Thrombotic microangiopathy (TMA) encompasses a range of disorders characterized by blood clotting in small blood vessels, leading to organ damage. It can manifest as various syndromes, including thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and others, each with distinct causes and pathophysiology. Thrombo-inflammation plays a significant role in TMA pathogenesis: inflammatory mediators induce endothelial injury and activation of platelet and coagulation cascade, contributing to microvascular thrombosis. Primary TMA, such as TTP, is primarily caused by deficient ADAMTS13 metalloproteinase activity, either due to antibody-mediated inhibition or intrinsic enzyme synthesis defects. In cancer patients, a significant reduction in ADAMTS13 levels and a corresponding increase in VWF levels is observed. Chemotherapy further decreased ADAMTS13 levels and increased VWF levels, leading to an elevated VWF/ADAMTS13 ratio and increased thrombotic risk. Drug-induced TMA (DITMA) can result from immune-mediated or non-immune-mediated mechanisms. Severe cases of COVID-19 may lead to a convergence of syndromes, including disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and TMA. Treatment of TMA involves identifying the underlying cause, implementing therapies to inhibit complement activation, and providing supportive care to manage complications. Plasmapheresis may be beneficial in conditions like TTP. Prompt diagnosis and treatment are crucial to prevent serious complications and improve outcomes.

Context: IntelliSep by Cytovale has received United States (U.S.) Food and Drug Administration (FDA) approval as a sepsis biomarker test. However, the clinical utility of this new test is not assessed in emergency departments. Objective: We investigated the clinical utility of this test using 44 patients visiting the emergency department at The University of Kansas Medical Center by comparing it with the monocyte distribution width (MDW) and other biomarkers including the von Willebrand factor (vWF) and ADAMTS13. Design and Methods: IntelliSep assesses the cellular host response via deformability cytometry of biophysical leukocyte properties and produces a score (IntelliSep Index; ISI: from 0.1 (lowest risk) to 10 (highest risk). We measured the ISI in 44 patients (19 high probability and 25 low probability of sepsis groups) using EDTA-anticoagulated blood. Left over plasma was used for measuring the plasma von Willebrand factor (vWF) and ADAMTS13 antigen by ELISA assays. The MDW was obtained during routine CBC analysis using a Beckman hematology analyzer. The lactate and high-sensitivity troponin I levels were measured using a Beckman analyzer. Procalcitonin was measured using a Cobas e801 analyzer. Results: The median ISI was twofold higher in the high-probability group than in the low-probability group (p < 0.01) while the median MDW was 34.5% higher in the high-probability group than in the low-probability group (p < 0.01). However, the correlation between the ISI and MDW was only modest (r = 0.66). In addition, significantly higher levels of plasma vWF antigen but lower levels of plasma ADAMTS13 antigen in the high-probability group were found, resulting in significantly higher vWF/ADAMTS13 ratios in the high-probability group than in the low-probability group. Conclusions: The new IntelliSep test along with vWF/ADAMTS13 ratios may be useful for the early diagnosis of sepsis in patients visiting the emergency department, which appears to be superior to the traditional marker, MDW.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal impairment, and fever. The etiology of TTP often involves a severe deficiency in ADAMTS13 activity, resulting in the accumulation of ultra-large von Willebrand factor multimers and subsequent microvascular thrombosis. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect multiple organ systems, and although the initial presentation of SLE with TTP is rare, it necessitates a comprehensive diagnostic and therapeutic approach. We present a case of a 27-year-old male with no significant past medical history who developed altered mental status, headache, and right-sided numbness, leading to the diagnosis of TTP and subsequent detection of SLE.

Clinical manifestations of triple X syndrome (karyotype 47, XXX) can include autoimmune diseases. We describe the occurrence of acquired thrombotic thrombocytopenic purpura (TTP), an autoimmune condition, refractory to plasmapheresis and rituximab in a patient with triple X syndrome who required vincristine administration for disease remission. To our knowledge, this rare coexistence is the first of its kind reported in Brazil.

Congenital (cTTP) and immune-mediated (iTTP) thrombotic thrombocytopenic purpura are serious and rare clotting disorders resulting from a deficiency in the ADAMTS13 enzyme. A systematic review was conducted using the Ovid® MEDLINE & Embase databases to synthesize the epidemiology and burden of cTTP and iTTP worldwide (from January 1, 2010, to February 6, 2020, with an update that covered the period January 1, 2020-February 11, 2022). Outcomes of interest were incidence and prevalence of TTP, incidence of acute episodes, mortality, burden of illness (eg complications, healthcare utilization, patient-reported outcomes) and disease management. A total of 221 eligible observational studies were included. The incidence rate of acute episodes ranged from 0.19-0.35 person-years in adult patients with cTTP, and 1.81-3.93 per million persons per year for iTTP in the general population. Triggers of acute episodes were similar for cTTP and iTTP, with pregnancy and infection the most commonly observed. Exacerbation in patients with iTTP varied widely, ranging from 2.4-63.1%. All-cause mortality was observed in 0-13.4% of patients with cTTP, across studies and follow-up periods, and in 1.1% (median follow-up: 0.4 years) to 18.8% (1 year) of patients with iTTP during acute episodes. Cardiovascular, renal, and neurological disease were common complications. TTP also led to work disturbances, feelings of anxiety and depression, and general activity impairment. TTP treatment regimens used were generally reflective of current treatment guidelines. The evidence identified describes a high patient burden, highlighting the need for effective treatment regimens leading to improvements in outcomes. Considerable evidence gaps exist, particularly for disease epidemiology, patient-reported outcomes, costs of disease management, and associated healthcare resource utilization. This review may help increase disease awareness and highlights the need for additional real-world studies, particularly in geographical regions outside the United States and Western Europe.

Introduction: Conventional practice in the management of acute TTP entails empirical treatment of suspected cases whilst awaiting confirmatory ADAMTS13 deficiency testing. Rapid ADAMTS13 assays offer increased accessibility and rapid diagnostics. The new automated HemosIL AcuStar® ADAMTS13 assay has seen increasing use among UK TTP Specialist Centres alongside the traditional ELISA method to confirm severe ADAMTS13 deficiency. Methods: A multi-centre retrospective case-control study was performed to review patients demonstrating discrepant ADAMTS13 activity results measured using rapid (AcuStar®) and ELISA assays in parallel from September 2019 to December 2021. Cases were compared with a cohort of suspected TTP patients exhibiting no difference in assay results and in relation to their presenting characteristics and pre-test probability of a diagnosis of TTP. Results: Where the clinical index of suspicion for TTP was high at presentation, acute TTP was confirmed using the AcuStar® assay < 0.2 IU/dL and subsequently < 10 IU/dL by ELISA with zero incidence of discrepancy. For patients with low clinical suspicion of acute TTP, a discrepancy between the AcuStar® and ELISA assay results was observed in 2% of cases; 5-10 IU/dL in AcuStar®, confirmed as >20 IU/dL by ELISA. A concurrent cancer diagnosis or sepsis was observed in 40% of discrepant cases. Conclusions: Where acute TTP is strongly suspected, there is a good correlation between the rapid AcuStar® ADAMTS13 assay and the conventional ELISA assay. Where the clinical suspicion of acute TTP is low, caution should be exercised in the interpretation of the ADAMTS13 activity using the AcuStar® assay. Accurate interpretation requires robust ADAMTS13 testing algorithms to be incorporated into diagnostic pathways.

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Allogeneic haematopoietic stem cell transplantation (allo-HSCT) can potentially cure malignant blood disorders and benign conditions such as haemoglobinopathies and immunologic diseases. However, allo-HSCT is associated with significant complications. The most common and debilitating among them is graft-versus-host disease (GVHD). In GVHD, donor-derived T cells mount an alloimmune response against the recipient. The alloimmune response involves several steps, including recognition of recipient antigens, activation and proliferation of T cells in secondary lymphoid organs, and homing into GVHD-targeted organs. Adhesion molecules on T cells and endothelial cells mediate homing of T cells into lymphoid and non-lymphoid tissues. In this study, we showed that Von Willebrand factor (VWF), an adhesion molecule secreted by activated endothelial cells, plays an important role in mouse models of GVHD. We investigated the effect of the VWF-cleaving protease ADAMTS13 on GVHD. We found that ADAMTS13 reduced the severity of GVHD after bone marrow transplantation from C57BL6 donor to BALB/C recipient mice. A recombinant VWF-A2 domain peptide also reduced GVHD in mice. We showed that ADAMTS13 and recombinant VWF-A2 reduced the binding of T cells to endothelial cells and VWF in vitro, and reduced the number of T cells in lymph nodes, Peyer\'s patches and GVHD-targeted organs in vivo. We identified LFA-1 (αLβ2) as the binding site of VWF on T cells. Our results showed that blocking T-cell homing by ADAMTS13 or VWF-A2 peptide reduced the severity of the GVHD after allo-HSCT, a potentially novel method for treating and preventing GVHD.

UNASSIGNED: The COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune pathways together with a systemic cytokine storm response and thrombotic venous or arterial complications. Factors predicting severe outcomes including venous and/or pulmonary thrombosis (VT) and death were identified, but the prognostic role of their combination was not addressed extensively.
UNASSIGNED: We investigated the role of prognostic factors from the coagulation or inflammatory pathways to better understand the outcome of the disease.
UNASSIGNED: For this, we prospectively studied 167 SARS-CoV-2-positive patients from admission in intensive care units (ICU) or emergency departments from four academic hospitals over a 14-month period. Besides standard biology, we assessed serum concentrations of inflammatory markers, coagulation factors and peripheral blood cells immunophenotyping.
UNASSIGNED: Thirty-nine patients (23.3%) developed VT and 30 patients (18%) died. By univariate analysis, C-reactive protein (CRP) level > 150 mg/L, interleukin-6 (IL-6) ≥ 20 pg/mL, D-dimers > 1,500 μg/L, ADAMTS13 activity ≤ 50%, Von.
UNASSIGNED: A combination of coagulation and inflammatory markers can refine the prognostication of severe outcome in COVID-19, and could be useful for the initial evaluation of other types of viral infection.

The management of immune thrombotic thrombocytopenic purpura (iTTP) has evolved significantly over the past several years. However, despite recent advances, there are limited tools available for patients with comorbidities that preclude either the utilization of available treatment modalities or evidence-based laboratory target levels. Literature to guide the management of such patients is sparse at best, and many complications associated with pre-existing comorbidities in the context of iTTP have not been reported. Here we describe the case of a patient with severe thrombocytopenia at baseline due to liver cirrhosis who developed iTTP. The challenges of the case in terms of pursuing disease-directed treatment, defining laboratory parameters to guide treatment, and mitigating the risks of bleeding and disease exacerbation are discussed. We offer our perspective in treating iTTP in the setting of severe baseline thrombocytopenia and high bleeding risk.