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1.
Eur Rev Med Pharmacol Sci ; 26(17): 6050-6056, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36111904

RESUMO

OBJECTIVE: The pre-analysis processing method of serum samples plays a very important role in the assurance of the quality of the entire test and the accuracy of the results. This study illustrates the importance of pretreatment methods of serum samples for the test results by comparing the effects of different pretreatment methods on the measurement of thyroid stimulating hormone (TSH) concentration in serum. SUBJECTS AND METHODS: In this study, the concentrations of TSH of 37 patients' serum, which were treated in six different ways including the reverse mixing times after blood collection, clotting time and conditions, centrifugal speed and time, were detected on Automatic Chemiluminescence Immunoassay Analyzer, and a comparative analysis of the different results was performed. RESULTS: For serum samples containing coagulants, the test results were significantly affected if the samples were not reversed mixing after collection. The abnormal results would be obtained with insufficient coagulation time, low reaction temperature, low centrifuge speed and insufficient centrifugation time. CONCLUSIONS: The pre-analysis processing of serum samples is the beginning of the entire inspection process. The quality of the entire inspection will not be guaranteed if the pre-analysis processing method is irregular. Therefore, clinical laboratories should pay more attention to the pretreatment process of samples to ensure the quality of the entire inspection process.


Assuntos
Antineoplásicos , Coagulantes , Humanos , Medições Luminescentes , Tireotropina
2.
Mult Scler Relat Disord ; 62: 103775, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35417817

RESUMO

BACKGROUND: The strong link between innate immunity and thrombosis/coagulation has recently been investigated in the light of antibodies directed against serine proteases of the coagulation pathway. The antibodies have been proposed as contributing factors to venous thromboembolism development and as key molecules in the initiation of signaling inflammatory pathways in neuroinflammatory diseases. Preliminary studies of Multiple Sclerosis (MS) progression characteristics with the reactivity of antibodies against coagulant components are limited. Considering the development of thrombosis at the early onset of MS, our study aimed to detect antibodies against coagulant components in MS and evaluate their possible association with the clinical profile of the disease. METHOD: A cross-sectional study was carried out to identify antibodies to factor(F)VIIa, thrombin, prothrombin, FXa, FXII, plasmin, and protein C in serum samples from 167 patients with MS and 40 healthy controls using the enzyme-linked immunosorbent assay. Statistical analysis was performed for the evaluation of the data. RESULTS: The analysis revealed a significantly higher prevalence of IgG in MS patients (n = 72, 43%) compared to HCs (n = 8, 20%, p < 0.01). Specifically, elevated anti-FVIIa (n = 19, 11.4%, mean activity p < 0.0001), anti-FXII (n = 12, 7.2%, mean activity p < 0.001) and anti-plasmin (n = 20, 12%, mean activity p < 0.01) levels were observed in patients compared to controls. Additionally, the highest scores of clinical characteristics like the expanded disability status scale and MS severity score were linked with IgG seropositivity against thrombin, whilst anti-FXII levels corresponded with the lowest disease progression. CONCLUSION: The findings of our study illustrate the presence of antibodies against serine proteases of the coagulation cascade in MS and demonstrate the association of antibody activity with disease progression. In particular, thrombin IgG seropositivity was demonstrated to be associated with worse outcomes and a severe disease phenotype. These observations suggest the implication of antibodies in patient monitoring and prognosis, and further evaluation may elucidate inflammatory cascades in which antibodies act as key mediators.


Assuntos
Coagulantes , Esclerose Múltipla , Trombose , Autoanticorpos , Coagulação Sanguínea , Estudos Transversais , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G , Trombina
3.
Platelets ; 33(7): 1065-1074, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-35285383

RESUMO

Prostacyclin (PGI2) analogues (epoprostenol, treprostonil, iloprost) are the cornerstone of pulmonary arterial hypertension (PAH) treatment. PGI2 analogues inhibit platelet reactivity, but their impact on coagulation and fibrinolysis parameters has not been elucidated. We compared platelet reactivity, thrombin generation, clot permeation, and lysis properties in patients with PAH treated with PGI2 analogues (n = 20) and those not receiving PGI2 analogues (n = 20). Platelet reactivity was lower in patients treated with PGI2 analogues, compared to the control group, as evaluated with arachidonic acid (ASPI), adenosine diphosphate (ADP), and thrombin receptor-activating peptide-6 (TRAP) tests (p = .009, p = .02, p = .007, respectively). In the subgroup analysis, both treprostinil and epoprostenol decreased platelet reactivity to the similar extent. There were no differences regarding thrombin generation, clot permeation, and lysis parameters in patients receiving and not receiving PGI2 analogues (p ≥ .60 for all). In the subgroup analysis, there were no differences regarding coagulation and fibrinolysis parameters between treprostinil, epoprostenol, and no PGI2 analogues. To conclude, patients with PAH treated with PGI2 analogues have reduced platelet reactivity, but similar clot formation and lysis parameters, compared to patients not receiving PGI2 analogues. Further randomized clinical trials are required to confirm these findings.


Assuntos
Carica , Coagulantes , Hipertensão Arterial Pulmonar , Coagulantes/farmacologia , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Fibrina , Fibrinólise , Humanos , Agregação Plaquetária , Prostaglandinas I/farmacologia , Trombina/farmacologia
4.
Carbohydr Polym ; 282: 119132, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35123764

RESUMO

Chitosan has many desirable attributes e.g. antimicrobial properties and promoting wound healing, and is used in various applications. This article first discusses how degree of deacetylation (DD) and molecular weight (MW) impacts on what level of bioactivities chitosan manifests, then introduces the "molecular chain configuration" model to explain various possible mechanisms of antimicrobial interactions between chitosan with different MW and different types of bacteria. Similarly, the possible pathways of how chitosan reacts with cancer and the body's immune system to demonstrate immune and antitumor effects are also discussed by using this model. Moreover, the possible mechanisms of how chitosan enhances coagulation and wound healing are also discussed. With these beneficial bioactivities in mind, the application of chitosan in surgery, tissue engineering and oncology is outlined. This review concludes that as chitosan demonstrates many beneficial bioactivities via multiple mechanisms, it is an important polymer with a promising future in medicine.


Assuntos
Quitosana , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Quitosana/química , Quitosana/farmacologia , Quitosana/uso terapêutico , Coagulantes/química , Coagulantes/farmacologia , Coagulantes/uso terapêutico , Humanos , Estrutura Molecular
5.
Sci Rep ; 12(1): 1814, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110612

RESUMO

Data on the use of activated prothrombin complex concentrate (aPCC) for the management of warfarin associated major bleeding is sparse. The objective of the study was to assess the achievement of effective clinical hemostasis using aPCC in patients presenting with major bleeding while on warfarin. We also assessed the safety of the drug. This retrospective study was conducted at a tertiary care teaching center in the USA where patients with major bleeding while receiving warfarin, and received aPCC were included. Efficacy of aPCC in achieving effective hemostasis was assessed according to the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. Efficacy was also assessed by achieving INR < 1.5 after treatment. The primary safety endpoint was the occurrence of any thromboembolic complications. A total of 67 patients were included in the study. The most common site for bleeding was intracerebral hemorrhage (n = 37, 55.2%), followed by gastrointestinal bleed (n = 26, 38.8%). Clinical hemostasis was achieved in 46 (68.7%) patients and of the 21 (31.3%) patients who did not achieve clinical hemostasis, 16 died. Thirty nine (58.2%) patients achieved INR < 1.5. Five (7.5%) patients developed thromboembolic complications. This study suggests that the use of aPCCs is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding.


Assuntos
Anticoagulantes/efeitos adversos , Fatores de Coagulação Sanguínea/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Coagulantes/uso terapêutico , Hemorragia Gastrointestinal/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Varfarina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Fatores de Coagulação Sanguínea/efeitos adversos , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/mortalidade , Coagulantes/efeitos adversos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/mortalidade , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tromboembolia/etiologia , Fatores de Tempo , Resultado do Tratamento
6.
Orthop Surg ; 14(1): 27-34, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34841675

RESUMO

OBJECTIVE: To evaluate the operative methods and clinical results of surgical treatment in a case series of 10 patients with hemophilic pseudotumors. METHODS: Ten patients with hemophilic pseudotumors who received surgical resection treatment in our hospital from October 2017 to June 2020 were retrospectively reviewed. All patients were hemophilia A (factor VIII deficiency).The age range was 20-51 years. Preoperative imaging examination revealed the size of irregular mass from 8.2 cm× 3.3 cm× 2.3 cm to 22.3 cm× 15.5 cm× 17.0 cm. With the supplementary of recombinant coagulation factor VIII, five cases received complete resection; one received resection and skin grafting; one received cytoreduction surgery as the pseudotumor closing to iliac vessel and nerve; three cases received complete resection and construction as bone destruction. The perioperative variables were recorded and all the patients were followed in the outpatient clinic. Clinical and radiological assessments were conducted. RESULTS: In these patients, the average intraoperative blood loss volume was 783.1 mL (range, 240-2100 mL). Six patients received blood transfusion during perioperative period. The average duration of surgery was 140.7 min (range, 110-240 min). All wounds healed smoothly and there was no infection or chronic sinus formation. The average length of hospital stay was 16.3 days (range, 12-25 days). There is no iatrogenic vascular nerve injury in our series. Complete follow-up was performed in all patients. Mean follow-up duration was 14.2 months (range, 6-26 months). One patient with pseudotumor in the thigh had a recurrence 1 year after operation, then secondary operation was performed. In three cases who received complete resection and construction, patient 8 obtained bone graft and late fixation. X-ray examination showed bone formation in the lesion at the 2-year follow-ups after operation. Patient 9 underwent knee replacement, his left knee showed flexion deformity in preoparation. At the last follow-up, range of motion was improved from 0° to 40° compared with preoperative status. Patient 10 had pseudotumor in the distal femur, received long bone graft and intramedullary nail fixation. CONCLUSIONS: Surgical resection for hemophilic pseudotumors is an effective and safe method. The choice of surgical procedure must be individualized according to the localization and progress of pseudotumor.


Assuntos
Doenças Ósseas/cirurgia , Hemofilia A/complicações , Adulto , Perda Sanguínea Cirúrgica , Doenças Ósseas/diagnóstico por imagem , Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Feminino , Hemofilia A/tratamento farmacológico , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
7.
Diagn Microbiol Infect Dis ; 102(2): 115592, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34839128

RESUMO

Staphylococcus pettenkoferi is a recently described coagulase-negative staphylococcal pathogen. We retrospectively reviewed 25 cases in which S. pettenkoferi was identified in routine cultures (12 blood, 13 other). Most were found with commensal flora and considered clinically insignificant, but its significance was uncertain in two cases from non-healing, deep foot wounds.


Assuntos
Antibacterianos/uso terapêutico , Coagulase/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Sepse/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/epidemiologia , Staphylococcus/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Coagulantes/uso terapêutico , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos , Sepse/epidemiologia , Centros de Atenção Terciária/estatística & dados numéricos , Atenção Terciária à Saúde/estatística & dados numéricos , Estados Unidos/epidemiologia
8.
Surg Clin North Am ; 102(1): 53-63, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34800389

RESUMO

An increasing number of patients are on anticoagulation for a variety of indications. Patients on anticoagulation who present to the hospital with life-threatening hemorrhage, whether trauma related or not, must be assessed for the reversal of anticoagulation. Identification of the type of anticoagulation, the timing of the most recent usage of anticoagulation, and the efficacy of the anticoagulation all have an impact on whether reversal agents should be used. There are a variety of reversal agents, both nonspecific and specific, that could be used for reversal; however, not all reversal agents work for all anticoagulation medication. As more anticoagulation medications are used and indications expand, providers must be aware of the reversal agents available and the efficacy and indications for these reversal agents.


Assuntos
Anticoagulantes/efeitos adversos , Coagulantes/uso terapêutico , Cuidados Críticos/métodos , Serviços Médicos de Emergência/métodos , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Assistência Perioperatória/métodos , Estado Terminal , Esquema de Medicação , Emergências , Hemorragia/etiologia , Humanos , Procedimentos Cirúrgicos Operatórios , Ferimentos e Lesões/complicações , Ferimentos e Lesões/terapia
9.
Int J Mol Sci ; 22(22)2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34830348

RESUMO

Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.


Assuntos
Afibrinogenemia/genética , Fibrinogênio/química , Doença de Parkinson/genética , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/química , alfa-Sinucleína/química , Afibrinogenemia/tratamento farmacológico , Afibrinogenemia/metabolismo , Afibrinogenemia/patologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Coagulantes/uso terapêutico , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Fibrinogênio/genética , Fibrinogênio/metabolismo , Regulação da Expressão Gênica , Humanos , Fígado/metabolismo , Fígado/patologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Inibidores de Proteases/uso terapêutico , Agregados Proteicos/efeitos dos fármacos , Dobramento de Proteína/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Deficiência de alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/patologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
10.
ACS Appl Mater Interfaces ; 13(37): 44013-44027, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34494427

RESUMO

Synergetic therapy includes the combination of two or more conventional therapeutic approaches and can be used for tumor treatment by combining the advantages and avoiding the drawbacks of each type of treatment. In the present study, truncated tissue factor (tTF)-EG3287 fusion protein-encapsulated gold nanorod (GNR)-virus-inspired mesoporous silica core-shell nanoparticles (vinyl hybrid silica nanoparticles; VSNP) (GNR@VSNP-tTF-EG3287) were synthesized to achieve synergetic therapy by utilizing selective vascular thrombosis therapy (SVTT) and photothermal therapy (PTT). By integrating the targeted coagulation activity of tTF-EG3287 and the high tumor ablation effect of GNR@VSNP, local hyperthermia could induce a high percentage of apoptosis of vascular endothelial cells by using near-infrared light. This provided additional phospholipid sites for tTF-EG3287 and enhanced its procoagulant activity in vitro. In addition, the nanoparticles, which had unique topological viral structures, exhibited superior cellular uptake properties leading to significant antitumor efficacy. The in vivo antitumor results further demonstrated an interaction between SVTT and PTT, whereas the synergetic therapy (SVTT and PTT) achieved an enhanced effect, which was superior to the respective treatment efficacy of each modality or the additive effect of their individual efficacies. In summary, the synthesized GNR@VSNP-tTF-EG3287 exerted synergetic effects and enhanced the antitumor efficiency by avoiding multiple injections and suboptimal administration. These effects simultaneously affected both tumor blood supply and cancer cell proliferation. The data suggested that the integration of SVTT induced by tTF-EG3287 and PTT could provide potential strategies for synergetic tumor therapy.


Assuntos
Antineoplásicos/uso terapêutico , Coagulantes/uso terapêutico , Nanotubos/química , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Coagulantes/química , Feminino , Ouro/química , Ouro/efeitos da radiação , Ouro/toxicidade , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanotubos/efeitos da radiação , Nanotubos/toxicidade , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Terapia Fototérmica , Porosidade , Coelhos , Proteínas Recombinantes de Fusão/química , Dióxido de Silício/química , Dióxido de Silício/efeitos da radiação , Dióxido de Silício/toxicidade , Tromboplastina/química , Tromboplastina/uso terapêutico , Trombose/induzido quimicamente , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Toxins (Basel) ; 13(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34437385

RESUMO

Snakebite envenomation is a serious neglected tropical disease, and its management is often complicated by the diversity of snake venoms. In Asia, pit vipers of the Ovophis species complex are medically important venomous snakes whose venom properties have not been investigated in depth. This study characterized the venom proteomes of Ovophis convictus (West Malaysia), Ovophis tonkinensis (northern Vietnam, southern China), and Ovophis okinavensis (Okinawa, Japan) by applying liquid chromatography-tandem mass spectrometry, which detected a high abundance of snake venom serine proteases (SVSP, constituting 40-60% of total venom proteins), followed by phospholipases A2, snake venom metalloproteinases of mainly P-III class, L-amino acid oxidases, and toxins from other protein families which were less abundant. The venoms exhibited different procoagulant activities in human plasma, with potency decreasing from O. tonkinensis > O. okinavensis > O. convictus. The procoagulant nature of venom confirms that consumptive coagulopathy underlies the pathophysiology of Ovophis pit viper envenomation. The hetero-specific antivenoms Gloydius brevicaudus monovalent antivenom (GbMAV) and Trimeresurus albolabris monovalent antivenom (TaMAV) were immunoreactive toward the venoms, and cross-neutralized their procoagulant activities, albeit at variably limited efficacy. In the absence of species-specific antivenom, these hetero-specific antivenoms may be useful in treating coagulotoxic envenomation caused by the different snakes in their respective regions.


Assuntos
Crotalinae , Proteoma , Proteínas de Répteis , Venenos de Víboras , Animais , Antivenenos/imunologia , Coagulantes/análise , Coagulantes/imunologia , Coagulantes/toxicidade , Humanos , L-Aminoácido Oxidase/análise , L-Aminoácido Oxidase/imunologia , L-Aminoácido Oxidase/toxicidade , Metaloproteases/análise , Metaloproteases/imunologia , Metaloproteases/toxicidade , Fosfolipases A2/análise , Fosfolipases A2/imunologia , Fosfolipases A2/toxicidade , Plasma/efeitos dos fármacos , Proteoma/análise , Proteoma/imunologia , Proteoma/toxicidade , Proteômica , Proteínas de Répteis/análise , Proteínas de Répteis/imunologia , Proteínas de Répteis/toxicidade , Serina Proteases/análise , Serina Proteases/imunologia , Serina Proteases/toxicidade , Venenos de Víboras/química , Venenos de Víboras/imunologia , Venenos de Víboras/toxicidade
12.
Rinsho Ketsueki ; 62(7): 781-789, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34349063

RESUMO

Blood coagulation factor VIII (FVIII) functions as a cofactor for activated factor IX on the phospholipid membrane in the coagulation reaction. FVIII deficiency causes hemophilia A, and conversely, the thrombotic patients show high FVIII levels. Therefore, FVIII is a key coagulant factor involved in the contradictory pathology of hemorrhage and thrombosis. From the crystal structure of the FVIII molecule and bispecific antibody that substitutes for FVIII cofactor function, FVIIIa function and role on the FXase complex are drawing attention. It has been also supported that a concept that the extrinsic coagulation system involved in the initial phase of the coagulation process, the intrinsic coagulation system involved in the thrombin burst, the anti-coagulation system by activated protein C pathway, and the fibrinolytic system involved the dissolving fibrin clot intertwine each other and progress during the coagulation reaction process. FVIII-related FVIIa coagulation system and FVIII-related plasmin regulation system have been also elucidated. We greatly expect that the developmental elucidation of thrombus formation mechanism (s) centered on FVIII/FVIIIa could lead to the development of more effective new FVIII product and antithrombotic drugs.


Assuntos
Coagulantes , Hemofilia A , Hemostáticos , Coagulação Sanguínea , Coagulantes/farmacologia , Fator VIII , Hemofilia A/tratamento farmacológico , Hemostasia , Humanos
13.
Clin Chem Lab Med ; 59(10): 1699-1708, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34192831

RESUMO

OBJECTIVES: Patients hospitalized because of community-acquired-pneumonia (CAP) are at risk of cardiovascular diseases. Although plasma procoagulant imbalance play a role, mechanisms are not completely understood. We aimed to investigate whether there is a measurable state of procoagulant imbalance following inflammation determined by CAP. METHODS: We analyzed blood from 51 CAP patients at admission and 51 healthy subjects (HS) for (i) pro and anticoagulants, (ii) thrombin generation (TG) with or without thrombomodulin (TM), which is the physiologic activator of the protein C anticoagulant pathway and(iii) by assessing the ratio between von Willebrand-factor (VWF) and its protease ADAMTS13. Thirty patients were re-analyzed one month after discharge when CAP was resolved. RESULTS: Median levels of TG parameters, including the endogenous thrombin potential (ETP), the ETP-TM-ratio (with/without TM), peak-thrombin and velocity index were higher in patients at baseline than HS. In particular, the median (IQR) ETP-TM-ratio in patients vs. HS was 0.88 (0.83-0.91) vs. 0.63 (0.48-0.71), p<0.001. Factor (F)VIII, a potent procoagulant involved in TG was higher in patients at baseline than HS [195 U/dL (100-388) vs. 127(108-145)], p<0.001]. The ratio of VWF/ADAMTS13 was higher at baseline than HS. Cumulatively, the findings indicate a state of pro-coagulant imbalance, which (although reduced), remained high [i.e., ETP-TM-ratio, 0.80 (0.74-0.84); FVIII, 152 U/dL (122-190)] one month after discharge when the infection was resolved. CONCLUSIONS: Patients with CAP possess a state of pro-coagulant imbalance, which remains substantially high, even when the infection is resolved. The findings suggest CAP patients as candidates for antithrombotic prophylaxis even after the resolution of infection. Clinical trials are warranted to assess the benefit/risk ratio of prophylaxis extension.


Assuntos
Coagulantes , Pneumonia , Fator VIII/metabolismo , Hospitais , Humanos , Alta do Paciente , Pneumonia/complicações , Trombina
14.
Lancet Haematol ; 8(7): e492-e502, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34171280

RESUMO

BACKGROUND: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual. FINDINGS: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred. INTERPRETATION: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care. FUNDING: Dutch Research Council (NWO)-ZonMw and Takeda.


Assuntos
Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Adulto , Coagulantes/farmacocinética , Esquema de Medicação , Procedimentos Cirúrgicos Eletivos , Fator VIII/farmacocinética , Hemofilia A/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Índice de Gravidade de Doença , Resultado do Tratamento
15.
Rev. cuba. med. mil ; 50(2): e766, 2021.
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1341431

RESUMO

Introducción: Las innovadoras estrategias para la estimación del riesgo cardiovascular que apelan al empleo de biomarcadores cardiacos de aterotrombosis, han evidenciado ser superiores en la estratificación del riesgo cardiovascular por encima de aquellas predicciones basadas exclusivamente en la evaluación de factores de riesgo tradicionales de manera aislada. Se realizó una revisión bibliográfica, análisis y categorización de diferentes artículos en las bases de datos Cumed, Lilacs, SciELO, Medline, los términos clave para la búsqueda fueron: homocisteína, lipoproteína (a) y riesgo cardiovascular, en español, inglés y portugués. Se consideraron artículos originales, de revisión, incluyendo revisiones sistemáticas y metaanálisis posteriores al año 2000. Objetivo: Analizar los biomarcadores cardiacos de aterotrombosis, involucrados en el desarrollo de la enfermedad cardiovascular aterosclerótica y sus complicaciones trombóticas. Desarrollo: La evidencia acumulada sustenta que biomarcadores cardiacos como la hiperhomocisteinemia, la hiperlipoproteinemia (a), el incremento de los niveles plasmáticos del fibrinógeno, el factor VII coagulante, el inhibidor del activador tisular del plasminógeno tipo 1 y la proteína C reactiva, son herramientas de gran utilidad para estratificar el riesgo cardiovascular en individuos de riesgo intermedio, o con riesgo inusual o de riesgo indefinido, esencialmente en el ámbito de la prevención primaria y secundaria de la enfermedad cardiovascular . Conclusiones: La identificación de biomarcadores emergentes de aterotrombosis predictivos adicionales, es trascendental para una prevención y terapéutica más eficaz de la enfermedad cardiovascular aterosclerótica(AU)


Introduction: Innovative cardiovascular risk estimation strategies that use cardiac biomarkers of atherothrombosis have been shown to be superior in cardiovascular risk stratification that those predictions based exclusively on the evaluation of traditional risk factors in isolation. A bibliographic review, analysis and categorization of different articles was performed in the databases Cumed, Lilacs, Scielo, Medline, the key terms for the search were: "homocysteine", "lipoprotein (a)" and "cardiovascular risk", in Spanish, English and Portuguese languages. Original review articles were considered, including systematic reviews and published meta-analyzes after 2000. Objective: To analyze some of the cardiac biomarkers of atherothrombosis that may be involved in the development of atherosclerotic cardiovascular disease and its thrombotic complications. Development: Accumulated evidence supports that cardiac biomarkers such as: hyperhomocysteinemia, hyperlipoproteinemia (a), increased plasma fibrinogen levels, coagulant factor VII, Plasminogen Tissue Activator Inhibitor type 1 and C-reactive protein are tools of Very useful for stratifying cardiovascular risk in those individuals with intermediate risk, or with unusual or undefined risk, essentially in the field of primary and secondary prevention of cardiovascular disease. Conclusions: The identification of additional predictive emergent atherothrombosis biomarkers is crucial for a more effective prevention and therapy of atherosclerotic cardiovascular disease(AU)


Assuntos
Humanos , Prevenção Primária , Coagulantes , Biomarcadores , Doenças Cardiovasculares , Hiper-Homocisteinemia , Hiperlipoproteinemias , Fatores de Risco , Fatores de Risco de Doenças Cardíacas
16.
Crit Care Med ; 49(10): e1025-e1036, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33967205

RESUMO

OBJECTIVES: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies. DATA SOURCES: Embase, Pubmed, Web of Science, and the Cochrane Library. STUDY SELECTION: Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage. DATA EXTRACTION: Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event. DATA SYNTHESIS: A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents. CONCLUSIONS: Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines.


Assuntos
Inibidores do Fator Xa/efeitos adversos , Fator Xa/farmacologia , Hemorragia/tratamento farmacológico , Protrombina/farmacologia , Proteínas Recombinantes/farmacologia , Coagulantes/administração & dosagem , Coagulantes/farmacologia , Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacologia , Humanos , Protrombina/administração & dosagem , Proteínas Recombinantes/administração & dosagem
17.
J Manag Care Spec Pharm ; 27(8): 996-1008, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33843253

RESUMO

BACKGROUND: The landscape for hemophilia A prophylaxis is rapidly expanding from factor VIII replacement therapy to include novel treatments such as nonfactor replacement therapies that may enhance coagulation (e.g., emicizumab) or inhibit anticoagulant pathways (e.g., fitusiran and concizumab). For payers, this expansion presents challenges in balancing well-established treatments with new options that cost more and have lesser known real-world safety and efficacy. OBJECTIVE: To evaluate likely coverage practices for hemophilia A prophylaxis therapies among U.S. payers given evolving real-world data on safety and efficacy. METHODS: A 3-round modified Delphi process was conducted with representatives of U.S. commercial health plans who had considerable expertise in managing populations of patients with hemophilia. Round 1 consisted of an online questionnaire; round 2 involved an online discussion about the aggregated results from round 1; and round 3 allowed participants to revise their responses from round 1 based on insights gained during round 2. Questions elicited ratings, rankings, and estimates on access restrictions based on given safety and efficacy information for hemophilia A prophylaxis therapies. Consensus was reached if ≥ 74% of panelists (14 of 19) were within 1 SD of the median group estimate during round 3. RESULTS: 19 Payers participated in the research. Among them, 94% dealt with commercial insurance, 94% with Medicare, and 81% with Medicaid; 79% had spent ≥ 5 years in their current role. Panelists reported limited access restrictions on hemophilia A prophylaxis therapies; the most common restrictions were prior authorization (n = 16, 84%) and quantity level limits (n = 13, 67%). Tiering and step therapy were reported by 7 respondents (39%). Respondents agreed that there was an 80% median likelihood that ≥ 9 additional patients with any safety event (e.g., thrombotic event, death) per year would trigger access restrictions, with the median likelihood of restrictions increasing to 95% for another ≥ 10 patients with safety events per year. Respondents also agreed that > 5 thrombotic events requiring treatment per patient per year would have a 98% median likelihood of leading to access restrictions and that ≥ 5 years of real-world safety and efficacy data would be highly likely (95% median likelihood) to affect coverage decisions. Noncoverage was highly unlikely (ranked fifth or sixth of 6 by 14 respondents), as was no restriction-coverage parity (ranked sixth of 6 by 10 respondents). All else being equal, cost continues to affect access policies, with respondents agreeing that a 13%-30% difference in net cost may lead to preferred formulary treatment for a drug with superior efficacy and noninferior safety, inferior efficacy and noninferior safety, or noninferior efficacy and inferior safety. CONCLUSIONS: Payers prefer treatments with well-understood efficacy, safety, and cost over newer treatments with uncertain long-term effects. Relatively unrestricted access to legacy and new hemophilia A prophylaxis will likely continue unless additional real-world safety concerns or major cost differences emerge. DISCLOSURES: Financial support for this study was provided by Takeda Pharmaceutical Company, which was involved in study concept and design. Graf, Tuly, Harley, and Pednekar are employees of PRECISIONheor, a research consultancy to the health and life sciences industries that was contracted by Takeda to conduct this study and write the manuscript. Batt served as a consultant on this project through PRECISIONheor.


Assuntos
Coagulantes/economia , Coagulantes/uso terapêutico , Hemofilia A/tratamento farmacológico , Cobertura do Seguro , Política Organizacional , Técnica Delfos , Custos de Medicamentos , Humanos , Entrevistas como Assunto , Pesquisa Qualitativa , Inquéritos e Questionários , Estados Unidos
18.
Commun Biol ; 4(1): 390, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758337

RESUMO

Coagulation factor IX (FIX) is a complex post-translationally modified human serum glycoprotein and high-value biopharmaceutical. The quality of recombinant FIX (rFIX), especially complete γ-carboxylation, is critical for rFIX clinical efficacy. Bioreactor operating conditions can impact rFIX production and post-translational modifications (PTMs). With the goal of optimizing rFIX production, we developed a suite of Data Independent Acquisition Mass Spectrometry (DIA-MS) proteomics methods and used these to investigate rFIX yield, γ-carboxylation, other PTMs, and host cell proteins during bioreactor culture and after purification. We detail the dynamics of site-specific PTM occupancy and structure on rFIX during production, which correlated with the efficiency of purification and the quality of the purified product. We identified new PTMs in rFIX near the GLA domain which could impact rFIX GLA-dependent purification and function. Our workflows are applicable to other biologics and expression systems, and should aid in the optimization and quality control of upstream and downstream bioprocesses.


Assuntos
Reatores Biológicos , Técnicas de Cultura de Células/instrumentação , Coagulantes/isolamento & purificação , Meios de Cultura/metabolismo , Fator IX/isolamento & purificação , Células Cultivadas , Cromatografia de Fase Reversa , Humanos , Conformação Proteica , Processamento de Proteína Pós-Traducional , Proteômica , Controle de Qualidade , Proteínas Recombinantes/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Carga de Trabalho
19.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671748

RESUMO

Fibrinogen is the first coagulation protein to reach critically low levels during traumatic haemorrhage. There have been no differential effects on clinical outcomes between the two main sources of fibrinogen replacement: cryoprecipitate and fibrinogen concentrate (Fg-C). However, the constituents of these sources are very different. The aim of this study was to determine whether these give rise to any differences in clot stability that may occur during trauma haemorrhage. Fibrinogen deficient plasma (FDP) was spiked with fibrinogen from cryoprecipitate or Fg-C. A panel of coagulation factors, rotational thromboelastography (ROTEM), thrombin generation (TG), clot lysis and confocal microscopy were performed to measure clot strength and stability. Increasing concentrations of fibrinogen from Fg-C or cryoprecipitate added to FDP strongly correlated with Clauss fibrinogen, demonstrating good recovery of fibrinogen (r2 = 0.99). A marked increase in Factor VIII, XIII and α2-antiplasmin was observed in cryoprecipitate (p < 0.05). Increasing concentrations of fibrinogen from both sources were strongly correlated with ROTEM parameters (r2 = 0.78-0.98). Cryoprecipitate therapy improved TG potential, increased fibrinolytic resistance and formed more homogeneous fibrin clots, compared to Fg-C. In summary, our data indicate that cryoprecipitate may be a superior source of fibrinogen to successfully control bleeding in trauma coagulopathy. However, these different products require evaluation in a clinical setting.


Assuntos
Transtornos da Coagulação Sanguínea/terapia , Coagulantes/uso terapêutico , Fibrinogênio/uso terapêutico , Hemorragia/complicações , Transtornos da Coagulação Sanguínea/etiologia , Coagulantes/administração & dosagem , Relação Dose-Resposta a Droga , Fator VIII/uso terapêutico , Fibrinogênio/administração & dosagem , Fibrinólise , Hemorragia/terapia , Humanos , Microscopia Confocal , Tromboelastografia , Trombina/metabolismo , Trombose/induzido quimicamente
20.
Thromb Haemost ; 121(10): 1337-1344, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33690868

RESUMO

Platelet activation is characterized by shape change, granule secretion, activation of fibrinogen receptor (glycoprotein IIb/IIIa) sustaining platelet aggregation, and externalization of negatively charged aminophospholipids contributing to platelet procoagulant activity. Epinephrine (EPI) alone is a weak platelet activator. However, it is able to potentiate platelet activation initiated by other agonists. In this work, we investigated the role of EPI in the generation of procoagulant platelets. Human platelets were activated with convulxin (CVX), thrombin (THR) or protease-activated receptor (PAR) agonists, EPI, and combination thereof. Platelet aggregation was assessed by light transmission aggregometry or with PAC-1 binding by flow cytometry. Procoagulant collagen-and-THR (COAT) platelets, induced by combined activation with CVX-and-THR, were visualized by flow cytometry as Annexin-V-positive and PAC-1-negative platelets. Cytosolic calcium fluxes were monitored by flow cytometry using Fluo-3 indicator. EPI increased platelet aggregation induced by all agonist combinations tested. On the other hand, EPI dose-dependently reduced the formation of procoagulant COAT platelets generated by combined CVX-and-THR activation. We observed a decreased Annexin-V-positivity and increased binding of PAC-1 with the triple activation (CVX + THR + EPI) compared with CVX + THR. Calcium mobilization with triple activation was decreased with the higher EPI dose (1,000 µM) compared with CVX + THR calcium kinetics. In conclusion, when platelets are activated with CVX-and-THR, the addition of increasing concentrations of EPI (triple stimulation) modulates platelet response reducing cytosolic calcium mobilization, decreasing procoagulant activity, and enhancing platelet aggregation.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Coagulantes/farmacologia , Epinefrina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Adolescente , Adulto , Idoso , Plaquetas/metabolismo , Sinalização do Cálcio , Venenos de Crotalídeos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Cinética , Lectinas Tipo C , Masculino , Pessoa de Meia-Idade , Glicoproteínas da Membrana de Plaquetas/agonistas , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Ativados por Proteinase/agonistas , Receptores Ativados por Proteinase/metabolismo , Trombina/farmacologia , Adulto Jovem
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