RESUMO
BACKGROUND: Patients with advanced chronic liver disease (ACLD) may develop a prothrombotic phenotype that seems to be more pronounced with more severe liver dysfunction. An imbalance of endogenous pro- and anticoagulants is not fully captured by routine coagulation assays. METHODS: In a cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement, we assessed thrombin generation (TGA) using two commercially available assays (Technothrombin and Thrombinoscope) with and without addition of soluble thrombomodulin (TM), as well as thrombin activity, alongside a panel of coagulation parameters. RESULTS: The cohort encompassed 37 patients (median age 55.3 years, mean HVPG 16 ± 5 mm Hg). In the TM-modified Thrombinoscope TGA, the endogenous thrombin generation potential (ETP) was significantly increased in Child-Pugh-Score (CPS) B/C patients (N = 23, 62 %) compared to CPS A patients (N = 14, 38 %) (ETP: 546 nM∗min (443-696) vs. 404 nM∗min (289-573), p = 0.028). Using the Technothrombin TGA without TM, patients with CPS B/C had decreased ETP compared to CPS A patients (ETP: 2792 ± 1336 nM∗min vs. 5040 ± 816 nM∗min, p < 0.001) and with addition of TM (final concentration: 5 nM; ETP: 2545 ± 1327 nM∗min vs. 4824 ± 929 nM∗min, p < 0.001). Thrombin activity levels were 0.6pM in median (0.2-1.6pM) and above the level of detectability (0.10pM) in 94.6 % of patients but were not correlated to severity of cirrhosis (CPS A 0.7pM vs CPS B/C 0.4pM, p = 0.377) nor to parameters of TGA. CONCLUSION: Thrombin plasma levels are elevated in liver disease patients without apparent correlation to TGA or severity of cirrhosis. TGAs can be modified with TM to enable protein C-dependent anticoagulation, but result in differences with regard to severity of liver disease.
Assuntos
Hipertensão Portal , Trombina , Humanos , Trombina/metabolismo , Cirrose Hepática/complicações , Coagulação Sanguínea , FenótipoRESUMO
Patients with cancer, both hematologic and solid malignancies, are at increased risk for thrombosis and thromboembolism. In addition to general risk factors such as immobility and major surgery, shared by non-cancer patients, cancer patients are exposed to specific thrombotic risk factors. These include, among other factors, cancer-induced hypercoagulation, and chemotherapy-mediated endothelial dysfunction as well as tumor-cell-derived microparticles. After an episode of thrombosis in a cancer patient, secondary thromboprophylaxis to prevent recurrent thromboembolism has long been established and is typically continued as long as the cancer is active or actively treated. On the other hand, primary prophylaxis, even though firmly established in hospitalized cancer patients, has only recently been studied in ambulatory patients. This recent change is mostly due to the emergence of direct oral anticoagulants (DOACs). DOACs have a shorter half-life than vitamin K antagonists (VKA), and they overcome the need for parenteral application, the latter of which is associated with low-molecular-weight heparins (LMWH) and can be difficult for the patient to endure in the long term. Here, first, we discuss the clinical trials of primary thromboprophylaxis in the population of cancer patients in general, including the use of VKA, LMWH, and DOACs, and the potential drug interactions with pre-existing medications that need to be taken into account. Second, we focus on special situations in cancer patients where primary prophylactic anticoagulation should be considered, including myeloma, major surgery, indwelling catheters, or immobilization, concomitant diseases such as renal insufficiency, liver disease, or thrombophilia, as well as situations with a high bleeding risk, particularly thrombocytopenia, and specific drugs that may require primary thromboprophylaxis. We provide a novel algorithm intended to aid specialists but also family practitioners and nurses who care for cancer patients in the decision process of primary thromboprophylaxis in the individual patient.
RESUMO
For patients with hemophilia A, replacement of deficient factor VIII (FVIII) using plasma-derived or recombinant FVIII (rFVIII) products to restore hemostatic control can reduce bleeding complications and preserve musculoskeletal function. Despite the clinical availability of several of these products, challenges remain in the treatment of hemophilia A, the most notable of which are the risk of inhibitor development and the limited half-life of existing FVIII concentrates, which can make prophylaxis burdensome for patients. The use of recombinant protein technology may lead to novel FVIII products with improved properties. This article describes the story of a unique recombinant FVIII protein, rVIII-SingleChain, which is currently in development. In contrast to native FVIII and other commercially available rFVIII preparations, rVIII-SingleChain uses a strong, covalent bond to connect the light and heavy chains, thereby creating a stable, single-chain rFVIII. It has enhanced intrinsic stability, better integrity after reconstitution, and a higher binding affinity to von Willebrand factor. The physicochemical profile of rVIII-SingleChain and preclinical data on its activity and phamacokinetics strengthened the rationale for its clinical investigation. Available data from the AFFINITY clinical trial program are promising; indicating that it has good hemostatic efficacy when used on demand, for prophylaxis, and in the surgical setting, and is also very well tolerated. A pediatric study and an extension study are ongoing as part of the AFFINITY program.
Assuntos
Fator VIII/uso terapêutico , Hemofilia A/terapia , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas Recombinantes/uso terapêuticoRESUMO
Musculoskeletal surgery is associated with a high risk of venous thrombosis and pulmonary embolism. The introduction of direct oral anticoagulants (DOAK) has broadened the possibilities for prevention of venous thromboembolism in the course of orthopedic and trauma surgery. Addressing this recent development, the Austrian Societies of Orthopedics and Orthopedic Surgery (ÖGO), Trauma Surgery (ÖGU), Hematology and Oncology (OeGHO) and of Anaesthesiology, Reanimation und Intensive Care Medicine (ÖGARI) have taken the initiative to create Austrian guidelines for the prevention of thromboembolism after total hip and knee replacement, hip fracture surgery, interventions at the spine and cases of minor orthopedic and traumatic surgery. Furthermore, the pharmacology of the DOAK and the pivotal trial data for each of the three currently available substances - apixaban, dabigatran, and rivaroxaban - are briefly presented. Separate chapters are dedicated to "anticoagulation and neuroaxial anesthesia" and "bridging".
Assuntos
Hematologia/normas , Procedimentos Ortopédicos/efeitos adversos , Procedimentos Ortopédicos/normas , Ortopedia/normas , Guias de Prática Clínica como Assunto , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , ÁustriaRESUMO
Interruption of an ongoing therapy with vitamin K antagonists (VKAs) is necessary in almost all patients undergoing major surgery. The purpose of the following expert recommendations is to provide easy to use guidance for the periprocedural management of patients on VKAs based on current evidence from the literature. Management of anticoagulation during the time of interruption of VKAs is based on balancing the thromboembolic (TE) risk of underlying conditions against the bleeding risk of the surgical procedure. VKAs should be stopped 37days prior to surgery. Low molecular weight heparin (LMWH) is used to cover ("bridge") the progressive pre-operative loss of anticoagulation and the slow post-operative onset of anticoagulant activity of VKAs. Patients with high risk of TE should receive a therapeutic dose of LMWH, patients with a moderate risk of TE should receive half of this dose. Patients with a low risk of TE do not need bridging therapy with LMWH. In case of an uneventful postoperative course, patients with a therapeutic pre-operative dose should be treated post-operatively with the same dose, starting on day 4 in case of major surgery and on day 2 in case of minor procedures. Patients with a half-therapeutic preoperative dose should be treated post-operatively with the same dose, starting on day 3 in case of major surgery and on day 1 in case of minor procedures. Therapy with VKAs should be re-instituted on the second post-operative day based on the preoperative dosage. Procedure-related post-operative thromboprophylaxis should be given irrespective of these recommendations on days without "bridging" anticoagulation.
Assuntos
Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/efeitos adversos , Cuidados Intraoperatórios/normas , Hemorragia Pós-Operatória/induzido quimicamente , Hemorragia Pós-Operatória/prevenção & controle , Tromboembolia/induzido quimicamente , Tromboembolia/prevenção & controle , Cirurgia Geral/normas , Alemanha , Humanos , Guias de Prática Clínica como AssuntoRESUMO
A recombinant fusion protein linking coagulation factor IX (FIX) with human albumin (rIX-FP) has been developed to facilitate hemophilia B treatment by less frequent FIX dosing. This first-in-human dose-escalation trial in 25 previously treated subjects with hemophilia B (FIX ≤ 2 IU/dL) examined the safety and pharmacokinetics of 25, 50, and 75 IU/kg rIX-FP. Patients in the 50-IU/kg cohort underwent a comparative pharmacokinetics assessment with their previous FIX product (plasma-derived or recombinant). No allergic reactions or inhibitors were observed. Four mild, possibly treatment-related adverse events were reported. In the 50-IU/kg cohort (13 subjects), the mean half-life of rIX-FP was 92 hours, more than 5 times longer than the subjects' previous FIX product. After 25 or 50 IU/kg rIX-FP administration, the baseline-corrected mean FIX activity remained elevated at day 7 (7.4 IU/dL and 13.4 IU/dL, respectively) and day 14 (2.5 IU/dL and 5.5 IU/dL, respectively). The incremental recovery of rIX-FP was higher than both recombinant and plasma-derived FIX (1.4 vs 0.95 and 1.1 IU/dL per IU/kg, respectively). These results demonstrated both the safety and improved pharmacokinetics of rIX-FP, thus indicating this new product with extended half-life as possibly able to control and prevent bleeding with less frequent injection.
Assuntos
Albuminas/metabolismo , Fator IX/metabolismo , Hemofilia B/metabolismo , Hemofilia B/terapia , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Feminino , Humanos , Infusões Intravenosas , Masculino , Prognóstico , Estudos Prospectivos , Segurança , Distribuição TecidualRESUMO
Assuntos
Corticosteroides/uso terapêutico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Trombopoetina/agonistas , Estudos Retrospectivos , Trombocitopenia/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Bleeding can be a major problem in patients on oral anticoagulation therapy. Beriplex P/N is a prothrombin complex concentrate (PCC) that has been developed for the rapid reversal of anticoagulation in patients requiring immediate haemostatic control. Beriplex P/N contains high concentrations of the coagulation factors II, VII, IX and X, together with the inhibitors protein C and protein S, and it can be rapidly prepared and administered at an infusion rate of up to 8.0 mL/min. The efficacy of Beriplex P/N in patients requiring emergency reversal of oral anticoagulation has been demonstrated in a prospective, open-label, uncontrolled study involving 43 patients; 17 with acute bleeding and 26 requiring emergency surgery. Beriplex P/N was administered at a dose of 25-50 IU/kg, according to baseline international normalised ratio (INR) in conjunction with vitamin K. Mean INR 30 minutes post-infusion was 1.18, and 93% of patients achieved an INR of Assuntos
Anticoagulantes/efeitos adversos
, Transtornos da Coagulação Sanguínea/induzido quimicamente
, Transtornos da Coagulação Sanguínea/tratamento farmacológico
, Fator IX/uso terapêutico
, Fator VII/uso terapêutico
, Fator X/uso terapêutico
, Protrombina/uso terapêutico
, Varfarina/efeitos adversos
, Ensaios Clínicos Fase III como Assunto
, Combinação de Medicamentos
, Humanos
RESUMO
BACKGROUND: The emergence of anticardiolipin antibodies in patients with systemic lupus erythematosus is a serious occurrence in regard to a high risk for thrombosis and thromboembolic complications, fetal loss, and renal insufficiency. In an observational analysis, we studied anticardiolipin antibodies during immunoadsorption therapy. METHODS: We analyzed the magnitude and time course of serum concentrations of the immunoglobulin G (IgG) and IgM subtypes of anticardiolipin antibodies (CIgG and CIgM) along with IgG and IgM, antinuclear antibodies, and antibodies to double-stranded DNA before and after single immunoadsorption sessions and their long-term course in 11 patients with systemic lupus erythematosus. RESULTS: Single immunoadsorption sessions (n = 842) led to a rapid decline in CIgG and CIgM levels by 62.94% +/- 21.60% and 42.02% +/- 22.14%, respectively (P < 0.0001), along with a corresponding decline in serum levels of antinuclear antibodies (65.04% +/- 18.83%), antibodies to double-stranded DNA (64.67% +/- 21.20%), IgG (58.11% +/- 16.84%), and IgM (32.15% +/- 15.58%). Reduction rates of CIgG and CIgM levels were greater when high initial concentrations (P < 0.0001) and low IgG levels (P < 0.0001) were present. Mean reductions in pretreatment values of CIgG and CIgM during 6 months of immunoadsorption therapy were 42.85% +/- 39.94% and 29.39% +/- 70.41% (mean number of sessions/patient = 21.55) and for the 1-year period were 63.20% +/- 22.49% and 58.05% +/- 40.16% (mean number of sessions/patient = 30.46). CONCLUSION: We observed that immunoadsorption therapy is an effective method to reduce anticardiolipin antibody levels rapidly and keep them at a low level in the long term.