRACT FROM AUTHOR]

Introduction: 4-F PCC is administered for reversal of factor Xa inhibitor-associated coagulopathy despite a lack of quality evidence demonstrating hemostatic efficacy. The aim of this study was to evaluate the hemostatic efficacy of 4-F PCC in intracerebral hemorrhage patients who received factor Xa inhibitors versus warfarin., Materials and Methods: This was a multi-center, retrospective, observational cohort study at a large healthcare system. Patients taking warfarin received 4-F PCC 25-50 units/kg based on the presenting INR, while patients taking a factor Xa inhibitor received 35 units/kg. The primary outcome was the percentage of patients with good or excellent hemostatic efficacy as assessed by modified Sarode scale, with neurologic outcomes assessed as a secondary endpoint. Patients were included in the primary outcome population if they had a repeat CT scan within 24 h., Results: One hundred fifty-seven patients were included in the primary outcome population; [warfarin (n = 76), factor Xa inhibitors (n = 81)]. Hemostatic efficacy was 83 % in the warfarin group versus 75 % in the factor Xa inhibitor group (p = 0.24). The hemostatic efficacy risk difference between the groups was 7.6 % (95 % CI 5.1 %, 20.2 %). Good neurologic outcome (mRS 0-2) at discharge was 17 % in warfarin patients versus 12 % in the factor Xa inhibitor patients (p = 0.40)., Conclusions: There was no significant difference in hemostatic efficacy or clinical outcomes between patients taking warfarin or a factor Xa inhibitor following reversal with 4-F PCC. This study provides further support that 4-F PCC can be used for the reversal of factor Xa inhibitor-associated coagulopathy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Miguel A. Escobar is a member of the consulting and advisory boards for CSL Behring, BioMarin, Genentech/Roche, Kedrion, NovoNordisk, Pfizer, Sanofi-Genzyme, and Takeda. Research support has been paid to the University of Texas from CSL Behring, Genentech, NovoNordisk, Sanofi-Genzyme, Takeda and UniQure. No pharmaceutical manufacturers had any impact on this study. The other authors declare no competing interests. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Abstract Bleeding heterogeneity observed in haemophilia A (HA) may attribute to that the available monitoring methods cannot appropriately reflect the coagulation profile. The present study aimed to develop a global approach by changing the clotting initiation way in rotational thromboelastometry (ROTEM) assay. ROTEM was run in Factor VIII (FVIII)-immune-depleted plasma to which different concentrations of recombinant VIII (rFVIII) had been added, and also in 31 patients with HA. The clotting activators were APTT reagent (1.2 × 10−3 of the dose used in the original APTT method) and recombinant tissue factor (0.02 pmol/L). In FVIII-immune-depleted plasma spiked with rFVIII, maximum velocity of coagulation reliably mirrored the rFVIII levels. This dose-response disappeared after the samples were pre-incubated with an antibody against TFPI, protein S, activated prothrombin complex concentrate or rFVIIa known to favour the extrinsic activation. In the HA patients with FVIII 0–0.21 IU/mL, APTT and ROTEM outcomes varied in significant correlations to FVIII activity; however, this correlation became non-significant when only samples with FVIII 0–0.05 IU/mL were included. Conclusions: The decreased coagulation in HA mostly result from deficiency/absence of FVIII; other pro-/anti-thrombotic proteins are also influential. The multiple effects may cause a mismatch between bleeding phenotype and FVIII concentrations. The ROTEM assay with the clotting activators i.e., tiny doses of APTT reagent and TF are more effective than the original APTT method as regards the assay sensitivity to influence by VIII activity and also to that by other pro-/anti-thrombotic proteins, showing the whole coagulation picture behind the phenotypic heterogeneity in HA. Highlights • Coagulation in haemophilia A (HA) decreases due to FVIII deficiency; other pro-/anti-thrombotic proteins are also influential. • An overall coagulation method is needed to detect the mismatch between the bleeding phenotype and FVIII activity in HA. • This study has modified ROTEM method by using tiny doses of APTT reagent and rTF as the clotting activators. • The modified ROTEM method may help to show whole coagulation picture behind the phenotypic heterogeneity in HA. [ABSTRACT FROM AUTHOR]

Background The “HERDOO2 rule” is a prospectively validated clinical decision rule used to identify low-risk women who can safely discontinue anticoagulants after completing 5–12 months of anticoagulant treatment for unprovoked venous thromboembolism. The VIDAS ® d -Dimer (DD) assay, a component of the rule, was used in the derivation and validation of the rule at half the usual diagnostic cut-point for exclusion of venous thrombosis. It is unknown if other commercial DD assays used at a corresponding cut-point will categorize patients at high concordance with the VIDAS ® DD. Objective To determine if other available automated quantitative DD assays have high enough concordance with the VIDAS ® DD assay to allow their use within the “HERDOO2” clinical decision rule. Methods Frozen plasma samples from a sub-set ( n  = 248) of female participants in the “HERDOO2” validation study were tested using five DD assays: VIDAS ® , Innovance ® , HemosIL ® , Tina-quant ® and Liatest ® , with duplicate testing for 50 samples. First, using the mean DD for 50 samples with duplicate results, we determined the optimal cut-point values for each test that corresponded with a VIDAS ® DD result of 250 μg/L using linear regression analysis. Next, kappa analysis was conducted on the DD results of the remaining 198 samples to determine concordance between each tested DD at the respective optimal cut-point and the VIDAS ® DD at 250 μg/L. In a separate analysis we determined the concordance at half the usual venous thrombosis exclusion cut-point. Results Regression analysis of the DD results in 50 samples identified the optimal cut-point for each DD assay to match a VIDAS ® DD cut-point of 250 μg/L: Innovance ® 177 μg/L, Liatest ® 233 μg/L, Tina-quant ® 48 μg/L and HemosIL ® 56 μg/L. Next, in 198 different samples, the concordance of VIDAS ® DD (≥250 μg/L or <250 μg/L) was explored at the optimal cut-point of the other DD assays. The concordance was poor for all DD assays: Innovance ® (kappa 0.38 (95% CI, 0.26–0.51)), Liatest ® (kappa 0.38 (95% CI, 0.25–0.50)), HemosIL ® (kappa 0.36 (95% CI, 0.23–0.49)) and Tina-quant ® (kappa 0.30 (95% CI, 0.16–0.43)). Similar poor concordance was identified using half of the diagnostic DD cut-point for each tested assay: Innovance ® (kappa 0.44 (95% CI, 0.32–0.56)), Liatest ® (kappa 0.38 (95% CI, 0.25–0.51)), HemosIL ® (kappa 0.04 (95% CI, −0.01—0.08)) and Tina-quant ® (kappa 0.04 (95% CI, −0.004–0.07)). Conclusion The “HERDOO2 rule” is the only prospectively validated clinical decision rule that can be used to identify low-risk women with unprovoked venous thrombosis who can safely discontinue anticoagulants. An important implementation issue is whether any commercial DD assay can be used in the HERDOO2 rule, and at what cut-point. Our analysis shows that the HemosIL ® , Innovance ® , Liatest ® and Tina-quant ® DD assays should not be used in the “HERDOO2” rule due to poor concordance with the VIDAS ® DD assay and unacceptable misclassification of women at high and low risk of recurrent venous thrombosis. [ABSTRACT FROM AUTHOR]

Introduction Factor V (FV) deficiency is a rare inherited coagulation disorder associated with bleeding tendency. As a result, it has been postulated that decreased FV activity may confer protection against venous thromboembolism and atherothrombotic cardiovascular events. Materials and methods Using the electronic database of the largest health care provider in Israel, we identified all adult individuals who were tested for FV activity between January 2004 and June 2017. Subjects with liver cirrhosis or FV Leiden mutation were excluded. FV activity was classified into three predefined categories; FV activity >50%, FV activity 30–50%, and FV activity ≤30%. Patients were followed from January 2004 to June 2017 for new atherothrombotic cardiovascular events (composite of myocardial infarction, stroke, and TIA) and venous thromboembolism (VTE). Results Overall 2021 individuals were included; 83.2% had FV activity >50%, 9.6% FV activity 30–50%, and 7.2% had FV activity ≤30%. Compared to individuals with FV activity >50% the adjusted HR for atherothrombotic cardiovascular events was 1.10 (95% CI, 0.63–1.90) in those with FV activity 30–50%, and 0.95 (0.49–1.8) in those with FV activity ≤30%. None of the patients with FV activity 30–50% had VTE during follow-up; therefore those with FV activity ≤50% were classified into one group. VTE incidence was lower in those with FV activity ≤50% compared to those with FV >50% activity; adjusted HR = 0.28 (0.09–0.91). Conclusion This study suggests that decreased FV activity might be associated with decreased incidence of VTE. No significant association appears to exist between FV activity and atherothrombotic cardiovascular events. [ABSTRACT FROM AUTHOR]

Introduction Congenital FXI deficiency, a coagulopathy associated with low bleeding risk but thrombotic protection, is usually diagnosed by prolonged APTT and confirmed by coagulation assays. Recent evidences suggest that FXI deficiency might be underestimated. Sensitive and reliable methods to detect FXI deficiency are required. Aim To examine the sensitivity of two methods and two contact activators on FXI deficiency screening. Methods 140 cases with FXI deficiency, 9 severe and 131 moderate, caused by 11different mutations were recruited. APTT and FXI:C were assessed in ACL-TOP 500coagulometer with silica-based (SynthASil) and ellagic acid-based (SynthAFax) reagents. F12 rs1801020 SNP was genotyped with Taqman probes. Results Severe FXI deficiency significantly prolonged APTT with both reagents. However, a high proportion of moderate deficiencies would not be detected using APTT, with false negatives of 22% for SynthASil and 12% for SynthAFax. False negatives results mainly corresponded to cases with qualitative deficiency (CRM +: p.Pro538Leu), which also had higher FXI coagulant activity. Using SynthASil, the common F12 rs1801020 variant, associated to low FXII levels, significantly prolonged APTT in moderate FXI deficiency subjects. FXI:C values were significantly higher with SynthAFax than with SynthASil (47.7 ± 12.7 vs. 40.4 ± 14.9), so SynthAFax rendered higher rate of false negatives than SynthASil (7% vs. 2%). Conclusions Moderate FXI deficiency, particularly CRM +, might be underestimated using current diagnostic methods. The activator, FXI and FXII levels may contribute to a higher rate of false negatives using APTT. Our results suggests that the best screening method for FXI deficiency is FXI:C using silica. [ABSTRACT FROM AUTHOR]

Objectives Screening of patients with sepsis for disseminated intravascular coagulation (DIC) has been recommended in several guidelines. However, DIC screening is still not widely accepted as an essential component of sepsis management, partly because of a lack of evidence that DIC screening has an effect on mortality. We investigated whether DIC screening was associated with a survival benefit in patients with sepsis. Design Post hoc analysis of a nationwide multicenter retrospective cohort study. Setting 42 intensive care units in Japan. Participants 2663 adult patients diagnosed as having severe sepsis: 1893 (71.1%) patients were considered candidates for and 770 (28.9%) patients were not considered candidates for International Society of Thrombosis and Hemostasis (ISTH) overt DIC screening on ICU day 1. Main outcome measures The primary outcome measure was all-cause in-hospital mortality. Patients were stratified according to whether DIC screening was performed at the time of ICU admission (day 1) to investigate the survival effect associated with DIC screening. We also evaluated survival benefit by classifying patients according to whether DIC screening was performed on day 1 and repeated on day 3. Effects of screening on mortality were assessed using Cox proportional hazards models adjusted by the inverse probability of treatment weighting (IPTW) method using propensity scoring. Results After adjustment for imbalances, ISTH overt DIC screening on day 1 was associated with significantly lower mortality (IPTW-adjusted HR: 0.836; 95% confidence interval [CI]: 0.711–0.984), and this association became even stronger when ISTH overt DIC screening was repeated on day 3 (IPTW-adjusted HR: 0.727; 95% CI: 0.597–0.884). Besides, we observed an almost comparable effect on mortality associated with DIC screening using the Japanese Association for Acute Medicine criteria. Conclusion DIC screening was associated with a reduction in mortality in patients with sepsis. This association could be even stronger by repeating DIC screening. [ABSTRACT FROM AUTHOR]

Background Due to the normal physiological need of pregnancy and childbirth, the haemostatic system of pregnant women is different from that of healthy non-pregnant women. The aim of this study was to establish trimester-specific reference intervals of coagulation screening tests and thrombophilia markers in pregnancies without complications of females with Han ethnicity from North China. Methods In total 744 Han healthy pregnant women (first trimester 207 cases, second trimester 222 cases and third trimester 315 cases) and 121 healthy non-pregnant women were recruited in North China. Eight tests―activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fib), d -Dimer, antithrombin (AT), protein C (PC) and free protein S (fPS)―were processed on ACL TOP automated coagulation analyzer. The non-parametric 2.5th–97.5th percentiles reference intervals were calculated to establish trimester-specific reference intervals. Results The reference intervals for APTT, PT, TT, Fib, d -Dimer, AT, PC, and fPS at first trimester were 26.4–41.9 s, 9.7–12.5 s, 11.7–17.0 s, 2.38–4.44 g/L, 0.01–0.31 μg/mL, 72–120%, 29–150%, 21–143%, respectively. At second trimester, the reference intervals were 24.4–35.8 s, 8.5–13.2 s, 10.0–16.0 s, 2.40–5.97 g/L, 0.05–0.73 μg/mL, 68–125%, 20–138%, 24–155%, respectively. At third trimester, the reference intervals were 25.6–34.9 s, 8.6–12.4 s, 11.1–15.5 s, 2.79–5.91 g/L, 0.14–2.82 μg/mL, 56–119%, 20–134%, 17–140%, respectively. From the first trimester to the third trimester, APTT, PT and TT presented shortened trends, Fib and d -Dimer presented increasing trends, AT, PC and fPS activity presented decreasing trends, respectively. Conclusions The trimester-specific reference intervals of coagulation screening tests and thrombophilia markers in pregnancies without complications of females with Han ethnicity from North China are presented in this study, which may provide effective evidence for doctors to accurately diagnose and treat the disease during pregnancy. [ABSTRACT FROM AUTHOR]

Background Several characteristics such as demographics, pre-existing conditions, surgical procedure, perioperative coagulopathy may predispose children undergoing cardiopulmonary bypass (CPB) to bleeding complications. As yet, studies on risk factors for postoperative bleeding have brought mixed results. The purpose of our study was therefore to retrospectively evaluate the parameters able to predict postoperative bleeding in a group of consecutive children undergoing cardiac surgery involving CPB. Methods We collected demographic and perioperative laboratory data, as well as intraoperative transfusion requirements and blood loss during the first 24 h after surgery in a group of consecutive children (aged ≥ 1 month) scheduled for cardiac surgery with CPB at Padua University Hospital between June 2014 and April 2015. Cases were patients who experienced a 24-h postoperative blood loss ≥ 80th percentile. Univariate and multivariate logistic regression analyses were performed to determine the independent parameters associated with a high 24-h postoperative chest tube drainage volume. Results Eighty-three children (M:F 38:45; age range 1–168 months) were enrolled. Age < 7.7 months (p 0.015), postoperative platelets < 109 × 10 9 /L (p 0.003) and postoperative D-dimer ≥ 2350 μg/L (p 0.007) were the variables most significantly and independently associated with excessive 24-h postoperative blood loss. Conclusions Although preliminary, our study identified younger age, lower postoperative platelet count and higher D-dimer plasma levels as possible risk factors for postoperative bleeding. As for coagulation parameters, our results suggested consumptive coagulopathy might cause a strong predisposition to postoperative bleeding in children. Large-scale prospective studies would provide insight into the early diagnosis and treatment of CPB-related coagulopathies. [ABSTRACT FROM AUTHOR]

Severe sepsis is almost invariably associated with systemic activation of coagulation. There is ample evidence that demonstrates a wide-ranging cross-talk between hemostasis and inflammation, which is probably implicated in the pathogenesis of organ dysfunction in patients with sepsis. Inflammation not only leads to initiation and propagation of coagulation activity, but coagulation also markedly influences inflammation. Molecular mechanisms that play a role in inflammation-induced effects on coagulation have been recognized in much detail. Pro-inflammatory cells and cyto- and chemokines can activate the coagulation system and downregulate crucial physiological anticoagulant mechanisms. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and endothelial cells and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Increased fibrin generation and impaired break down lead to deposition of (micro)vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. The foundation of the management of coagulation in sepsis is the explicit and thorough treatment of the underlying disorder by antibiotic treatment and source control measures. Adjunctive strategies focused at the impairment of coagulation, including anticoagulants and restoration of physiological anticoagulant mechanisms, may supposedly be indicated and have been found advantageous in experimental and initial clinical trials. [ABSTRACT FROM AUTHOR]

Introduction Factor XIII (FXIII) cross-links fibrin, completing blood coagulation. Congenital FXIII deficiency is managed with plasma-derived FXIII (pdFXIII) or recombinant FXIII (rFXIII) concentrates. Aim As the mechanisms protecting patients with low FXIII levels (< 5 IU/dL) from spontaneous bleeds remain unknown we assessed the interplay between thrombin generation (TG), fibrin formation and clot kinetics before and after FXIII administration in three patients with FXIII deficiency. Methods Patients received initially rFXIII (35 IU/kg, A-subunit) following with pdFXIII at 1250 IU or 2500 IU (12–30 IU/kg) monthly. TG (CAT), thromboelastometry (ROTEM), prothrombin fragments F1 + 2, fibrinogen and FXIII activity (FXIII:C) were measured at baseline and one-hour recovery. Results FXIII was at the target level of 20 ± 6 IU/dL at the 4-week trough. rFXIII corrected FXIII to 98 ± 15 and high-dose pdFXIII to a level of 90 ± 6, whereas low-dose/half dose pdFXIII reached 45 ± 4 IU/dL. Although fibrinogen (Clauss Method) was normal, coagulation in FIBTEM was impaired, which FXIII administration tended to correct. CAT implied 1.6- to 1.9-fold enhanced TG, which FXIII administration normalized. Inhibition of fibrin polymerization by Gly-Pro-Arg-Pro peptide mimicked FXIII deficiency in CAT by enhancing TG both in control and FXIII recovery plasma. Antithrombin, α2-macroblobulin–thrombin complex and prothrombin were normal, whereas F1 + 2 were elevated compatible with in vivo TG. Discussion FXIII deficiency impairs fibrinogen function and fibrin formation simultaneously enhancing TG on the poorly polymerizing fibrin strands, when fibrin’s antithrombin I -like function is absent. Our study suggests an inverse link between low FXIII levels and enhanced TG modifying structure-function relationship of fibrin to support hemostasis. [ABSTRACT FROM AUTHOR]

Cancer survivors are at an increased risk of thromboembolism compared to the general pediatric population. Anticoagulant therapy decreases the risk of thromboembolism in cancer patients. We hypothesized that pediatric cancer survivors are in a chronically hypercoagulable state compared to healthy controls. Children who survived for more than five years from cancer diagnosis at the UT Health Science Center at San Antonio Cancer Survivorship Clinic were compared to healthy controls. The exclusion criteria were recent NSAID use or a history of coagulopathy. Coagulation analysis included platelet count, thrombin-antithrombin complexes (TAT), plasminogen activator inhibitor (PAI), routine coagulation assays, and thrombin generation with and without thrombomodulin. We enrolled 47 pediatric cancer survivors and 37 healthy controls. Platelet count was significantly lower in cancer survivors at a mean of 254 × 10 9 /L (95%CI: 234-273 × 10 9 /L) compared at 307 × 10 9 /L (283-331 × 10 9 /L) in healthy controls (p < 0.001), although not outside the normal range. Routine coagulation assays showed no differences, except for a significantly lower prothrombin time (PT) in cancer survivors (p < 0.004). Cancer survivors has significantly elevated biomarkers of the procoagulant state, such as TAT and PAI, compared to healthy controls (p < 0.001). A multiple logistic regression model controlling for age, BMI, gender, and race/ethnicity documented that a low platelet count, short prothrombin clot time, and higher procoagulant biomarkers (TAT and PAI) were significantly associated with past cancer therapy. Survivors of childhood cancer have a persistent procoagulant imbalance for more than five years after diagnosis. Further studies are needed to establish whether procoagulant imbalance increases the risk of thromboembolism in childhood cancer survivors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

• Fibrinogen quantity or quality deficiency can lead both to bleeding and thrombotic phenotype. • Fibrinogen FGA , FGB and FGG genes were sequenced in 17 patients by next-generation sequencing. • Variants leading to fibrinogen deficiency were found in all patients. • Eight novel variants were described. [ABSTRACT FROM AUTHOR]

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. [ABSTRACT FROM AUTHOR]

Major bleeding with low molecular weight heparin (LMWH) therapy occurs in up to 5% of patients and its anticoagulation is only partially reversed by protamine sulfate. We studied the ability of ciraparantag (PER977), a novel agent that reverses LMWH in preclinical studies, to reverse LMWH in healthy volunteers. Methods In this phase 1/2 trial, 4 cohorts of 10 healthy volunteers received escalating doses of ciraparantag (100 to 300 mg) or placebo (8:2 ratio) approximately 4 h after a single subcutaneous dose of enoxaparin, 1.5 mg/kg. Safety, pharmacokinetic and pharmacodynamic effects were assessed. Results Complete reversal of enoxaparin anticoagulation, measured by a reduction of whole blood clotting time, was observed in all subjects who received a single ciraparantag dose ranging from 100 mg to 300 mg. The anticoagulation reversal occurred rapidly after bolus injection and persisted for the duration of the study. At 12 h and 24 h, the differences in whole blood clotting time in the treated group compared to placebo were no longer significant, consistent with the decline in enoxaparin concentrations and anticoagulation effects. No procoagulant signals were detected as measured by D-dimer, F1.2, and tissue factor pathway inhibitor levels. Ciraparantag was well tolerated with only transient, minor side effects. Conclusion Ciraparantag reverses the whole blood clotting time induced by enoxaparin in a dose related manner and produces no procoagulant signal or deleterious adverse events in doses up to 300 mg. [ABSTRACT FROM AUTHOR]