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1.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575869

RESUMO

Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder.


Assuntos
Análise Mutacional de DNA , Deficiência do Fator V/genética , Deficiência do Fator V/terapia , Fator V/genética , Adolescente , Coagulação Sanguínea , Transtornos Herdados da Coagulação Sanguínea/genética , Testes de Coagulação Sanguínea , Plaquetas/metabolismo , Pré-Escolar , Códon sem Sentido , DNA Complementar/metabolismo , Saúde da Família , Feminino , Mutação da Fase de Leitura , Humanos , Masculino , Paquistão , Proteínas Recombinantes/química , Análise de Sequência de DNA , Espanha
2.
Hamostaseologie ; 41(5): 400-402, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34492713

RESUMO

In this case report we present a previously healthy 21-year-old male with extensive thromboembolism in the setting of asymptomatic COVID-19 infection and heterozygous factor V Leiden mutation with no additional thrombophilic risk factors.


Assuntos
COVID-19/complicações , Fator V/genética , SARS-CoV-2 , Tromboembolia/complicações , Tromboembolia/genética , Infecções Assintomáticas , COVID-19/diagnóstico , COVID-19/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Heterozigoto , Humanos , Masculino , Tromboembolia/terapia , Adulto Jovem
3.
J Pak Med Assoc ; 71(7): 1780-1784, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34410246

RESUMO

OBJECTIVE: To determine the association of Factor V Leiden / prothrombin gene mutation in Pakistani women with adverse pregnancy outcomes. Method: The prospective study was conducted at the Aga Khan University Hospital, Karachi, from January 1 to December 31, 2016, and comprised females > 40 years having history of two or more foetal losses with no apparent aetiology. Restriction fragment length polymorphism- Polymerase chain reaction was performed using MnlI and HindIII restriction enzymes for factor V Leiden G1691A and prothrombin gene mutation G20210A. Females with two or more consecutive normal pregnancies were enrolled as the control group. Data was analysed using SPSS 19. RESULTS: Of the 172 participants with a mean age of 29.3±5.9 years (range: 19-38 years). 86(50%) each were healthy controls and those with recurrent pregnancy loss. There were 238 livebirths among the controls compared to 13 in the other group. Factor V Leiden G1691A was identified in 2(2.3%) women, and prothrombin gene mutation G20210A in 1(1.2%) woman in the patient group, while no mutation was identified in the control group. CONCLUSIONS: The prevalence of Factor V Leiden / prothrombin gene mutation in women with recurrent pregnancy loss was found to be very low.


Assuntos
Resultado da Gravidez , Protrombina , Adulto , Fator V/genética , Feminino , Humanos , Mutação , Gravidez , Resultado da Gravidez/epidemiologia , Resultado da Gravidez/genética , Estudos Prospectivos , Protrombina/genética , Adulto Jovem
4.
Am J Case Rep ; 22: e932286, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326300

RESUMO

BACKGROUND The association between sarcoidosis and pulmonary embolism (PE) has been described in the literature, but little is known about the origin of hypercoagulability and hypofibrinolysis in sarcoidosis. PE is a multifactorial disease that is rarely caused by a single risk factor, and might be expected in disabling sarcoidosis. No data are available, however, about sarcoidosis being a risk factor for venous thromboembolism in factor V Leiden thrombophilia. CASE REPORT We describe a case of a 40-year-old man with asymptomatic sarcoidosis. Diagnosis was based on abnormal chest radiology (enlargement of hilar and mediastinal lymph nodes), confirmed by histopathological examination (noncaseating granulomas involving the mediastinal lymph nodes). No therapy was proposed due to good exercise tolerance, normal pulmonary function test, and absence of extrapulmonary involvement. The patient was followed up for 5 years until he developed progressive exertional dyspnea and chest pain. Plasma D-dimers, serum NT-proBNP, and troponin were increased. A computed tomography angiogram confirmed PE. Factor V Leiden thrombophilia was diagnosed following a search for risk factors for thromboembolism. Spontaneous remission of the chest lymphadenopathy was observed on anticoagulation therapy. Different potential mechanisms that relate sarcoidosis to venous thromboembolism are discussed. CONCLUSIONS PE is a potentially fatal condition and may complicate sarcoidosis, a clinically insignificant condition. Sarcoidosis patients with new symptomatology and PE with a high concentration of plasma D-dimers merit extra consideration. In certain clinical situations, sarcoidosis may be considered as a risk factor for deep vein thrombosis/PE. The anti-inflammatory and anti-fibrotic properties of anticoagulation warrant further study.


Assuntos
Embolia Pulmonar , Sarcoidose , Trombofilia , Tromboembolia Venosa , Trombose Venosa , Resistência à Proteína C Ativada , Adulto , Fator V/genética , Humanos , Masculino , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiologia , Sarcoidose/complicações , Sarcoidose/diagnóstico , Trombofilia/complicações , Trombofilia/diagnóstico , Trombofilia/genética , Trombose Venosa/diagnóstico , Trombose Venosa/etiologia
6.
Intern Med ; 60(16): 2663-2666, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34121013

RESUMO

Acquired coagulation factor V (FV) inhibitors are rare disorders in which antibodies against FV develop under various conditions. We herein report the case of a 71-year-old woman with FV inhibitor during radiochemotherapy for pancreatic cancer. Multiple purpuras suddenly appeared on her bilateral upper limbs with prolonged coagulation data (APTT 97.3 seconds). The FV activity was less than 3% and the FV inhibitor was positive (1.7 B.U./mL). Oral prednisolone induced a rapid normalization of the coagulation data and FV activity and a rapid disappearance of FV inhibitor within 7 days. Early diagnosis and treatment may therefore be important in cases of FV inhibitor.


Assuntos
Inibidores dos Fatores de Coagulação Sanguínea , Fator V , Corticosteroides , Idoso , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Feminino , Humanos
7.
Blood ; 137(22): 3011-3013, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081120

Assuntos
Fator V , Fator Va
8.
BMJ Case Rep ; 14(6)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183315

RESUMO

Infliximab, an antitumour necrosis factor alpha (TNF-alpha)agent, is a cornerstone of treatment of inflammatory bowel disease with a favourable and well-tolerated side effect profile. While the majority of side effects associated with infliximab have been well established, the pathophysiology of infliximab-associated thrombosis remains controversial and poorly defined. We present a case of a young woman with ulcerative colitis who presented with a right ventricular thrombus and bilateral pulmonary emboli after initiation of infliximab and was subsequently found to have underlying factor V Leiden and prothrombin gene mutation. Clinicians should be aware of this potential adverse event associated with anti-TNF agents, especially in individuals with predisposing prothrombotic mutations such as factor V Leiden or prothrombin gene mutation.


Assuntos
Colite Ulcerativa , Embolia Pulmonar , Trombose , Colite Ulcerativa/tratamento farmacológico , Fator V , Feminino , Humanos , Infliximab/efeitos adversos , Embolia Pulmonar/induzido quimicamente , Embolia Pulmonar/diagnóstico por imagem , Trombose/induzido quimicamente , Inibidores do Fator de Necrose Tumoral
10.
J Am Heart Assoc ; 10(11): e020025, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33998271

RESUMO

Background The prothrombotic defect factor V Leiden (FVL) may confer higher risk of ST-segment-elevation myocardial infarction (STEMI), compared with non-ST-segment-elevation acute coronary syndrome, and may be associated with more myocardial necrosis caused by higher thrombotic burden. Methods and Results Patients without history of cardiovascular disease were selected from 2 clinical trials conducted in patients with acute coronary syndrome. FVL was defined as G-to-A substitution at nucleotide 1691 in the factor V (factor V R506Q) gene. Odds ratios were calculated for the association of FVL with STEMI adjusted for age and sex in the overall population and in the subgroups including sex, age (≥70 versus <70 years), and traditional cardiovascular risk factors. The peak biomarker levels (ie, creatine kinase-myocardial band and high-sensitivity troponin I or T) after STEMI were contrasted between FVL carriers and noncarriers. Because of differences in troponin assays, peak high-sensitivity troponin levels were converted to a ratio scale. The prevalence of FVL mutation was comparable in patients with STEMI (6.0%) and non-ST-segment-elevation acute coronary syndrome (5.8%). The corresponding sex- and age-adjusted odds ratio was 1.06 (95% CI, 0.86-1.30; P=0.59) for the association of FVL with STEMI. Subgroup analysis did not show any differences. In patients with STEMI, neither the median peak creatine kinase-myocardial band nor the peak high-sensitivity troponin ratio showed any differences between wild-type and FVL carriers (P for difference: creatine kinase-myocardial band=0.33; high sensitivity troponin ratio=0.54). Conclusions In a general population with acute coronary syndrome, FVL did not discriminate between a STEMI or non-ST-segment-elevation acute coronary syndrome presentation and was unrelated to peak cardiac necrosis markers in patients with STEMI. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00391872 and NCT01761786.


Assuntos
Síndrome Coronariana Aguda/sangue , Fator V/metabolismo , Miocárdio/patologia , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/diagnóstico , Biomarcadores/sangue , DNA/genética , Análise Mutacional de DNA , Eletrocardiografia , Fator V/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Necrose/sangue , Necrose/diagnóstico , Necrose/etiologia , Fenótipo , Estudos Retrospectivos , Fatores de Risco
11.
Clin Chim Acta ; 519: 247-254, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34015304

RESUMO

BACKGROUND: Thrombophilia is a substantial source of indisposition and mortality in several countries, including Arab populations. Deep venous thrombosis (DVT) with or without pulmonary embolism (PE) is the prevalent clinical manifestation of thrombophilia. While many genetic risk factors for DVT are known, almost all associated with hemostasis, many genetic factors remain unexplained. Nowadays, Next Generation Sequencing (NGS) offers a potential solution that allows several candidate genes to be analyzed simultaneously at a reasonable expense. METHODS: We performed variant screening in the thrombophilia associated genes in Factor V Leiden (FVL) mutation-negative patients using Ion Torrent Next-generation sequencing (NGS). Ion AmpliSeq panel for 18 genes was designed. Twenty-nine unrelated patients with idiopathic VTE were recruited for NGS. RESULTS: We were able to identify 19 variants (1 novel and 18 previously reported) in 10 out of 18 targeted genes. Pathogenic variants were identified in 22 patients demonstrating mutation detection rates of 76%. Previously reported variants in the F5, MTHFR, PROS1, PROC, F8, F9, SERPINA10, SERPIND1, and HRG genes were recognized in 21 patients. More than one variant in the targeted genes was detected in some of the patients with VTE. We identified SERPINA10 recurrent variant p.(R88*) in seven patients representing 32% of VTE cases. Additionally, we report one novel variant c.356G > T, p.(G119V) in the F7 gene, considered to be pathogenic in this study. CONCLUSIONS: Our studies finding illustrates the ability of targeted next-generation sequencing to uncover uncommon/unknown genetic variants that may predispose to thrombophilia. The finding of the novel variant in the F7 gene extends the spectrum of variants affecting thrombosis. While a comparatively small number of subjects have been included in our cohort, the findings summarize the possible genetic features of thrombophilia.


Assuntos
Trombofilia , Tromboembolia Venosa , Fator V/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Arábia Saudita , Trombofilia/genética , Tromboembolia Venosa/genética
12.
Clin J Gastroenterol ; 14(4): 1142-1146, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34003444

RESUMO

A 42-year-old man presented with 6 months of unexplained left lower quadrant abdominal pain and hematochezia accompanied by weight loss despite extensive evaluations. Stool studies for pathogens were unrevealing, but an abdominal contrast-enhanced computed tomography revealed findings of chronic inferior mesenteric vein thrombosis. Colonoscopy demonstrated ulcerated strictures and gangrene confined to the sigmoid and descending colons, and biopsies confirmed changes of chronic irreversible colon ischemia. A homozygous Factor V Leiden mutation was diagnosed. The patient underwent colectomy and was treated with lifelong anticoagulation. While mesenteric venous thrombosis is a well-recognized cause of colon ischemia in hypercoagulable states, thrombosis of the inferior mesenteric vein is uncommon; when chronic it is rarely clinically apparent. Similarly, while Factor V Leiden mutation is a common hereditary thrombophilia, it uncommonly causes mesenteric venous thrombosis, and homozygotes of the mutation typically present earlier in the fourth decade and with non-mesenteric venous thromboembolism. This case is valuable and adds to the existing literature in describing a rare, clinically atypical, and late index presentation of homozygous Factor V Leiden mutation as chronic inferior mesenteric vein thrombosis yielding irreversible colon ischemia.


Assuntos
Isquemia Mesentérica , Trombofilia , Trombose , Trombose Venosa , Adulto , Colo , Fator V , Humanos , Isquemia/etiologia , Masculino , Veias Mesentéricas/diagnóstico por imagem , Trombose Venosa/etiologia , Trombose Venosa/genética
13.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(3): 430-437, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34018361

RESUMO

Objective: To investigate the effect of E74-like factor 5 (ELF5) overexpression on the growth and invasion ability of colorectal cancer cells and its effect on tumor formation in nude mice. Methods: Human colorectal cancer SW480 and HT-29 cells were divided into 5 groups: the lentivirus (LV)- GFP group transfected with empty vector LV- GFP, the LV- ELF5 group transfected with recombinant LV- ELF5, the shRNA-NC group transfected with empty vector shRNA-NC, the shRNA- ELF5 group transfected with recombinant shRNA- ELF5, and the control group, not transfected with any vector. Seventy-two h after transfection, the cell supernatant containing lentivirus was collected. The mRNA expression level of ELF5 in each group was examined by real-time fluorescent quantitative PCR (RT-qPCR). The protein expression levels of ELF5, apoptosis-related cleaved Caspase-3/Caspase-3 and cleaved Caspase-9/Caspase-9, and invasion-related E-cadherin and N-cadherin were checked with Western blot. CCK-8 was used to check cell viability. Colony formation experiment was done to evaluate colony formation rate. Flow cytometry was used to assess cell apoptosis. Transwell migration assay was used to examine cell invasion. TUNEL assay was used to examine the apoptosis of tissues cells. Immunohistochemistry test was done to determine the expression of E-cadherin and N-cadherin in tissues. 20 BALB/c nude mice were put into 4 groups (5 in each group): LV- GFP group, shRNA-NC group, LV- ELF5 group, and shRNA- ELF5 group. Recombinant lentiviral SW480 cell supernatants were subcutaneously injected into nude mice to construct nude mice tumorigenesis models and the volume changes of transplanted tumors were monitored. On the 30th day, transplanted tumor tissues from the nude mice were extracted and the tumor mass was measured. Western blot was done to measure the expression of ELF4 protein in the transplanted tumors. TUNEL staining was used to check cell apoptosis in the tissues, and the positive expression of N-cadherin in the transplanted tumor was measured by immunohistochemical tests. Results: Compared with the control group, there was no statistically significant difference in the indicators of the two cell lines in the LV- GFP group and shRNA-NC group. The results of Western blot and RT-qPCR showed that the ELF5 protein and mRNA of the LV- ELF5 group of the two cell lines were up-regulated ( P<0.05, compared with those of the LV- GFP group), and the ELF5 protein and mRNA of the shRNA- ELF5 group were down-regulated ( P<0.05). The ELF5 overexpression system and interference system were successfully constructed. Compared with the LV- GFP group, data from the LV- ELF5 group showed that cell viability and colony formation rate ( P<0.05) were reduced, SW480 and HT-29 cell apoptosis was promoted, cleaved Caspase-3/Caspase-3 and cleaved Caspase-9/Caspase-9 protein expression was up-regulated ( P<0.05), cell invasion was inhibited, and the expression of E-cadherin protein was up-regulated while the expression of N-cadherin protein was down-regulated ( P<0.05). After ELF5 interference, the above-mentioned expression of cells demonstrated an opposite trend ( P<0.05, comparing shRNA- ELF5 group with shRNA-NC group). In vivo experimental results indicated that ELF5 overexpression reduced tumor volume and tumor mass ( P<0.05), promoted cell apoptosis in tissues ( P<0.05), and inhibited N-cadherin protein expression ( P<0.05). When ELF5 expression was inhibited, the above mentioned experimental results showed the opposite trend. Conclusion: In vivo and in vitro experiments showed that ELF5 overexpression could promote the apoptosis of colorectal cancer cells and inhibit the growth and invasion of colorectal cancer cells.


Assuntos
Neoplasias do Colo , Fator V , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Proteínas de Ligação a DNA , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fatores de Transcrição , Transfecção
14.
Zhonghua Xue Ye Xue Za Zhi ; 42(4): 302-307, 2021 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-33979974

RESUMO

Objective: To analyze the clinical phenotype and molecular pathogenesis of nine patients with hereditary factor Ⅴ (FⅤ) deficiency. Methods: Nine patients with hereditary FⅤ deficiency who were admitted to the Institute of Hematology and Blood Diseases Hospital from April 1999 to September 2019 were analyzed. The activated partial thromboplastin time, prothrombin time, and FⅤ procoagulant activity (FⅤ∶C) were measured for phenotypic diagnosis. High-throughput sequencing was employed for the F5 gene mutation screening, Sanger sequencing was adopted to confirm candidate variants and parental carrying status, Swiss-model was used for three-dimensional structure analysis, and ClustalX v.2.1 was used for homologous analysis. Results: The FⅤ∶C of the nine patients ranged from 0.1 to 10.6. Among them, eight had a hemorrhage history, with kin/mucosal bleeding as the most common symptom (three cases, 37.5%) , whereas one case had no bleeding symptom. There were five homozygotes and four compound heterozygotes. A total of 12 pathogenic or likely pathogenic mutations were detected, of which c.6100C>A/p.Pro2034Thr, c.6575T>C/p.Phe2192Ser, c.1600_1601delinsTG/p. Gln534*, c.4713C>A/p.Tyr1571*, and c.952+5G>C were reported for the first time. Conclusion: The newly discovered gene mutations enriched the F5 gene mutation spectrum associated with hereditary FⅤ deficiency. High-throughput sequencing could be an effective method to detect F5 gene mutations.


Assuntos
Deficiência do Fator V , Fator V/genética , Deficiência do Fator V/genética , Testes Genéticos , Heterozigoto , Homozigoto , Humanos , Mutação , Linhagem
16.
J Thromb Haemost ; 19(7): 1697-1708, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33829620

RESUMO

BACKGROUND: The prothrombinase complex consists of factors Xa (FXa) and Va (FVa) on an anionic phospholipid surface and converts prothrombin into thrombin. Both coagulation factors require activation before complex assembly. We recently identified TIX-5, a unique anticoagulant tick protein that specifically inhibits FXa-mediated activation of FV. Because TIX-5 inhibited thrombin generation in blood plasma, it was concluded that FV activation by FXa contributes importantly to coagulation. OBJECTIVE: We aimed to unravel the structure-function relationships of TIX-5. METHOD: We used a structure model generated based on homology with the allergen Der F7. RESULTS: Tick inhibitor of factor Xa toward FV was predicted to consist of a single rod formed by several beta sheets wrapped around a central C-terminal alpha helix. By mutagenesis we could show that two hydrophobic loops at one end of the rod mediate the phospholipid binding of TIX-5. On the other end of the rod an FV interaction region was identified on one side, whereas on the other side an EGK sequence was identified that could potentially form a pseudosubstrate of FXa. All three interaction sites were important for the anticoagulant properties of TIX-5 in a tissue factor-initiated thrombin generation assay as well as in the inhibition of FV activation by FXa in a purified system. CONCLUSION: The structure-function properties of TIX-5 are in perfect agreement with a protein that inhibits the FXa-mediated activation on a phospholipid surface. The present elucidation of the mechanism of action of TIX-5 will aid in deciphering the processes involved in the initiation phase of blood coagulation.


Assuntos
Anticoagulantes , Inibidores do Fator Xa , Coagulação Sanguínea , Fator V , Fator Va , Fator Xa , Inibidores do Fator Xa/farmacologia , Humanos , Protrombina , Trombina , Tromboplastina
17.
Angiology ; 72(9): 861-866, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33783233

RESUMO

Autologous cell therapy (ACT) is a new treatment for patients with no-option critical limb ischemia (NO-CLI). We evaluated the factors involved in the nonresponse to ACT in patients with CLI and diabetic foot. Diabetic patients (n = 72) with NO-CLI treated using ACT in our foot clinic over a period of 8 years were divided into responders (n = 57) and nonresponders (n = 15). Nonresponder was defined as an insufficient increase in transcutaneous oxygen pressure by <5 mm Hg, 3 months after ACT. Patient demographics, diabetes duration and treatment, and comorbidities as well as a cellular response to ACT, limb-related factors, and the presence of inherited thrombotic disorders were compared between the 2 groups. The main independent predictors for an impaired response to ACT were heterozygote Leiden mutation (OR 10.5; 95% CI, 1.72-4) and homozygote methylenetetrahydrofolate reductase (MTHFR 677) mutation (OR 3.36; 95% CI, 1.0-14.3) in stepwise logistic regression. Univariate analysis showed that lower mean protein C levels (P = .041) were present in nonresponders compared with responders. In conclusion, the significant predictors of an impaired response to ACT in diabetic patients with NO-CLI were inherited thrombotic disorders.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/complicações , Transplante de Células , Pé Diabético/cirurgia , Isquemia/cirurgia , Resistência à Proteína C Ativada/complicações , Resistência à Proteína C Ativada/genética , Idoso , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/genética , Transplante de Células/efeitos adversos , Estado Terminal , Pé Diabético/complicações , Pé Diabético/diagnóstico , Fator V/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Isquemia/complicações , Isquemia/diagnóstico , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Mutação , Medição de Risco , Fatores de Risco , Transplante Autólogo , Falha de Tratamento
18.
Int Wound J ; 18(5): 616-625, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33686673

RESUMO

Livedoid vasculopathy (LV) is considered a disease of hypercoagulability. Association of LV with genetic variants is poorly characterised and large-scale genetic association studies have not been performed. The aim of the study was to systematically review variants in LV patients and to analyse the available clinical data. A systematic search of the literature in PubMed and Embase databases was performed to identify articles investigating genetic variation in LV patients. Thirty studies or case reports were identified that reported 265 LV patients tested for at least one out of six genetic variations. Among them, PAI-1 -675 4G/5G was the most common, accounting for 85.26% (81/95). Heterozygous 4G/5G was the major genotype. PAI-1 A844G, MTHFR C677T, and MTHFR A1298C were the second, third, and fourth most common variants in LV patients. Prothrombin G20210A and Factor V G1691A were mainly present in LV patients from Europe, North America, and South America. This review highlights the associations between LV and genetic variants. The distribution of variants may be geographically or ethnicity dependent; however, large sample case-control studies are needed to clarify associations.


Assuntos
Homocistinúria , Protrombina , Estudos de Casos e Controles , Fator V/genética , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Protrombina/genética
19.
Blood Coagul Fibrinolysis ; 32(5): 344-348, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33769317

RESUMO

Congenital factor V deficiency (FVD) is a rare bleeding disorder. In this study, we investigated the genetic basis in an African American patient with factor V activity 3%. Custom sequence capture and targeted next-generation (NGS) sequencing of the F5 gene were undertaken followed by PCR and Sanger sequencing. Two novel variants were identified. In silico analyses correlated clinically with the patient's factor V activity and hemorrhagic tendency. A review of the literature regarding these genomic alterations is presented. We described two novel mutations causing moderate FVD. The first, Chr1:g.169483698C>A with cDNA change (F5):c.6529-1G>T, occurred in a conserved nucleotide at the canonical acceptor splice site of intron 24. The second, Chr1:g.169515775C>T with cDNA change (F5):c.1667G>A, was a missense variant of exon 11, affecting a highly conserved amino acid in the A2 domain. Further research into the mechanisms of F5 mutations leading to FVD and residual factor V expression are needed.


Assuntos
Deficiência do Fator V/genética , Fator V/genética , Adulto , Feminino , Humanos , Mutação de Sentido Incorreto , Isoformas de Proteínas/genética
20.
J Thromb Haemost ; 19(7): 1653-1665, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33773040

RESUMO

BACKGROUND: Elucidating the molecular pathogenesis underlying East Texas bleeding disorder (ET) led to the discovery of alternatively spliced F5 transcripts harboring large deletions within exon 13. These alternatively spliced transcripts produce a shortened form of coagulation factor V (FV) in which a large portion of its B-domain is deleted. These FV isoforms bind tissue factor pathway inhibitor alpha (TFPIα) with high affinity, prolonging its circulatory half-life and enhancing its anticoagulant effects. While two missense pathogenic variants highlighted this alternative splicing event, similar internally deleted FV proteins are found in healthy controls. OBJECTIVE: We identified a novel heterozygous 832 base pair deletion within F5 exon 13, termed F5-Atlanta (F5-ATL), in a patient with severe bleeding. Our objective is to investigate the effect of this deletion on F5 and FV expression. METHODS & RESULTS: Assessment of patient plasma revealed markedly elevated levels of total and free TFPI and a FV isoform similar in size to the FV-short described in ET. Sequencing analyses of cDNA revealed the presence of a transcript alternatively spliced using the ET splice sites, thereby removing the F5-ATL deletion. This alternative splicing pattern was recapitulated by heterologous expression in mammalian cells. CONCLUSIONS: These findings support a mechanistic model consisting of cis-acting regulatory sequences encoded within F5 exon 13 that control alternative splicing at the ET splice sites and thereby regulate circulating FV-short and TFPIα levels.


Assuntos
Transtornos da Coagulação Sanguínea , Fator V , Processamento Alternativo , Animais , Transtornos da Coagulação Sanguínea/genética , Éxons , Fator V/genética , Humanos , Mutação , Splicing de RNA
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