Thrombotic Thrombocytopenic Purpura Research Articles

Mean platelet volume and platelet distribution width in the prediction of treatment response in immune thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a multicenter study

Mean platelet volume and platelet distribution width in the prediction of treatment response in immune thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a multicenter study

Diagnosis and clinical management of thrombotic thrombocytopenic purpura (TTP): a consensus statement from the TTP Catalan group.

Thrombotic thrombocytopenic purpura (TTP) is a low prevalence disease characterized by severe deficiency of the enzyme ADAMTS13, leading to the development of thrombotic microangiopathy (TMA) and often resulting in severe organ disfunction. TTP is an extremely serious condition and, therefore, timely and appropriate treatment is critical to prevent life-threatening complications.Over the past 25 years, significant advances in the understanding of the pathophysiology of immune TTP have led to the development of readily available techniques for measuring ADAMTS13 levels, as well as new drugs that are particularly effective in the acute phase and in preventing relapses. These developments have improved the course of the disease.Given the complexity of the disease and its various clinical and laboratory manifestations, early diagnosis and treatment can be challenging.To address this challenge, a group of experienced professionals from the Catalan TTP group have developed this consensus statement to standardize terminology, diagnosis, treatment and follow up for immune TTP, based on currently available scientific evidence in the field. This guidance document aims to provide healthcare professionals with a comprehensive tool to make more accurate and timely diagnosis of TTP and improve patient outcomes.

Diagnosis of thrombotic thrombocytopenic purpura: easy-to-use fiber optic surface plasmon resonance immunoassays for automated ADAMTS-13 antigen and conformation evaluation

BackgroundLaboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS-13 activity ranges between 10% and 20%. To prevent misdiagnosis, open ADAMTS-13 conformation gained clinical attention as a novel biomarker, especially to diagnose acute iTTP in patients with diagnostic undecisive ADAMTS-13 activity. Plasma ADAMTS-13 conformation analysis corrects for ADAMTS-13 antigen, with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians. ObjectivesTo design ADAMTS-13 antigen and conformation assays on automated, easy-to-use fiber optic surface plasmon resonance (FO-SPR) technology to promote assay accessibility and diagnose challenging iTTP patients. MethodsADAMTS-13 antigen and conformation assays were designed on FO-SPR technology. Plasma of 20 healthy donors and 20 acute iTTP patients were quantified, and data from FO-SPR and ELISA reference assays were compared. ResultsFollowing assay design, both antigen and conformation FO-SPR assays were optimized and characterized, presenting strong analytical sensitivity (detection limit of 0.001 μg/mL) and repeatability (interassay variation of 14.4%). Comparative analysis suggested positive correlation (Spearman r of 0.92) and good agreement between FO-SPR and ELISA assays. As expected, FO-SPR assays showed a closed or open ADAMTS-13 conformation in healthy donors and acute iTTP patients, respectively. ConclusionBoth ADAMTS-13 antigen and conformation assays were transferred onto automated, easy-to-use FO-SPR technology, displaying potent analytical sensitivity and reproducibility. ADAMTS-13 antigen and conformation were determined for healthy donors and acute iTTP patients showing strong correlation with ELISA reference. Introducing FO-SPR technology in clinical context could support routine diagnosis of acute iTTP patients, notably when ADAMTS-13 activity fluctuates between 10% and 20%.

A machine learning approach to predict mortality due to immune-mediated thrombotic thrombocytopenic purpura

BackgroundMortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models. ObjectivesTo validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index. MethodsWe analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm. ResultsIn our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively. ConclusionThe USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.

Diagnostic methods for thrombotic thrombocytopenic purpura

Diagnostic methods for thrombotic thrombocytopenic purpura

Immune-mediated thrombotic thrombocytopenic purpura landscaping in Gulf countries: a real-world evidence study (ATHENA Study)

Immune-mediated thrombotic thrombocytopenic purpura landscaping in Gulf countries: a real-world evidence study (ATHENA Study)

L’ère des nanocorps et anticorps thérapeutiques en hémostase

AbstractTherapeutic antibodies are now an integral part of the therapeutic arsenal in the treatment of many conditions, including haemostasis. They are all humanized monoclonal antibodies (suffix : zumab) that can partially restore hemostasis (emicizumab, concizumab), or used as an antidote (idarucizumab) to antagonize the effect of certain anticoagulant (dabigatran) or platelet antiagregants (bentra-cimab, still under study). Others therapeutic antibodies have been or may be used for their own antiagregant properties (abciximab, discontinued in September 2019, or the future anti-GPVI antiagregant glencozimab, still under study). As for caplacizumab, it is a nanobody indicated in the acute phase of acquired throm-botic thrombocytopenic purpura.

Apadamtase Alfa: First Approval.

Apadamtase alfa (ADAMTS13, recombinant-krhn; ADZYNMA), a human recombinant form of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), is being developed by Takeda under license from KM biologics for thrombotic thrombocytopenic purpura (TTP) and sickle cell disease. On 9 November 2023, apadamtase alfa was approved in the USA for prophylactic and on-demand enzyme replacement therapy (ERT) in paediatric and adult patients with congenital TTP. Apadamtase alfa is under regulatory review for congenital TTP in the EU and Japan, and is under clinical development for immune-mediated TTP in several countries worldwide. Clinical development of apadamtase alfa for vaso-occlusive crisis related to sickle cell anaemia is underway in the USA. This article summarizes the milestones in the development of apadamtase alfa leading to this first approval in the USA for congenital TTP.

Successful Treatment of Acquired Thrombotic Thrombocytopenic Purpura With Caplacizumab Combined With Plasma Exchanges and Immune Suppression in 3 Children.

Acquired thrombotic thrombocytopenic (aTTP) purpura is a life-threatening condition that can lead to devastating thromboembolic events. Recently, caplacizumab has been shown to rapidly restore platelet numbers and reduce the risk of severe end-organ damage when added to plasma exchanges (PEXs) and immunosuppression (IST). Here, we report the outcomes in 3 children with aTTP who were treated with caplacizumab in combination with PEXs and IST. In all 3 patients, platelet count increased to >15,000/mm 3 in 24 h and normalized on day 4, whereas normalization of ADAMTS13 activity >50% and elimination of the inhibitor was achieved after 18 to 89 days. Epistaxis was observed in 2 patients and was the only side effect related to caplacizumab. Caplacizumab is a promising agent for first-line treatment of children with aTTP.

HHV8-Positive Multicentric Castleman's Disease and Thrombotic Thrombocytopenic Purpura among HIV-Positive Patients.

Castleman's disease (CD) and thrombotic thrombocytopenic purpura (TTP) are rare diseases, and their association remains extremely uncommon.We report a case of multicentric CD (MCD) with TTP in a 53-year-old male patient with HIV.Only five patients, including ours, have been reported as having both MCD and TTP, with all five having HHV8 and four having HIV. Thus, coinfection with HHV8 and HIV may be a potential pivotal factor in the occurrence of MCD with TTP.

Pregnancy as a susceptible state for thrombotic microangiopathies.

Pregnancy and the postpartum period represent phases of heightened vulnerability to thrombotic microangiopathies (TMAs), as evidenced by distinct patterns of pregnancy-specific TMAs (e.g., preeclampsia, HELLP syndrome), as well as a higher incidence of nonspecific TMAs, such as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, during pregnancy. Significant strides have been taken in understanding the underlying mechanisms of these disorders in the past 40 years. This progress has involved the identification of pivotal factors contributing to TMAs, such as the complement system, ADAMTS13, and the soluble VEGF receptor Flt1. Regardless of the specific causal factor (which is not generally unique in relation to the usual multifactorial origin of TMAs), the endothelial cell stands as a central player in the pathophysiology of TMAs. Pregnancy has a major impact on the physiology of the endothelium. Besides to the development of placenta and its vascular consequences, pregnancy modifies the characteristics of the women's microvascular endothelium and tends to render it more prone to thrombosis. This review aims to delineate the distinct features of pregnancy-related TMAs and explore the contributing mechanisms that lead to this increased susceptibility, particularly influenced by the "gravid endothelium." Furthermore, we will discuss the potential contribution of histopathological studies in facilitating the etiological diagnosis of pregnancy-related TMAs.

Real-World Data Analysis of Patients Affected by Immune-Mediated Thrombotic Thrombocytopenic Purpura in Italy.

Background: The therapeutic management of immune-mediated thrombotic thrombocytopenic purpura (iTTP) has recently benefited from the introduction of caplacizumab, an agent directed at the inhibition of platelet aggregation. This real-world analysis investigated the epidemiology and the demographic and clinical characteristics of iTTP patients in Italy before and after caplacizumab introduction in 2020. Methods: Hospitalized adults with iTTP were included using the administrative databases of healthcare entities covering 17 million residents. Epidemiological estimates of iTTP considered the 3-year period before and after caplacizumab introduction. After stratification by treatment with or without caplacizumab, iTTP patients were characterized for their baseline features. Results: The annual incidence before and after 2020 was estimated in the range of 4.3-5.8 cases/million and 3.6-4.6 cases/million, respectively. From 2018 to 2022, 393 patients with iTTP were included, and 42 of them were treated with caplacizumab. Caplacizumab-treated patients showed better clinical outcomes, with tendentially shorter hospital stays and lower mortality rates (no treated patients died at either 1 month or 3 months after caplacizumab treatment initiation, compared to 10.5% and 11.1% mortality rates at 1 and 3 months, respectively, of the untreated ones). Conclusions: These findings may suggest that caplacizumab advent provided clinical and survival benefits for patients with iTTP.

Pathogenic Factors of Shiga Toxigenic Escherichia coli

The Shigatoxigenic Escherichia coli (STEC) are bacterial enteropathogens responsible for some intensive clinical syndromes such as bloody diarrhoea, hemorrhagic colitis, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and renal failure. These pathotypes come under the Enterohemorrhagic Escherichia coli (EHEC) group. Monogastric farm animals such as pigs, horses, chickens, ducks, turkeys and aquatic animals like shellfish, fishes, and wild animals can act as major spillover hosts of STEC strains and could serve as the potential source of infection. The pathogen is notorious as a quickly emergent strain with acquired characteristics like different variants of Shigatoxin, many antibiotic degrading enzymes, Intimin, Enterohemolysin, Auto-agglutination Adhesins, Catalase-peroxidase, Zinc metalloprotease, Subtilase cytotoxin, tolerance to multiple adverse conditions, and biofilm formation. The bacteria are known for its long survival in different adverse physical-chemical conditions. The formation of biofilm is one of the major factors responsible for their persistence. Multidrug resistance is another related trait contributing to the high mortality rate of these strains. STEC strains are good candidates for studying the emergence of pathogens with acquired characteristics like genes. In this article, various virulent traits and multidrug resistance that enabled the strain to emerge as a serious public health menace were reviewed.

Persistent ADAMTS13 inhibitor delays recovery of ADAMTS13 activity in caplacizumab-treated Japanese patients with iTTP

AbstractFor patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), caplacizumab, a nanobody against von Willebrand factor A1 domain, has become crucial. Delayed normalization of ADAMTS13 activity during caplacizumab therapy has been identified. In a retrospective analysis, we compared platelet count, ADAMTS13 activity, its inhibitor, and anti-ADAMTS13 immunoglobulin G (IgG) levels in acute iTTP cases treated with caplacizumab (n = 14) or without it (n = 16). The median time from initial therapeutic plasma exchange (TPE) to the first rituximab administration was 12 days in the caplacizumab group (n = 11) and 10 days in the group without caplacizumab (n = 13). We evaluated ADAMTS13-related parameters at onset and once a week until day 28 after the first TPE. The number of days until the platelet counts reached ≥150 × 109/L was significantly shorter in the caplacizumab group than in the non-caplacizumab group. The median ADAMTS13 activity levels on days 14, 21, and 28 were significantly lower in the caplacizumab group. The median titers of the ADAMTS13 inhibitor and anti-ADAMTS13 IgG on the same days were significantly higher in the caplacizumab group. Furthermore, the median number of days from the first TPE until finally achieving an ADAMTS13 activity of ≥10% was significantly longer in the caplacizumab group than in the non-caplacizumab group (42 vs 23 days, P = .014). We observed delayed ADAMTS13 activity recovery and continued inhibitor and anti-ADAMTS13 IgG detection in patients with acute iTTP on caplacizumab, possibly because of the decreased number of TPEs and delayed frontline rituximab.

In vitro test methods for evaluating high molecular weight polyethylene oxide polymer induced hemolytic and thrombotic potential

To combat opioid abuse, the U.S. Food and Drug Administration (FDA) released a comprehensive action plan to address opioid addiction, abuse, and overdose that included increasing the prevalence of abuse-deterrent formulations (ADFs) in opioid tablets. Polyethylene oxide (PEO) has been widely used as an excipient to deter abuse via nasal insufflation. However, changes in abuse patterns have led to unexpected shifts in abuse from the nasal route to intravenous injection. Case reports identify adverse effects similar to thrombotic thrombocytopenic purpura (TTP) syndrome following the intravenous (IV) abuse of opioids containing PEO excipient. Increased risk of IV opioid ADF abuse compared to clinical benefit of the drug led to the removal of one opioid product from the market in 2017. Because many generic drugs containing PEO are still in development, there is interest in assessing safety consistent with generic drug regulation and unintended uses. Currently, there are no guidelines or in vitro assessment tools to characterize the safety of PEO excipients taken via intravenous injection. To create a more robust excipient safety evaluation tool and to study the mechanistic basis of HMW PEO-induced TMA, a dynamic in vitro test system involving blood flow through a needle model has been developed.

A rare case of hereditary thrombotic thrombocytopenic purpura in a toddler

A rare case of hereditary thrombotic thrombocytopenic purpura in a toddler

TEMPORARY REMOVAL: Mortalité maternelle de causes indirectes (hors AVC, maladies cardiovasculaires et infections) en France 2016–2018

Maternal deaths from indirect obstetric cause result from a preexisting condition or a condition that occurred during pregnancy without obstetric causes but was aggravated by the physiological effects of pregnancy. Twenty-nine deaths with an indirect cause related to a preexisting condition, excluding circulatory diseases or infections, were analysed by the expert committee. Pre-pregnancy pathology was documented in 16 women (epilepsy, n=7; amyloid angiopathy, n=1; Dandy-Walker syndrome, n=1; autoimmune diseases, n=3; diffuse infiltrative pneumonitis, n=1; thrombotic thrombocytopenic purpura, n=1; ovarian cancer in fragile X, n=1; major sickle cell disease, n=1). In 13 women, the pathology was unknown before pregnancy (breast cancer, n=9, epilepsy diagnosed during pregnancy, n=1, brain tumours, n=2 meningioma type, macrophagic activation syndrome, n=1). Death was associated with neoplastic or tumour pathology in 13 women (45%). At the same time, epilepsy was responsible for the death of 8 women (27%), making it the most common cause of death. For both neoplasia and epilepsy, about 50% of deaths were preventable, mainly due to undiagnosed and/or delayed treatment in the case of cancer and failure to monitor or adjust treatment in the case of epilepsy. Pre-conception counselling is therefore strongly recommended if a woman has a known chronic medical condition prior to pregnancy. Finally, if there is a family history of breast cancer, a breast examination is strongly recommended from the first visit during pregnancy, and any breast lumps should be investigated as soon as possible to avoid delaying appropriate treatment.

Stress-induced hyperglycemia is associated with the mortality of thrombotic thrombocytopenic purpura patients

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy with a rapid progression and high mortality rate. We aimed to explore early risk factors for mortality in patients with TTP.MethodsWe conducted a retrospective analysis of 42 TTP patients that were admitted to our hospital between 2000 and 2021, with a median age of 49 (29–63) years. Risk factors for mortality were evaluated using multivariate logistic regression. Receiver operating characteristic curve analysis was used to determine the cut-off value of glucose for predicting mortality in patients, which was validated by comparison to a similar cohort in the published literature.ResultsElevated glucose level and reduced red blood cells (RBC) counts were risk factors for mortality in patients with TTP (glucose, odds ratio and 95% confidence interval: 2.476 [1.368–4.484]; RBC, odds ratio and 95% confidence interval: 0.095 [0.011–0.799]). The area under the curve of glucose was 0.827, and the cut-off value was 9.2 mmol/L, with a sensitivity of 75.0% and specificity of 95.8%. A total of 26 cases from the validation cohort had a sensitivity of 71.0% and a specificity of 84.0%. The change trends of the TTP-related laboratory indices differed during hospitalization.ConclusionHyperglycemia at admission and unstable blood glucose levels during hospitalization may be potential predictors of mortality for TTP patients. The improved prognosis was associated with the recovery of platelet counts and a significant decrease in serum lactate dehydrogenase after five days of treatment.

Mechanism underlying severe deficiency of plasma ADAMTS-13 activity in immune thrombotic thrombocytopenic purpura

BackgroundImmune-mediated thrombotic thrombocytopenic purpura is caused by autoantibodies against ADAMTS-13, a plasma enzyme that cleaves von Willebrand factor. However, the mechanism resulting in severe deficiency of plasma ADAMTS-13 activity remains controversial. ObjectivesTo determine the mechanism of autoantibody-mediated severe deficiency of plasma ADAMTS13 activity in immune-mediated thrombotic thrombocytopenic purpura. MethodsFluorescence resonance energy transfer-VWF73 was used to determine plasma ADAMTS-13 activity. Enzyme-linked immunosorbent assay (ELISA) was used to determine anti–ADAMTS-13 immunoglobulin G. ELISA and capillary electrophoresis–based Western blotting were employed to assess plasma ADAMTS-13 antigen. ResultsWe showed that plasma ADAMTS-13 antigen levels varied substantially in the samples collected on admission despite all showing plasma ADAMTS-13 activity of <10 IU/dL (or <10% of normal level) using either ELISA or Western blotting. More severe deficiency of plasma ADAMTS-13 antigen (<10%) was detected in admission samples by ELISA than by capillary Western blotting. There was a significant but moderate correlation between plasma ADAMTS-13 activity and ADAMTS-13 antigen by either assay method, suggesting that severe deficiency of plasma ADAMTS-13 activity is not entirely associated with low levels of ADAMTS-13 antigen. ConclusionWe conclude that severe deficiency of plasma ADAMTS-13 activity primarily resulted from antibody-mediated inhibition, but the accelerated clearance of plasma ADAMTS-13 antigen via immune complexes may also contribute significantly to severe deficiency of plasma ADAMTS-13 activity in a subset of patients with acute immune-mediated thrombotic thrombocytopenic purpura.

Importance of Prenatal Genetic Counselling: An Experience with Hereditary Thrombotic Thrombocytopenic Purpura

Importance of Prenatal Genetic Counselling: An Experience with Hereditary Thrombotic Thrombocytopenic Purpura