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2.
Int J Hematol ; 111(6): 795-802, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32166693

RESUMO

Congenital dysfibrinogenemia (CD) is a rare disorder of hemostasis. The majority of cases are caused by heterozygous missense mutations in one of the three fibrinogen genes. Patients with CD may experience bleeding and thrombosis, but many are asymptomatic. To better describe the clinical, laboratory, and genotypic picture of CD, we evaluated 31 patients from seven unrelated families using standard coagulation tests and genetic analysis. The clinical phenotype consisted of bleeding in 13/31 (42%) patients; other patients (18/31; 58%) were asymptomatic. Among patients with bleeding, symptoms were mostly in single anatomical sites, with variable intensity of bleeding. Compared to results from a previous large systematic survey, our results showed a similar mean bleeding score, but a higher incidence of bleeding episodes without thrombotic complications. In the present study, we identified three known pathogenic point mutations in the FGA (c.95G > A, c.104G > A) and FGB (c.586C > T) genes. The variants of CD identified in this cross-sectional study were either asymptomatic or had bleeding manifestations and showed similar laboratory features, irrespective of genotype. Results from genetic and clinical studies will continue to yield valuable information on the structure and function of the fibrinogen molecule.

4.
J Cardiovasc Pharmacol ; 75(4): 333-335, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31895873

RESUMO

BACKGROUND: Several studies demonstrated that proton pump inhibitors (PPIs) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, it is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels. AIM OF STUDY: The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF. METHODS: This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2-week period of PPI withdrawal with Hemoclot Thrombin Inhibitor Assay. RESULTS: The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after 2 weeks of PPI withdrawal (97.2 ± 79.7 vs. 163.8 ± 105.5 ng/mL; P < 0.05). Moreover, significantly higher peak dabigatran levels were observed after 2 weeks of PPI withdrawal (142.4 ± 102.8 vs. 255 ± 129.5 ng/mL; P ≤ 0.001). CONCLUSIONS: This study showed that a 2-week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF.

5.
Semin Thromb Hemost ; 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31887760

RESUMO

Sequencing of the gene encoding for von Willebrand factor (VWF) has brought new insight into the physiology of VWF as well as its pathophysiology in the context of von Willebrand disease (VWD). Molecular testing in VWD patients has shown high variability in the overall genetic background of this condition. Almost 600 mutations and many disease-causing mechanisms have been described in the 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to types 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next-generation sequencing methods that are more cost- and time-effective. Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (type 1), appear to be free of mutations in VWF. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO possibly affecting VWF levels, and such findings will need further validation studies.

6.
J Diabetes Res ; 2019: 5158308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886279

RESUMO

Type 2 diabetes (T2D) is an independent risk factor of stroke and systemic embolism in patients with atrial fibrillation (AF), and T2D patients with AF-associated stroke seem to have worse clinical outcome and higher risk of unfavorable clinical course compared to individuals without this metabolic disorder. Long-term anticoagulation is indicated in majority of T2D patients with AF to prevent adverse AF-associated embolic events. Direct oral anticoagulants (DOACs), direct oral thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, have emerged as a preferred choice for long-term prevention of stroke in AF patients offering potent and predictable anticoagulation and a favorable pharmacology with low risk of interactions. This article reviews the current data regarding the use of DOACs in individuals with T2D and AF.

8.
Semin Thromb Hemost ; 45(8): 846-850, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31537027

RESUMO

Dabigatran etexilate, a direct thrombin inhibitor, is now frequently used for long-term pharmacological prevention of stroke or systemic embolism in patients with atrial fibrillation. However, such long-term dabigatran therapy (DT) significantly increases the risk of upper gastrointestinal (GI) bleeding. This increased risk of gastric bleeds might be reduced with gastroprotective agents, such as proton pump inhibitors (PPIs). PPIs coadministrated with dabigatran reduce the risk of upper GI bleeding in patients on long-term oral DT. Nevertheless, there is heated discussion regarding interactions between PPI and dabigatran that lead to decreases in dabigatran plasma levels. This article reviews up to date data about the risk of gastric bleeding on dabigatran, the impact of PPI on the reduction of gastric bleeding, and the interaction between PPI and dabigatran leading to decreased dabigatran plasma levels.

10.
Pediatr Cardiol ; 40(7): 1431-1438, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31327027

RESUMO

Venous thromboembolism (VTE) is a rare, but life-threatening disease in those who have not reached their adulthood. This condition is usually treated with heparin or low molecular weight heparins which require parenteral administration and, in case of unfractionated heparin, also frequent laboratory monitoring and dose adjustment. Direct oral anticoagulants (DOACs)-direct thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban-are currently frequently used for the prevention and treatment of VTE in adult population. In fact, these agents offer several advantages compared to traditional agents, such as oral route of administration, short on-set and off-set of action, predictable pharmacologic profile with low risk of food and drug interactions, and no need for routine laboratory assessment of anticoagulant activity. However, clinical experience with these directly acting oral anticoagulants in pediatric population is very limited as these drugs had been tested and are used mostly in adult individuals. This article reviews the current data from pre- and post-marketing studies reporting the use of DOACs for the treatment of VTE in pediatric patients.


Assuntos
Inibidores do Fator Xa/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Criança , Ensaios Clínicos como Assunto , Inibidores do Fator Xa/farmacologia , Humanos
11.
J Thromb Thrombolysis ; 48(4): 619-622, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31264059

RESUMO

Very limited but promising experiences with the use of direct factor Xa inhibitors for the treatment of heparin-induced thrombocytopenia (HIT) have been reported. This contribution features our first experience with the use of apixaban (without a pre-treatment with parenteral anticoagulant) to treat a case of HIT which developed in a patient after multiple heart replacement surgery. Apixaban was effective, well tolerated and safe. An apixaban-calibrated chromogenic anti-Xa activity assessment was used to monitor apixaban activity throughout the therapy. Patient continued on apixaban for the prevention of thrombosis in the settings of atrial fibrillation. No ischemic or bleeding events occurred during the clinical follow up and the platelet count was stable. Our experience suggests that apixaban might be effectively used for the treatment of HIT and for the long-term prevention of embolism in patients after multiple valve replacement with biological prostheses and atrial fibrillation.

13.
J Thromb Thrombolysis ; 47(1): 140-145, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30288664

RESUMO

Proton pump inhibition (PPI) reduces gastrointestinal bleeding on direct oral anticoagulants. However, PPI may affect dabigatran on-treatment levels; and there is no information regarding the effect of PPI on xabans on-treatment activity. Thus, the aim of this study was to determine the impact of PPI on therapeutic anti-Xa activity in rivaroxaban- and apixaban-treated patients with atrial fibrillation (AF). This single-centre pilot prospective study enrolled 77 consecutive xabans-treated patients (42 rivaroxaban-treated and 35 apixaban-treated patients) with AF. PPI was administrated in 44 patients. Trough and peak anti-Xa activity was assessed with factor Xa-calibrated anti-Xa chromogenic analysis. There were no significant differences in trough anti-Xa activity comparing PPI-treated patients and patients without PPI (80.5 ± 66.5 ng/mL in PPI group vs. 71.6 ± 64.1 ng/mL in non-PPI group, p = 0.57, Table 2). Similarly, there were no significant differences in peak anti-Xa activity between compared groups (175.2 ± 102.5 ng/mL in PPI group vs. 202.9 ± 84.1 ng/mL in non-PPI group, p = 0.21). This pilot study did not reveal significant changes in xabans on-treatment anti-Xa activity according the PPI status.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Anticoagulantes/farmacologia , Interações Medicamentosas , Inibidores do Fator Xa/uso terapêutico , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/tratamento farmacológico , Humanos , Projetos Piloto , Estudos Prospectivos , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico
15.
Am J Ther ; 26(3): e308-e313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28452843

RESUMO

BACKGROUND: Proton pump inhibition (PPI) administrated together with dabigatran reduces the risk of gastrointestinal hemorrhage. However, there is a discussion regarding possible PPI-dabigatran interaction that may reduce the efficacy of this therapy. STUDY QUESTION: To determine the impact of concomitant PPI on dabigatran plasma levels in patients with nonvalvular atrial fibrillation (NV-AF). STUDY DESIGN: A pilot prospective study in patients with NV-AF on dabigatran therapy was performed; 31 patients were enrolled. PPI with either omeprazole or pantoprazole was administrated in 19 patients. MEASURES AND OUTCOMES: Blood samples were taken for the assessment of the dabigatran trough and peak levels. Dabigatran concentration was measured with the Hemoclot Thrombin Inhibitor Assay. RESULTS: There were significant differences in dabigatran trough level comparing patients treated with PPI and patients without PPI (58.86 ± 36.76 ng/mL vs. 110.72 ± 88.47 ng/mL, P < 0.05). Similarly, there were significant differences in dabigatran peak level between compared groups (88.0 ± 20.5 ng/mL vs. 174.4 ± 139.64 ng/mL, P < 0.05). CONCLUSIONS: This pilot study demonstrated the interaction between PPI and dabigatran levels in patients with NV-AF.


Assuntos
Anticoagulantes/farmacocinética , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/farmacocinética , Hemorragia Gastrointestinal/prevenção & controle , Inibidores da Bomba de Prótons/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Dabigatrana/efeitos adversos , Interações Medicamentosas , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Pantoprazol/administração & dosagem , Pantoprazol/farmacocinética , Projetos Piloto , Estudos Prospectivos , Inibidores da Bomba de Prótons/administração & dosagem
16.
Clin Appl Thromb Hemost ; 24(8): 1199-1207, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30041546

RESUMO

The monitoring of coagulation by viscoelastometric methods-thromboelastography and rotational thromboelastometry-may detect the contributions of cellular and plasma components of hemostasis. These methods might overcome some of the serious limitations of conventional laboratory tests. Viscoelastic testing can be repeatedly performed during and after surgery and thus provides a dynamic picture of the coagulation process during these periods. Several experiences with the use of these methods in cardiovascular surgery have been reported, but there is perspective for more frequent use of these assays in the assessment of platelet response to antiplatelet therapy and in the assessment of coagulation in patients on long-term dabigatran therapy. This article reviews the current role and future perspectives of thromboelastography and thromboelastometry in the management of cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/cirurgia , Procedimentos Cirúrgicos Cardiovasculares , Tromboelastografia/métodos , Humanos
17.
Drugs Aging ; 35(6): 539-544, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29736814

RESUMO

BACKGROUND: The number of elderly individuals with non-valvular atrial fibrillation (NV-AF) requiring long-term anticoagulation is rising. The pharmacokinetics of oral anticoagulants in elderly individuals may differ from that for younger patients. The aim of this study was to assess the dabigatran levels in elderly patients with NV-AF. PATIENTS AND METHODS: A pilot prospective post-marketing study in patients with NV-AF on dabigatran therapy was performed; we enrolled 21 consecutive elderly patients (aged ≥ 75 years) on a reduced dabigatran regimen (110 mg twice daily) and compared them with 13 younger (≤ 70 years) individuals on reduced dabigatran therapy due to renal impairment and with 16 younger patients on standard dabigatran therapy (150 mg twice daily). Blood samples were taken for the assessment of dabigatran trough and peak levels. Dabigatran levels were measured with the Hemoclot® Thrombin Inhibitor Assay. RESULTS: There were significant differences in dabigatran trough levels when comparing elderly patients on reduced dabigatran with non-elderly patients on reduced dabigatran (99.3 ± 73.6 vs 51.6 ± 25.6 ng/mL; p < 0.01). Similarly, the detected dabigatran peak levels were significantly higher in elderly patients on reduced dabigatran compared with non-elderly patients on reduced dabigatran (173.4 ± 116.2 vs 116.1 ± 19.1 ng/mL; p < 0.01). No significant differences in dabigatran trough and peak levels were found when comparing elderly patients on reduced dabigatran with non-elderly patients on standard dabigatran therapy. CONCLUSION: This pilot study demonstrated that elderly patients on reduced dabigatran exhibit significantly higher dabigatran levels than younger individuals on a reduced regimen, and similar levels compared with younger individuals on standard dabigatran.


Assuntos
Anticoagulantes/sangue , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/sangue , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Dabigatrana/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos
18.
J Cardiovasc Pharmacol ; 72(1): 71-76, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29738377

RESUMO

Proton pump inhibition (PPI) administered together with antiplatelet and anticoagulant agents reduces the risk of gastrointestinal hemorrhage. Several novel antithrombotic agents have been recently introduced for patients with acute coronary syndrome (prasugrel and ticagrelor) or for patients requiring long-term anticoagulation (dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban). In fact, these agents might offer even stronger inhibition of platelets or coagulation compared with older agents; therefore, the need for gastroprotection might be even stronger when these new agents are used for long-term antithrombotic therapy. On the contrary, there are several reports regarding an adverse interaction between PPI and antithrombotic agents connected with a reduction in antithrombotic therapy on-treatment levels, implicating a higher risk of thrombosis. This interaction was demonstrated in clopidogrel-treated patients and more recently also in dabigatran-treated patients. This article discusses a possible novel antithrombotic therapy/PPI interaction leading to higher risk of thrombosis.


Assuntos
Anticoagulantes/efeitos adversos , Fibrinolíticos/efeitos adversos , Hemorragia Gastrointestinal/prevenção & controle , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Trombose/induzido quimicamente , Trombose/prevenção & controle , Tomada de Decisão Clínica , Interações Medicamentosas , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Medição de Risco , Fatores de Risco
19.
Blood Coagul Fibrinolysis ; 29(4): 369-373, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29538002

RESUMO

: The number of patients with nonvalvular atrial fibrillation (NV-AF) who require long-term anticoagulation and also have a higher risk of bleeding is increasing. Recently, there is no information regarding real on-treatment anti-Xa activity in patients with NV-AF and a higher risk of bleeding who receive oral factor Xa inhibitors. The aim of this study was to determine trough and peak anti-Xa activity in these patients. This single-centre pilot study enrolled 41 patients with NV-AF and a higher risk of bleeding defined as Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score at least 3 points. Twenty-one patients were treated with rivaroxaban and 17 patients were treated with apixaban. The trough and peak samples of these patients were tested for anti-Xa activity with factor Xa-calibrated anti-Xa chromogenic analysis. The detected trough anti-Xa activity was 63.2 ±â€Š44.4 ng/ml. There was a significant increase in peak anti-Xa activity up to 170.3 ±â€Š99.6 ng/ml (P < 0.001) observed. There were no significant differences in trough (52.4 ±â€Š41.9 vs. 76.0 ±â€Š45.4 ng/ml; P = 0.12) and peak (187.2 ±â€Š122.5 vs. 151.5 ±â€Š64.0 ng/ml; P = 0.27) anti-Xa activity between rivaroxaban-treated and apixaban-treated patients. This study demonstrated the anti-Xa activity in oral factor Xa inhibitor-treated patients with NV-AF and a higher risk of bleeding. No significant differences in this activity between rivaroxaban-treated and apixaban-treated patients were found.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Fator Xa/efeitos dos fármacos , Hemorragia/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes , Fibrilação Atrial/complicações , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Risco , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico
20.
Diabetes Res Clin Pract ; 135: 172-177, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29175298

RESUMO

AIMS: Type 2 diabetes (T2D) is connected with several abnormalities in haemostasis; and with higher risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NV-AF). However, it is recently unknown whether T2D affects the activity of direct oral anticoagulants (DOACs). The aim of this study was to determine the impact of T2D on DOACs activity in patients with NV-AF. METHODS: This pilot prospective study enrolled totally 65 patients with NV-AF (20 dabigatran-treated, 110 mg/twice daily; 28 rivaroxaban-treated, 15 mg/daily; 17 apixaban-treated, 5 mg/twice daily). 25 patients had T2D (8 dabigatran-treated, 11 rivaroxaban-treated, and 6 apixaban-treated). DOAC activity was tested with Hemoclot® Thrombin Inhibitor assay in dabigatran-treated patients, and with factor Xa-calibrated anti-Xa chromogenic analysis in rivaroxaban- and apixaban-treated patients prior and two hours after drug administration. RESULTS: There were no significant differences in dabigatran baseline (62.1 ±â€¯8.0 vs. 51.8 ±â€¯38.9 ng/ml, p = .76) and 2-h-post-drug-administration (91.7 ±â€¯57.2 vs. 72.2 ±â€¯33.2 ng/ml, p = .48) activity comparing T2D and non-diabetic patients. Similarly, no significant differences were found in rivaroxaban baseline (35.9 ±â€¯22.5 vs. 55.3 ±â€¯45.1 ng/ml, p = .19) and 2-h-post-drug-administration (145.7 ±â€¯74.1 vs. 202.6 ±â€¯135.0 ng/ml, p = .22) anti-Xa activity. In addition, no significant differences were present in apixaban baseline (96.0 ±â€¯54.5 vs. 63.9 ±â€¯36.8 ng/ml, p = .24) and 2-h-post-drug-administration (151.0 ±â€¯78.3 vs. 151.7 ±â€¯59.1 ng/ml, p = .98) anti-Xa activity between T2D and non-diabetic patients. CONCLUSIONS: This pilot study did not detect differences in DOACs activity according to T2D status in patients with NV-AF.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia , Fibrilação Atrial/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos
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