ADAMTS13 is conventionally regarded as the protease whose severe deficiency causes thrombotic thrombocytopenic purpura (TTP). By cleaving shear-unfolded ultra-large and high-molecular-weight von Willebrand factor (VWF), ADAMTS13 limits a platelet- and leukocyte-adhesive vascular scaffold. We propose a narrower and testable extension of this biology to cancer: an imbalance between VWF burden and ADAMTS13 processing capacity may act as a context-dependent modifier or amplifier of thromboinflammation in selected VWF-rich, shear-exposed tumor vascular niches, but is not established as an initiating or universally rate-limiting cause of cancer-associated thrombosis. We define "relative ADAMTS13 insufficiency" as a research phenotype rather than a diagnosis or evidence of causality. It refers to ADAMTS13 activity outside the severe-deficiency range, typically ≥10%, together with increased VWF burden and a disproportionately low ADAMTS13 activity/VWF antigen ratio (ADAMTS13:Act/VWF: Ag). This phenotype is mechanistically nonspecific and may reflect increased VWF release, impaired whole-molecule VWF clearance, reduced ADAMTS13 production, stability, or availability, functional inhibition of proteolysis, reduced VWF susceptibility to cleavage, or shared upstream inflammation. Human evidence from COVID-19 and cancer remains predominantly associative, whereas tumor-relevant perturbation studies provide preclinical causal support in defined models. The causal importance of the VWF-ADAMTS13 axis in human tumors nevertheless remains unproven. We therefore position this module within a broader thromboinflammatory network that includes complement activation, neutrophil extracellular traps, platelet activation, and tissue factor-thrombin-fibrin pathways. ICI-associated endothelial phenotypes are distinguished from rare ICI-associated immune TTP with categorical severe ADAMTS13 deficiency. Candidate interventions are accordingly presented as mechanistic research nodes requiring staged validation rather than as established oncology therapies.

Factor VIII (FVIII) circulates as an inactive procofactor and is converted to its active form (FVIIIa) by proteolytic cleavage at Arg372, Arg740, and Arg1689. Although these cleavage events are well characterized, their individual contributions to FVIII activation and hemostatic function remain incompletely defined. To address this, we engineered a FVIII variant (FVIII-2RKR) in which the B-domain and acidic region 3 region were replaced with a PACE/furin processing site, generating a molecule that requires only cleavage at Arg372 for conversion to FVIIIa. FVIII-2RKR exhibited markedly increased apparent activity in plasma-based assays, shortened thrombin generation lag time, and enhanced factor Xa (FXa) generation compared with B-domain-deleted FVIII, whereas both proteins were functionally equivalent following thrombin activation. FVIII-2RKR was cleaved more rapidly at Arg372 by thrombin and FXa, demonstrating that processing at Arg740 and Arg1689 regulates the rate of Arg372 cleavage rather than directly contributing to cofactor activity. In hemophilia A mice, FVIII-2RKR consistently enhanced early hemostatic function across ferric chloride, laser injury, and tail bleeding models, achieving improved efficacy at lower doses. Despite reduced half-life due to impaired von Willebrand factor (vWF) binding, FVIII-2RKR remained effective in vWF-deficient mice, indicating that vWF is not required for local FVIII function at sites of vascular injury. Together, these findings define distinct roles for FVIII activation cleavage sites and demonstrate that processing at Arg740 and Arg1689 regulates activation through Arg372, linking the rate of FVIII activation to hemostatic efficacy in vivo.

We studied the effects of the nitrosative stress modulator peroxynitrite on changes in key markers of the endothelial-mesenchymal transition (EndMT) in primary endothelial cell cultures in vitro. Peroxynitrite exposure significantly increased the relative content of endothelial markers (platelet adhesion molecules (CD31) and von Willebrand factor) and reduced the levels of mesenchymal markers (fibronectin and vimentin). These findings suggest that peroxynitrite may inhibit EndMT in vitro.

Thrombotic thrombocytopenic purpura (TTP) is a rare and rapidly life-threatening thrombotic microangiopathy. Disseminated microvascular thrombosis and resulting ischemia are the critical events determining outcome, if left untreated. The pathogenic hallmark is a severe deficiency of the plasma metalloprotease ADAMTS13, resulting in impaired cleavage of ultra-large von Willebrand factor (vWF) multimers leading to platelet aggregation. The vast majority of TTP cases are acquired and immune-mediated, depleting ADAMTS13 through autoantibodies. In contrast, congenital deficiency of ADAMTS13 affects a minority of patients. Measurement of ADAMTS13 activity is the cornerstone for diagnosis and implementation of treatment. However, clinical prediction scores support early therapeutic decision-making when results are pending. Plasma exchange, immunosuppression and more recently, the anti-vWF nanobody caplacizumab, are the central pillars for treatment of immune-mediated TTP. Caplacizumab prevents microvascular thrombosis during the acute episode but does not address the autoimmune-mediated ADAMTS13 depletion, underscoring the importance of plasma exchange and immunosuppression. Congenital TTP was previously treated using ADAMTS13 replacement through regular plasma infusions, but provision of recombinant ADAMTS13 has recently transformed treatment in these patients. Despite major advances, relapse remains a persistent threat for patients, making structured, long-term follow-up necessary. Diagnostic advances may help improve relapse prediction and corresponding therapeutic management. This review summarizes current concepts in the pathophysiology, diagnosis, clinical management of TTP and highlights recent therapeutic advancements and future challenges.

Vascular endothelial cells express abundant sialylated glycans, but their function remains unclear. To determine the role of endothelial overall sialylation, which is controlled by Slc35a1, in adult mice. We generated mice with inducible deletion of Slc35a1 in endothelial cells (iEHC Slc35a1[-/-]) using tamoxifen-inducible Cdh5Cre[ERT2]. Induced deletion of Slc35a1 in adulthood caused progressive weight loss, anemia, and spontaneous intestinal bleeding. Adult intestinal villus capillaries exhibited disorganized networks, loss of vascular integrity, and bleeding. Multiplexed Error-Robust Fluorescence in Situ Hybridization spatial transcriptomic analysis revealed downregulation of endothelial genes essential for angiogenesis and endothelial specialization, including Vegfr2, Cdh5, and Plvap. Immunostaining confirmed loss of VEGFR2, disorganized VE-cadherin junctions, and impaired PLVAP-dependent capillary fenestration. Endothelial Slc35a1 deletion also reduced endothelial von Willebrand factor expression and plasma multimerization, indicating impaired hemostatic function. Our results reveal new roles for Slc35a1-dependent endothelial sialylation in maintaining the fate and integrity of the intestinal microvascular network in adult mice.

Hemophilia A is an inherited bleeding disorder due to factor VIII (FVIII) deficiency and is characterized by recurrent bleeding and progressive joint damage. For the last two decades, treatment strategies have expanded from FVIII replacement therapy to include extended half-life products, non-factor therapies, rebalancing agents, and gene therapy. These advances have improved clinical outcomes but also introduced long-term safety considerations that require careful evaluation.

Pediatric essential thrombocythemia (ET) is extremely rare and frequently lacks identifiable driver mutations. We report a case of a 5-year-old male with ET harboring a novel CALR exon 9 frameshift mutation complicated by acquired von Willebrand syndrome. The patient presented with purpura, extreme thrombocytosis (1900 × 10[9] /L), and reduced von Willebrand factor activity. Antiplatelet therapy was avoided because of bleeding risk, and anagrelide was initiated. Treatment was associated with reduction in platelet count and improvement in von Willebrand factor activity. This case expands the molecular spectrum of pediatric CALR-mutated ET and highlights the importance of individualized management in children with extreme thrombocytosis.

Severe hemophilia A is exceptionally rare among preterm infants. Qwing to immature coagulation system and nonspecific bleeding manifestations, the condition is readily misdiagnosed as other neonatal hemorrhagic disorders, such as vitamin K deficiency, neonatal sepsis and thrombocytopenia. Delayed diagnosis will greatly increase the risk of severe complications, particularly intracranial hemorrhage. Herein, we report a case of genetically confirmed severe hemophilia A in a 34-week preterm infant without family history of hemophilia. Treatment comprised sequential adminnistration of coagulation factor VIII repalcement and emicizumab. We futher analyze the clinical characteristics, diagnostic difficulties and standardized management principles of hemophilia A in preterm infants, so as to improve clinicians' awareness, reduce misdiagnosis and missed diagnosis, and optimize the long-term prognosis of affected infants.