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 × 10[9]/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.

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.

Microangiopathic hemolytic anemia (MAHA) is a form of Coombs-negative hemolysis characterized by mechanical fragmentation of erythrocytes, producing schistocytes on the peripheral blood smear. When accompanied by thrombocytopenia and neurological features, the presentation closely resembles thrombotic thrombocytopenic purpura (TTP), a hematological emergency requiring urgent plasma exchange. However, advanced malignancy can produce an almost identical thrombotic microangiopathy (TMA) that responds poorly to plasma exchange, and for which the definitive treatment is control of the underlying cancer. We report a 77-year-old woman with metastatic breast cancer and extensive osseous metastatic disease who presented with nausea, palpitations, generalized weakness, and transient neurological symptoms. Investigations revealed severe anemia, moderate but rapidly progressive thrombocytopenia, markedly elevated lactate dehydrogenase, elevated indirect bilirubin, undetectable haptoglobin, a negative direct antiglobulin test, and schistocytes on the blood smear. Brain magnetic resonance imaging showed acute bilateral frontal ischemic infarctions. Although early coagulopathy and active cancer yielded an intermediate PLASMIC score, TTP could not be excluded. Empiric plasma exchange and high-dose corticosteroids produced no hematological improvement, and the patient died shortly thereafter. ADAMTS13 testing was delayed by a pre-analytical error. The clinical course and lack of response favored malignancy-associated MAHA with disseminated intravascular coagulation over TTP. This case underscores that in patients with disseminated malignancy, MAHA with thrombocytopenia and neurological signs should raise early suspicion of cancer-associated TMA, even while TTP is treated empirically.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa); however, current knowledge of its underlying drivers and therapeutic interventions remain limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as a regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach, we demonstrate that EZH2 regulates multilineage cell states and identify the RNA-binding protein Tristetraprolin (TTP) as a contributor to the response to EZH2 therapy through its role in RNA stability and translational regulation. Combined pharmacological inhibition of EZH2 and PI3K/mTORC1 produces superior antitumor activity in murine and human models of phenotypic plasticity, with greatest efficacy observed when combined with castration. Together, these findings identify EZH2-PI3K/mTORC1 signaling as a therapeutic vulnerability in phenotypically plastic PCa and reveal TTP-associated regulatory programs as contributors to targeted therapy response.

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.

Intracranial hypertension (IH) is a frequent and serious complication of acute brain injury, strongly influencing morbidity and mortality. While invasive intracranial pressure (ICP) monitoring is standard, it has limitations. Intracranial compliance (ICC) offers additional insight into the brain's ability to handle changes in volume. Noninvasive ICP waveform analysis, such as the peak 2 (P2)/peak 1 (P1) ratio and time to peak (TTP), shows promise in evaluating ICC and detecting IH. The brain4care (B4C) system provides continuous, noninvasive monitoring for neurocritical care. We systematically reviewed studies comparing B4C with invasive ICP monitoring, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. MEDLINE, Embase, and the Scientific Electronic Library Online were searched for clinical studies from 2016 to May 2025 reporting quantitative B4C parameters in patients undergoing invasive ICP monitoring. Two reviewers evaluated studies, extracted data, and assessed quality using the Newcastle-Ottawa Scale. Sixteen studies involving 826 patients with acute brain injury were reviewed. The P2/P1 ratio, frequently assessed, showed high sensitivity (26.8-100%) and variable specificity (45.5-96.5%) for IH, with moderate to good accuracy (area under the curve [AUC] 0.71-0.83). TTP was less consistent, although a 0.3 threshold gave 92% specificity in the largest study. All studies demonstrated qualitative morphological concordance between B4C-derived and invasive ICP waveforms. The overall methodological quality was moderate, with frequent limitations related to comparability, confounder adjustment, and follow-up. B4C noninvasive monitoring provides reliable reflections of ICC and shows strong correlation with IH, consistently aligning with invasive ICP waveform patterns. This approach is well tolerated as an adjunct for dynamic, physiology-driven neurocritical care. Further prospective, multicenter studies are necessary to clearly define its clinical utility and support safe integration into standard practice.

Circulating tumor DNA (ctDNA) serves as a non-invasive liquid biopsy technique, offering potential utility in the prognostic evaluation of multiple myeloma (MM). In this study, we performed a systematic review and updated meta-analysis to analyze the association between ctDNA and the prognosis of patients diagnosed with MM. A comprehensive literature search was performed across PubMed, Embase, Web of Science, and the Cochrane Library to retrieve relevant literature published up to May 29, 2025, assessing the impact of ctDNA on survival outcomes in patients with MM. The survival outcomes included overall survival (OS), progression-free survival (PFS), and time to progression (TTP). A total of 948 MM patients from 14 studies were included in the analysis. Patients with detectable ctDNA exhibited a significantly increased risk of aggressive disease progression (hazard ratio [HR], 3.21; 95% confidence interval [CI], 1.98-5.18) and reduced OS (HR, 3.97; 95% CI, 2.24-7.04). Subgroup analyses consistently indicated that ctDNA positivity was associated with accelerated disease progression, irrespective of race, disease status, treatment, or ctDNA detection method. In subgroups defined by relapsed or refractory MM (RRMM) and Oceanian or Caucasian race, ctDNA positivity was significantly correlated with poorer OS. However, the associations were not significant in newly diagnosed MM (NDMM) or among Asian patients. Therefore, we conclude that ctDNA is a potential predictor of inferior survival outcomes in MM patients.