ADAMTS13 Activity Research Articles

Comparison of quantitative and qualita- tive characteristics of the system von Willebrand factor — metalloprotease ADAMTS13 in patients with acute myocardial in farction and is chemic stroke

Introduction. The hemostasis system plays a key role in the pathogenesis of cardiovascular diseases.Aim — to evaluate changes in quantitative and qualitative characteristics of ADAMTS13 metalloprotease and von Willebrand factor an tigen (vWF:Ag) in patients with acute myocardial in farction (AMI) and is chemic stroke (IS).Patients and methods. The study in cluded 110 patients aged 42–95 years (median age — 64 years), of which: 65 patients with AMI aged 42–81 years (median age — 56 years) who had coronary artery thrombosis during an giography, as well as 45 patients with IS aged 40–95 years (median age — 70 years) with diagnosed cerebral artery thrombosis. All patients were tested for ADAMTS13 an tigen, ADAMTS13 activity, an tibodies to ADAMTS13 and vWF:Ag. Blood samples were obtained during an giography (arterial and venous blood) and 24 and 120 hours after an giography (venous blood).Results. In the group of patients with AMI, an in crease in the values of the vWF:Ag in dicator was revealed, which went beyond the upper limit of the reference in terval. In patients with IS, at the beginning of the study, this in dicator was within the reference in terval and was statistically significantly lower compared to patients with AMI but in creased after 24 hours and peaked at 120 hours. When an alyzing changes in the ADAMTS13:Ag in dicator, it was found that it was statistically significantly higher at all points of the study in the group of patients with AMI, compared with the group of patients with IS, however, the values of this in dicator did not go beyond the reference in terval in patients of both groups. At the same time, the ADAMTS13:AC in dex at all points of the study was statistically significantly higher in patients with IS, compared with the group of patients with AMI, and the ADAMTS13:AB in dex. On the contrary, in the group of AMI patients, this in dicator was statistically significantly higher in all points of the study when compared with that for the group of patients with IS.Conclusion. The study of two pathogenetic models of thrombosis demonstrated the absence of a relationship between the vWF:Ag in dex and the quantitative or qualitative characteristics of the ADAMTS13 metalloprotease. At the same time, an in crease in ADAMTS13:AB in AMI can be considered as the reason for the decrease in ADAMTS13:AC in these patients.

ADAMTS13 Biomarkers in Management of Immune Thrombotic Thrombocytopenic Purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare but potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13, a metalloprotease that cleaves endothelium-derived ultralarge von Willebrand factor. Standard of care for iTTP including therapeutic plasma exchange, caplacizumab, and immunosuppressives, known as triple therapy, has led to a significant reduction in the disease-related mortality rate. The first International Society of Thrombosis and Haemostasis TTP guideline stresses the importance of having plasma ADAMTS13 activity testing in the algorithm for diagnosis and management of iTTP. However, the predictive role of assessing plasma ADAMTS13 activity and inhibitors or other ADAMTS13-related parameters in patients with acute iTTP and during remission has not been systematically evaluated. To review and assess the predictive values of testing plasma ADAMTS13 activity, antigen, and inhibitors or anti-ADAMTS13 immunoglobulin G at various stages of disease in outcomes of iTTP. Peer-reviewed publications and personal experience. We conclude that assessing ADAMTS13 biomarkers is not only essential for establishing the initial diagnosis, but also crucial for risk stratification and the early detection of disease recurrence. This may guide therapeutic interventions during acute episodes and for long-term follow-up of iTTP patients.

Prognostic factors in thrombotic thrombocytopenic purpura

Abstract Objectives Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy with no standardized prognostic model to predict mortality. The aim of the study is to determine parameters associated with TTP-related mortality. Methods In this cross-sectional, retrospective study, 77 TTP patients, treated with therapeutic plasma exchange between 2001 and 2019 in Ankara University Faculty of Medicine were included. Results There was no significant relationship between ADAMTS13 inhibitor levels, activity and mortality. Median number of plasmapheresis was 10 (2–32), higher in patients with complete response. Anemia, kidney injury and LDH levels were associated with survival; there was no significant relationship between platelet counts at the time of diagnosis and mortality. Mortality was lower in patients with platelet counts above 100 × 109/L and normalized LDH after treatment. Hemoglobin, albumin, LDH and creatinine levels at the time platelet counts exceeded 50 × 109/L were associated with survival. Conclusions We determined several clinical and laboratory parameters associated with mortality. Fewer numbers of plasmapheresis was associated with mortality; thus other treatments as rituximab and caplacizumab should be considered early in non-responders. Including changes in laboratory parameters may be considered in prognostic scoring systems to be developed in the future.

Hereditary thrombotic thrombocytopenic purpura and COVID‐19: Impacts of vaccination and infection inrare disease

1 IntroductionSevere COVID‐19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune‐mediated TTP associated with COVID‐19 or SARS‐CoV‐2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce. 2 MethodWe conducted a survey among adult patients of the International Hereditary TTP Registry about SARS‐CoV‐2 vaccination, COVID‐19, and occurrence of acute hTTP episodes. 3 ResultsOf 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty‐five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA‐1273 vaccine. Twelve (14%) patients had COVID‐19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment. 4 DiscussionThe risk of an acute episode triggered by COVID‐19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS‐CoV‐2.

ADAMTS13 protease or lack of von Willebrand factor protects irradiation and melanoma‐induced thrombotic microangiopathy in zebrafish

BackgroundSevere deficiency of plasma ADAMTS13 activity may result in potentially fatal thrombotic thrombocytopenic purpura and relative deficiency of plasma ADAMTS13 activity may be associated with adverse outcomes of certain malignancies. Here, we report the role of ADAMTS13 or lack of von Willebrand factor (VWF) in reducing irradiation and melanoma‐induced thrombotic microangiopathy (TMA) and mortality in zebrafish. MethodsZebrafish melanoma cell line (ZMEL) was injected subcutaneously into wild‐type (wt), adamts13−/− (a13−/−), von Willebrand factor (vwf−/−), and a13−/−vwf−/− zebrafish following total body irradiation; the tumor growth, its gene expression pattern, the resulting thrombocytopenia, and the mortality were determined. ResultsTotal body irradiation at 30 Gy alone resulted in a transient thrombocytopenia in both wt and a13−/− zebrafish. However, thrombocytopenia occurred earlier and more profound in a13−/− than in wt zebrafish, which was resolved 2 weeks following irradiation alone. An inoculation of ZMEL following the irradiation resulted in more severe and persistent thrombocytopenia, as well as earlier death in a13−/− than in wt zebrafish. The vwf−/− or a13−/−vwf−/− zebrafish were protected from developing severe thrombocytopenia following the same maneuvers. RNA‐sequencing revealed significant differentially expressed genes associated with oxidation–reduction, metabolism, lipid, fatty acid and cholesterol metabolic processes, steroid synthesis, and phospholipid efflux in the melanoma explanted from a13−/− zebrafish compared with that from the wt controls. ConclusionsOur results indicated that plasma ADAMTS13 or lack of VWF may offer a significant protection against the development of irradiation‐ and/or melanoma‐induced TMA. Such a microenvironment may directly affect melanoma cell phenotypes via alternation in the oxidation–reduction and lipid metabolic pathways.

PRESENTATION OF ACUTE CEREBROVASCULAR ACCIDENT IN A YOUNG ADULT WITH THROMBOTIC THROMBOCYTOPENIA PURPURA (TTP)

PRESENTATION OF ACUTE CEREBROVASCULAR ACCIDENT IN A YOUNG ADULT WITH THROMBOTIC THROMBOCYTOPENIA PURPURA (TTP)

Clinical features and neurological outcomes in pediatric immune-mediated thrombotic thrombocytopenic purpura: A report from a large pediatric hematology center.

Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and severely reduced or absent ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) activity, with varying degrees of organ dysfunction. As TTP is rare in pediatrics, most of the medical and scientific literature has largely reported on adult patients. As a result, limited data exist regarding the clinical features, comorbidities, treatment response, and long-term outcomes in pediatric patients with immune-mediated TTP. A single-center retrospective cohort study was conducted of all children and adolescents presenting to Children's Healthcare of Atlanta, Atlanta, Georgia, between the years 2001 and 2021 with immune-mediated TTP (iTTP). Clinical features, treatments, and outcomes, including long-term neurocognitive function, were analyzed. Eighteen individuals were identified, six of whom had a total of 10 relapses, amounting to 28 episodes overall. Thirty-eight percent of the patients experienced exacerbations but, ultimately, 85% achieved a clinical response and clinical remission. Only one in-hospital death occurred (mortality rate 5.5%). Seventy-three percent of analyzed patients demonstrated long-term neurocognitive abnormalities, including cognitive delay, learning difficulties, and severe depression. Children and adolescents recovering from iTTP are at high risk for neurocognitive deficits from initial and possibly ongoing microvascular disease. Due to risk for long-term neurological deficits, we recommend neuropsychological testing in addition to monitoring of other organ functions in all children with TTP, as well as long-term surveillance of ADAMTS13 activity during remission to detect and promptly treat early relapse.

Alteration of plasma von Willebrand factor in the treatment of retinal vein occlusion with cystoid macular edema.

Retinal vein occlusion (RVO) is a major retinal disease caused by venous thrombosis. Although several studies have proposed an association between venous thrombosis and von Willebrand factor (VWF), the association between RVO and VWF remains unclear. We aimed to investigate the association between RVO and VWF and the alteration of VWF levels under anti-vascular endothelial growth factor (VEGF) treatment. We enrolled 55 patients with RVO involved cystoid macular edema. They received intravitreal injection of anti-VEGF drugs, either ranibizumab or aflibercept. We examined the clinical data and measured plasma VWF antigen and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity to identify variabilities during treatment. At baseline, there was no significant difference between the RVO group and age-matched controls in both VWF antigen and ADAMTS13 activity levels, but ADAMTS13 activity was significantly lower in central RVO than in branch RVO (P = 0.015). In branch RVO, VWF antigen was negatively correlated with central choroidal thickness (r = −0.51, P < 0.001). In branch RVO after anti-VEGF treatment, VWF antigen levels decreased significantly from 134% at baseline to 109% at 1 day (P = 0.002) and 107% at 1 month (P = 0.030) after treatment. In contrast, ADAMTS13 activity showed no significant difference during this period. In branch RVO at 1 month after treatment, VWF antigen was negatively correlated with central choroidal thickness (r = −0.47, P = 0.001). Our findings suggest an association between VWF and central choroidal thickness in patients with branch RVO, thus the measurement of VWF may be useful for evaluating disease activity and prognosis.

Teaching NeuroImage: Partially Reversible Widespread Leukoencephalopathy Associated With Atypical Hemolytic Uremic Syndrome.

A 43-year-old woman presented with altered mental status and hypertension. She had a 3-day history of oliguria. The blood test detected microangiopathic hemolytic anemia, thrombocytopenia, and severe kidney injury. The absence of shiga-like toxin, ADAMTS13 autoantibodies, and normal ADAMTS13 activity were consistent with a diagnosis of atypical hemolytic uremic syndrome (aHUS) and then confirmed by a renal biopsy. Genetic tests ( CFH, CFHR1-5, MCP/CD46, CFI, C3, CFB, THBD , and DGKE ) were unremarkable. Nevertheless, a history of anemia and kidney failure in her younger brother suggested a genetic etiology.

Molecular Pathogenesis of Endotheliopathy and Endotheliopathic Syndromes, Leading to Inflammation and Microthrombosis, and Various Hemostatic Clinical Phenotypes Based on "Two-Activation Theory of the Endothelium" and "Two-Path Unifying Theory" of Hemostasis.

Endotheliopathy, according to the “two-activation theory of the endothelium”, can be triggered by the activated complement system in critical illnesses, such as sepsis and polytrauma, leading to two distinctly different molecular dysfunctions: (1) the activation of the inflammatory pathway due to the release of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor-α, and (2) the activation of the microthrombotic pathway due to the exocytosis of hemostatic factors, such as ultra-large von Willebrand factor (ULVWF) multimers and FVIII. The former promotes inflammation, including inflammatory organ syndrome (e.g., myocarditis and encephalitis) and multisystem inflammatory syndrome (e.g., cytokine storm), and the latter provokes endotheliopathy-associated vascular microthrombotic disease (VMTD), orchestrating thrombotic thrombocytopenic purpura (TTP)-like syndrome in arterial endotheliopathy, and immune thrombocytopenic purpura (ITP)-like syndrome in venous endotheliopathy, as well as multiorgan dysfunction syndrome (MODS). Because the endothelium is widely distributed in the entire vascular system, the phenotype manifestations of endotheliopathy are variable depending on the extent and location of the endothelial injury, the cause of the underlying pathology, as well as the genetic factor of the individual. To date, because the terms of many human diseases have been defined based on pathological changes in the organ and/or physiological dysfunction, endotheliopathy has not been denoted as a disease entity. In addition to inflammation, endotheliopathy is characterized by the increased activity of FVIII, overexpressed ULVWF/VWF antigen, and insufficient ADAMTS13 activity, which activates the ULVWF path of hemostasis, leading to consumptive thrombocytopenia and microthrombosis. Endothelial molecular pathogenesis produces the complex syndromes of inflammation, VMTD, and autoimmunity, provoking various endotheliopathic syndromes. The novel conceptual discovery of in vivo hemostasis has opened the door to the understanding of the pathogeneses of many endotheliopathy-associated human diseases. Reviewed are the hemostatic mechanisms, pathogenesis, and diagnostic criteria of endotheliopathy, and identified are some of the endotheliopathic syndromes that are encountered in clinical medicine.

Siglec-5 and Siglec-14 mediate the endocytosis of ADAMTS13

BackgroundThe plasma metalloprotease ADAMTS13 regulates the thrombotic activity of the von Willebrand factor (VWF). ADAMTS13 is highly glycosylated and its carbohydrate chains are capped with sialic acid (SA). Thus, ADAMTS13 may interact with carbohydrate- and/or SA-binding plasma membrane receptors that are involved in the clearance of various plasma proteins. We have investigated ADAMTS13 endocytosis via Siglecs, which were originally identified as SA-binding immunoreceptor family proteins expressed on leukocytes and are also known as endocytic receptors. Materials and methodsEndocytic internalization of fluorescently labeled ADAMTS13 into HEK293 cells expressing Siglecs was examined via fluorescence microscopy. In vitro binding of ADAMTS13 to the extracellular region of Siglec-5 was examined. Plasma ADAMTS13 activity in human Siglec-5-expressing mice was measured. Results and conclusionsSiglec-5- and Siglec-14-expressing cells internalized not only full-length ADAMTS13 (FL) but also the truncated form (MDTCS) at least partly in an SA-independent manner. Replacement of the V-set domain of Siglec-14 with that of Siglec-3 abrogated the internalization of ADAMTS13. ADAMTS13 directly bound to the extracellular region of Siglec-5 in vitro. Expression of Siglec-5 in the mouse liver resulted in a significant decrease in plasma ADAMTS13 activity. These results suggest that Siglec-5 and Siglec-14, which have nearly identical ligand-binding domains, may contribute to the regulation of plasma ADAMTS13 levels as endocytic receptors for ADAMTS13.

Von Willebrand Factor and Platelet Levels before Conditioning Chemotherapy Indicate Bone Marrow Regeneration following Autologous Hematopoietic Stem Cell Transplantation

Autologous hematopoietic stem cell transplantation (HSCT) is often complicated by hemostatic and thrombotic events associated with endothelial cell injury. Thrombotic complications are affected by a disturbed balance between platelets, circulating von Willebrand factor (VWF), and its specific protease, ADAMTS13. HSCT-associated endothelial dysfunction, impaired hemostasis, and inflammation are interrelated processes, and research on the complex interplay of conditioning regimens from engraftment to bone marrow regeneration remains intensive. This prospective observational study comparing lymphoma and multiple myeloma (MM) patients who underwent autologous HSCT explored how platelet count, VWF level, ADAMTS13 activity, and C-reactive protein (CRP) level as potential markers (1) vary in response to therapy, (2) differ between the 2 groups, and (3) correlate with the remission state at 100 days after HSCT. We correlated the quantitative changes in platelet count and levels of VWF, ADAMTS13, and CRP with one another during HSCT and in the remission state in 45 patients with lymphoma and 59 patients with MM who underwent autologous HSCT between 2010 and 2013 at the University of Debrecen. Samples were collected at the start of conditioning chemotherapy, on the day of stem cell transplantation, and at 5, 11, and 100 days following HSCT. CRP levels peaked when platelet counts dropped to a minimum, and these changes were much more pronounced in the lymphoma group. VWF level was the highest, with lower ADAMTS13 activity, at platelet engraftment in both patient groups equally. Diagnostic evidence indicative of thrombotic complications was not found. In the lymphoma group, VWF level prior to conditioning had statistically significant correlations with platelet count, CRP level, and hemoglobin concentration at the time of bone marrow regeneration (P < .001) and during the remission state (P=.034). In the MM group, platelet count before conditioning was correlated with platelet count (P < .001) and white blood cell count (P=.012) at the time of bone marrow regeneration. The statistically significant correlation of the markers at the time of bone marrow regeneration with the preconditioning VWF levels in lymphoma and with the preconditioning platelet counts in MM might indicate the clinical significance of the bone marrow niches of arterioles and megakaryocytes, respectively, where the stem cells are located and regulated. Because preconditioning VWF levels are associated with remission after HSCT in lymphoma patients, VWF should be screened before conditioning, along with the markers used in HSCT protocols, to optimize personalized treatment and reduce therapeutic risks.

Pseudomonas aeruginosa Infection Presenting as Microangiopathic Hemolytic Anemia and Thrombocytopenia

A 28 year-old female with congenital human immunodeficiency virus infection presented with microangiopathic hemolytic anemia and thrombocytopenia secondary to multi-drug resistant Pseudomonas aeruginosa pulmonary infection. Initial management for thrombotic thrombocytopenic purpura (TTP) was discontinued when normal ADAMTS13 activity was found. There are several infectious etiologies that can exhibit microangiopathic hemolytic anemia and thrombocytopenia mimicking TTP including P. aeruginosa. This case highlights the importance of following guidelines regarding dual antibiotic coverage for P. aeruginosa infection as antibiotic resistance can develop during the course of treatment.

Contribution of ADAMTS13‐independent VWF regulation in sickle cell disease

BackgroundVon Willebrand factor (VWF) is elevated in sickle cell disease (SCD) and contributes to vaso‐occlusion through its thrombogenic properties. VWF is regulated by ADAMTS13, a plasma protease that cleaves VWF into less bioactive multimers. Independent investigations have shown VWF to be elevated in SCD, whereas measurements of ADAMTS13 have been variable. ObjectivesWe assessed ADAMTS13 activity using multiple activity assays and measured levels of alternative VWF‐cleaving proteases in SCD. Methods/ PatientsPlasma samples were collected from adult patients with SCD (n = 20) at a single institution when presenting for routine red cell exchange transfusion therapy. ADAMTS13 activity was measured by FRETS‐VWF73, Technozym ADAMTS‐13 Activity ELISA kit and a full‐length VWF digestion reaction. Alternative VWF‐cleaving proteases were identified by ELISA. A cell culture model was used to study the impact of SCD stimuli on endothelial ADAMTS13 and alternative VWF‐cleaving proteases. ResultsADAMTS13 activity was found to be moderately deficient across the SCD cohort as assessed by activity assays using a VWF A2 domain peptide substrate. However, SCD plasma showed preserved ability to digest full‐length VWF, suggesting assay‐discrepant results. Neutrophil and endothelial‐derived proteases were found to be elevated in SCD plasma. Matrix metalloproteinase 9 specifically showed preferential cleavage of full‐length VWF. Upregulation of alternative VWF‐cleaving proteases occurred in endothelial cells exposed to SCD stimuli such as heme and hypoxia. ConclusionsThis is the first demonstration of accessory plasma enzymes contributing to the regulation of VWF in a specific disease state and may have implications for assessing the VWF/ADAMTS13 axis in other settings.

Assay for ADAMTS-13 Activity with Flow Cytometric Readout.

A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) is a metalloprotease that regulates the size of circulating von Willebrand factor (vWF) multimers. Severe lack of ADAMTS-13 activity [<10% of normal (0.1 IU/mL)] leads to thrombotic thrombocytopenic purpura (TTP), a specific type of thrombotic microangiopathy (TMA). Timely determination of plasma ADAMTS-13 activity is essential to discriminate TTP from other types of TMA with respect to adequate treatment. Identification of the minimal substrate motif for ADAMTS-13 within the A2 domain of vWF (vWF73) as well as the generation of monoclonal antibodies (mAbs) that specifically recognize the ADAMTS-13 cleavage site enabled the development of a variety of methods for determination of plasma ADAMTS-13 activity. In order to further extend the range of analytical platforms applicable for quantitative determination of plasma ADAMTS-13 activity, a specific, vWF/mAb-based assay with flow cytometric readout was developed and validated. Basic assay characteristics include a total assay time of 80 to 90 min, a near linear dynamic range from 0.005 (lower limit of quantification) to 0.2 IU/mL, and intra- and interassay coefficients of variation below 5 and 30% at input plasma ADAMTS-13 activities of 0.015 and ≤0.050 IU/mL, respectively. When compared to the results obtained with a commercially available quantitative ADAMTS-13 activity ELISA, analysis of 18 plasma samples obtained from patients with suspected TTP revealed full agreement of results with respect to the clinical 0.1 IU/mL TTP threshold. Based on these data, it is assumed that the described assay principle can be successfully transferred to virtually all laboratories that have a flow cytometer available.

ADAMTS13 levels in a plasma-derived FVIII concentrate: A potential therapeutic option for patients with congenital thrombotic thrombocytopenic purpura

IntroductionTreatment of congenital thrombotic thrombocytopenic purpura (cTTP), a disease characterized by the congenital deficiency of ADAMTS13, remains a challenge as there are no specific treatments available yet, other than therapy based on the use of fresh frozen plasma (FFP). Since cTTP is caused by low levels of ADAMTS13 protein, commercially available coagulation factor concentrates have been considered as potential ADAMTS13 source in place of FFP. The study aimed to validate the therapeutic potential of a plasma-derived factor VIII (FVIII) product as a source of ADAMTS13. MethodsThe quantitation of ADAMTS13 activity levels in eight lots of a plasma-derived FVIII product, (Koāte®) was carried out with three different methodologies: a Fluorescence Resonance Energy Transfer (FRET) assay, a chemiluminescence assay, and a chromogenic ELISA. ADAMTS13 protein antigen levels were measured by the FRET technique as well. In addition, von Willebrand factor (VWF) activity (VWF ristocetin cofactor, VWF:RCo, and VWF collagen binding, VWF:CB) and antigen (VWF:Ag) were measured using chemiluminescence assays. Qualification protocols were applied to the methods used. ResultsThe results showed high levels of ADAMTS13 in all eight Koāte® lots analyzed, with antigen and activity levels respectively of 10.72 IU/ml ± 3.94 and 5.62 IU/ml ± 1.39. Despite the significant content of ADAMTS13, VWF integrity seems not to be affected (0.81 ± 0.15 VWF:RCo/VWF:Ag and 0.75 ± 0.15 VWF:CB/VWF:Ag ratios). ConclusionsThese findings suggest that Koāte® could be a potential candidate for the treatment of cTTP, warranting evaluation in a clinical trial.

Validation of PLASMIC score in a cohort of patients with suspected thrombotic microangiopathy in an academic medical centre.

The PLASMIC score is a rapid and inexpensive clinical assessment tool for predicting severe ADAMTS13 deficiency (<10% activity) in patients with suspected thrombotic thrombocytopenic purpura (TTP). The score includes 7 parameters: absence of active cancer, patient not having received stem cell transplant or organ transplant, platelet count <30×109/L, haemolysis, mean corpuscular volume <90 fl, International Normalized Ratio <1.5, and serum creatinine <2 mg/dL. In this retrospective study, we evaluated a cohort of 59 consecutive patients with suspected thrombotic microangiopathy who had been referred to the Hemostasis and Thrombosis Center of the "Federico II" University of Naples, Italy, for measurement of ADAMTS13 activity. Relevant clinical and laboratory information were collected for all patients. The PLASMIC score was calculated in 52 of the 59 patients included in the study. In the high-risk group (PLASMIC score 6 or 7), 12 out of 20 patients (60%) had ADAMTS13 <10%. Interestingly, all 6 patients (100%) with PLASMIC score 7 had ADAMTS13 <5%. In the intermediate risk group (score 5), only one case out of 17 (5.9%) had ADAMTS 13 <10%. In the low-risk group (score 0-4), none of the patients had severe ADAMTS13 deficiency. The collected data enabled the sensitivity and specificity of PLASMIC score in TTP to be calculated, achieving 92% (95% CI: 0.80-0.98) and 79% (95% CI: 0.66-0.89), respectively. The PLASMIC score was seen to be a very efficient tool in distinguishing between patients with severe ADAMTS13 deficiency from those without, with an AUC of 0.92 (95% CI: 0.82-1.0; p<0.001). In our cohort, a high-risk PLASMIC score successfully predicted patients with severe ADAMTS13 deficiency, allowing the clinician to quickly define the best therapeutic approach, especially useful for those clinicians not used to the diagnosis and treatment of thrombotic microangiopathies.

Incidence of thrombotic microangiopathies in Quebec: insight from a laboratory centralizing ADAMTS-13 testing

BackgroundThrombotic microangiopathies (TMA) are serious medical conditions requiring a prompt diagnosis to adapt treatment. The determination of ADAMTS-13 activity enables discriminating thrombotic thrombocytopenic purpura (TTP) from other forms of TMA. The purpose of this study was to provide an estimate of the incidence of TTP and TMA in the Canadian Quebec province using data collected from a laboratory centralizing ADAMTS-13 testing for the whole province.ResultsFrom 2012 to 2019, 846 patients were evaluated for plasma ADAMTS-13 activity due to a suspicion of TMA. TTP was identified in 147 patients. Of these, 118 patients with a median age of 51.5 years and a male–female ratio of 1:1.4 had their first episode of TTP during the study period. The number of ADAMTS-13 tests performed and the number of patients with suspected TMA increased annually by 19% and 21% respectively. While the incidence of non-TTP TMA increased annually, that for TTP remained unchanged. This averaged 10.2 (95% CI 5.9–14.4) per million persons per year for suspected non-TTP TMA and 1.8 (95% CI 1.3–2.4) for confirmed TTP. The incidence rate of TMA other than TTP was higher in the age group 70–79 years (21.8; 95% CI 5.4–38.1) for females and in the age group 80–89 years (24.4; 95% CI 7.2–41.7) for males compared to other age groups. The incidence rate of TTP was higher in the age group 40–49 years (4.0; 95% CI 2.0–5.9) for women and in the age group 60–69 years (3.4; 95% CI 1.1–5.6) for men compared to other age groups.ConclusionThe analysis of centralized data measuring ADAMTS-13 activity allowed us to adequately establish the incidence rate and demographic characteristics of TMA, particularly TTP, in Quebec. TTP incidence remained stable while suspected non-TTP TMA steadily increased from 2012 to 2019.

Epidemiology, treatment patterns, clinical outcomes, and disease burden among patients with immune‐mediated thrombotic thrombocytopenic purpura in the United States

BackgroundImmune‐mediated thrombotic thrombocytopenic purpura (iTTP) is a life‐threatening thrombotic microangiopathy. Due to its rarity, epidemiology and real‐world outcomes data are scarce. ObjectivesThe aim was to assess epidemiology, treatment patterns, clinical outcomes, and disease burden in patients with iTTP in the United States. MethodsThis longitudinal, retrospective observational study of the Optum‐Humedica database included patients with an iTTP diagnosis (≥1 documented ADAMTS13 activity less than 10% or one or more iTTP episodes) from January 2007 to December 2019. ResultsOf 666 patients with an iTTP diagnosis between October 2015 and December 2019, 302 (45%) had one or more iTTP episodes. The pooled annual incidence of documented iTTP during this period was 3.43/million, and the annual incidence of one or more iTTP episodes was 1.81/million. Patients with one or more iTTP episodes received a median of six therapeutic plasma exchange (TPE) sessions per episode; 86% received corticosteroids, and 59% received rituximab. Exacerbations occurred in 17% (52/302) and relapse in 11% (34/302); 34% (103/302) had one or more thromboembolic events. Mortality rates during the study period were 25% (167/666) among all patients with iTTP diagnosis, and 14% (41/302) among patients with one or more iTTP episodes. In the assessment of disease burden (January 2007 to September 2019), patients in the iTTP cohort (n = 514) presented with a mean of 14 comorbidities, compared with 3 in a matched non‐iTTP cohort (n = 2570). In a cluster analysis, duration of iTTP episode and mortality rate were greater in older versus younger patients. ConclusionsDespite treatment with TPE and immunosuppressants, patients with iTTP have high risk of morbidity and mortality, demonstrating the need for more effective therapies.

The Challenges in Diagnosis and Management of Acquired Thrombotic Thrombocytopenic Purpura: Consensus Report from Three Gulf Countries.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare hematological emergency characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, and multiorgan failure due to autoimmune-mediated deficiency in ADAMTS-13 activity. Currently, plasma exchange, with or without steroids, is the frontline option for the management of aTTP. The treatment should be started promptly once the disorder is clinically suspected. Besides, immunomodulators were studied in patients with aTTP to achieve stable remission and reduce the risk of relapse in patients with suboptimal response to plasma exchange; however, clinical trials showed equivocal results. Published data on early diagnosis, referral, and treatment patterns of aTTP patients in the member nations of the Arabian Gulf Cooperation Council (GCC) are still lacking. Therefore, the present consensus report aimed to present an overview of aTTP situation in GCC by bringing together a panel of experts from three GCC nations, to share their views on current trends and practices regarding aTTP. The experts discussed challenges including the lack of reliable data regarding the incidence of aTTP in GCC and delayed results of ADAMTS-13 activity testing. Limited patient access to tertiary centers and low level of awareness about the aTTP clinical spectrum among general practitioners are other challenges. The experts agreed that there is a need for national and regional consensus regarding the diagnosis and treatment of aTTP in the Gulf region.