Seminars in thrombosis and hemostasis最新文献

The American Society of Hematology-International Society on Thrombosis and Haemostasis-National Hemophilia Foundation-World Federation of Hemophilia 2021 International Guidelines (IGL) on von Willebrand disease (VWD) have pointed out many challenges, mainly in the diagnostic approach of VWD patients. To determine the impact of these IGL on the current clinical and laboratory diagnosis of Italian VWD patients, we have recently conducted a survey among 43 centers affiliated with the Italian Association of Hemophilia Centers (AICE). Directors and colleagues responsible for the management of VWD patients were invited to report in a detailed questionnaire how IGL recommendations about the assessment of the specific activities of von Willebrand Factor (VWF) could be applied at their local sites. Results from such a survey showed that bleeding assessment tools, VWF antigen, and factor VIII procoagulant are currently in use in all centers. The automated assays for platelet-dependent VWF activity with or without ristocetin described in IGL have been used since 2021 in 37/43 (86%) centers. Among other laboratory tests, VWF collagen binding, ristocetin-induced platelet agglutination, multimeric analysis, VWF propeptide, VWF:FVIII binding assay were available in 49, 63, 26, 7, and 28% of AICE, respectively. Analyses of VWF gene defects are available only at 3/43 (7%) centers. Desmopressin (DDAVP) infusion trials at diagnosis, with measurements of VWF activities at 1 and 4 hours post-DDAVP, is currently performed at 38/43 (88%) centers. Based on this information, a simplified clinical diagnosis using a few automated tests before and after DDAVP has been proposed. Such a diagnostic approach will be validated prospectively in a large cohort of Italian VWD patients.

The mainstay of treatment for persons with hemophilia A (PwHA) with severe bleeding phenotype is prophylaxis. The pharmacokinetic (PK) profile of native factor VIII (FVIII) imposes the need for rather frequent intravenous injections to ensure effective prophylaxis, but this represents a relevant treatment burden and is associated with suboptimal adherence to treatment. In this light, the advent of extended half-life (EHL) FVIII molecules has improved prophylaxis feasibility and outcomes by favoring treatment individualization and tailoring protection according to specific clinical and nonclinical needs. Different technologies have been used to enhance FVIII PK properties including Fc-fusion and conjugation with polyethylene glycol. Data from clinical development programs for such molecules, together with growing real-world experience, have shown numerous benefits related to the use of EHL FVIII in PwHA. Recently a new class of ultra-long-acting EHL FVIII has been developed to further improve protection against bleeding episodes and achieve the ambitious goal of providing PwHA with hemostatic protection in the nonhemophilia range over longer time periods, hence ensuring very low bleeding rates and improving joint health and quality of life. In this review, the achievements and perspectives of replacement therapies for PwHA are summarized and discussed.

Non-factor replacement therapies (NFTs) have been developed to address the limitations of conventional replacement therapies, aiming to improve hemostasis and provide enhanced protection against bleeding episodes and long-term joint damage for patients both with and without inhibitors. Factor VIII (FVIII)-mimetic agents, such as emicizumab, have transformed the management of hemophilia A with inhibitors, offering a lower treatment burden and an effective alternative for those without inhibitors as well. Rebalancing agents, including anti-tissular factor pathway inhibitor agents (concizumab and marstacimab) and serpin inhibitors like fitusiran, have shown promising efficacy for patients with hemophilia B with inhibitors and other hemophilia subtypes. Administered subcutaneously, NFTs generate stable thrombin levels and feature a long half-life, which can shift severe hemophilia toward a milder phenotype. These therapies are effective regardless of inhibitor status and hold potential for application in other bleeding disorders. Evaluating the potential thrombotic risk after implementing mitigation measures, along with the development of anti-drug antibodies (ADAs), remain critical areas for further analysis. NFTs pose additional challenges due to their complex mechanism of action and the absence of a standardized laboratory assessment method. Unresolved issues include optimal management strategies for major surgeries and tailored approaches for safe use in older populations. This review highlights the progress and future potential of NFTs in treating persons with hemophilia.

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder which can be life-threatening. AHA is due to autoantibodies against coagulation factor VIII. Disease onset may be idiopathic (approximately half of the cases) or triggered by autoimmune disorders, cancers, drugs, infections, or pregnancy. Besides treating the underlying disorder, specific AHA treatments include management of bleeding and inhibitor eradication. Various first-line and second-line hemostatic and immunosuppressive agents are currently available for the management of AHA. Recently, the hemostatic drug emicizumab and the immunosuppressive drug rituximab have been the object of intense research from investigators as innovative promising therapies for AHA. This narrative review will be focused on the current status of the clinical use of these two off-label therapeutic agents in AHA.

Anti-platelet factor 4 (PF4) antibody-mediated disorders are a heterogenous group of diseases characterized by the presence of highly pathogenic immunoglobulins G directed against PF4 and/or PF4/heparin complexes. These antibodies are able to activate platelets, neutrophils and monocytes, thus resulting in thrombocytopenia and a hypercoagulable state. Five different forms of anti-PF4 antibody-mediated disorders have been identified: i) classic heparin-induced thrombocytopenia (cHIT) mediated by heparin and certain polyanionic drugs; ii) autoimmune HIT (aHIT) characterized by the presence of anti-PFA/polyanion antibodies that can strongly activate platelets even in the absence of heparin; iii) spontaneous HIT (spHIT) characterized by thrombocytopenia and thrombosis without proximate exposure to heparin, with two subtypes: (a) post-total knee arthroplasty, and cardiac surgery using cardiopulmonary bypass or extracorporeal membrane oxygenation, and (b) post-infections; iv) vaccine-induced immune thrombotic thrombocytopenia (VITT) characterized by thrombocytopenia, arterial and venous thrombosis, or secondary hemorrhage after receiving adenoviral vector vaccines for COVID-19; v) VITT-like disorders triggered by adenoviral infections. Though extremely rare and largely unknown, there has been growing interest in the VITT syndrome in recent years due to its clinical relevance. Timely detection of these antibodies is crucial for the diagnosis and treatment of anti-PF4 antibody-mediated disorders, via anti-PF4 antibody immunoassays using several antibody-capture systems (e.g., ELISA based, particle gel, turbidimetry) and functional assays (e.g., serotonin release assay or heparin-induced platelet activation). We aimed to present the latest on laboratory findings, clinical characteristics and therapeutic approaches for anti-PF4 antibody-mediated disorders.

Coagulation factors are intrinsically expressed in various brain cells, including astrocytes and microglia. Their interaction with the inflammatory system is important for the well-being of the brain, but they are also crucial in the development of many diseases in the brain such as stroke and traumatic brain injury. The cellular effects of coagulation are mediated mainly by protease-activated receptors. In this review, we sum up the role of the coagulation cascade in the development of different diseases including psychiatric disorders. In inflammatory diseases such as multiple sclerosis, fibrinogen activates microglia and suppresses the differentiation of oligodendrocytes, leading to axonal damage and suppression of remyelination. In ischemic stroke, thrombin activity is associated with the size of infarction, and the inhibition of either thrombin- or protease-activated receptor 1 promotes neuronal survival and reduces the size of infarction. Patients suffering from Alzheimer's disease express higher levels of thrombin, which in turn damages the endothelium, increases blood-brain barrier permeability, and induces cell apoptosis. In major depressive disorder, a positive correlation is present between prothrombotic states and suicidality. Moreover, both protein S deficiency and antiphospholipid antibodies are associated with schizophrenia and there is an effect of warfarin on psychosis-free intervals. Studying the coagulation in the brain could open a new door in understanding and treating neurological and psychiatric disorders, and extensive research should be conducted in this field.

The purpose of this study is to (1) estimate and compare the prevalence of venous thromboembolism (VTE) in children (age 0 to ≤21) with versus without cystic fibrosis (CF); (2) investigate putative associations between specific gastrointestinal (GI) manifestations and the development of VTE among children with CF. This was a multicenter case-control analysis among patients aged 0 to ≤ 21 years between 2010 and 2020, using the TriNetX Research Network. Data queries included ICD-9/10 (International Classification of Diseases-9th/10th Revision) diagnosis codes. Bivariate associations with VTE among CF patients were compared using Chi-square testing for categorical variables and Student's t-test for continuous variables. We used multivariable logistic regression to test for independent associations of GI manifestations with VTE among children with CF, with adjustment for other salient covariates. There was a total of 7,689 children with and 22,327,660 without CF. The frequency of occurrence of VTE was increased nearly 20-fold among those with, as compared with without CF (130 vs. 7 per 10,000 patients). Acute pancreatitis (adjusted odd ratio [aOR] = 3.80, [95% confidence interval, CI: 2.00-7.22]), biliary disease (aOR = 2.17 [95% CI: 1.17-4.03]), gastrostomy status (aOR = 2.01 [95% CI: 1.27-3.18]), and malabsorption/malnutrition (aOR = 2.41 [95% CI: 1.52-3.82]) were each associated with a higher likelihood of VTE among children with CF. In conclusion, we found a significantly increased frequency of VTE occurrence and association of specific GI diseases as independent risk factors for VTE among children with CF compared with those without.

22q11.2 deletion syndrome (22q11.2DS) is one of the most common congenital malformation syndromes resulting from disrupted embryonic development of pharyngeal pouches. The classical triad of symptoms described by Angelo DiGeorge is frequently accompanied by hematological and immune disorders. While it is well-established that patients with 22q11.2DS have an increased risk of recurrent autoimmune cytopenias, including immune thrombocytopenia, the platelet abnormalities in this population are more complex and multifaceted. Given this issue, we conducted a comprehensive literature review on platelet disorders in 22q11.2DS using accessible databases (PubMed and Scopus). We aimed to outline previous studies limitations and most urgent challenges concerning thrombocytopenia in these patients. One characteristic finding frequently observed in 22q11.2DS is mild macrothrombocytopenia caused presumably by the loss of one GP1BB allele, encoding the element of the GPIb-IX-V complex. This structure plays a central role in thrombocyte adhesion, aggregation, and subsequent activation. Recent studies suggest that defective megakaryopoiesis and impaired vasculogenesis may strongly influence platelet and hemostasis disorders in 22q11.2DS. Furthermore, the phenotypic manifestation may be modulated by epigenetic factors and gene expression modifiers located outside the deletion region. Although the final hemorrhagic phenotype is typically mild, these patients may require more frequent transfusions following major surgical procedures. Despite the risk of thrombocytopenia and thrombocytopathy, there is a lack of large-scale research on hematological anomalies in 22q11.2DS, and the available results are often inconclusive. Given the complexity of hemostatic disorders, it is essential to establish specific recommendations for perioperative management and autoimmune cytopenias treatment within this population.

Congenital heart disease (CHD) is a risk factor for thromboembolism (TE). Data describing the rate of, and risk factors associated with, recurrent TE in children with CHD are limited. We prospectively evaluated TE recurrence risk in children with CHD and acute TE and investigated clinical risk factors associated with recurrent TE. Patients < 21 years of age with CHD and acute TE were enrolled in a single-institutional prospective inception cohort study (July 2013-April 2024). Descriptive statistics summarized variables including CHD and thrombus characteristics, antithrombotic regimens, bleeding, and recurrent TE. Multivariable logistic regression determined risk factors for recurrent TE. Among 40 children with CHD and acute TE, 13 (33%) developed ≥ 1 recurrent TE (arterial n = 1 [6%], venous n = 15 [83%], venous + arterial n = 2 [11%]) at a median time of 86 (interquartile range, 45-112) days postdiagnosis of the index TE. One-year cumulative incidence of recurrent TE was 38%. Twelve (67%) recurrent TE events were central venous catheter (CVC)-related. In univariable analyses, immobility (46% vs. 7%, p = 0.01), the presence of a CVC (69% vs. 30%, p = 0.02), and lower extremity index venous TE (89% vs. 41%, p = 0.04) were associated with TE recurrence. After adjustment for other potential risk factors via multivariable logistic regression, immobility (adjusted odds ratio [OR] 13.2, 95% confidence interval [CI] 1.16-151.3, p = 0.04) and the presence of a CVC (adjusted OR 5.28, 95% CI 1.03-27.1, p = 0.05) remained as independent risk factors for recurrent TE. The 1-year risk of TE recurrence was high among pediatric patients with CHD and acute TE. Immobility and the presence of CVC were independent risk factors for recurrent TE. Multicenter prospective cohort studies are warranted to substantiate and expand upon these important findings.