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1.
Ann Hematol ; 98(3): 581-588, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30446804

RESUMO

The thrombopoietin receptor agonist romiplostim is used for the long-term treatment of chronic immune thrombocytopenia (ITP). ITP patients have an increased thrombotic risk, which could be exacerbated if romiplostim increased platelet hyperreactivity or caused spontaneous platelet aggregation. To investigate this possibility, this study examined platelet function in romiplostim-treated ITP patients and healthy subjects. Light transmission platelet aggregometry utilizing arachidonic acid, collagen, epinephrine, ristocetin, ADP, and saline (to assess spontaneous aggregation) was performed for each subject. In addition, the ADP AC50 (ADP concentration that induced half-maximal aggregation) was determined for each patient as a sensitive measurement of altered platelet reactivity. Fifteen ITP patients and 7 healthy subjects entered the study. All ITP patients had active disease and were receiving weekly romiplostim as the sole ITP-directed therapy. Platelet aggregation in response to the strong agonists arachidonic acid, collagen, and ristocetin was not significantly different between ITP patients and healthy subjects (P = 0.2442, P = 0.0548, and P = 0.0879, respectively). Platelet aggregation in response to weak agonists was significantly reduced in ITP patients compared with that in healthy subjects: median (range) aggregation to ADP, 45% (15-84%) versus 89% (70-95%) (P = 0.0010), and epinephrine, 21% (1.6-90%) versus 88% (79-94%) (P = 0.0085). The median AC50 of ADP was threefold higher in ITP patients versus that in healthy subjects (6.3 µM vs 2.1 µM) (P = 0.0049). Significant spontaneous aggregation was not observed in any patient. Platelets from romiplostim-treated ITP patients do not show evidence for spontaneous aggregation or hyperreactivity, but instead have a modestly reduced aggregation response to ADP and epinephrine.


Assuntos
Transtornos Plaquetários/induzido quimicamente , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Difosfato de Adenosina/farmacologia , Adulto , Idoso , Ácido Araquidônico/farmacologia , Colágeno/farmacologia , Epinefrina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Púrpura Trombocitopênica Idiopática/sangue , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologia , Ristocetina/farmacologia , Trombofilia/induzido quimicamente , Trombopoetina/efeitos adversos , Trombopoetina/farmacologia , Adulto Jovem
2.
Biomed Pharmacother ; 110: 275-284, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30513505

RESUMO

The hypercoagulable state occurs in a group of prothrombotic disorders associated with an increased risk for thromboembolic events, but it is difficult to diagnose due to the lack of available biomarkers. This study aimed to investigate systematic changes of urinary proteome in acute hypercoagulable state induced by certain antifibrinolytics. To reduce the effects of both genetic and environmental factors on the urinary proteome, we used a rat model of acute hypercoagulable state induced by an antifibrinolytic agent ε-aminocaproic acid, resembling human hypercoagulable state. Urine samples were collected during acute hypercoagulable state for analysis by liquid chromatography-tandem mass spectrometry (LCMS/MS). Of 65 significantly changed proteins in acute hypercoagulable state, 38 proteins had human orthologs, and 18 proteins were identified as stable in normal human urine. None of the identified proteins have been found to be clotting factors, but 4 proteins are known to be involved in the regulation of blood coagulation factors. Two proteins were verified as the markers associated with acute hypercoagulable state by Western blot analysis. In addition, four common differential urinary proteins have been found in acute hypercoagulable state induced by another antifibrinolytics tranexamic acid. These four proteins are potential biomarkers for early diagnosis of hypercoagulable state to prevent the development of thrombotic diseases.


Assuntos
Ácido Aminocaproico/toxicidade , Antifibrinolíticos/toxicidade , Modelos Animais de Doenças , Proteoma/metabolismo , Trombofilia/urina , Animais , Biomarcadores/urina , Relação Dose-Resposta a Droga , Masculino , Proteoma/genética , Distribuição Aleatória , Ratos , Ratos Wistar , Trombofilia/induzido quimicamente , Trombofilia/genética
3.
J Thromb Haemost ; 16(9): 1686-1699, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29975003

RESUMO

Platelets can contribute to tumor progression and metastasis. Cancer patients are at increased risk of thrombosis, and advanced stages of cancer are associated with thrombocytosis or increased platelet reactivity. Tyrosine kinase inhibitors (TKIs) are widely used as a targeted strategy for cancer treatment, with the aim of prolonging progression-free survival of the patients. Because of their broad kinase target spectrum, most TKIs inevitably have off-target effects. Platelets rely on tyrosine kinase activity for their activation. Frequently observed side effects are lowering of platelet count and inhibition of platelet functions, whether or not accompanied by an increased bleeding risk. In this review, we aim to give insights into: (i) 38 TKIs that are currently used for the treatment of different types of cancer, either on the market or in clinical trials; (ii) how distinct TKIs can inhibit activation mechanisms in platelets; and (iii) the clinical consequences of the antiplatelet effects of TKI treatment. For several TKIs, the knowledge on affinity for their targets does not align with the published effects on platelets and reported bleeding events. This review should raise awareness of the potential antiplatelet effects of several TKIs, which will be enhanced in the presence of antithrombotic drugs.


Assuntos
Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Terapia de Alvo Molecular/efeitos adversos , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Trombofilia/etiologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Interleucina-6/biossíntese , Metástase Neoplásica , Proteínas de Neoplasias/fisiologia , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neovascularização Patológica/etiologia , Neovascularização Patológica/fisiopatologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/fisiologia , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/fisiologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/fisiologia , Trombocitose/etiologia , Trombofilia/induzido quimicamente , Trombofilia/prevenção & controle , Trombopoetina/biossíntese
4.
J Thromb Haemost ; 16(9): 1700-1710, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29956472

RESUMO

Hereditary thrombocytopenias (HTPs) constitute a heterogeneous group of diseases characterized by a reduction in platelet count and a potential bleeding risk. As a result of advances in diagnostic methods, HTPs are increasingly being identified, and appear to be less rare than previously thought. Most HTPs do not have effective treatments, except for platelet transfusion when bleeding occurs and in preparation for procedures associated with a risk of bleeding. Preliminary clinical evidence suggests that thrombopoietin receptor agonists (TPO-RAs) with an established use in the treatment of certain acquired thrombocytopenias are well tolerated and provide clinical benefits in patients with some forms of HTP. These drugs may therefore be considered for the treatment of HTPs in clinical practice. However, caution and close monitoring are recommended, owing to the absence of long-term safety data and the potential risks posed by prolonged bone marrow stimulation in certain HTPs. In this review, we summarize the available clinical data on TPO-RAs in the treatment of HTPs, and discuss their use in patients with these disorders. We believe that TPO-RAs will play a major role in the treatment of HTPs, particularly myosin heavy chain 9-related disease, Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and thrombocytopenia caused by THPO mutations.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Benzoatos/efeitos adversos , Benzoatos/farmacologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Neoplasias Hematológicas/etiologia , Humanos , Hidrazinas/efeitos adversos , Hidrazinas/farmacologia , Mielofibrose Primária/etiologia , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologia , Risco , Trombocitopenia/genética , Trombofilia/induzido quimicamente , Trombopoese/efeitos dos fármacos , Trombopoetina/efeitos adversos , Trombopoetina/farmacologia
5.
Int J Dermatol ; 57(5): 572-574, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29336027

RESUMO

BACKGROUND: Calciphylaxis is a devastating multifactorial disorder of the subcutaneous fat that is known to be associated with hypercoagulability. Recent literature has proposed subclassifying patients with calciphylaxis as having warfarin-associated or warfarin-unassociated disease. AIM: We aimed to determine whether patients with warfarin-associated calciphylaxis differ clinically from patients with warfarin-unassociated calciphylaxis. MATERIALS AND METHODS: We performed a subgroup analysis of patients with nonuremic calciphylaxis from a previously studied cohort and compared clinical and outcomes features of patients who were taking warfarin at the time of disease onset to those of patients who were not. RESULTS: Nineteen patients with nonuremic calciphylaxis were identified, including 10 (53%) who had been on warfarin at the time of disease onset and 9 (47%) who had not. Of all clinical and outcomes parameters tested, no significant differences were detected between the two groups. DISCUSSION AND CONCLUSIONS: Though this study is limited by its retrospective nature and the relatively small number of patients studied, available data do not support subclassifying patients with nonuremic calciphylaxis as having warfarin-associated or warfarin-unassociated disease. Rather, the body of literature would suggest that identification and correction of underlying disorders of hypercoagulability should be prioritized.


Assuntos
Anticoagulantes/efeitos adversos , Calciofilaxia/induzido quimicamente , Calciofilaxia/classificação , Varfarina/efeitos adversos , Adulto , Fatores Etários , Idoso , Anticoagulantes/administração & dosagem , Calciofilaxia/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Valores de Referência , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Trombofilia/induzido quimicamente , Trombofilia/epidemiologia , Trombofilia/fisiopatologia , Varfarina/administração & dosagem
6.
Arterioscler Thromb Vasc Biol ; 38(1): 266-274, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29097362

RESUMO

OBJECTIVE: Combined oral contraceptives induce a reversible hypercoagulable state with an enhanced risk of venous thromboembolism, but the underlying mechanism(s) remain unclear. Subjects on combined oral contraceptives also demonstrate a characteristic resistance to APC (activated protein C) in the thrombin generation assay. Here, we report the potential role of plasma factor IXa (FIXa) as a mechanism for hormone-induced systemic hypercoagulability. APPROACH AND RESULTS: A novel assay was used to determine FIXa activity in plasma samples from volunteer blood donors. Plasma from 36 premenopausal females on hormonal contraception and 35 not on hormonal contraception, 35 postmenopausal females, and 10 males were analyzed for FIXa activity, total PS (protein S), total tissue factor pathway inhibitor (TFPI), and TFPI-α antigen. Premenopausal females on hormonal contraception demonstrated significantly increased FIXa activity and decreased TFPI-α compared with the other groups. Remarkably, FIXa values were not normally distributed in the hormonal contraception group, but skewed toward the high end. Plasma FIXa activity inversely correlated with both TFPI-α and total PS antigen. Ex vivo determination of TF-dependent FIX activation in FV-deficient plasma demonstrated that inhibitory anti-TFPI antibodies enhanced FIXa generation by 2- to 3-fold, whereas addition of 75 nmol/L PS reduced FIXa generation by ≈2-fold. Further, increasing FIXa concentration enhanced APC resistance during TF-triggered plasma thrombin generation. CONCLUSIONS: Elevation of plasma FIXa activity in association with reductions in TFPI-α and PS is a potential mechanism for systemic hypercoagulability and resistance to APC in premenopausal females on hormonal contraception.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Anticoncepcionais Orais Combinados/administração & dosagem , Fator IXa/metabolismo , Pré-Menopausa/sangue , Resistência à Proteína C Ativada/sangue , Resistência à Proteína C Ativada/induzido quimicamente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Proteína S/metabolismo , Fatores de Risco , Fatores Sexuais , Trombofilia/sangue , Trombofilia/induzido quimicamente , Regulação para Cima , Adulto Jovem
9.
J Investig Med ; 66(4): 733-738, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29248890

RESUMO

We assessed time of thrombotic events (venous thromboembolism (VTE)) after starting testosterone therapy (TT) in 21 men who sustained 23 VTE. The density of thrombotic events was greatest at 3 months after starting TT, with a rapid decline in events by 10 months. The 21 cases with VTE on TT differed from 110 patient controls with unprovoked VTE, not taking TT (VTE-no TT) for Factor V Leiden heterozygosity (FVL) (33 per cent vs 13 per cent, P=0.037), for high lipoprotein (a) (Lp(a)) (55 per cent vs 17 per cent, P=0.012), and for the lupus anticoagulant (33 per cent vs 4 per cent, P=0.003). These differences between cases and VTE-no TT controls were independent of age and gender. TT can interact with underlying thrombophilia-hypofibrinolysis promoting VTE. We suggest that TT should not be started in subjects with known thrombophilia. Coagulation screening, particularly for the FVL , Lp(a), and the lupus anticoagulant should be considered before starting TT, to identify men at high VTE risk who have an adverse risk/benefit ratio for TT.


Assuntos
Testosterona/efeitos adversos , Trombofilia/induzido quimicamente , Tromboembolia Venosa/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Embolia Pulmonar/induzido quimicamente , Acidente Vascular Cerebral/induzido quimicamente , Fatores de Tempo
11.
Indian J Pathol Microbiol ; 60(1): 50-56, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28195091

RESUMO

CONTEXT: Thromboembolism in children with acute lymphoblastic leukemia (ALL) is most commonly reported after the initiation of antileukemic therapy, indicating a possible interaction of disease and therapy. AIMS: To study the effect of induction chemotherapy on coagulation parameters in pediatric ALL patients. SETTINGS AND DESIGN: Thirty-seven newly diagnosed patients of ALL up to 18 years of age were evaluated along with 30 age- and sex-matched controls. SUBJECTS AND METHODS: At the time of diagnosis (day 0), various coagulation parameters were tested. These were sequentially analyzed on day 14 (after the completion of L-asparaginase doses) and on day 28 of therapy (after the completion of induction). Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, protein C (PC) activity, and protein S (PS) activity were done by a clot-based method. Antithrombin (AT) assay was performed by chromogenic method. D-dimer (D-DI), tissue plasminogen activator (tPA), and plasminogen activator inhibitor type 1 (PAI-1) levels were assayed by ELISA method. STATISTICAL ANALYSIS USED: The statistical analysis was done using Statistical Package for Social Sciences version 17.0. RESULTS: No major change in PT and APTT was observed during chemotherapy; however, fibrinogen levels declined significantly (P = 0.04), following L-asparaginase treatment. D-DI levels were significantly raised at diagnosis (P < 0.001) and throughout induction therapy (P < 0.001). PC, PS, and AT were reduced in the initial part of induction, followed by a rise in the second half of therapy, reaching their respective baseline levels (P < 0.05). The tPA levels were significantly reduced in the patients at diagnosis and throughout therapy (P < 0.001). PAI-1 levels were comparable to controls at presentation and showed a rising trend during therapy. CONCLUSIONS: The results of this study indicated that both the malignant process and the drugs used in combined chemotherapy cause thrombin activation, decrease in natural inhibitors, and hypofibrinolysis, resulting in hypercoagulability. Thus, ALL per se is a hypercoagulable state and the prothrombotic condition at the time of diagnosis gets enhanced during induction chemotherapy.


Assuntos
Antineoplásicos/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Quimioterapia de Indução/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trombofilia/induzido quimicamente , Adolescente , Antineoplásicos/administração & dosagem , Antitrombinas/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Trombina/metabolismo
12.
PLoS One ; 12(1): e0169976, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28081568

RESUMO

Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions.


Assuntos
Lipopolissacarídeos , Trombofilia/induzido quimicamente , Trombofilia/fisiopatologia , Doença Aguda , Animais , Biomarcadores/sangue , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Leucopenia/induzido quimicamente , Masculino , MicroRNAs/sangue , Neutrófilos/metabolismo , Neutrófilos/patologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos , Ratos Wistar , Trombofilia/imunologia , Fatores de Tempo
13.
Clin Appl Thromb Hemost ; 23(7): 775-785, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27301402

RESUMO

Vascular thrombosis, both arterial and venous, is a condition associated with significant morbidity and mortality. There are multiple risk factors for thrombosis, both congenital and acquired, and in the majority of cases, these risk factors are not modifiable. Over the past 2 decades, multiple drugs (both illegal and legal) have been associated with increased risk of thrombosis. However, due to limited scientific literature regarding the prothrombotic tendencies of these drugs, there is a concomitant limited understanding of the pathophysiology of drug-induced thrombosis. As drugs are one of the few modifiable risk factors for thrombosis, further study and dissemination of knowledge regarding drug-associated and drug-induced thrombosis are essential and have the potential to lead to decreased future incidence of thrombosis. The mechanisms at the basis of the thrombophilic activity of these drugs are variable and sometimes still ill recognized. Increased levels of clotting factors, reduction in coagulation natural inhibitors, decreased fibrinolysis, activated clotting factors, increased blood viscosity, endothelial damage, and increased platelet number and activation are the most frequent causes. Arterial steal or coronary arteries no flow has also been implicated. In some cases due to the intake of several drugs, more than one mechanism is present in a given patient. The purpose of the present review is to analyze all the drugs demonstrated to be potentially thrombotic. It is hoped that a prudent use or nonuse of these drugs might result in a reduction of thrombosis-associated diseases.


Assuntos
Trombofilia/induzido quimicamente , Trombose/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Trombose/etiologia
14.
Am J Ther ; 24(1): e3-e11, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27145188

RESUMO

BACKGROUND: Cardiotoxicity remains an important adverse reaction of chemotherapy used in the treatment of breast cancer, leading to increased morbidity and mortality. DATA SOURCES: Anthracyclines, taxanes, and trastuzumab are the most commonly used cytotoxic drugs for the treatment of breast cancer. Cardiotoxicity may vary from asymptomatic forms to irreducible heart failure and death. AREAS OF UNCERTAINTY: Susceptibility for the occurrence of chemotherapy-induced cardiotoxicity and treatment resistance is multifactorial, with interindividual variability, determined by the interaction between genetic and phenotypic factors. Implementation of pharmacogenomic findings into clinical practice might be useful, to predict cardiotoxicity and to allow appropriate therapeutic measures. RESULTS AND CONCLUSIONS: This review will summarize the cellular mechanisms of chemotherapy-induced cardiotoxicity in breast cancer patients and will discuss the role of the genetic susceptibility for cardiac dysfunction.


Assuntos
Antineoplásicos/efeitos adversos , Arritmias Cardíacas/genética , Neoplasias da Mama/tratamento farmacológico , Cardiomiopatias/genética , Insuficiência Cardíaca/genética , Hipertensão/genética , Isquemia Miocárdica/genética , Trombofilia/genética , Antraciclinas/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Cardiomiopatias/induzido quimicamente , Cardiotoxicidade/genética , Docetaxel , Doxorrubicina/efeitos adversos , Epirubicina/efeitos adversos , Feminino , Predisposição Genética para Doença , Insuficiência Cardíaca/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Isquemia Miocárdica/induzido quimicamente , Paclitaxel/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Taxoides/efeitos adversos , Trombofilia/induzido quimicamente , Trastuzumab/efeitos adversos
15.
Clin Appl Thromb Hemost ; 23(8): 973-979, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27582022

RESUMO

We compared thrombophilia and hypofibrinolysis in 6 men with Klinefelter syndrome (KS), without previously known familial thrombophilia, who had sustained deep venous thrombosis (DVT)-pulmonary emboli (PE) or mesenteric artery thrombosis on testosterone replacement therapy (TRT). After the diagnosis of KS, TRT had been started in the 6 men at ages 11, 12, 13, 13, 19, and 48 years. After starting TRT, DVT-PE or mesenteric artery thrombosis was developed in 6 months, 1, 11, 11, 12, and 49 years. Of the 6 men, 4 had high (>150%) factor VIII (177%, 192%, 263%, and 293%), 3 had high (>150%) factor XI (165%, 181%, and 193%), 1 was heterozygous for the factor V Leiden mutation, and 1 was heterozygous for the G20210A prothrombin gene mutation. None of the 6 men had a precipitating event before their DVT-PE. We speculate that the previously known increased rate of DVT-PE and other thrombi in KS reflects an interaction between prothrombotic, long-term TRT with previously undiagnosed familial thrombophilia. Thrombophilia screening in men with KS before starting TRT would identify a cohort at increased risk for subsequent DVT-PE, providing an optimally informed estimate of the risk/benefit ratio of TRT.


Assuntos
Fator V , Síndrome de Klinefelter , Mutação de Sentido Incorreto , Protrombina , Embolia Pulmonar , Testosterona/efeitos adversos , Trombofilia , Trombose Venosa , Adulto , Idoso , Substituição de Aminoácidos , Fator V/genética , Fator V/metabolismo , Feminino , Humanos , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/tratamento farmacológico , Síndrome de Klinefelter/genética , Masculino , Artérias Mesentéricas , Pessoa de Meia-Idade , Protrombina/genética , Protrombina/metabolismo , Embolia Pulmonar/sangue , Embolia Pulmonar/induzido quimicamente , Fatores de Risco , Testosterona/administração & dosagem , Trombofilia/sangue , Trombofilia/induzido quimicamente , Trombofilia/genética , Trombose Venosa/sangue , Trombose Venosa/induzido quimicamente , Trombose Venosa/genética
16.
Acta Pol Pharm ; 74(3): 987-994, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-29513969

RESUMO

Our aim of the present study was to evaluate the anticoagulant effect of sulfated polysaccharides (SPS) from Codium dwarkense Bergesen in ic-carrageenan induced hypercoagulable state in Wistar albino rats. 48 Wistar albino rats of either sex were randomly divided into 6 groups - disease control, active control, treatment lowmand high dose and preventive low and high dose. K-Carrageenan (3 mg/kg) single dose intravenously was given in rat tail vein at pre-decided time to produce hypercoagulable state. Baseline, 24, 48 and 72 hours duration blood samples were collected for PT, INR, aPTT, platelet count and fibrinogen level, FDP and D-Dimer measurements. At the end of experiment, animals were sacrificed for histopathology analysis of lung, liver and mesentery. Sulfated polysaccharide (SPS) significantly restored altered coagulation parameters (PT, INR, aPTI, platelet count and fibrinogen level) without affecting fibrinolytic parameters (FDP and D-Dimer). Administration of SPS both as a treatment and preventive therapy reduced the number of microthrombi along with less structural damage in histopathology of lung, liver and mesentery. Heparin served as active control and its administration significantly prolonged aPT' and restored PT. This study shows, anticoagulant activity of SPS extracted from Codium dwarkense Bergesen in Wistar albino rats.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Carragenina , Clorófitas/química , Polissacarídeos/farmacologia , Trombofilia/tratamento farmacológico , Trombose/prevenção & controle , Animais , Anticoagulantes/isolamento & purificação , Biomarcadores/sangue , Testes de Coagulação Sanguínea , Feminino , Masculino , Camundongos , Polissacarídeos/isolamento & purificação , Ratos Wistar , Trombofilia/sangue , Trombofilia/induzido quimicamente , Trombose/sangue , Trombose/induzido quimicamente , Fatores de Tempo
17.
Am J Pathol ; 186(5): 1221-33, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26968340

RESUMO

Tuberculosis (TB) remains a global health concern. Trehalose 6'6-dimycolate (TDM) activates innate inflammation and likely also stimulates chronic inflammation observed during disease progression. Noninfectious models using purified TDM oil/water emulsions elicit pathologic findings observed in patients with TB. We introduce a new TDM model that promotes inflammatory lung pathologic findings and vascular occlusion and hemorrhage. C57BL/6 and BALB/c mice were injected with 10 µg of i.p. TDM in light mineral oil (TDM-IP). At day 7, another injection of 10 µg of i.v. TDM in oil/water emulsion was given (TDM-IV). The i.p./i.v. TDM (TDM-IVIP) group was compared with mice injected once with i.v. or i.p. TDM. The responses to TDM-IP, TDM-IV, or TDM-IPIV were consistent between mouse strains. Mice that received TDM-IV and TDM-IPIV had inflammatory pathologic findings with increases in inflammatory and T-cell cytokines, and the TDM-IPIV group had further enhancement of IL-10 and granulocyte-macrophage colony-stimulating factor. The TDM-IPIV group had increased CD4(+) T cells in lung tissue, significantly increased coagulation, decreased clot formation time, and increased maximum clot firmness. Masson's trichrome staining revealed increased deposition of collagen in the occluded vasculature. TDM-IPIV promotes a hypercoagulopathy state, independent of inflammation. This new model argues that TDM is sufficient to generate the hypercoagulopathy observed in patients with TB.


Assuntos
Adjuvantes Imunológicos/toxicidade , Fatores Corda/toxicidade , Trombofilia/induzido quimicamente , Animais , Antígenos CD/metabolismo , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Imunidade Inata/efeitos dos fármacos , Pulmão/irrigação sanguínea , Pulmão/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Neutrófilos/imunologia , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/patologia , Pneumopatia Veno-Oclusiva/induzido quimicamente , Pneumopatia Veno-Oclusiva/imunologia , Pneumopatia Veno-Oclusiva/patologia , Tromboelastografia/métodos , Trombofilia/imunologia , Trombofilia/patologia
18.
Am J Hematol ; 91(5): E293-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26910388

RESUMO

In patients with immune thrombocytopenia (ITP) refractory to corticosteroids and intravenous immunoglobulins (IVIG), splenectomy may result at higher risk of peri-operative complications and, for this reason, potentially contraindicated. The thrombopoietin receptor agonists (TPO-RAs) romiplostim and eltrombopag have shown high therapeutic activity in primary ITP, but data of efficacy and safety regarding their use in preparation for splenectomy are missing. Thirty-one adult patients, median age 50 years, with corticosteroids and/or IVIG refractory persistent and chronic ITP who were treated with TPO-RAs (romiplostim= 24; eltrombopag= 7) with the aim to increase platelet count and allow a safer execution of splenectomy were retrospectively evaluated. Twenty-four patients (77%) responded to the use of TPO-RAs with a median platelet count that increased from 11 × 10(9) /L before starting TPO-RAs to 114 × 10(9) /L pre-splenectomy, but a concomitant treatment with corticosteroids and/or IVIG was required in 19 patients. Twenty-nine patients underwent splenectomy while two patients who responded to TPO-RAs subsequently refused surgery. Post-splenectomy complications were characterized by two Grade 3 thrombotic events (1 portal vein thrombosis in the patient with previous history of HCV hepatitis and 1 pulmonary embolism), with a platelet count at the time of thrombosis of 260 and 167 × 10(9) /L, respectively and one Grade 3 infectious event. TPO-RAs may represent a therapeutic option to improve platelet count and reduce the risk of peri-operative complications in ITP candidates to splenectomy. An increased risk of post-splenectomy thromboembolic events cannot be ruled out and thromboprophylaxis with low-molecular weight heparin is generally recommended.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Pré-Medicação , Cuidados Pré-Operatórios/métodos , Púrpura Trombocitopênica Idiopática/cirurgia , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Esplenectomia , Trombopoese/efeitos dos fármacos , Trombopoetina/uso terapêutico , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Terapia Combinada , Resistência a Medicamentos , Feminino , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Imunoglobulinas Intravenosas/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Veia Porta , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Embolia Pulmonar/induzido quimicamente , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Estudos Retrospectivos , Terapia de Salvação , Trombofilia/induzido quimicamente , Trombopoetina/administração & dosagem , Trombopoetina/efeitos adversos , Trombose Venosa/induzido quimicamente , Trombose Venosa/etiologia , Trombose Venosa/prevenção & controle , Adulto Jovem
19.
Blood Coagul Fibrinolysis ; 27(6): 717-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26588446

RESUMO

A 20-year-old male with asymptomatic inherited type 1 antithrombin deficiency and a family history of thrombosis started injecting himself with testosterone 250 mg intramuscularly twice weekly for 5 weeks. He presented to the hospital with progressive dyspnea on exertion, chest pain and hemoptysis. Workup revealed bilateral submassive pulmonary embolism and proximal right lower extremity deep vein thrombosis. He was treated with intravenous (IV) unfractionated heparin and underwent catheter-directed thrombolysis with alteplase to the main pulmonary arteries. Postprocedure, he remained on IV alteplase infusion for 24 h and unfractionated heparin in the intensive care unit. Concomitantly he received plasma-derived antithrombin concentrate. He was transitioned to subcutaneous enoxaparin twice daily and discharged from the hospital on oral rivaroxaban 15 mg twice a day. This case highlights the heightened thrombogenic effect of anabolic steroids in the setting of underlying thrombophilia especially in younger subjects.


Assuntos
Fibrinolíticos/uso terapêutico , Congêneres da Testosterona/efeitos adversos , Testosterona/efeitos adversos , Terapia Trombolítica/métodos , Trombofilia/induzido quimicamente , Antitrombinas/sangue , Dor no Peito/sangue , Dor no Peito/induzido quimicamente , Dor no Peito/tratamento farmacológico , Dispneia/sangue , Dispneia/induzido quimicamente , Dispneia/tratamento farmacológico , Enoxaparina/uso terapêutico , Hemoptise/sangue , Hemoptise/induzido quimicamente , Hemoptise/tratamento farmacológico , Humanos , Injeções Intramusculares , Masculino , Embolia Pulmonar/sangue , Embolia Pulmonar/induzido quimicamente , Embolia Pulmonar/tratamento farmacológico , Trombofilia/sangue , Trombofilia/congênito , Trombofilia/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Trombose Venosa/sangue , Trombose Venosa/induzido quimicamente , Trombose Venosa/tratamento farmacológico , Adulto Jovem
20.
J Thromb Haemost ; 13(9): 1568-75, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26178535

RESUMO

BACKGROUND: Myocardial infarction (MI) and ischemic stroke (IS) are acute forms of arterial thrombosis and share some, but not all, risk factors, indicating different pathophysiological mechanisms. OBJECTIVE: This study aims to determine if hypercoagulability has a differential effect on the risk of MI and IS. PATIENTS AND METHODS: We reviewed the results from the Risk of Arterial Thrombosis in Relation to Oral Contraceptives study, a population-based case-control study involving young women (< 50 years) with MI, non-cardioembolic IS and healthy controls. From these data, relative odds ratios (ORIS /ORMI ) and their corresponding confidence intervals for all prothrombotic factors that were studied in both subgroups were calculated. RESULTS: Twenty-nine prothrombotic risk factors were identified as measures of hypercoagulability. Twenty-two of these risk factors (21/29, 72%) had a relative odds ratios > 1; for 12 (41%), it was > 2; and for 5 (17%), it was > 2.75. The five risk factors with the largest differences in associations were high levels of activated factor XI (FXI) and FXII, kallikrein, the presence of lupus anticoagulans, and a genetic variation in the FXIII gene. CONCLUSION: In young women, prothrombotic factors are associated more with the risk of IS than with MI risk, suggesting a different role of hypercoagulability in the mechanism leading to these two diseases.


Assuntos
Isquemia Encefálica/epidemiologia , Infarto do Miocárdio/epidemiologia , Trombofilia/epidemiologia , Adulto , Fatores Etários , Isquemia Encefálica/etiologia , Estudos de Casos e Controles , Comorbidade , Intervalos de Confiança , Anticoncepcionais Orais/efeitos adversos , Diabetes Mellitus/epidemiologia , Fator XIII/genética , Fator XIIa/análise , Fator XIa/análise , Feminino , Mortalidade Hospitalar , Humanos , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Calicreínas/análise , Inibidor de Coagulação do Lúpus/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Países Baixos/epidemiologia , Razão de Chances , Risco , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Trombofilia/sangue , Trombofilia/induzido quimicamente , Trombofilia/complicações , Adulto Jovem
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