RESUMO
BACKGROUND: Coagulopathy is common in multitrauma patients and repletion of procoagulant factor deficiency with fresh frozen plasma (FFP) improves hemostasis. Optimal kaolin-thromboelastography thresholds for FFP transfusion in trauma patients have not been well established. STUDY DESIGN: Adult trauma patients with an Injury Severity Score ≥15 were included in this retrospective observational cohort study. The primary end point was area under the receiver operating characteristic curve (AUROC) for reaction time (R-time) to detect procoagulant factor deficiency, as reflected by an elevated international normalized ratio (INR) or aPTT. Test characteristics for the optimal R-time threshold calculated in our study were compared against thresholds recommended by the American College of Surgeons for FFP transfusion. RESULTS: Six hundred and ninety-four pairs of thromboelastography and conventional coagulation tests were performed in 550 patients, with 144 patients having additional pairs of tests after the first hour. The R-time was able to detect procoagulant factor deficiency (INR ≥1.5 AUROC 0.80; 95% CI, 0.75 to 0.85; aPTT ≥40 seconds AUROC 0.85; 95% 0.80 to 0.89) and severe procoagulant factor deficiency (INR ≥2.0 AUROC 0.82; 95% CI, 0.73 to 0.99; aPTT ≥60 seconds AUROC 0.89; 95% CI, 0.81 to 0.98) with good accuracy. Optimal thresholds to maximize sensitivity and specificity were 3.9 minutes for detection of INR ≥1.5, 4.1 minutes for detection of aPTT ≥40 seconds, 4.3 minutes for detection of INR ≥2.0, and 4.3 for detection of aPTT ≥60 seconds. Currently recommended R-time thresholds for FFP transfusion had 100% specificity for detecting procoagulant factor deficiency, but low sensitivity (3% to 7%). CONCLUSIONS: R-time can detect procoagulant factor deficiency in multitrauma patients with good accuracy, but currently recommended R-time thresholds are highly specific and not sensitive. Use of low-sensitivity thresholds might result in undertreatment of many patients with procoagulant factor deficiency.
Assuntos
Transtornos de Proteínas de Coagulação/diagnóstico , Tempo de Reação , Tromboelastografia/métodos , Ferimentos e Lesões/complicações , Adulto , Idoso , Área Sob a Curva , Transfusão de Sangue , Transtornos de Proteínas de Coagulação/etiologia , Transtornos de Proteínas de Coagulação/terapia , Feminino , Humanos , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Plasma , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Ferimentos e Lesões/terapiaRESUMO
Molecular strategies tailored to promote/correct the expression and/or processing of defective coagulation factors would represent innovative therapeutic approaches beyond standard substitutive therapy. Here, we focus on the molecular mechanisms and determinants underlying innovative approaches acting at DNA, mRNA and protein levels in inherited coagulation factor deficiencies, and in particular on: (i) gene editing approaches, which have permitted intervention at the DNA level through the specific recognition, cleavage, repair/correction or activation of target sequences, even in mutated gene contexts; (ii) the rescue of altered pre-mRNA processing through the engineering of key spliceosome components able to promote correct exon recognition and, in turn, the synthesis and secretion of functional factors, as well as the effects on the splicing of missense changes affecting exonic splicing elements; this section includes antisense oligonucleotide- or siRNA-mediated approaches to down-regulate target genes; (iii) the rescue of protein synthesis/function through the induction of ribosome readthrough targeting nonsense variants or the correction of folding defects caused by amino acid substitutions. Overall, these approaches have shown the ability to rescue the expression and/or function of potentially therapeutic levels of coagulation factors in different disease models, thus supporting further studies in the future aimed at evaluating the clinical translatability of these new strategies.
Assuntos
Transtornos de Proteínas de Coagulação/genética , Transtornos de Proteínas de Coagulação/terapia , Terapia Genética/métodos , Animais , Fatores de Coagulação Sanguínea/genética , Sistemas CRISPR-Cas , DNA/genética , Edição de Genes/métodos , Humanos , RNA Mensageiro/genéticaRESUMO
The deficiency of fibrinogen, prothrombin, factor V (FV), FVII, FVIII, FIX, FX, FXI, and FXIII, called rare coagulation disorders (RCDs), may result in coagulopathies leading to spontaneous or posttrauma and postsurgery hemorrhages. RCDs are characterized by a wide variety of symptoms, from mild to severe, which can vary significantly from 1 disease to another and from 1 patient to another. The most typical symptoms of all RCDs are mucosal bleedings and bleeding at the time of invasive procedures, whereas other life-threatening symptoms such as central nervous system bleeding and hemarthroses are mostly present only in some deficiencies (afibrinogenemia, FX, and FXIII). At variance with hemophilia A and B and von Willebrand disease, RCDs are much less prevalent, ranging from 1 case in 500 000 to 1 in 2 million in the general population. Their clinical heterogeneity associated with the low number of patients has led to a delay in the development of appropriate therapies. Indeed, a similar heterogeneity can also be found in the treatment products available, ranging from the specific recombinant proteins to treat FVII- and FXIII-deficient patients to the complete absence of specific products to treat patients with FII or FV deficiencies, for whom prothrombin complex concentrates or fresh frozen plasma are, to date, the only option. The recent development of novel hemostatic approaches for hemophilia, such as the use of nonsubstitutive therapy as RNA interference, anti-tissue factor pathway inhibitor, and the gene therapy aimed at improving the patient's quality of life may also have an important role in the treatment of patients with RCDs in the future.
Assuntos
Transtornos de Proteínas de Coagulação/terapia , Doenças Raras/terapia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Fatores de Coagulação Sanguínea/uso terapêutico , Transfusão de Componentes Sanguíneos , Coagulantes/uso terapêutico , Transtornos de Proteínas de Coagulação/complicações , Gerenciamento Clínico , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Doenças Raras/complicações , Proteínas Recombinantes/uso terapêuticoRESUMO
Direct oral anticoagulants (DOACs) are small molecule inhibitors of the coagulation proteases thrombin and factor Xa that demonstrate comparable efficacy to warfarin for several common indications, while causing less serious bleeding. However, because their targets are required for the normal host-response to bleeding (hemostasis), DOACs are associated with therapy-induced bleeding that limits their use in certain patient populations and clinical situations. The plasma contact factors (factor XII, factor XI, and prekallikrein) initiate blood coagulation in the activated partial thromboplastin time assay. While serving limited roles in hemostasis, pre-clinical and epidemiologic data indicate that these proteins contribute to pathologic coagulation. It is anticipated that drugs targeting the contact factors will reduce risk of thrombosis with minimal impact on hemostasis. Here, we discuss the biochemistry of contact activation, the contributions of contact factors in thrombosis, and novel antithrombotic agents targeting contact factors that are undergoing pre-clinical and early clinical testing.
Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Coagulação Sanguínea , Animais , Fatores de Coagulação Sanguínea/genética , Transtornos de Proteínas de Coagulação/diagnóstico , Transtornos de Proteínas de Coagulação/epidemiologia , Transtornos de Proteínas de Coagulação/etiologia , Transtornos de Proteínas de Coagulação/terapia , Terapia Combinada , Avaliação Pré-Clínica de Medicamentos , Hemostasia , Humanos , Terapia de Alvo Molecular , Ligação Proteica , Trombina/metabolismoRESUMO
Congenital factor deficiencies (CFDs) refer to inherited deficiency of coagulation factors in the blood. A total of 481 patients with CFDs, who were diagnosed and followed at our Pediatric Hematology and Oncology Clinic between 1990 and 2015, were retrospectively evaluated. Of the 481 cases, 134 (27.8%) were hemophilia A, 38 (7.9%) were hemophilia B, 57 (11.8%) were von Willebrand disease (vWD), and 252 (52.3%) were rare bleeding disorders (RBDs). The median age of the patients at the time of diagnosis and at the time of the study was 4.1 years (range: 2 months to 20.4 years) and 13.4 years (range: 7 months to 31.3 years), respectively. The median duration of the follow-up time was 6.8 years (range: 2.5 months to 24.8 years). One hundred nineteen (47.2%) of 252 patients with RBDs were asymptomatic, 49 (41.1%) of whom diagnosed by family histories, 65 (54.6%) through preoperative laboratory studies, and 5 (4.2%) after prolonged bleeding during surgeries. Consanguinity rate for the RBDs was 47.2%. Prophylactic treatment was initiated in 80 patients, 58 of whom were hemophilia A, 7 were hemophilia B, 13 were RBDs, and 2 were vWD. Significant advances have been achieved during the past 2 decades in the treatment of patients with CFDs, particularly in patients with hemophilias. The rarity and clinical heterogeneity of RBDs lead to significant diagnostic challenges and improper management. In this regard, multinational collaborative efforts are needed with the hope that can improve the management of patients with RBDs.
Assuntos
Transtornos de Proteínas de Coagulação/congênito , Transtornos de Proteínas de Coagulação/diagnóstico , Transtornos de Proteínas de Coagulação/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
Recently several variants of clotting factors have shown a peculiar behavior so that they appear as new defects. The factors involved are FII, FV and FIX. Prothrombin deficiency is usually associated with bleeding. Recently a few prothrombin abnormalities involving Arg396 mutations, have been demonstrated to show antithrombin resistance with the consequent appearance of a thrombophilic state and venous thromboses in young age. The same is true for an abnormal FIX (FIX Padua). The thrombotic manifestations in the latter condition are also venous. The abnormal FIX (FIX Padua) is characterized by a great increase in FIX activity whereas FIX antigen is only slightly increased. The condition is due to an Arg338Lys mutation. The increased intrinsic clotting activity of this abnormal FIX is being investigated as a useful therapeutic approach in homophile B patients. Another new clotting disorder is represented by two abnormal FV (FV East Texas and FV Amsterdam). These are characterized by a deletion of part of the B domain of FV resulting in a "short" FV. The condition is characterized by a mild bleeding tendency due to high levels of Tissue Factor pathway inhibitor. The "short" factor V is in fact resistant to the action of Tissue Factor pathway inhibitor which is sharply increased in these patients. These new clotting entities have again demonstrated that the study of patients who show a tendency to venous thrombosis or a mild bleeding condition that cannot be explained on the basis of our current concepts of blood coagulation, may represent "new" coagulation disorders. All persons interested in thrombotic or hemorrhagic disorders should be informed about these new clinical and laboratory conditions.
Assuntos
Fatores de Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/metabolismo , Transtornos de Proteínas de Coagulação , Transtornos de Proteínas de Coagulação/sangue , Transtornos de Proteínas de Coagulação/classificação , Transtornos de Proteínas de Coagulação/genética , Transtornos de Proteínas de Coagulação/terapia , HumanosRESUMO
Rare diseases are defined as life-threatening or chronically debilitating diseases with a prevalence of less than one per 2000 according to the European Union or one per 1250 according to the USA. Congenital rare bleeding disorders RBD are reported in most populations, with incidence varying from 1 in 5000 (Hemophilia A), 1:30,000 (Hemophilia B) to much rarer (1:500,000 for FVII deficiency, 1-3 million for Prothrombin or FXIII deficiency). Acquired Hemophilia A is also a rare bleeding disorder with estimated frequency of 1 in million. Most RBDs are inherited as autosomal recessive (AR); however, heterozygous carriers with varying degrees of corresponding factor deficiency may render an unpredictable propensity for bleeding. In patients with bleeding symptoms, laboratory assessment and especially molecular techniques currently enable accurate diagnosis and may provide tools for prenatal and family counseling. Currently hemostasis control is mainly based upon replacement of the missing coagulation factors (unless presence of inhibitors renders it impossible), however future gene therapy and disruptive, non-replacement alternatives may be promising for patients with RBD.
Assuntos
Transtornos de Proteínas de Coagulação/diagnóstico , Hemorragia/diagnóstico , Doenças Raras/diagnóstico , Animais , Coagulação Sanguínea , Fatores de Coagulação Sanguínea/uso terapêutico , Transtornos de Proteínas de Coagulação/sangue , Transtornos de Proteínas de Coagulação/genética , Transtornos de Proteínas de Coagulação/terapia , Terapia Genética/métodos , Hemorragia/sangue , Hemorragia/genética , Hemorragia/terapia , Humanos , Doenças Raras/sangue , Doenças Raras/genética , Doenças Raras/terapiaRESUMO
Coagulopathy in critically ill patients is common and often multifactorial. Fresh frozen plasma (FFP) is commonly used to correct this either prophylactically or therapeutically. FFP usage is mainly guided by laboratory tests of coagulation, which have been shown to have poor predictive values for bleeding. Viscoelastic tests are an attractive option to guide hemostatic therapy, but require rigorous evaluation. The past few years have seen a gradual reduction in national use of FFP potentially due to an increased awareness of risks such as transfusion-related acute lung injury, patient blood management strategies to reduce transfusion in general, and increased awareness of the lack of high-quality evidence available to support FFP use. Within critical care, FFP is administered before invasive procedures/surgery, to treat major traumatic and nontraumatic hemorrhage, disseminated intravascular coagulation, and for urgent warfarin reversal if first-line agents, such as prothrombin complex concentrate (PCC) are not available. Alternative agents such as fibrinogen concentrate and PCC need further evaluation through large-scale clinical trials.
Assuntos
Fatores de Coagulação Sanguínea , Transfusão de Componentes Sanguíneos/métodos , Transtornos de Proteínas de Coagulação/terapia , Plasma , HumanosRESUMO
Blood transfusion frequently consists in bringing blood components in patients presenting with global deficiency of cells or of certain factors allowing, i.e. hemostasis or oxygenation; transfusion is thus performed on a short period, or on a period that corresponds to the recovery of the bone marrow (that is deficient either quantitatively or qualitatively). In some other circumstances, patients must receive transfusions as the one treatment of their pathology; this can be for life, when the deficiency has a genetic origin, or episodically in the case of autoimmune disorders. Once hemotherapy is initiated, one must appreciate the balance between the benefits and the risks or overload, and adjust with subtractions and exchanges (of blood components). This paper presents examples of two cases: hemotherapy in sickle cell patients, and patients undergoing plasma exchange programs.
Assuntos
Remoção de Componentes Sanguíneos , Transfusão de Sangue , Medicina Transfusional/métodos , Anemia Falciforme/terapia , Doenças Autoimunes/terapia , Remoção de Componentes Sanguíneos/efeitos adversos , Remoção de Componentes Sanguíneos/métodos , Remoção de Componentes Sanguíneos/estatística & dados numéricos , Transfusão de Sangue/métodos , Transfusão de Sangue/estatística & dados numéricos , Transtornos de Proteínas de Coagulação/terapia , Humanos , Troca Plasmática/efeitos adversos , Troca Plasmática/métodos , Reação TransfusionalAssuntos
Transtornos Hemorrágicos , Adulto , Criança , Feminino , Humanos , Masculino , Gravidez , Afibrinogenemia/diagnóstico , Afibrinogenemia/epidemiologia , Afibrinogenemia/genética , Afibrinogenemia/terapia , Fatores de Coagulação Sanguínea/administração & dosagem , Fatores de Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/uso terapêutico , Testes de Coagulação Sanguínea , Transtornos de Proteínas de Coagulação/diagnóstico , Transtornos de Proteínas de Coagulação/epidemiologia , Transtornos de Proteínas de Coagulação/genética , Transtornos de Proteínas de Coagulação/terapia , Gerenciamento Clínico , Fibrinogênio/genética , Fibrinogênio/uso terapêutico , Hemorragia/prevenção & controle , Transtornos Hemorrágicos/diagnóstico , Transtornos Hemorrágicos/epidemiologia , Transtornos Hemorrágicos/genética , Transtornos Hemorrágicos/terapia , Complicações Hematológicas na Gravidez/terapia , Proteínas Recombinantes/uso terapêuticoRESUMO
As compared to haemophilia, although the clinical features and the management strategies for rare coagulation factor deficiencies are discussed, little is known about them. This study was undertaken to assess the distribution, clinical presentation and treatment of patients with rare coagulation factor deficiency disorders in a cross-sectional population of India. Blood samples and other clinical details from patients suspected of rare coagulation factor deficiencies were collected by the Haemophilia Treatment Centers across India and were diagnosed at National Institute of Immunohaematology, Mumbai. A total of 321 cases of rare clotting factor deficiencies were diagnosed, of which 88% were severe, 10% moderate and 2% mild. Commonest deficiency encountered was factor XIII (FXIII) (30%) followed by FX (15.6%), FVII (15%), fibrinogen (12.1%), FXI (9%), combined V and VIII deficiency (5.6%) and congenital multiple vitamin K-dependent coagulation factor deficiency (MCFD, 2.1%). Major representation of these deficiencies was from Southern and Western India (82%). Mucocutaneous bleeding was the commonest clinical presentation (59%); intracranial (IC) haemorrhage was seen in 18% of the patients; menorrhagia was an important clinical pointer in women in the reproductive age group (78%); 8% of the severe cases had no history of bleeding and 73% of the FXIII deficiency cases had umbilical stump bleeding. The major therapeutic products used was fresh frozen plasma (64%), cryoprecipitate (15%), whole blood (15%), antifibrinolytics (5%) and recombinant FVIIa (1%). A distinct pattern in the distribution of rare clotting factor deficiencies was observed which was based on multiple factors that include ethnicity and the available diagnostic facilities in different regions of this vast country.
Assuntos
Transtornos de Proteínas de Coagulação/epidemiologia , Programas de Rastreamento , Doenças Raras/epidemiologia , Adolescente , Criança , Pré-Escolar , Transtornos de Proteínas de Coagulação/terapia , Estudos Transversais , Feminino , Humanos , Índia/epidemiologia , Lactente , Masculino , Doenças Raras/terapia , Adulto JovemRESUMO
Rare bleeding disorders (RBDs) comprise the inherited deficiencies of coagulation factors such as fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, FXI, and FXIII, and are usually transmitted as autosomal recessive disorders. RBDs are characterized by a wide variety of symptoms from mild to severe; however, due to their rarity, only little information is available on the adequate management of patients affected with these deficiencies. Moreover, the limitations of laboratory assays and the lack of a definitive consensus concerning their classification have prevented adoption of optimal approaches to their individual management. To overcome these limitations, new strategies are therefore necessary, such as the establishment of global collaborations and networks among treatment centers, as well as increasing support provided by public health organizations.
Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/terapia , Transtornos da Coagulação Sanguínea/classificação , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/terapia , Técnicas de Laboratório Clínico/métodos , Transtornos de Proteínas de Coagulação/diagnóstico , Transtornos de Proteínas de Coagulação/terapia , Humanos , Cooperação InternacionalRESUMO
The use of therapeutic plasma has increased in France by more than 40% since 2002. This growth may be explained by the improvement in transfusion safety, the diminution of the risk of transmission of pathogens and the regained confidence of the physicians in blood products. Therapeutic plasma also benefits from additional procedures to reduce infectious (securisation) or immunological risks (selection of blood donors). Its application in massive transfusions has undergone a significant evolution over the last few years. A proactive attitude favouring early and important use of plasma on the basis of pre-established protocols is advocated henceforth. The prescription of therapeutic plasma for other indications must be guided by the results of biological tests and an evaluation of the haemorrhagic risk. Despite regular updating of the guidelines for good transfusion practice, plasma is still sometimes prescribed for prophylactic purposes in situations where the biological and/or clinical criteria do not justify it. Moreover, it is not recommended to use fresh frozen plasma in cases of deficiency of coagulation factors if the specific concentrates are available as intravenous fluids. Complementary clinical studies will be necessary to evaluate, in certain indications, the real benefits of the transfusion of plasma and the interest of replacing it by concentrates of coagulant factors (fibrinogen, prothrombin complex).
Assuntos
Transfusão de Componentes Sanguíneos , Plasma , Anticoagulantes/efeitos adversos , Perda Sanguínea Cirúrgica , Procedimentos Cirúrgicos Cardíacos , Transtornos de Proteínas de Coagulação/terapia , Coagulação Intravascular Disseminada/terapia , Hemorragia/induzido quimicamente , Hemorragia/terapia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/terapia , Falência Hepática/terapia , Transplante de Fígado , Troca Plasmática , Hemorragia Pós-Operatória/terapia , Microangiopatias Trombóticas/terapiaRESUMO
PURPOSE OF REVIEW: By definition, rare factor deficiencies have a prevalence of less than 200,000 in the US population, or an incidence of less than one in 2000 in Europe. The very small numbers of patients with rare disorders present challenges in diagnosis, evaluation of bleeding risk and treatment. Use of new assays, full genome sequencing, and global clotting assays will significantly improve diagnosis of patients with rare bleeding disorders. RECENT FINDINGS: In addition to new assays available for monitoring patients, new therapy, both recombinant and plasma derived, is now available. Registries and clinical trials have demonstrated decreased bleeding and improved outcomes when patients are treated with these agents. Expanding international registries have been initiated to correlate genotype and bleeding phenotype in conjunction with global assays. SUMMARY: Ongoing research continues to expand our understanding of the pathophysiology of rare factor deficiencies. This work complements medical practice to incorporate early diagnosis and new treatment options for patients, resulting in safer and less sensitizing regimens and much improved clinical outcomes.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Transtornos de Proteínas de Coagulação/terapia , Doenças Raras/terapia , Transtornos de Proteínas de Coagulação/diagnóstico , Transtornos de Proteínas de Coagulação/genética , Humanos , Doenças Raras/diagnóstico , Doenças Raras/genéticaRESUMO
Evaluating the patient's individual bleeding history with a standardized questionnaire, using "point-of-care" - methods for coagulation analyses and providing autologous transfusion techniques are preconditions of a modern coagulation management. Therapy of coagulopathic patients should be based on structured hemotherapy algorithms. Surgical haemostasis and the maintenance of the basic conditions for haemostasis are elementary requirements for an effective therapy. In cases of diffuse bleeding, early antifibrinolytic therapy should be considered. Coagulation factor deficiencies should be corrected "goal-directed" using coagulation factor concentrates. Transfusion of fresh frozen plasma is only indicated in the clinical setting of massive transfusions. DDAVP and transfusion of platelet concentrates are options to optimize primary haemostasis. In cases of on-going bleeding, recombinant activated coagulation factor VII represents an option for "ultima-ratio" therapy.
Assuntos
Coagulação Sanguínea , Reação Transfusional , Algoritmos , Antifibrinolíticos/uso terapêutico , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Testes de Coagulação Sanguínea , Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue/mortalidade , Transtornos de Proteínas de Coagulação/terapia , Desamino Arginina Vasopressina/uso terapêutico , Hemostasia , Humanos , Hipotensão Controlada , Cuidados Intraoperatórios , Plasma , Transfusão de Plaquetas , Sistemas Automatizados de Assistência Junto ao LeitoRESUMO
We present the case of a patient submitted to augmentation mammaplasty who developed 2 hematoma episodes as a result of von Willebrand's disease, which was not previously diagnosed. As a routine part of preoperative evaluation, the patient should always be tested for von Willebrand's disease. This disease affects 1-3 percent of the population and occurs twice as often as hemophilia. In our case, the patient recovered quite satisfactorily. Preventive and therapeutic approaches are discussed in this paper.
Os autores relatam o caso de uma paciente submetida a mamaplastia de aumento, não diagnosticada previamente como portadora de doença de von Willebrand, que teve dois episódios de hematoma no pós-operatório. Entre os distúrbios de coagulação, a doença de von Willebrand deve ser considerada na avaliação pré-operatória, pois afeta cerca de 1 por cento a 3 por cento da população, não é diagnosticada na maioria das pessoas, além de ser duas vezes mais frequente que a hemofilia. A paciente evoluiu bem no pós-operatório e medidas preventivas e terapêuticas são discutidas neste artigo.
Assuntos
Humanos , Feminino , Adulto , História do Século XXI , Complicações Pós-Operatórias , Doenças de von Willebrand , Transtornos da Coagulação Sanguínea , Mamoplastia , Transtornos de Proteínas de Coagulação , Hematoma , Complicações Pós-Operatórias/cirurgia , Complicações Pós-Operatórias/terapia , Doenças de von Willebrand/cirurgia , Doenças de von Willebrand/patologia , Doenças de von Willebrand/terapia , Transtornos da Coagulação Sanguínea/cirurgia , Mamoplastia/efeitos adversos , Mamoplastia/métodos , Transtornos de Proteínas de Coagulação/cirurgia , Transtornos de Proteínas de Coagulação/terapia , Hematoma/cirurgia , Hematoma/complicaçõesRESUMO
Substitutive therapy has significantly ameliorated the quality of life of patients with coagulation factor deficiencies. However, there are some limitations that support research towards alternative therapeutic approaches. Here we focus on the rescue of coagulation factor biosynthesis by targeting the RNA processing and translation, which would permit restoration of the altered gene expression while maintaining the gene regulation in the physiological tissues. The essential prerequisite of the three reported RNA-based correction approaches (i-iii), which rely on mutation types and are applicable even to large size mRNAs, is the presence in cells of the precursor (pre-mRNA) or mature mRNA forms. (i) In the F7 gene, modification of the small nuclear RNA U1 (U1 snRNA), the key component of the spliceosomal U1 ribonucleoprotein, re-directs correct usage of a mutated exon-intron junction, triggering synthesis of correct mRNA and secretion of functional factor (F)VII. (ii) Spliceosome-mediated RNA trans-splicing (SMaRT) between mutated and engineered pre-mRNAs produces normal FVIII mRNA and secretion of functional protein. (iii) Aminoglycoside drugs induce ribosome readthrough and suppress premature translation termination caused by nonsense mutations in FVII, VIII and IX. The rescued expression levels ranged from very low (aminoglycosides) to moderate (U1 snRNA and SMaRT), which could result in amelioration of the disease phenotypes. These findings prompt further studies aimed at demonstrating the clinical translatability of RNA-based strategies, which might open new avenues in the treatment of coagulation factor deficiencies.
Assuntos
Transtornos de Proteínas de Coagulação/terapia , Proteínas Mutantes/antagonistas & inibidores , RNA/uso terapêutico , Fatores de Coagulação Sanguínea/genética , Terapia Genética , Humanos , Proteínas Mutantes/efeitos dos fármacos , Proteínas Mutantes/genética , Splicing de RNARESUMO
Inherited antithrombin deficiency is estimated to carry a 50% risk of a venous thrombotic complication during each pregnancy and puerperium. We present a case of a female with heterozygous type I antithrombin deficiency who presented with a central nervous system transverse sinus thrombosis in the third trimester of pregnancy despite the use of therapeutic doses of low molecular weight heparin, as venous thromboembolic prophylaxis, since conception. A successful pregnancy outcome was achieved with the combined use of therapeutic anticoagulation and regular plasma-derived antithrombin concentrate infusions to normalize her antithrombin levels. This case lends further debate to the issue of whether antithrombin concentrate, in addition to anticoagulation, should be routinely administered for venous thromboembolic prophylaxis during pregnancy and the puerperium to women with inherited antithrombin deficiency. This point may become more relevant as further experience is gained with the use of recombinant human antithrombin.