Severe sepsis following cardiac surgery may be accompanied by a thrombotic microangiopathy (TMA)-like syndrome distinct from classic immune-mediated thrombotic thrombocytopenic purpura (TTP) and overt disseminated intravascular coagulation (DIC). We report a 62-year-old man who developed sepsis after mitral valve replacement, complicated by thrombocytopenia (nadir 45 × 10⁹/L), microangiopathic hemolysis (2.6% schistocytes), and multiple organ dysfunction. Laboratory findings revealed marked dysregulation of the von Willebrand factor (vWF)/ADAMTS13 axis, with markedly elevated vWF antigen levels (548%), moderately reduced ADAMTS13 activity (32.8%), and negative ADAMTS13 inhibitors. Despite meeting criteria for sepsis-induced coagulopathy (SIC), the patient did not fulfill diagnostic criteria for overt DIC, as fibrinogen levels remained elevated and D-dimer elevation was limited. The patient improved with comprehensive sepsis management and supportive care, including adjunctive plasma infusion. Marked vWF/ADAMTS13 imbalance with preserved fibrinogen and limited D-dimer elevation may help distinguish sepsis-associated TMA-like syndrome from overt DIC.

The factor VIII (FVIII) B domain, a large and heavily glycosylated region, is crucial for FVIII secretion, although its structural and functional roles remain incompletely understood. Although the B domain is dispensable for cofactor activity, previous research hints at multiple, yet unverified, functional roles. Here, we used an integrative hybrid approach to generate detailed structural models of glycosylated and furin-cleaved full-length FVIII (Gly/FC-FL-FVIII) that include the B domain, using AlphaFold2 predictions. These models were further refined and validated with biophysical data from atomic force microscopy (AFM) and cryogenic electron microscopy of recombinant and plasma-derived FL-FVIII proteins. Additionally, we modeled a FL-FVIII-von Willebrand factor (VWF) complex with both the B domain and D'-D3 domains to investigate B-domain interactions during intracellular processing. Our results suggest that the B domain functions largely as an independent domain encircling the FVIII core. AFM studies revealed that VWF tails are associated with globular FVIII structures. Structural analysis indicated that B-domain glycosylation enhances stability, supports proper folding, and promotes efficient trafficking through the endoplasmic reticulum-Golgi pathway. We propose that, within the Golgi, the B domain may unfold around FVIII via furin cleavages, facilitating essential interactions with partners such as VWF. Our models also suggest that the B domain shields key FVIII epitopes, potentially reducing immune interference and inhibiting premature activation. This study presents a novel structural model of the FVIII B domain and FL-FVIII, offering critical insights into previously unexplored aspects of B-domain function and its essential role in FVIII biology.

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.