Diagnosis of Hereditary TTP Caused by Homozygosity for a Rare Complex ADAMTS13 Allele After Salmonella Infection in a 43-Year-Old Asylum Seeker
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ABSTRACT:
SUBMITTER: Wendt R
PROVIDER: S-EPMC7959797 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Project description:With timely and effective treatment, most patients with thrombotic thrombocytopenic purpura (TTP) survive the acute TTP episode. In addition to the risk of relapse, TTP survivors have higher all-cause mortality than the general population and increased rates of chronic morbidities, including hypertension, depression, and mild cognitive impairment. We conducted this retrospective-prospective cohort study to determine the incidence and prevalence of stroke after recovery from acute TTP and to test the hypothesis that lower ADAMTS13 activity after recovery from TTP is associated with an increased risk of stroke during remission. Of 170 consecutive patients treated for TTP at The Johns Hopkins Hospital from 1995 through 2018, 14 (8.2%) died during the index episode and 19 were observed for less than 1 month after recovery. Of the remaining 137 patients, 18 (13.1%) developed stroke unrelated to an acute TTP episode over a median observation period of 3.08 years, which is fivefold higher than the expected prevalence of 2.6% from an age- and sex-matched reference population (P = .002). ADAMTS13 activity during remission was measured in 52 patients and was >70% in 44.2%, 40% to 70% in 23.1%, 10% to 39% in 25%, and <10% in 7.7%. Stroke after recovery from acute TTP occurred in 0% (0 of 22) of patients with normal remission ADAMTS13 activity (>70%) and in 27.6% (8 of 29) of patients with low ADAMTS13 activity (?70%; P = .007). In conclusion, stroke is common after recovery from TTP and is associated with reduced ADAMTS13 activity during remission.
| S-EPMC7022317 | biostudies-literature
Project description:This study sought correlates of relapse tendency in TTP by examining gene expression profiles in peripheral blood leukocytes from patients with acquired ADAMTS13-deficient TTP in remission and matched healthy controls for global gene expression and autoantibodies.
2013-03-07 | GSE36418 | GEO
Project description:This study sought correlates of relapse tendency in TTP by examining gene expression profiles in peripheral blood leukocytes from patients with acquired ADAMTS13-deficient TTP in remission and matched healthy controls for global gene expression and autoantibodies. Total RNA was isolated from PAXgene RNA tubes from 39 patients with with acquired ADAMTS13-deficient TTP (all patients had relapsed) and 39 healthy controls.
2013-03-07 | E-GEOD-36418 | biostudies-arrayexpress
Project description:BackgroundThe World Health Organization recommends exclusive breastfeeding for the first six months after childbirth. However, breastfeeding is influenced by organizational, social, geopolitical, and cultural factors, which are understudied in the migrant population. This study aimed to assess the knowledge, attitudes, beliefs, and practices of refugee, migrant, and asylum-seeking mothers living in Lisbon.MethodsA sociodemographic questionnaire and a Breastfeeding Knowledge, Attitudes, and Beliefs, and Practices questionnaire were used to gather information regarding baseline breastfeeding knowledge, attitudes and beliefs, and practices towards breastfeeding.ResultsOnly 40% of the mothers received antenatal counselling regarding the benefits and management of breastfeeding. Of the 20 responses, 10 (50%) mothers were found to have fair breastfeeding knowledge, 14 (70%) had fair attitudes and beliefs, and 12 (60%) had fair breastfeeding practices. Correlation analysis indicated a positive correlation between mothers' breastfeeding attitudes (r = 0.531, p < 0.05) and their breastfeeding knowledge. There was no statistically significant correlation between the mothers' breastfeeding attitudes, beliefs, and practices.ConclusionsThe findings of this study suggest that healthy breastfeeding behaviours can be stimulated by receiving proper counselling from health professionals. Countries must focus on improving breastfeeding practices, as they still fail to do all they can to promote, protect, and support breastfeeding globally. Universal interventions are necessary to improve breastfeeding, regardless of migrant or refugee status.
| S-EPMC10848452 | biostudies-literature
Project description:Asylum seekers frequently experience potentially traumatic events (PTEs), but the type and frequency vary depending on the country of origin. The cumulative effect of multiple PTEs and other stressors expose asylum seekers to a significant risk of mental ill health. The aim of the study was to examine the prevalence of PTEs, depression and anxiety symptoms, risk for psychological trauma, psychotropic medication use and previous mental health diagnoses among adult asylum seekers in the Asylum Seekers Health and Wellbeing (TERTTU) Survey (n = 784 respondents, participation rate 78.6%). A substantial majority (88.7%, 95% CI 86.9-90.3) of asylum seekers reported one or more PTEs before arriving to Finland. PTEs during the asylum-seeking journey were reported at 12.0% (95% CI 10.7-13.4), however, when examined by region of origin, the proportion was 34.5% (95% CI 29.5-39.8) for asylum seekers from Africa (excluding North Africa). Significant symptoms of depression were reported by 41.7% (95% CI 39.6-43.9) of asylum seekers and symptoms of anxiety by 34.2% (95% CI 32.1-36.2). Half of the asylum seekers were assessed as having at least a medium-risk for psychological trauma. Prevalence rates were higher among females and asylum seekers from Africa. This study highlights the importance of using screening tools to identify asylum seekers with severe mental health problems that may need referral to further assessment and treatment. Asylum seekers from Africa (excluding North Africa) should be given additional attention in initial health screenings and examinations.
| S-EPMC8297147 | biostudies-literature
Project description:Primary hyperoxaluria (PH) Type 1 is a rare, genetic disorder caused by deficiency of the liver enzyme alanine-glyoxylate aminotransferase, which is encoded by AGXT gene. We report a 2-year-old South Indian Tamil child with nephrocalcinosis due to PH Type 1, in whom a homozygous genotype for two missense mutations in the AGXT gene was found: first, a C to G transversion (c. 32C>G) in exon 1 resulting in the amino acid substitution p.Pro11Arg; second, a T to A transversion (c. 167T>A) in exon 2 resulting in p.Ile56Asn. A therapy based on potassium citrate and pyridoxine was started. This is the first report of molecular testing-proven childhood onset-PH Type 1 from South India and is notable for the co-occurrence of two missense mutations in one AGXT allele, which might lead to different and more severe phenotype than each mutation alone. To the best of our knowledge, AGXT allele carrying two already known mutations has not been previously reported.
| S-EPMC5590421 | biostudies-literature
Project description:Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an autoimmune disorder caused by the development of autoantibodies targeting different domains of ADAMTS13. Profiling studies have shown that residues R568, F592, R660, Y661, and Y665 within exosite-3 of the spacer domain provide an immunodominant region of ADAMTS13 for pathogenic autoantibodies that develop in patients with iTTP. Modification of these 5 core residues with the goal of reducing autoantibody binding revealed a significant tradeoff between autoantibody resistance and proteolytic activity. Here, we employed structural bioinformatics to identify a larger epitope landscape on the ADAMTS13 spacer domain. Models of spacer-antibody complexes predicted that residues R568, L591, F592, K608, M609, R636, L637, R639, R660, Y661, Y665, and L668 contribute to an expanded epitope within the spacer domain. Based on bioinformatics-guided predictions, we designed a panel of N-glycan insertions in this expanded epitope to reduce the binding of spacer domain autoantibodies. One N-glycan variant (NGLY3-ADAMTS13, containing a K608N substitution) showed strongly reduced reactivity with TTP patient sera (28%) as compared with WT-ADAMTS13 (100%). Insertion of an N-glycan at amino acid position 608 did not interfere with processing of von Willebrand factor, positioning the resulting NGLY3-ADAMTS13 variant as a potential novel therapeutic option for treatment of iTTP.
| S-EPMC9635527 | biostudies-literature
Project description:Purpose: The coronavirus disease 2019 (COVID-19) pandemic presents health care challenges to asylum seekers living in congregate encampments, including those along the U.S.-Mexico border. It is necessary to understand the impact of the pandemic among this population to address health care needs, reduce transmission, and diminish COVID-19-related morbidity. Methods: Thirty interviews were conducted with asylum seekers and health care professionals in a temporary camp in Matamoros, Mexico to determine challenges, perceptions, and effects of the COVID-19 pandemic. Interviews were coded in NVivo12 by using a team-based approach. Results: The pandemic caused significant mental health burdens but no perceived adverse physical effects, with the U.S. border closure and health care access barriers as more pressing concerns. Participants reported access to information about COVID-19 but had varied levels of knowledge and adherence to disease reduction strategies due to camp conditions. Most participants believed that they had special protection from COVID-19, including strong immune systems or from God. The nongovernmental organizations providing health care and sanitation faced multiple challenges to implement new policies to manage COVID-19. The institution of required temperature checks and quarantine of COVID-19 positive patients led to distrust, decreased seeking of health care services among asylum seekers, and possible underreporting of COVID-19 cases. Conclusion: Our findings among asylum seekers in a Matamoros camp highlight the challenges to implementing disease reduction policies in low-resource congregate camps. Policies to address disease outbreaks focusing on the social determinants of health, health care access barriers, and community engagement may be more acceptable to asylum seekers, suggesting the need for effective strategies to provide prevention information that complements such measures.
| S-EPMC8080921 | biostudies-literature
Project description:Absent or severely diminished activity of ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) resulting in the intravascular persistence and accumulation of highly thrombogenic ultra large von Willebrand factor (UL-VWF) multimers is the pathophysiological mechanism underlying thrombotic thrombocytopenic purpura. Reduced VWF-cleaving protease levels, however, are not uniquely restricted to primary thrombotic microangiopathy (TMA), e.?g. thrombotic thrombocytopenic purpura, but also occur in other life-threatening thrombocytopenic conditions: severely decreased ADAMTS13 activity is seen in severe sepsis, disseminated intravascular coagulation (DIC) and complicated malarial infection. The clinical relevance of these secondary thrombotic microangiopathies is increasingly recognised, but its therapeutic implications have not yet been determined. The presence of a secondary TMA in certain diseases may define patient groups which possibly could benefit from ADAMTS13 replacement or a VWF-targeting therapy. This short-review focuses on the role of UL-VWF multimers in secondary TMA and discusses the potential of investigational therapies as candidates for the treatment of TTP. In conclusion, prospective clinical trials on the effectiveness of protease replacementin vivo seem reasonable. Carefully selected patients with secondary TMA may benefit from therapies primarily intended for the use in patients with TTP.
| S-EPMC4745134 | biostudies-literature
Project description:Infection or inflammation may precede and trigger formation of microvascular thrombosis in patients with acquired thrombotic thrombocytopenic purpura (TTP). However, the mechanism underlying this clinical observation is not fully understood. Here, we show that human neutrophil peptides (HNPs) released from activated and degranulated neutrophils inhibit proteolytic cleavage of von Willebrand factor (VWF) by ADAMTS13 in a concentration-dependent manner. Half-maximal inhibitory concentrations of native HNPs toward ADAMTS13-mediated proteolysis of peptidyl VWF73 and multimeric VWF are 3.5 μM and 45 μM, respectively. Inhibitory activity of HNPs depends on the RRY motif that is shared by the spacer domain of ADAMTS13. Native HNPs bind to VWF73 (KD = 0.72 μM), soluble VWF (KD = 0.58 μM), and ultra-large VWF on endothelial cells. Enzyme-linked immunosorbent assay (ELISA) demonstrates markedly increased plasma HNPs1-3 in most patients with acquired autoimmune TTP at presentation (median, ∼170 ng/mL; range, 58-3570; n = 19) compared with healthy controls (median, ∼23 ng/mL; range, 6-44; n = 18) (P < .0001). Liquid chromatography plus tandem mass spectrometry (LC-MS/MS) reveals statistically significant increases of HNP1, HNP2, and HNP3 in patient samples (all P values <.001). There is a good correlation between measurement of HNPs1-3 by ELISA and by LC-MS/MS (Spearman ρ = 0.7932, P < .0001). Together, these results demonstrate that HNPs1-3 may be potent inhibitors of ADAMTS13 activity, likely by binding to the central A2 domain of VWF and physically blocking ADAMTS13 binding. Our findings may provide a novel link between inflammation/infection and the onset of microvascular thrombosis in acquired TTP and potentially other immune thrombotic disorders.
| S-EPMC4937355 | biostudies-literature