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2.
Hematology Am Soc Hematol Educ Program ; 2019(1): 426-432, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808842

RESUMO

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis, pregnancy morbidity, or nonthrombotic manifestations in patients with persistently positive antiphospholipid antibodies (aPL). Conventional APS treatment focuses on antithrombotic strategies, which are usually ineffective for the microvascular and nonthrombotic manifestations of aPL. Using a case-based presentation, this review focuses on the role of immunosuppression in nonobstetric APS, including B-cell inhibition (rituximab, belimumab, and bortezomib), complement inhibition (eculizumab), mechanistic target of rapamycin inhibition (sirolimus), vascular endothelial cell modulation (defibrotide), statins, and traditional rheumatologic disease-modifying agents (hydroxychloroquine, mycophenolate mofetil, azathioprine, and cyclophosphamide).

3.
Eur J Rheumatol ; 6(4): 207-211, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31657703

RESUMO

OBJECTIVE: iBook on Antiphospholipid Syndrome (APS) did not exist before our work, and hence the utility of an Apple iBook as a teaching method in APS for medical students has never been assessed. Our objective was to evaluate medical students' improvement of knowledge and satisfaction with an interactive APS iBook, in comparison with conventional teaching methods. METHODS: An iBook designer with the guidance of a medical team developed the APS iBook in both French and English. Second-year medical students, naïve of APS knowledge, were enrolled from two institutions. For the "teaching intervention", participants were randomly assigned to three groups: a) APS iBook with interactive capability; b) printed copy of the APS iBook material; and c) classroom lecture presentation of the APS iBook material by a physician-scientist experienced in APS. The participants filled a standardized medical questionnaire about APS before and after teaching interventions to determine the relative change of knowledge. Participants were asked to fill out a standardized satisfaction survey. After 20 weeks of the intervention, recall capability of students was tested. RESULTS: A total of 233 second-year medical students were enrolled (iBook group: 73; print group: 79, and lecture group: 81). Relative change of knowledge was not different between the iBook group and the printed material group; additionally, it was significantly higher in the lecture group than the two other methods. Satisfaction was significantly higher in both the lecture and the iBook groups than the print group, on several dimensions including overall quantitative satisfaction, subjective enhanced knowledge, interactivity, quality of content, comprehensibility, and pleasure of learning. Recall capability of students (n=109, 47%) was not significantly different among groups. CONCLUSION: The APS iBook is as effective as printed material in improving medical student's knowledge, although a classroom lecture was the most effective method when compared to self-learning methods. Among self-learning methods, medical students are more satisfied with the APS iBook, whereas the recall capability was not different among groups. These results suggest that the APS iBook will help medical students in their curriculum and increase the awareness of APS among the community.

4.
Autoimmun Rev ; 18(11): 102395, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520800

RESUMO

BACKGROUND: According to criteria for the classification of Systemic Lupus Erythematosus (SLE), thrombocytopenia is one of the disease-defining hematologic disorders. Since the recognition of Antiphospholipid Syndrome (APS), thrombocytopenia was frequently reported but several studies yielded contradictory results on the association between aPL-positivity and thrombocytopenia. METHODS: We evaluated the role of antiphospholipid antibodies (aPL) and different aPL profiles on the risk of thrombocytopenia in SLE patients by conducting a systematic review and meta-analysis of available literature from 1987 to 2018. MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcomes (thrombocytopenia). Two reviewers extracted study characteristics and outcome data from published reports. Estimates were pooled using random effects models and sensitivity analyses. We followed the PRISMA guidelines for all stages of the meta-analysis. PROSPERO registration number: CRD42015027378. RESULTS: From 3278 articles identified, 53 studies met inclusion criteria amounting to 9019 SLE patients. Twenty-nine percent of aPL-positive SLE patients had thrombocytopenia compared to 15.1% in aPL-negative SLE patients. The overall pooled Odds Ratio (OR) for thrombocytopenia in aPL positive patients was 2.48 (95% CI; 2.10-2.93). Among aPL subtypes, the risk of thrombocytopenia was highest for lupus anticoagulant (OR = 3.56 [95% CI, 2.57-5.25]), IgM anti-ß2-GP1(OR = 2.87 [95% CI; 2.57-5.25]), IgG and IgM anticardiolipin antibodies (OR = 1.87 [95% CI; 1.52-2.31] and OR = 1.73 [95% CI; 1.36-2.19] respectively). CONCLUSIONS: The occurrence of thrombocytopenia was strongly determined by various aPL profiles in SLE patients. While the association between IgM antibodies and other APS manifestations including thrombosis is debated, IgM isotypes are helpful in the risk stratification of thrombocytopenia in SLE.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Lúpus Eritematoso Sistêmico/epidemiologia , Trombocitopenia/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Fatores de Risco , Trombocitopenia/imunologia
5.
Curr Rheumatol Rep ; 21(10): 56, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31493005

RESUMO

PURPOSE OF REVIEW: Diffuse alveolar hemorrhage (DAH) is a rare but devastating manifestation of antiphospholipid syndrome (APS) patients with or without other systemic autoimmune diseases. Data regarding diagnosis and treatment are limited to case series. We review diagnostic and therapeutic strategies employed in APS patients with DAH and discuss our experience in managing these complex patients. RECENT FINDINGS: Pulmonary capillaritis likely contributes to the pathogenesis, however is only observed in half of the biopsies. Corticosteroids induce remission in the majority of patients, however almost half recur and require a steroid-sparing immunosuppressive to maintain remission. Cyclophosphamide- or rituximab-based regimens achieve the highest remission rates (50%); other strategies include intravenous immunoglobulin, plasmapheresis, mycophenolate mofetil, and/or azathioprine. Given the rarity of DAH in APS, treatment is guided by interdisciplinary experience. Why certain patients achieve full remission with corticosteroids while others require immunosuppressive agents is unknown; future research should focus on the pathophysiology and optimal management.

6.
J Thromb Haemost ; 17(12): 2069-2080, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31364274

RESUMO

BACKGROUND: Variability remains a challenge in lupus anticoagulant (LA) testing. OBJECTIVE: To validate LA test performance between Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Core laboratories and examine agreement in LA status between Core and local/hospital laboratories contributing patients to this prospective registry. METHODS: Five Core laboratories used the same reagents, analyzer type, protocols, and characterized samples for LA validation. Non-anticoagulated registry samples were retested at the corresponding regional Core laboratories and anticoagulated samples at a single Core laboratory. Categorical agreement and discrepancies in LA status between Core and local/hospital laboratories were analyzed. RESULTS: Clotting times for the reference/characterized plasmas used for normalized ratios were similar between Core laboratories (CV <4%); precision and agreement for LA positive/negative plasma were similar (all CV ≤5%) in the four laboratories that completed both parts of the validation exercise; 418 registry samples underwent LA testing. Agreement for LA positive/negative status between Core and local/hospital laboratories was observed in 87% (115/132) non-anticoagulated and 77% (183/237) anticoagulated samples. However, 28.7% (120/418) of samples showed discordance between the Core and local/hospital laboratories or equivocal LA results. Some of the results of the local/hospital laboratories might have been unreliable in 24.7% (41/166) and 23% (58/252) of the total non-anticoagulated and anticoagulated samples, respectively. Equivocal results by the Core laboratory might have also contributed to discordance. CONCLUSIONS: Laboratories can achieve good agreement in LA performance by use of the same reagents, analyzer type, and protocols. The standardized Core laboratory results underpin accurate interpretation of APS ACTION clinical data.

7.
Semin Arthritis Rheum ; 49(3): 464-468, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31153708

RESUMO

OBJECTIVES: To assess whether patients with antiphospholipid syndrome (APS) and history of recurrent thrombosis have higher levels of adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) when compared to patients without recurrent thrombosis. METHODS: In this cross-sectional study of antiphospholipid antibody (aPL)-positive patients, we identified APS patients with a history of documented thrombosis from the AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry"). Data on aPL-related medical history and cardiovascular risk factors were retrospectively collected. The aGAPSS was calculated at Registry entry by adding the points corresponding to the risk factors: three for hyperlipidemia, one for arterial hypertension, five for positive anticardiolipin antibodies, four for positive anti-ß2 glycoprotein-I antibodies and four for positive lupus anticoagulant test. RESULTS: The analysis included 379 APS patients who presented with arterial and/or venous thrombosis. Overall, significantly higher aGAPSS were seen in patients with recurrent thrombosis (arterial or venous) compared to those without recurrence (7.8 ±â€¯3.3 vs. 6 ±â€¯3.9, p<0.05). When analyzed based on the site of the recurrence, patients with recurrent arterial, but not venous, thrombosis had higher aGAPSS (8.1 ± SD 2.9 vs. 6 ±â€¯3.9; p<0.05). CONCLUSIONS: Based on analysis of our international large-scale Registry of aPL-positive patients, the aGAPSS might help risk stratifying patients based on the likelihood of developing recurrent thrombosis in APS.

8.
Cell Host Microbe ; 26(1): 100-113.e8, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31227334

RESUMO

Given the immense antigenic load present in the microbiome, we hypothesized that microbiota mimotopes can be a persistent trigger in human autoimmunity via cross-reactivity. Using antiphospholipid syndrome (APS) as a model, we demonstrate cross-reactivity between non-orthologous mimotopes expressed by a common human gut commensal, Roseburia intestinalis (R. int), and T and B cell autoepitopes in the APS autoantigen ß2-glycoprotein I (ß2GPI). Autoantigen-reactive CD4+ memory T cell clones and an APS-derived, pathogenic monoclonal antibody cross-reacted with R. int mimotopes. Core-sequence-dependent anti-R. int mimotope IgG titers were significantly elevated in APS patients and correlated with anti-ß2GPI IgG autoantibodies. R. int immunization of mice induced ß2GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human ß2GPI autoantibodies and autoimmune pathologies. Together, these data support a role for non-orthologous commensal-host cross-reactivity in the development and persistence of autoimmunity in APS, which may apply more broadly to human autoimmune disease.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Autoimunidade , Linfócitos B/imunologia , Clostridiales/imunologia , Reações Cruzadas , Linfócitos T/imunologia , Adulto , Idoso , Animais , Síndrome Antifosfolipídica/patologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Feminino , Trato Gastrointestinal/microbiologia , Humanos , Imunoglobulina G/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Adulto Jovem , beta 2-Glicoproteína I/imunologia
9.
Thromb Res ; 175: 32-36, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30685523

RESUMO

BACKGROUND: The APS ACTION International Clinical Database and Repository includes a secure web-based data capture system storing patient information including demographics, antiphospholipid antibodies (aPL)-related medical history, and aPL tests. Despite efforts at harmonization, inter-assay variability remains a problem in aPL testing. As a clinical repository open to researchers, ensuring comparability between assays and consistency in results between APS ACTION laboratories is essential to the validity of studies emerging from this network. OBJECTIVE: To assess the level of agreement between an aPL-registry inclusion and core laboratory (core lab) anticardiolipin antibody (aCL) and anti-ß2-glycoprotein-I antibody (aß2GPI) ELISA testing results. METHODS: Patients are recruited from 25 international centers based on positive aPL tests at inclusion. All samples are retested at the corresponding national APS ACTION core lab to confirm aPL positivity based on standard validated protocols. We analysed the categorical agreement, degree of linear association, and correlation between inclusion (local laboratory) and core lab aPL tests. Samples were included in this study only if results of aPL testing with ELISA at baseline were available. RESULTS: 497 registry samples underwent confirmatory aPL tests. Categorical agreement between the inclusion and core lab values, as expressed by Cohen's kappa coefficients, ranged between 0.61 and 0.80 (as substantial agreement). The correlation between quantitative results in the aCL and aß2GPI was better for IgM and IgA compared to IgG (Spearman rho 0.789 and 0.666 vs. 0.600 for aCL and rho 0.892 and 0.744 vs. 0.432 for aß2GPI). CONCLUSIONS: The results of inclusion for aCL and aß2GPI tests used for recruitment into the registry were in agreement to the results obtained by the APS ACTION core laboratories; aCL and aß2GPI results showed very good categorical agreement. This agreement increased when considering high titer (>40 units) samples. APS ACTION is a reliable and useful research resource for APS.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Bases de Dados Factuais , Feminino , Humanos , Masculino
10.
Clin Immunol ; 206: 53-62, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29510235

RESUMO

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder marked by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). At the present time, treatment is primarily focused on anticoagulation. However, there is increasing awareness of the mechanisms involved in APS pathogenesis, which has led to the trial of novel therapies targeting those mechanisms. Following a brief review of the etiopathogenesis of and current management strategies in APS, this paper focuses on the evidence for these potential, targeted APS treatments, e.g., hydroxychloroquine, statins, rituximab, belimumab, eculizumab, defibrotide, sirolimus, and peptide therapy.

11.
Arthritis Care Res (Hoboken) ; 71(1): 134-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29669399

RESUMO

OBJECTIVE: Although systemic lupus erythematosus (SLE) is the most common autoimmune disease associated with antiphospholipid antibodies (aPL), limited data exist regarding the impact of SLE on the clinical phenotype of aPL-positive patients. The primary objective of this study was to compare the clinical, laboratory, and treatment characteristics of aPL-positive patients with SLE with those of aPL-positive patients without SLE. METHODS: A secure web-based data capture system was used to store patient demographic characteristics and aPL-related clinical and laboratory characteristics. Inclusion criteria included positive aPL according to the updated Sapporo classification criteria. Antiphospholipid antibody-positive patients fulfilling the American College of Rheumatology criteria for the classification of SLE ("aPL with SLE") and those with no other autoimmune diseases ("aPL only") were included in the analysis. RESULTS: Six hundred seventy-two aPL-positive patients were recruited from 24 international centers; 426 of these patients did not have other autoimmune disease, and 197 had SLE. The frequency of thrombocytopenia, hemolytic anemia, low complement levels, and IgA anti-ß2 -glycoprotein I (anti-ß2 GPI) antibodies was higher in the aPL-positive patients with SLE, whereas the frequency of cognitive dysfunction and IgG anti-ß2 GPI antibodies was higher in the aPL-only group. The frequency of arterial and venous thromboses (including recurrent) as well as pregnancy morbidity was similar in the 2 groups. The prevalence of cardiovascular disease risk factors at the time of entry into the registry entry did not differ between the 2 groups, with the exception of current smoking, which was more frequent in aPL-positive patients with SLE. CONCLUSION: Although the frequencies of thrombosis and pregnancy morbidity are similar in aPL-positive patients with and those without SLE, the diagnosis of SLE in patients with persistently positive aPL is associated with an increased frequency of thrombocytopenia, hemolytic anemia, low complement levels, and positive IgA anti-ß2 GPI antibodies.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/epidemiologia , Bases de Dados Factuais , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/epidemiologia , Fenótipo , Adulto , Síndrome Antifosfolipídica/diagnóstico , Feminino , Humanos , Internacionalidade , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Gravidez , Sistema de Registros
12.
Curr Rheumatol Rep ; 20(11): 66, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30203272

RESUMO

PURPOSE OF REVIEW: To update our previous literature review and management recommendations on risk stratification and primary thrombosis prophylaxis in persistently antiphospholipid antibody (aPL)-positive individuals. RECENT FINDINGS: The estimated annual thrombosis incident rate (ATIR) among aPL-positive individuals with or without systemic autoimmune disease (SAIDx) is 0 to 5.3%, probably very low (< 1%/year) in those with no other SAIDx and thrombosis risk factors. Risk stratification based on aPL profile, age, additional SAIDx, and traditional cardiovascular disease (CVD) or venous thrombosis risk factors is crucial to determine the risk of first thrombosis in aPL-positive patients. The protective effect of low-dose aspirin for primary thrombosis prophylaxis prevention is not supported by randomized controlled data. Hydroxychloroquine is protective against thrombosis in aPL-positive SLE patients; however, its role in aPL-positive individuals with other SAIDx remains uncertain. Statins downregulate proinflammatory and prothrombotic biomarkers among antiphospholipid syndrome (APS) patients and may have a role in aPL-positive individuals with high CVD risk. The optimal primary thrombosis prevention strategy in patients with clinically significant aPL profiles should include (a) regular screening and elimination of non-aPL thrombosis risk factors, (b) optimal management of concomitant SAIDx,


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Trombose/prevenção & controle , Anticoagulantes/uso terapêutico , Humanos , Prevenção Primária/métodos , Medição de Risco/métodos , Trombose/etiologia
14.
Eur J Rheumatol ; 5(2): 92-95, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30185355

RESUMO

OBJECTIVE: To investigate trends in Internet search volumes linked to Antiphospholipid Syndrome (APS), using Big Data monitoring and data mining. METHODS: Based on the large amount of data generated by Google Trends and scientific search tools (SCOPUS, Medline/Pubmed, and ClinicalTrails.gov), we performed a longitudinal analysis based on the term "antiphospholipid" in a 5-year web-based research. RESULTS: Google Trends captured that APS-related digital interest was generally steady in the study period (Relative Search Volume [RSV] mean value 71.1±9.3% [95%CI 55.6-89.4], median 72.0), with no significant peak based on different seasons (e.g. winter vs. summer time). When comparing the APS-related digital interest with search volumes generated in the same time period for Inherited Thrombophilias (IT) and Systemic Lupus Erythematosus (SLE), we found a digital interest 35-times higher for APS than for IT (RSV mean value 71.1±9.3% [95%CI 55.6-89.4] vs. 2±3.2% [95%CI 0.7-7.4]). When compared to SLE, APS reached a similar RSV, showing a comparable digital interest (RSV mean value 71.1±9.3% [95%CI 55.6-89.4] vs. 87±11.8% [95%CI 60.7-107.9]). When adjusting for relative search volumes of Google Trends, we found a relative prevalence of search volumes of 35.5% in Europe, 12.3% in the United States, 11.5% in South America, 11.2% in Australia, 9.2% in Canada, 9.2% in Japan, and 5.1% in India. We observed an overall similar distribution of search volumes from Google Trends compared to results from Medline/Pubmed, SCOPUS, and ClinicalTrials.gov. In brief, the United States and Europe (mainly Italy, the United Kingdom, Spain, France, and Germany) presented the higher RSV. Similarly, these countries showed a higher number of research publications and on-going trials in the field of APS. CONCLUSION: In this study, we demonstrated that the interest in APS is not equally distributed globally. Thus, geopolitical differences might represent a challenge when attempting to estimate the prevalence of APS or designing worldwide investigations in APS. Combining the expanding framework of infodemiology with scientific networking collaborative efforts, such as AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION), will help better define the syndrome in terms of prevalence, event occurrence ratios, and thrombosis risk assessment.

17.
Rheumatology (Oxford) ; 57(7): 1264-1270, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29660074

RESUMO

OBJECTIVES: The objective of this study was to assess the effect that triple therapy (anticoagulation plus CS plus plasma exchange and/or IVIGs) has on the mortality risk of patients with catastrophic APS (CAPS) included in the CAPS Registry. METHODS: Patients from the CAPS Registry were grouped based on their treatments: triple therapy; drugs included in the triple therapy but in different combinations; and none of the treatments included in the triple therapy. The primary endpoint was all-cause mortality. Multivariate logistic regression models were used to compare mortality risk between groups. RESULTS: The CAPS Registry cohort included 525 episodes of CAPS accounting for 502 patients. After excluding 54 episodes (10.3%), a total of 471 patients with CAPS were included [mean (s.d.) age 38.5 years (17); 68.2% female; primary APS patients 62%]. Overall, 174 (36.9%) patients died. Triple therapy was prescribed in 189 episodes (40.1%), other combinations in 270 (57.3%) and none of those treatments in 12 episodes (2.5%); the mortality rate in the three groups was 28.6, 41.1 and 75%, respectively. Triple therapy was positively associated with a higher chance of survival when compared with non-treatment [adjusted odds ratio (OR) = 9.7, 95% CI: 2.3, 40.6] or treatment with other combinations of drugs included in the triple therapy (adjusted OR = 1.7, 95% CI: 1.2, 2.6). No statistical differences were found between patients that received triple therapy with plasma exchange or IVIGs (P = 0.92). CONCLUSION: Triple therapy is independently associated with a higher survival rate among patients with CAPS.

18.
Pain Pract ; 18(4): 532-538, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28742241

RESUMO

OBJECTIVES: The primary objective of this case series was to report the use of cervical epidural steroid injection in the management of neck pain and stiffness secondary to spondyloarthropathy in cases refractory to conservative therapy. METHODS: This was a case report series on three patients with diagnosis of spondyloarthropathy who presented with severe stiffness and non-radicular axial neck pain refractory to conservative therapy. All patients received cervical epidural steroid injections with significant improvement of their axial neck pain and stiffness. RESULTS: Cervical epidural steroid injections may be effective to improve the axial neck pain and stiffness in patients with diagnosis of spondyloarthropathy refractory to conservative management. Thus, we believe that epidural steroid injections should be considered in the management of patients with spondyloarthopathies.


Assuntos
Corticosteroides/administração & dosagem , Manejo da Dor/métodos , Dor Intratável/tratamento farmacológico , Espondiloartropatias/tratamento farmacológico , Vértebras Cervicais , Feminino , Humanos , Injeções Epidurais , Masculino , Pessoa de Meia-Idade , Cervicalgia/tratamento farmacológico
19.
Thromb Res ; 161: 43-51, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29178990

RESUMO

INTRODUCTION: Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. MATERIAL AND METHODS: We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (<5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. RESULTS: We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). CONCLUSIONS: As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.


Assuntos
Sulfatos de Condroitina/metabolismo , Trombose/genética , Sequenciamento Completo do Genoma/métodos , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/metabolismo , Adulto Jovem
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