Type 2B von Willebrand disease (VWD) is a rare qualitative variant, accounting for ∼5% of all VWD cases. It is characterized by increased affinity of abnormal von Willebrand factor (VWF) for the platelet glycoprotein Ibα receptor, resulting in enhanced clearance of both high-molecular-weight VWF multimers and platelets from circulation. The management of women with type 2B VWD during pregnancy and the postpartum period poses unique challenges due to complex hemostatic abnormalities, a high risk of bleeding complications, and a lack of evidence-based guidelines. A recent systematic review, international registry analysis, and global physician survey highlighted several unmet clinical needs in this population, including gaps in early diagnosis, prenatal counseling, pregnancy monitoring, and peripartum management. In response, the International Society on Thrombosis and Haemostasis Scientific Subcommittees on VWF and on Women’s Health Issues in Thrombosis and Haemostasis collaborated to develop consensus-based guidance for the management of type 2B VWD in pregnancy and postpartum. Using the real-time Delphi methodology, 14 international experts reviewed 26 initial statements on diagnosis, monitoring, and treatment. After 2 rounds of anonymous voting and revisions based on participants’ feedback, consensus was achieved on 25 statements. These consensus statements, grounded in the best available evidence and expert opinion, aim to standardize care, guide management, and improve clinical outcomes for women with type 2B VWD during pregnancy and postpartum.

Marstacimab, a monoclonal antibody that inhibits tissue factor pathway inhibitor, is approved for prophylactic use in individuals with hemophilia A or B without inhibitors. We present efficacy and safety for individuals with inhibitors. The open-label, single-arm, phase 3 study evaluated once-weekly subcutaneous flat-dose marstacimab in males aged 12 to <75 years with severe hemophilia A or moderately severe to severe hemophilia B. Participants with inhibitors received bypassing agents (on-demand or routine prophylaxis) during a 6-month observational phase (OP) before entering a 12-month active treatment phase (ATP) with marstacimab. Primary end points were annualized bleeding rate (ABR) of treated bleeds and safety. Of 60 participants with inhibitors in the OP, 51 entered the ATP and received marstacimab. In the on-demand group (n = 48), mean estimated ABR declined from 19.78 (95% confidence interval [CI], 16.12-24.27) in the OP to 1.39 (95% CI, 0.85-2.29) during the ATP (ABR ratio, 0.07 [95% CI, 0.042-0.118]; 2-sided P< .0001). Results were consistent by hemophilia type (ABR ratio, 0.05 [hemophilia A, n = 40]; 0.13 [hemophilia B, n = 8]). Participants reported significant improvements in health-related quality of life. Adverse events were common but mostly mild; 1 treatment-related grade 3 skin rash led to discontinuation. Antidrug antibodies were detected in 19.6% of participants, with no apparent effect on efficacy or safety. In participants with inhibitors, marstacimab was associated with reduced bleeding rates and an acceptable safety profile, with no thromboembolic events. Marstacimab may be a viable treatment option for people with hemophilia A or B with inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT03938792. ClinicalTrials.gov identifier: NCT03938792.

Introduction Despite the known haemostatic action of emicizumab (Hemlibra) in haemophilia A patients, its role in the prevention and control of bleeding in high-demand haemostatic situations, such as major surgery, remains to be determined. Patients receiving regular emicizumab prophylaxis often require concomitant factor VIII (FVIII) therapy during major surgery to prevent uncontrolled bleeding and to promote postoperative healing. However, there are limited prospective surgical data relating to concomitant FVIII and emicizumab use. Simoctocog alfa (Nuwiq) is a B-domain deleted recombinant FVIII produced in a human cell line without chemical modification or protein fusion with proven efficacy as surgical prophylaxis in adult and paediatric patients. The Nuwiq for Perioperative management Of patients With haemophilia A on Emicizumab Regular prophylaxis (NuPOWER) study aims to examine perioperative efficacy and safety of simoctocog alfa in haemophilia A patients on emicizumab prophylaxis undergoing major surgery.Methods and analysis NuPOWER is a prospective, open-label, single-arm, multicentre study that will be conducted at approximately 15 centres worldwide. Up to 28 male patients ≥12 years with severe haemophilia A and no FVIII inhibitors will be recruited. All patients must be receiving regular emicizumab prophylaxis and scheduled to undergo a major surgical procedure during which concomitant simoctocog alfa will be administered. The primary endpoint is the overall haemostatic efficacy of simoctocog alfa, adjudicated by an independent data monitoring committee using a pre-defined algorithm, and will consider intraoperative and postoperative efficacy assessments by the surgeon and investigator, respectively. Secondary endpoints include intraoperative haemostatic efficacy, postoperative haemostatic efficacy, number of allogeneic blood products transfused, perioperative FVIII plasma levels (as measured by FVIII activity) and thrombin generation, and safety parameters. In the era of non-factor therapy, NuPOWER will generate valuable prospective data on concomitant use of simoctocog alfa and emicizumab prophylaxis in patients with severe haemophilia A undergoing major surgery.Ethics and dissemination Ethical approval has been received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki. This work will be disseminated by publication of peer-reviewed manuscripts and presentations at scientific meetings.Trial registration number CT EU 2022-502060-21-00; NCT05935358.

The milestone of treating and preventing venous thromboembolism (VTE) is the application of anticoagulants. For many years the cornerstone was the use of vitamin K antagonists (VKAs), but it was associated with numerous obstacles and complications. With the introduction of a new generation of direct oral anticoagulants (DOAC), some of the difficulties, such as delayed onset/offset of the action, individual dose modifications, inhibition of several coagulation factors, need for frequent monitoring of prothrombin time, multiple drug interactions, have been overcome, while maintaining an adequate safety profile. Therefore, DOACs have rapidly replaced VKAs as a standard of care in the treatment and prevention of VTE, as well as in the prevention of ischemic complications in patients with non-valvular atrial fibrillation. However, the expected consequence of the use of anticoagulant drugs is increased bleeding risk. Several randomized and retrospective studies have analyzed the risk of bleeding associated with the use of DOACs compared to VKAs and between DOACs. It has been clearly shown that intracranial hemorrhage risk is decreased with DOAC compared to VKA, while most studies have shown that the risk of major bleeding is the same or even lower with DOAC. Considering DOAC's efficacy, excellent safety, and simple application compared with VKAs, it does not surprise their increasingly frequent application in everyday clinical practice. Will VKAs gradually become a part of history, or will their use be limited to a specific, clearly defined population? The time has to show.

Antiphospholipid antibodies (aPL antibodies) are a heterogeneous group of autoantibodies that target anionic phospholipids or phospholipid-binding proteins. They can be associated with numerous clinical manifestations in almost all areas of clinical medicine, but antiphospholipid syndrome (APS) is the most precisely defined entity. The most common clinical manifestations of aPL are thrombosis in any part of the circulation, as well as pregnancy complications in the form of miscarriage or premature birth due to preeclampsia, eclampsia, or placental insufficiency. According to the modified Sapporo classification of 2006, thrombosis and/or pregnancy complications represent the clinical criteria for diagnosing APS. However, in approximately a quarter of patients with APS, additional clinical manifestations are present, which are not accepted as criteria for APS. Interestingly, these manifestations can be associated with aPL antibodies even in the absence of thrombosis or pregnancy morbidity, i.e., without the presence of the criteria for definitive APS. Recognizing non-criteria manifestations is highly significant because it can draw attention to the possible presence of aPL antibodies and indicate the presence of APS or the risk of its occurrence. The latest classification was published in 2023 by the American College of Rheumatology/European Alliance of Rheumatology Associations (ACR/EULAR). It expanded the list of clinical criteria for the recognition of antiphospholipid syndrome. This classification demonstrates higher specificity but lesser sensitivity in recognizing APS than earlier criteria. At present, the application of the ACR/EULAR criteria is primarily intended for research purposes, i.e., selecting study subjects, rather than for diagnosing APS in everyday clinical practice.

The authors regret the affiliation of Clinical Pathology Department, Faculty of Medicine, Mansoura University, Egypt was omitted for Maha Othman. This has been corrected and added as below. The authors would like to apologise for any inconvenience caused. Diagnosis and management of severe congenital protein C deficiency (SCPCD): Communication from the SSC of the ISTHJournal of Thrombosis and HaemostasisVol. 20Issue 7PreviewSevere congenital protein C deficiency (SCPCD) is rare and there is currently substantial variation in the management of this condition. A joint project by three Scientific and Standardization Committees of the ISTH: Plasma Coagulation Inhibitors, Pediatric/Neonatal Thrombosis and Hemostasis, and Women’s Health Issues in Thrombosis and Hemostasis, was developed to review the current evidence and help guide on diagnosis and management of SCPCD. We provide a summary of the clinical presentations, differential diagnoses, appropriate investigations to confirm the diagnosis, approaches for management of the acute situation, and options for long‐term management including subsequent pregnancies. Full-Text PDF Open Access

BACKGROUND:Management of women with type 2B von Willebrand disease (VWD) during pregnancy is challenging because of dysfunctional von Willebrand factor (VWF) and the complexity resulting from discrepant VWF/factor VIII (VWF/FVIII) levels, impaired platelet-dependent VWF activity, progressive thrombocytopenia, and risks associated with the use of desmopressin. There is a lack of high-quality evidence to support clinical decision making.OBJECTIVES:In this study, we examined the current diagnostic and management approaches and outcomes in women with VWD during pregnancy.METHODS:Data were collected via 3 avenues: literature review, an international registry, and an international survey on physicians' practices for the management of pregnancy in women with VWD. The registry and survey were supported by the International Society on Thrombosis and Haemostasis.RESULTS:Data on clinical and laboratory features, management and bleeding complications, and pregnancy outcomes of a total of 55 pregnancies from 49 women across the globe (literature: 35, registry: 20) and data reported by 112 physicians were analyzed. We describe the largest dataset on pregnancies in women with type 2B VWD available to date. The data highlight the following key issues: a) bleeding complications remain a concern in these patients, b) the target safe VWF level and the ideal monitoring approach are unknown, c) there is a wide range of hemostatic management practices in the type and timing of treatment, and d) physicians have diverse views on the mode of delivery and use of neuraxial anesthesia.CONCLUSION:We conclude that an international consensus and guidance are critically required for better care and improved outcomes in this patient cohort.

[This corrects the article DOI: 10.1002/rth2.12690.].

Introduction: Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by arterial or venous thromboses and/or spontaneous abortions associated with a persistently elevated level of antiphospholipid antibodies. To date, no clear relationship has been established between levels and types of autoimmune antibodies and clinical manifestations of APS, which can range from mild coagulation disorders to life-threatening conditions. Aim: The aim of this study is to examine the relation between antiphospholipid antibody type and titer and the most common clinical manifestations of APS. Materials and methods: The retrospective study included 32 patients with a confirmed laboratory finding of elevated antiphospholipid antibodies, who came for follow-up examinations to the Hemophilia Unit of the University Clinical Center of Serbia, between June 1, 2017 and December 31, 2018. Data on patients were taken from their medical records. Basic demographic data, type and titer of antiphospholipid antibodies, and their association with the present clinical manifestations of APS were analyzed using standard statistical methods. Results: There was no significant difference regarding the frequency of positive results for lupus anticoagulant, anti-cardiolipin, and anti-beta-2-GP-I antibodies, between the symptomatic and asymptomatic group. The percentage of persons with simultaneous positivity for two or all three antiphospholipid antibodies was the same in both groups of subjects. Conclusion: As opposed to previous studies, our study did not demonstrate a correlation between the titer of antiphospholipid antibodies and the clinical manifestations of APS. Symptomatic and asymptomatic patients did not significantly differ in the frequency of elevated antibodies. These results indicate that the presence of other factors, which are as yet little-known, is necessary for the clinical manifestations of APS.

REFERENCES 1. Graux C, Cools J, Melotte C, et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 2004;36:1084-9. 2. Ragg S, Zehentner BK, Loken MR, Croop JM. Evidence for BCR/ABL1-positive T-cell acute lymphoblastic leukemia arising in an early lymphoid progenitor cell. Pediatr Blood Cancer 2019;66:e27829. 3. Govaerts I, Jacobs K, Vandepoel R, Cools J. JAK/STAT pathway mutations in T-ALL, including the STAT5B N642H mutation, are sensitive to JAK1/JAK3 inhibitors. Hemasphere 2019;3:e313. 4. Sharma P, Rana S, Sreedharanunni S, et al. An evaluation of a fluorescence in situ hybridization strategy using air-dried blood and bone-marrow smears in the risk stratification of pediatric B-lineage acute lymphoblastic leukemia in resource-limited settings. J Pediatr Hematol Oncol 2021;43:e481-5. 5. Graux C, Stevens-Kroef M, Lafage M, et al. Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia. Leukemia 2009;23:125-33. 6. Deenik W, Beverloo HB, van der Poel-van de Luytgaarde SC, et al. Rapid complete cytogenetic remission after upfront dasatinib monotherapy in a patient with a NUP214-ABL1-positive T-cell acute lymphoblastic leukemia. Leukemia 2009;23:627-9. 7. Li X, Ping N, Wang Y, et al. Case report: a case with Philadelphia chromosome positive T-cell lymphoblastic lymphoma and a review of literature. Front Oncol 2021;10:584149. 8. Jain P, Kantarjian H, Jabbour E, et al. Clinical characteristics of Philadelphia positive T-cell lymphoid leukemias-(De novo and blast phase CML). Am J Hematol 2017;92:E3-4. 9. Ballerini P, Busson M, Fasola S, et al. NUP214-ABL1 amplification in t(5;14)/HOX11L2-positive ALL present with several forms and may have a prognostic significance. Leukemia 2005; 19:468-70. 10. Barber KE, Martineau M, Harewood L, et al. Amplification of the ABL gene in T-cell acute lymphoblastic leukemia. Leukemia 2004;18:1153-6. 11. Kim HJ, Woo HY, Koo HH, Tak EY, Kim SH. ABL oncogene amplification with p16(INK4a) gene deletion in precursor T-cell acute lymphoblastic leukemia/lymphoma: report of the first case. Am J Hematol 2004;76:360-3. 12. Chen Y, Zhang L, Huang J, et al. Dasatinib and chemotherapy in a patient with early T-cell precursor acute lymphoblastic leukemia and NUP214-ABL1 fusion: a case report. Exp Ther Med 2017;14:3979-84. 13. Peterson JF, Pitel BA, Smoley SA, et al. Detection of a cryptic NUP214/ABL1 gene fusion by mate-pair sequencing (MPseq) in a newly diagnosed case of pediatric T-lymphoblastic leukemia. Cold Spring Harb Mol Case Stud 2019;5:a003533. 14. De Keersmaecker K, Lahortiga I, Graux C, et al. Transition from EML1-ABL1 to NUP214-ABL1 positivity in a patient with acute T-lymphoblastic leukemia. Leukemia 2006;20:2202-4. 15. Bernasconi P, Calatroni S, Giardini I, et al. ABL1 amplification in T-cell acute lymphoblastic leukemia. Cancer Genet Cytogenet 2005;162:146-50.

Severe congenital protein C deficiency (SCPCD) is rare and there is currently substantial variation in the management of this condition. A joint project by three Scientific and Standardization Committees of the ISTH: Plasma Coagulation Inhibitors, Pediatric/Neonatal Thrombosis and Hemostasis, and Women's Health Issues in Thrombosis and Hemostasis, was developed to review the current evidence and help guide on diagnosis and management of SCPCD. We provide a summary of the clinical presentations, differential diagnoses, appropriate investigations to confirm the diagnosis, approaches for management of the acute situation, and options for long‐term management including subsequent pregnancies. We finally provide a set of recommendations to help in this regard.

Introduction. D-dimer is formed during plasmin-mediated proteolysis of cross-linked fibrin; hence it serves as a biomarker of activated coagulation and fibrinolysis. Clinical significance. Measurement of D-dimer is most commonly used to exclude venous thromboembolism, and in the diagnosis of disseminated intravascular coagulation. For the diagnosis of venous thromboembolism D-dimer is part of the validated algorithm, which includes an assessment of clinical pre-test probability to guide further investigation. Due to very high negative predictive values, average levels of D-dimer are sufficient for ruling out venous thromboembolism in patients with low-medium pre-test clinical probability. However, in patients with high pre-test probability, the measurement of D-dimer is of limited value. Similarly, normal values of D-dimer reliably exclude disseminated intravascular coagulation. On the other hand, elevated values of D-dimer have low specificity for this condition and should be evaluated in a validated scoring system developed for the diagnosis of disseminated intravascular coagulation. Recently, measurement of D-dimer has been increasingly applied to assess the risk of venous thrombosis recurrence in women and to decide on the duration of anticoagulant therapy after the first unprovoked venous thrombosis. Elevated D-dimer level is an essential characteristic of COVID-19 - associated coagulopathy. The degree of coagulopathy and D-dimer levels correlate with the clinical severity of the disease and higher mortality, most likely reflecting increased activation of the coagulation system in the microcirculation of various organs, primarily the lungs. Conclusion. D-dimer is one of the most often used hemostasis test, validated so far for diagnosis of venous thromboembolism and disseminated intravascular coagulation.

Venous thromboembolism (VTE) is a multifactorial disease that can possibly affect any part of venous circulation. The risk of VTE increases by about 2 fold in pregnant women and VTE is one of the major causes of maternal morbidity and mortality. For decades superficial vein thrombosis (SVT) has been considered as benign, self-limiting condition, primarily local event consequently being out of scope of well conducted epidemiological and clinical studies. Recently, the approach on SVT has significantly changed considering that prevalence of lower limb SVT is twice higher than both deep vein thrombosis (DVT) and pulmonary embolism (PE). The clinical severity of SVT largely depends on the localization of thrombosis, when it concerns the major superficial vein vessels of the lower limb and particularly the great saphenous vein. If untreated or inadequately treated, SVT can potentially cause DVT or PE. The purpose of this review is to discuss the complex interconnection between SVT and risk factors in pregnancy and to provide evidence-based considerations, suggestions, and recommendations for the diagnosis and treatment of this precarious and delicate clinical entity.

Normal pregnancy associated with complex changes of hemostasis, leading to hypercoagulability states. The presence of acquired or genetic prothrombotic risk factors might affect the proper maternal-fetal circulation and result in pregnancy loss. Hence, the screening for the novel prothrombotic variants associated with pregnancy loss would be beneficial. Our aim was to investigate the potential association of recently reported c.*64_*66del variant in prothrombin gene with the etiology of pregnancy loss. Study included 105 women with pregnancy loss and 155 controls. Analyses in patients? plasma samples, as well as in vitro analyses on transfected Cos-7 cell line were performed in order to investigate the mechanism by which this variant could perturb the coagulation and lead to pregnancy loss. Analyses in patients' DNA and plasma samples involved: DNA sequencing and PCR-RFLP assay for detection of FII c.*64_*66del variant, routine thrombophilia screening, thrombin generation assay and Western blot analysis of prothrombin plasma level. In vitro analyses included transient transfections of Cos-7 cell line with wild-type and c.*64_*66del mutated constructs of pCIneo?SV40 expression vector. Real-Time PCR and Western blot analysis were used to determine the effect of FII c.*64_*66del variant on mRNA and protein level in constructs. Three women in patients group (2.9%) were detected as heterozygous carriers of FII c.*64_*66del, while none was found among controls. The carriers routine thrombophilia parameters were in reference range and similar prothrombin plasma level in FII c.*64_*66del carriers and non-carriers were detected. The endogenous thrombin potential was slightly increased in FII c.*64_*66del carriers compared to control plasma, but this difference was not statistically significant. Results of in vitro analyses showed significantly decreased prothrombin mRNA and protein level for c.*64_*66del variant compared to wild-type. Results of our pilot study have shown a trend of higher prevalence of FII c.*64_*66del variant in women with pregnancy loss. However, further studies are needed to completely elucidate whether FII c.*64_*66del variant affects prothrombin expression during pregnancy and to account its potential role in etiology of pregnancy loss.

INTRODUCTION:The impact of activated blood and endothelial cells on the thrombosis in myeloproliferative neoplasms (MPN) has not yet been clarified. We prospectively analyzed correlation between circulating leukocyte-platelet aggregates and soluble selectins to thrombosis occurrence in MPN, in the context of standard and cardiovascular risk factors, and different clinical and biological characteristics.METHODS:Flow cytometric analysis of neutrophil-platelet (Neu-Plt) and monocyte-platelet (Mo-Plt) aggregates in peripheral blood, as well as quantification of soluble E-/L-/P-selectins by enzyme immunoassay, was performed on 95 newly diagnosed MPN patients.RESULTS:During the follow-up, thrombosis occurred in 12.6% MPN patients (arterial 9.4%, venous 3.2%), with a mean time of 39 months. The overall incidence rate of main thrombotic events was 4.36 per 100 patient-years. The incidence of arterial hypertension (HTA) was significantly higher in patients with thrombosis, compared to those without thrombosis (P < .05). The level of soluble P-selectin was significantly higher in patients with thrombosis compared to those without thrombosis (346.89 ng/mL vs 286.39 ng/mL, P = .034). The mean level of Neu-Plt (26.7% vs 22.4%) and Mo-Plt (17.8% vs 12.3%) aggregates did not differ significantly between the groups with and without thrombosis. A multivariate COX proportional hazard regression model confirmed an independent predictive significance of Mo-Plt aggregates (HR = 1.561, 95% CI: 1.007-2.420, P = .046), as well as the cumulative effect of Mo-Plt aggregates and HTA (HR = 1.975, 95%CI: 1.215-3.212, P = .006) for thrombosis occurrence.CONCLUSION:Monocyte-platelet aggregates represent an independent risk factor for thrombosis occurrence, further on supported by HTA.

Coagulopathy in COVID-19 represents a thrombo-inflammatory condition, and it is one of the most important causes of morbidity and mortality in this disease. The occurrence of coagulopathy correlates with the intensity of the inflammatory response to SARS-Cov-2 virus infection, and its presence is characterized by laboratory markers of blood hypercoagulability and clinically pronounced prothrombotic condition. Although the mechanism of coagulopathy is not fully elucidated, dysregulated and overemphasized immune responses mediated by inflammatory cytokines, complement activation, leukocyte activation with release of free nucleic acids and histones into the circulation, hypoxia and endothelial damage play a very important role in its development. Thrombosis can occur in all parts of the circulatory system and is most often localized in the microcirculation and venous part of the vasculature. A number of studies have shown that the presence of thrombotic pulmonary embolism can be demonstrated by objective methods in approximately 15% of COVID-19 patients treated in intensive care units, while the incidence of total venous thromboembolism in this group of patients is over 20% despite antithrombotic prophylaxis. Although much less common than venous thrombosis, arterial thrombosis may also occur in COVID-19 patients, most often in the form of myocardial infarction, ischemic stroke and peripheral artery occlusion. Damage to the endothelium under the influence of virus or inflammatory response, activation of platelets and coagulation system with fibrin deposition leads to extensive thrombosis in the microcirculation of lungs and other tissues and directly contributes to respiratory failure, ARDS or multiorgan failure. Therefore, coagulopathy in COVID-19 is an integral part of the pathophysiological mechanism of the disease and contributes to its clinical manifestation and progression. Main laboratory characteristics of COVID-19 coagulopathy are elevated values of D-dimer in the blood, which occurs in the process of decomposition of precipitated fibrin under the action of fibrinolytic enzymes in the microcirculation of the lungs and other organs. Therefore, D-dimer values reflect the intensity of the inflammation in the lungs and have prognostic significance in recognizing patients at risk of serious complications and unfavorable course of the disease. In contrast to disseminated intravascular coagulation in sepsis, severe thrombocytopenia and hypofibrinogenemia as well as bleeding tendencies are rare in COVID-19 coagulopathy. Due to the high frequency and important role of coagulopathy in morbidity and mortality, the use of anticoagulant therapy is recommended in all hospitalized patients. However, the optimal way of treating coagulopathy and the intensity of antithrombotic prophylaxis are not known, and represent the subject of intensive research.