RESUMO
BACKGROUND: Coagulation factor V (FV) deficiency is a rare bleeding disorder that is usually managed with fresh-frozen plasma. Patients with nonsense mutations may respond to treatment with readthrough agents. OBJECTIVES: To investigate whether the F5 p.Arg1161Ter mutation, causing severe FV deficiency in several patients, would be amenable to readthrough therapy. METHODS: F5 mRNA and protein expression were evaluated in a F5 p.Arg1161Ter-homozygous patient. Five readthrough agents with different mechanisms of action, i.e. G418, ELX-02, PTC-124, 2,6-diaminopurine (2,6-DAP), and Amlexanox, were tested in in vitro and ex vivo models of the mutation. RESULTS: The F5 p.Arg1161Ter-homozygous patient showed residual F5 mRNA and functional platelet FV, indicating detectable levels of natural readthrough. COS-1 cells transfected with the FV-Arg1161Ter cDNA expressed 0.7% FV activity compared to wild-type. Treatment with 0-500 µM G418, ELX-02, and 2,6-DAP dose-dependently increased FV activity up to 7.0-fold, 3.1-fold, and 10.8-fold, respectively, whereas PTC-124 and Amlexanox (alone or in combination) were ineffective. These findings were confirmed by thrombin generation assays in FV-depleted plasma reconstituted with conditioned media of treated cells. All compounds except ELX-02 showed some degree of cytotoxicity. Ex vivo differentiated megakaryocytes of the F5 p.Arg1161Ter-homozygous patient, which were negative at FV immunostaining, turned positive after treatment with all 5 readthrough agents. Notably, they were also able to internalize mutant FV rescued with G418 or 2,6-DAP, which would be required to maintain the crucial platelet FV pool in vivo. CONCLUSION: These findings provide in vitro and ex vivo proof-of-principle for readthrough-mediated rescue of the F5 p.Arg1161Ter mutation.
Assuntos
Códon sem Sentido , Deficiência do Fator V , Humanos , Fator V/genética , Fator V/metabolismo , Deficiência do Fator V/tratamento farmacológico , Deficiência do Fator V/genética , Aminopiridinas , MutaçãoAssuntos
Tratamento Farmacológico da COVID-19 , Clorpromazina/uso terapêutico , Deficiência do Fator V/tratamento farmacológico , Hemorragia/tratamento farmacológico , Soluço/tratamento farmacológico , Metoclopramida/uso terapêutico , COVID-19/complicações , COVID-19/fisiopatologia , COVID-19/virologia , Deficiência do Fator V/complicações , Deficiência do Fator V/fisiopatologia , Deficiência do Fator V/virologia , Testes Hematológicos , Hemorragia/complicações , Hemorragia/fisiopatologia , Hemorragia/virologia , Soluço/complicações , Soluço/fisiopatologia , Soluço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Tomografia Computadorizada por Raios X , Resultado do TratamentoAssuntos
Antifibrinolíticos/uso terapêutico , Transtornos da Coagulação Sanguínea/sangue , Deficiência do Fator V/tratamento farmacológico , Contagem de Plaquetas , Ácido Tranexâmico/uso terapêutico , Antifibrinolíticos/farmacologia , Transtornos da Coagulação Sanguínea/genética , Plaquetas/efeitos dos fármacos , Deficiência do Fator V/sangue , Deficiência do Fator V/complicações , Deficiência do Fator V/genética , Fibrinolisina/biossíntese , Fibrinólise/efeitos dos fármacos , Hemartrose/tratamento farmacológico , Hemartrose/etiologia , Hematoma/tratamento farmacológico , Hematoma/etiologia , Hemorragia/prevenção & controle , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/prevenção & controle , Estudos Prospectivos , Ácido Tranexâmico/farmacologia , Cicatrização/efeitos dos fármacosRESUMO
Quebec platelet disorder (QPD) is a condition that causes delayed-onset bleeding after hemostatic challenges. While there are interventional spine procedure (ISP) guidelines for managing patients on blood thinners or with common bleeding disorders, there are none for approaching patients with unique coagulopathies. We report a patient with QPD and extensive history of postprocedural bleeding complications (PPBCs) who presented with chronic cervical facet pain. After consulting a hematologist and administering antifibrinolytic agent with platelet transfusions, the patient underwent medial branch nerve blocks (MBNBs) followed by radiofrequency ablation (RFA) without experiencing PPBCs. A comprehensive team approach is critical to maximize patient safety when performing an ISP in such a population.
Assuntos
Antifibrinolíticos/uso terapêutico , Deficiência do Fator V/complicações , Cervicalgia/terapia , Deficiência do Fator V/tratamento farmacológico , Humanos , Bloqueio Nervoso , Pacientes Ambulatoriais , Transfusão de Plaquetas , Ablação por Radiofrequência , Resultado do Tratamento , Articulação ZigapofisáriaRESUMO
Deficiencies or excessive activation of the fibrinolytic system can result in severe, lifelong bleeding disorders. The most severe clinical phenotype is caused by α2-Antiplasmin (α2-AP) deficiency which results in excess fibrinolysis due to the inability to inhibit plasmin. Another bleeding disorder due to a defect in the fibrinolytic pathway results from Plasminogen activator inhibitor-1 (PAI-1) deficiency causing enhanced fibrinolysis due to the decreased inhibition of plasminogen activators resulting in increased conversion of plasminogen to plasmin. Both these disorders are rare and have an autosomal recessive pattern of inheritance. They can remain undetected as routine coagulation and platelet function tests are normal. A unique gain-of-function defect in fibrinolysis causes the Quebec platelet disorder (QPD) which is characterized by profibrinolytic platelets containing increased urokinase-type plasminogen activator (uPA) in the α-granules. A high index of suspicion based on clinical phenotype along with the availability of specialized hemostasis testing is required for timely and accurate diagnosis. Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot. The purpose of this review is to summarize the pathogenesis, clinical phenotype, approaches to diagnosis and treatment for these three major disorders of fibrinolysis.
Assuntos
Antifibrinolíticos/uso terapêutico , Deficiência do Fator V , Fibrinólise/genética , Transtornos Hemorrágicos , Inibidor 1 de Ativador de Plasminogênio/deficiência , Ácido Tranexâmico/uso terapêutico , alfa 2-Antiplasmina/deficiência , Plaquetas/metabolismo , Plaquetas/patologia , Deficiência do Fator V/tratamento farmacológico , Deficiência do Fator V/genética , Deficiência do Fator V/metabolismo , Deficiência do Fator V/patologia , Transtornos Hemorrágicos/sangue , Transtornos Hemorrágicos/tratamento farmacológico , Transtornos Hemorrágicos/genética , Transtornos Hemorrágicos/metabolismo , Transtornos Hemorrágicos/patologia , Humanos , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , alfa 2-Antiplasmina/efeitos dos fármacos , alfa 2-Antiplasmina/genéticaRESUMO
RATIONALE: Acquired inhibitors of coagulation are antibodies that either inhibit the activity or increase the clearance of a clotting factor. Acquired factor V deficiency is a rare coagulation disorder, and it can sometimes be life threatening. PATIENT CONCERNS: We describe a case of a 90-year-old Japanese male with acquired factor V deficiency. He was previously misdiagnosed with congenital factor V deficiency when he presented with hemoptysis and a negative factor V inhibitor test result at a different hospital 5 years earlier. Coagulopathy recurred with ecchymosis when he sustained a bruise after falling on a bush. DIAGNOSIS: Although the factor V inhibitor test result was negative and a mixing study suggested a deficiency pattern, we diagnosed the patient with acquired factor V deficiency on the basis of no history of bleeding diathesis, a lack of response to multiple fresh frozen plasma transfusion, and clinical response to corticosteroid therapy. INTERVENTIONS: Intravenous methylprednisolone was administered at 500âmg/day for 3 days, followed by oral prednisolone at 1âmg/kg/day. OUTCOMES: Coagulation test results improved and symptoms resolved 2 weeks after corticosteroid administration. LESSONS: This case report suggests that clearance-facilitating antibodies exist without the presence of neutralizing inhibitors. When patients present with coagulation factor V deficiency in the absence of coagulation inhibitors, acquired factor V deficiency should also be considered.
Assuntos
Deficiência do Fator V/tratamento farmacológico , Glucocorticoides/uso terapêutico , Metilprednisolona/uso terapêutico , Idoso de 80 Anos ou mais , Deficiência do Fator V/diagnóstico , Humanos , Masculino , Tempo de Tromboplastina ParcialAssuntos
Deficiência do Fator V/tratamento farmacológico , Fator VIIa/uso terapêutico , Menorragia/diagnóstico , Adolescente , Deficiência do Fator V/complicações , Deficiência do Fator V/patologia , Feminino , Humanos , Menorragia/etiologia , Plasma/química , Proteínas Recombinantes/uso terapêutico , Índice de Gravidade de DoençaAssuntos
Anemia Refratária com Excesso de Blastos/complicações , Doenças Autoimunes/etiologia , Azacitidina/uso terapêutico , Deficiência do Fator V/etiologia , Fator V/imunologia , Idoso de 80 Anos ou mais , Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Azacitidina/efeitos adversos , Diagnóstico Precoce , Deficiência do Fator V/tratamento farmacológico , Deficiência do Fator V/imunologia , Hemorragia Gengival/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Tempo de Tromboplastina Parcial , Prednisona/uso terapêutico , Tempo de ProtrombinaRESUMO
INTRODUCTION: Severe congenital factor V (FV) deficiency is a rare bleeding disorder characterized by very low/undetectable levels of FV. Fresh frozen plasma is the standard treatment for bleeding manifestations. Recently, a novel plasma-derived FV concentrate has been developed. AIM: To evaluate the "in vitro" ability of the novel FV concentrate to normalize clotting times and generate normal amount of thrombin in plasma collected from patients with severe FV deficiency. METHODS: Prothrombin time (PT), activated partial thromboplastin time (aPTT), FV activity and antigen levels and thrombin generation were measured pre- and postspiking of plasma samples of 10 patients with increasing doses of FV concentrate (from 0 to 100 IU/dL). RESULTS: Prothrombin time and activated partial thromboplastin time ratios as well as all thrombin generation parameters were fully corrected by the addition of FV concentrate at a final concentration of 25 IU/dL. However, the addition of FV at a concentration of 1-3 IU/dL was already sufficient to correct peak height and endogenous thrombin potential (but not lag time and time to peak) after activation with 5 pmol/L tissue factor. FV activity and antigen levels showed a linear response to supplementation with the novel FV concentrate. CONCLUSION: The novel plasma-derived FV concentrate was effective to correct "in vitro" severe FV deficiency in patients. The optimal FV concentration to fully normalize both global clotting times and thrombin generation parameters using the novel plasma-derived FV concentrate was 25 IU/dL.
Assuntos
Deficiência do Fator V/tratamento farmacológico , Fator V/uso terapêutico , Plasma/metabolismo , Adulto , Idoso , Testes de Coagulação Sanguínea , Fator V/farmacologia , Deficiência do Fator V/metabolismo , Deficiência do Fator V/fisiopatologia , Feminino , Hemostasia/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Trombina/biossínteseRESUMO
INTRODUCTION: Activated protein C resistance (APCr) leads to hypercoagulability and is due, often but not exclusively, to Factor V Leiden (FVL). The aim of this study was to assess the ex vivo and in vitro interference of the direct factor Xa inhibitor rivaroxaban (RIV) on a prothrombinase-based assay for APCr detection. METHODS: An ex vivo study was performed on fresh plasma samples obtained from 44 subjects with FV wild-type and seven with FVL heterozygous, all treated with RIV. An in vitro study was performed on 15 plasma samples (six from normal subjects, six from heterozygous, and three from homozygous FVL carriers, all frozen specimens) spiked with RIV. RIV concentration was evaluated using a chromogenic assay, and APCr was evaluated by a prothrombinase-based assay. RESULTS: No significant interference of RIV on APCr results obtained by a prothrombinase-based assay was observed for drug concentrations up to 400 ng/mL in FV wild-type and FVL carriers (homozygous and heterozygous). These results were confirmed both ex vivo and in vitro. CONCLUSIONS: RIV did not significantly interfere with the prothrombinase-based assay used for the assessment of APCr, and this was observed to occur independently of FV status. However, only concentrations up to 400 ng/mL were tested and, therefore, what occurs in the presence of higher doses remains to be investigated.
Assuntos
Resistência à Proteína C Ativada/genética , Coagulação Sanguínea/efeitos dos fármacos , Deficiência do Fator V/sangue , Deficiência do Fator V/genética , Fator V/genética , Heterozigoto , Rivaroxabana/farmacologia , Tromboplastina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Testes de Coagulação Sanguínea , Monitoramento de Medicamentos , Deficiência do Fator V/diagnóstico , Deficiência do Fator V/tratamento farmacológico , Feminino , Homozigoto , Humanos , Itália , Masculino , Rivaroxabana/uso terapêuticoRESUMO
: Acquired factor V deficiency (AFVD) is a rare haemostatic disorder that is primarily because of the development of factor V inhibitors. Approximately, 200 cases have been reported and the greatest portion of these cases was because of bovine thrombin exposure. We report a case of a man who presented with haematuria followed by multiple haemorrhages associated with an elevated prothrombin time and an activated partial thromboplastin time. A workup revealed reduced factor V activity and a factor V inhibitor level of 1.9âBU, which were likely secondary to a urinary tract infection. Using corticosteroids, we successfully eliminated the inhibitor and controlled the bleeding. We review the published literature to identify the conditions that are associated with nonbovine thrombin AFVD. We assume that AFVD should be kept in mind for patients who present with multiple haemorrhages.
Assuntos
Deficiência do Fator V/diagnóstico , Fator V/imunologia , Hematúria , Hemorragia , Infecções Urinárias/patologia , Corticosteroides/uso terapêutico , Animais , Autoanticorpos/sangue , Testes de Coagulação Sanguínea , Bovinos , Diagnóstico Diferencial , Fator V/antagonistas & inibidores , Deficiência do Fator V/tratamento farmacológico , Deficiência do Fator V/etiologia , Hemorragia/tratamento farmacológico , Transtornos Hemorrágicos , Humanos , Masculino , Pessoa de Meia-Idade , Trombina , Infecções Urinárias/complicaçõesRESUMO
: Combined factor V and factor VIII deficiency is an extremely rare bleeding disorder for which research is lacking. We present the case of a 33-year-old man requiring repeat mitral valve replacement. A multidisciplinary team approach was utilized to minimize his risk of bleeding which included the use of plasma exchange, intravenous factor replacement, and platelet transfusion. This approach created an operative experience that did not require blood transfusion or the use of other hemostatic medications.
Assuntos
Deficiência do Fator V/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Cirurgia Torácica/métodos , Adulto , Testes de Coagulação Sanguínea , Humanos , MasculinoAssuntos
Deficiência do Fator V/tratamento farmacológico , Fator VIII/uso terapêutico , Fator V/metabolismo , Hemofilia A/tratamento farmacológico , Hemorragia/tratamento farmacológico , Rituximab/uso terapêutico , Esteroides/uso terapêutico , Idoso , Doença Crônica , Feminino , Humanos , Terapia de Imunossupressão , Recidiva , Resultado do TratamentoRESUMO
Due to rarity of factor V (FV) deficiency, there have been only a few case reports in Korea. We retrospectively analysed the clinical-laboratory features of FV deficiency in 10 Korean patients. Between January 1987 and December 2013, 10 case reports published in a Korean journal or proceedings of Korea Society on Thrombosis and Hemostasis were reviewed. Severity is defined as mild (> 5% of factor activity), moderate (1%-5%), and severe (< 1%). The median age at diagnosis, six males and four females, was 26 years (range, 1 month-73 years). Six of 10 patients were classified as moderate, three as mild, and one as severe disease. Eight patients were diagnosed as inherited FV deficiency. The most frequent symptoms were mucosal tract bleedings (40%) such as epistaxis, and menorrhagia in female. Hemarthroses and postoperative bleeding occurred in one and four patients, respectively. Life-threatening bleeding episodes occurred in the peritoneal cavity (n = 2), central nerve system (n = 1), and retroperitoneal space (n = 1). No lethal haemorrhages happened to patients with mild disease. The majority of bleeding episodes were controlled with local measures and fresh-frozen plasma replacement. Two acquired FV deficient-patients showing life-threatening haemorrhages received the immunosuppressive therapy, but one of them died from postoperative bleeding complications. Despite the small sample size of this study due to rarity of the disease, we found that Korean patients with FV deficiency had similar clinical manifestations and treatment outcomes shown in previous studies.
Assuntos
Deficiência do Fator V/patologia , Adolescente , Adulto , Idoso , Povo Asiático , Transfusão de Sangue , Criança , Bases de Dados Factuais , Deficiência do Fator V/tratamento farmacológico , Feminino , Hemorragia/etiologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Lactente , Masculino , Pessoa de Meia-Idade , Plasma , República da Coreia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
UNLABELLED: ESSENTIALS: Combined factor V (FV) and factor VIII (FVIII) deficiency (CF5F8D) is an autosomal recessive coagulation disorder. Desmopressin acetate (DDAVP) was intravenously infused in 20 adult patients with CF5F8D. DDAVP can enhance FVIII levels but has no effect on FV levels in patients with CF5F8D. DDAVP can be substituted for FVIII concentrates in patients with CF5F8D. OBJECTIVES: Combined factor V (FV) and FVIII deficiency (CF5F8D) is a rare inherited autosomal recessive double-gene disorder most frequently seen in the Middle East. Although affected individuals have deficiency of two coagulation factors (range 5-30%), their bleeding tendencies are similar to patients who have deficiency of a single coagulation factor at the same level. The mainstay of their treatment is infusion of FVIII concentrate and fresh frozen plasma. Here, the effect of intravenous infusion of desmopressin acetate (DDAVP) on elevation of coagulation FV and FVIII was investigated through a clinical trial in May 2015. PATIENTS AND METHODS: In a registered controlled trial, DDAVP (dosage 0.3 µg kg(-1) ) was intravenously infused into 20 adult patients with CF5F8D over 20 min. After an hour, blood samples were collected and plasma levels of FV and FVIII were measured. RESULTS AND CONCLUSION: This study revealed that DDAVP can enhance FVIII levels but has no effect on FV plasma concentration in patients with CF5F8D. Based on these findings, FVIII concentrates may be substituted for DDAVP in patients with CF5F8D.
Assuntos
Desamino Arginina Vasopressina/uso terapêutico , Deficiência do Fator V/tratamento farmacológico , Fator VIII/metabolismo , Fator V/metabolismo , Hemofilia A/tratamento farmacológico , Hemostasia/efeitos dos fármacos , Hemostáticos/uso terapêutico , Adulto , Biomarcadores/sangue , Testes de Coagulação Sanguínea , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/efeitos adversos , Deficiência do Fator V/sangue , Deficiência do Fator V/complicações , Deficiência do Fator V/diagnóstico , Feminino , Hemofilia A/sangue , Hemofilia A/complicações , Hemofilia A/diagnóstico , Hemostáticos/administração & dosagem , Hemostáticos/efeitos adversos , Humanos , Infusões Intravenosas , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Adulto JovemRESUMO
We report the case of a 59-year-old Chinese man who showed an asymptomatic coagulation factor V deficiency pattern after second intravenous treatment with ceftazidime. Normal pooled plasma failed to correct the abnormalities in a mixing test, and the presence of factor V inhibitor was confirmed by the Bethesda method. The coagulopathy was not corrected by transfusion of fresh frozen plasma and prothrombin complex concentrate, but rather by treatment with prednisone and withdrawal of dubious drugs. The findings reported here should prompt clinicians to watch for drug-induced coagulation factor deficiency.
Assuntos
Antibacterianos/efeitos adversos , Ceftazidima/efeitos adversos , Deficiência do Fator V/induzido quimicamente , Deficiência do Fator V/tratamento farmacológico , Fator V/antagonistas & inibidores , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Testes de Coagulação Sanguínea , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Ceftazidima/uso terapêutico , Humanos , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/patologia , Masculino , Pessoa de Meia-Idade , Plasma , Prednisona/uso terapêutico , Protrombina/uso terapêutico , Tomografia Computadorizada por Raios XAssuntos
Deficiência do Fator V/complicações , Hemofilia A/complicações , Adulto , Desamino Arginina Vasopressina/uso terapêutico , Fator V/metabolismo , Deficiência do Fator V/tratamento farmacológico , Deficiência do Fator V/genética , Fator VIII/metabolismo , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Proteínas de Transporte Vesicular/genética , Adulto JovemRESUMO
Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes. QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors. The genetic cause of the disorder is a tandem duplication mutation of the uPA gene, PLAU, which upregulates uPA expression in megakaryocytes by an unknown mechanism. The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins. The gain-of-function defect in fibrinolysis is thought to be central to the pathogenesis of QPD bleeding as the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis. The purpose of this review is to summarize current knowledge on QPD pathogenesis and the recommended approaches to QPD diagnosis and treatment.