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Our Coagulation Disorders Unit in Helsinki, Finland, provides 24/7 services for local and national hospitals and colleagues upon requests regarding bleeding and thrombosis diagnostics and management, including follow-up. The unit has a tight connection between the clinic and laboratory, and its maintenance and sharing knowledge and observations have been priorities, already for over 20 years and will continue to be of major importance. The consultation service is provided by phone during daytime and on-call hours, and in written form sent electronically to the consulting stakeholders. Thrombosis and hemostasis-targeted outpatient clinics are also available for the patients referred to the center. Writing local guidance and official guidelines, Nordic, European and international collaboration, and educational activities including social communication are critical elements for the Coagulation Disorders Unit. Alertness to acute coagulation abnormalities, such as occurred during COVID-19 and vaccine-induced thrombosis and thrombocytopenia, and development of strategies to manage cross-disciplinary problems are topics which call upon broad networking. The Nordic community has an ongoing historical meeting, which has been circulating among coagulation centers for the past 56 years. At the European level, the European Association of Haemophilia and Allied Disorders focuses on bleeding disorders and their management, including safety surveillance. The International Society of Thrombosis and Haemostasis offers excellent basic and clinical benchmarks for any Coagulation Disorders Unit. We hope that the description of the development and implementation of our Coagulation Disorders Unit in Helsinki achieves international interest and broadens international collaboration. Finally, we congratulate STH on its great contributions around the globe and for providing a vivid forum to foster the discipline of thrombosis and hemostasis.
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Trastornos de la Coagulación Sanguínea , COVID-19 , Humanos , Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos de la Coagulación Sanguínea/terapia , Finlandia , SARS-CoV-2 , TrombosisRESUMEN
As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear-cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non-factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person-centred, holistic, multi-disciplinary approach to support and optimise long-term physical functioning and overall quality of life.
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Hemofilia A , Humanos , Anciano , Hemofilia A/complicaciones , Hemofilia A/terapia , Hemofilia A/epidemiología , Calidad de Vida , Factores de Coagulación Sanguínea , Envejecimiento , ComorbilidadRESUMEN
INTRODUCTION: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted. AIM: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB). METHODS: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years. RESULTS: We report on 104 patients aged 15-84 years from the MoHem study. Overall, EQ-5D utility was .85 (median) (Q1-Q3 0.73-1.0) with corresponding visual analogue scale (VAS) 80 (70-90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41-50 years displayed lower utility (p = .02) and VAS (p < .01) than the Norwegian population norm. Patients on prophylaxis aged 35-54 years reported higher PA than those treated on-demand (p = .01). CONCLUSION: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia.
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Hemofilia A , Artropatías , Persona de Mediana Edad , Humanos , Hemofilia A/tratamiento farmacológico , Calidad de Vida , Estudios Transversales , Artropatías/complicaciones , Factor IX/uso terapéutico , Ejercicio FísicoRESUMEN
BACKGROUND: Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile. TREATMENT GOALS: The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care. These outcomes also do not address the complexity of health-related quality of life impacted by haemophilia and its treatment. CONCLUSION: Capitalizing on the major potential of therapeutic innovations, 'Normalization' of haemostasis, as a concept, should include the aspiration of enabling individuals to live as normal a life as possible, free from haemophilia-imposed limitations. To achieve this-being supported by the data reviewed in this manuscript-the concept of haemostatic and life Normalization needs to be explored and debated within the wider multidisciplinary teams and haemophilia community.
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OBJECTIVES: To investigate the role of pretreatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in the prediction of response to sequential intravesical therapy, gemcitabine and docetaxel (Gem/Doce), given to patients with bacille Calmette-Guérin (BCG)- naïve high-risk non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A retrospective analysis was conducted on 115 patients who received intravesical Gem/Doce for high-risk NMIBC between January 2011 and December 2021. Data were computed as the median (interquartile range [IQR]) or mean (standard deviation [sd]). Cox regression analysis was performed to determine if neutrophilia, NLR, platelet counts, and PLR before instillation therapy were predictive of recurrence-free survival (RFS) and overall survival (OS). Predictive performance was estimated using Uno's C-statistic. RESULTS: The median (IQR) follow-up for the overall cohort was 23 (13-36) months. The mean (sd) values for NLR, PLR and platelet counts were 3.4 (2.3), 142.2 (85.5), and 225.2 (75.1) × 109/L, respectively. NLR was associated with RFS, with a hazard ratio of 1.32 (95% confidence interval CI 1.19-1.46). Concordance analysis showed that NLR had a good ability to predict RFS (C-index: 0.7, P < 0.01). The PLR and platelet count were not associated with RFS and did not predict recurrence. In terms of OS, none of these cellular inflammatory markers showed any prediction value. CONCLUSION: Pre-treatment NLR provides some predictive accuracy for RFS in high-risk BCG-naïve patients receiving Gem/Doce. Further prospective trials are needed to validate this finding.
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INTRODUCTION: Therapeutic plasma exchange (TPE), with solvent/detergent (S/D)-treated plasma as replacement fluid, is an extracorporeal blood purification technique with major impact on both coagulation and lipids. Our previous in vitro study showed that S/D-plasma enhances thrombin generation by lowering intact protein S (PS) levels. AIMS: To evaluate the impact of altered lipid balance on coagulation phenotype during heparin-anticoagulated TPE with S/D-plasma, and to investigate whether the lowered intact PS levels with concomitant procoagulant phenotype, are recapitulated in vivo. METHODS: Coagulation biomarkers, thrombin generation with Calibrated Automated Thrombogram (CAT), and lipid levels were measured before and after the consecutive 1st, 3rd and 5th episodes of TPE performed to six patients with Guillain-Barré syndrome or myasthenia gravis. The effects of in vitro dilution of S/D-plasma on thrombin generation were explored with CAT to mimic TPE. RESULTS: Patients did not have coagulation disorders, except elevated FVIII. Intact PS, lipoproteins, especially LDL, Apolipoprotein CIII (ApoC3) and ApoB/ApoA1 ratio declined (p < 0.05). In contrast, VLDL and triglyceride levels stayed intact. CAT lag time shortened (p < 0.05). In vitro dilution of S/D plasma with co-transfused Ringer's lactate and 4% albumin partially reduced its procoagulant phenotype in CAT, which is mainly seen as peak thrombin, and modestly shortened lag time. CONCLUSIONS: After the five settings of TPE using S/D-plasma in vivo, which associated with heparinization and reduced coagulation factor activities, our observations of declining natural anticoagulant intact PS and apolipoproteins refer to rebalance of the hemostatic and lipid profiles.
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Apolipoproteínas , Intercambio Plasmático , Proteína S , Trombina , Humanos , Intercambio Plasmático/métodos , Masculino , Trombina/metabolismo , Apolipoproteínas/sangre , Femenino , Persona de Mediana Edad , Proteína S/metabolismo , Adulto , AncianoRESUMEN
BACKGROUND: Several neurovascular procedures require temporary occlusion of cerebral arteries, leading to ischemia of unpredictable length, occasionally causing brain infarction. Experimental models of cerebral ischemia-reperfusion injury have established that platelet adhesion and coagulation play detrimental roles in reperfusion injury following transient cerebral ischemia. Therefore, in a model of cerebral ischemia-reperfusion injury (IRI), we investigated the therapeutic potential of a dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic which is able to bind to vascular injury sites. METHODS: Brain ischemia was induced in mice by transient occlusion of the right middle cerebral artery for 60 min. APAC, unfractionated heparin (UFH) (both at heparin equivalent doses of 0.5 mg/kg), or vehicle was intravenously administered 10 min before or 60 min after the start of ischemia. At 24 h later, mice were scored for their neurological and motor behavior, and brain damage was quantified. RESULTS: Both APAC and UFH administered before the onset of ischemia reduced brain injury. APAC and UFH pretreated mice had better neurological and motor functions (p < 0.05 and p < 0.01, respectively) and had significantly reduced cerebral infarct sizes (p < 0.01 and p < 0.001, respectively) at 24 h after transient occlusion compared with vehicle-treated mice. Importantly, no macroscopic bleeding complications were observed in either APAC- or UFH-treated animals. However, when APAC or UFH was administered 60 min after the start of ischemia, the therapeutic effect was lost, but without hemorrhaging either. CONCLUSIONS: Pretreatment with APAC or UFH was safe and effective in reducing brain injury in a model of cerebral ischemia induced by transient middle cerebral artery occlusion. Further studies on the use of APAC to limit ischemic injury during temporary occlusion in neurovascular procedures are indicated.
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Lesiones Encefálicas , Isquemia Encefálica , Daño por Reperfusión , Ratones , Animales , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Encéfalo/metabolismo , Heparina/farmacología , Heparina/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
INTRODUCTION: Good health-related quality of life (HRQoL) is an important goal in the treatment of persons with haemophilia B (PwHB). Studies focusing on this population are limited, however, and data are insufficient. AIM: To assess the HRQoL in PwHB and to compare this to data on persons with haemophilia A (PwHA), as well as to evaluate the impact of joint health on HRQoL and to identify areas of insufficient care. METHODS: The B-NORD study enrolled persons with severe haemophilia B and matched controls with haemophilia A. HRQoL was assessed using the EQ-5D-3L questionnaire and joint health using Haemophilia Joint Health Score 2.1 (HJHS). RESULTS: The EQ-5D-3L was completed by 63 PwHB and 63 PwHA. Mobility problems were reported by 46% of PwHB and 44% of PwHA, pain/discomfort by 62% and 56%, and anxiety/depression by 33% and 17%, respectively. No significant difference was observed between PwHA and PwHB in EQ-5D profiles, level sum score, EQ-5D index (PwHB mean .80, PwHA mean .83, p = .24), or EQ VAS score (PwHB: mean 70, PwHA: mean 77, p = .061). Linear regression adjusted for age demonstrated that an increase in HJHS score was associated with a significant decrease in both EQ-5D index (B -.003, R2 .22) and EQ VAS score (B -.37, R2 .17). CONCLUSION: Despite the majority of patients being treated with prophylaxis, impaired HRQoL was reported in both PwHB and PwHA. No differences in HRQoL were found between the two groups. Impaired joint health had a significant negative impact on HRQoL.
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Hemofilia A , Hemofilia B , Humanos , Estado de Salud , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Hemofilia B/complicaciones , Modelos Lineales , Calidad de Vida , Encuestas y CuestionariosRESUMEN
Pathogenic variants of the X-linked FLNA gene encoding filamin A protein have been associated with a wide spectrum of symptoms, including the recently described pulmonary phenotype with childhood-onset panlobular emphysema. We describe three female patients from two families with novel heterozygous FLNA variants c.5837_2del and c.508C > T. Analysis of immunofluorescence of peripheral blood smears and platelet function was performed for all patients. FLNA-negative platelets were observed, suggesting that these variants result in the loss of a functional protein product. All three patients also had periventricular nodular heterotopia and panlobular emphysema. However, they had considerably milder symptoms and later age of onset than in the previously reported cases. Therefore, patients with pathogenic FLNA variants should be studied actively for lung involvement even in the absence of pronounced respiratory symptoms. Conversely, any patient with unexplained panlobular emphysema should be analyzed for pathogenic FLNA variants. We also suggest that immunofluorescence analysis is a useful tool for investigating the pathogenicity of novel FLNA variants.
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Heterotopia Nodular Periventricular , Enfisema Pulmonar , Niño , Femenino , Filaminas/genética , Humanos , Mutación , Heterotopia Nodular Periventricular/diagnóstico , Heterotopia Nodular Periventricular/genética , FenotipoRESUMEN
INTRODUCTION: Majority of haemophilia A patients in our comprehensive care centre have switched from standard half-life (SHL) to extended half-life (EHL) FVIII products in a short time. AIM: We compared the clinical and laboratory outcomes between SHL and EHL FVIII prophylaxis in product switchers. METHODS: This is a retrospective inception cohort of all adult haemophilia A patients switched to EHL (rFVIIIFc or rFVIII-PEG) prophylaxis in our centre. Dosing, product utilization, annualized bleed rates (ABR), treatment regimen and pharmacokinetics by Web Accessible Population Pharmacokinetic Service (WAPPS)-Hemo were compared between SHL and EHL. RESULTS: We included 38 patients, whose median age was 38 years (range 17-75). Median FVIII dose was 23 IU/kg for SHL versus 25 IU/kg for EHL. After switching, weekly infusions decreased by 29% from median 2.8 (every 2.5 days) to 2.0 (every 3.5 days) (P = <.001) and factor consumption for prophylaxis by 17% from 60 to 50 IU/kg/week (P = <.001). Weekly infusions decreased in 71% and FVIII utilization in 55% of patients. ABR remained low (1.0 for SHL and .5 for EHL, respectively). In pharmacokinetics, the half-life of FVIII increased from median 13 to 21 h after switching. Times above .01 and .03 IU/ml improved from 85 to 131 h and from 65 to 106 h. Half-lives of the SHL products and von Willebrand factor levels predicted half-lives with the EHL products. CONCLUSIONS: Our cohort study confirms the successful experience of switching to EHL FVIII products, with decreased infusion frequency, factor consumption and excellent clinical efficacy.
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Hemofilia A , Adolescente , Adulto , Anciano , Humanos , Persona de Mediana Edad , Adulto Joven , Estudios de Cohortes , Factor VIII/farmacocinética , Semivida , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Hemorragia/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
INTRODUCTION: Platelet function tests are used to screen and diagnose patients with possible inherited platelet function defects (IPFD). Some acquired platelet dysfunction may be caused by certain drugs or comorbidities, which need to be excluded before testing. AIMS: To identify current practice among centres performing platelet function tests in Northern Europe. METHODS: A total of 14 clinical centres from Sweden (six), Finland (two), Denmark (two), Norway (one), Estonia (two) and Iceland (one) completed the survey questionnaire, the population capture area of about 29.5 million. RESULTS: Six of the 14 (42.8%) centres providing platelet function assessment represent comprehensive treatment centres (EUHANET status). A Bleeding score (BS) or ISTH bleeding assessment tool (ISTH BAT score) is evaluated in 11/14 (78.6%) centres and family history in all. Five/14 centres (35.7%) use structured preanalytical patient instructions, and 10/14 (71.4%) recorded questionnaire on the preassessment of avoidance of any drugs or natural products affecting platelet functions. Preliminary investigations of screening tests of coagulation are performed in 10/14 (71.4%), while in 4/14 (28.6%), the diagnostic work-up of IPFD and von Willebrand disease (VWD) is performed simultaneously. The work-up of IPFD includes peripheral blood smear in 10/14 (71.4%), platelet aggregometry in all, flow cytometry in 10/14 (71.4%) and Platelet Function Analysis (PFA) in 3/11 (28.6%). Molecular genetic diagnosis is available in 7/14 (50%) centres. CONCLUSIONS: The considerable variability in the current practice illustrates the need for harmonization between the Northern European centres according to the international registers (i.e. EUHASS) and IPFD guidelines (ISTH, EHA).
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Trastornos de las Plaquetas Sanguíneas , Enfermedades de von Willebrand , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Plaquetas , Europa (Continente) , Hemorragia/diagnóstico , Humanos , Pruebas de Función Plaquetaria , Enfermedades de von Willebrand/diagnósticoRESUMEN
BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is triggered by nCOV-19 adenovirus-vectored vaccines against SARS-CoV2. Pathogenesis has been mainly related to platelet activation via PF4-reactive antibodies that activate platelets and may cross-react with heparin. Data concerning optimal anticoagulation are anecdotal, and so far, there are scattered reports of danaparoid use in VITT management. Danaparoid has good efficacy and safety in treatment of heparin-induced thrombocytopenia. We report here our experience of the administration and monitoring danaparoid in VITT. METHODS: We diagnosed a series of six hospitalized cases of VITT, based on the international diagnostic guidance. All VITT-related data were from the local electronic medical and laboratory record system and were analyzed with IBM SPSS Statistics. RESULTS: Predominately women in their late 40's developed VITT on average 24 days (range 9-59) after the first ChAdOx1 dose. Clinical presentation included single or multiple venous and/or arterial thrombosis, moderate thrombocytopenia and high D-dimer levels. After detecting PF4 antibodies subcutaneous danaparoid was our first-line antithrombotic treatment with an average duration of three weeks. The median plasma anti-FXa activity was in the lower part of the therapeutic range and during the first week of danaparoid administration clinical symptoms, platelet counts, and fibrin turnover resolved or significantly improved. The average duration of hospital admission was 10 days [2-18]. One patient died but the other five patients recovered completely. CONCLUSIONS: The clinical outcomes of our small cohort align with the earlier published reports, and support danaparoid as a rational option for the initial anticoagulation of VITT patients.
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BACKGROUND: Thrombotic complications are synergistic and associated with orthopedic procedures, trauma, and malignancy. Because cancer enhances coagulation activity and vice versa, we assessed preoperative biomarkers for survival and complications after treatment of pathologic fractures in non-spinal skeletal metastases. PATIENTS/METHODS: Our study population comprised 113 actual or impending pathologic fractures in 100 patients admitted to two referral centers. Laboratory variables were collected retrospectively from patient records and analyzed related to incidence of pulmonary embolism (PE) and mortality (Kaplan-Meier and Cox regression analyses and biomarker quartiles). RESULTS: Preoperative coagulation variables were high without exceptions. PE occurred in 12 patients at 36 post-operative days at incidence of 11% in the lower and 13% in the upper extremity fractures. Patients with fibrinogen exceeding 5 g/l (log-rank 0.022) developed PE earlier (5 to 15 days postoperatively) than others. Also, mean patient survival with normal fibrinogen range (2-4 g/l) was 34 months, whereas it halved upon elevated fibrinogen (log-rank p = 0.009). Survival in patients with FVIII levels under 326 IU/dl (Q3) was 22 months, but only 7 months if FVIII exceeded 326 IU/dl (log-rank p = 0.002). Combined elevated fibrinogen and FVIII predicted survival: for patients with levels below threshold limits was 22 months versus only 7 months when both variables exceeded the ranges (log-rank p < 0.001). Multivariate analysis to control confounders supported an independent role of fibrinogen and FVIII for survival. CONCLUSIONS: Our study has established fibrinogen and FVIII as potential preoperative contributors of survival and complications after treatment of metastatic fractures. These results highlight the need for novel anticoagulation and thromboprophylaxis strategies among these patients.
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Antiplatelet and anticoagulant drugs are classified antithrombotic agents with the purpose to reduce blood clot formation. For a successful treatment of many known complex cardiovascular diseases driven by platelet and/or coagulation activity, the need of more than one antithrombotic agent is inevitable. However, combining drugs with different mechanisms of action enhances risk of bleeding. Dual anticoagulant and antiplatelet (APAC), a novel semisynthetic antithrombotic molecule, provides both anticoagulant and antiplatelet properties in preclinical studies. APAC is entering clinical studies with this new exciting approach to manage cardiovascular diseases. For a better understanding of the biological function of APAC, comprehensive knowledge of its structure is essential. In this study, atomic force microscopy (AFM) was used to characterize APAC according to its structure and to investigate the molecular interaction of APAC with von Willebrand factor (VWF), since specific binding of APAC to VWF could reduce platelet accumulation at vascular injury sites. By the optimization of drop-casting experiments, we were able to determine the volume of an individual APAC molecule at around 600 nm3, and confirm that APAC forms multimers, especially dimers and trimers under the experimental conditions. By studying the drop-casting behavior of APAC and VWF individually, we depictured their interaction by using an indirect approach. Moreover, in vitro and in vivo conducted experiments in pigs supported the AFM results further. Finally, the successful adsorption of APAC to a flat gold surface was confirmed by using photothermal-induced resonance, whereby attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) served as a reference method.
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Anticoagulantes/análisis , Heparina/análogos & derivados , Microscopía de Fuerza Atómica/métodos , Inhibidores de Agregación Plaquetaria/análisis , Proteoglicanos/análisis , Heparina/análisis , Humanos , Espectroscopía Infrarroja por Transformada de Fourier/métodosRESUMEN
INTRODUCTION: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. MATERIAL AND METHODS: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). CLINICAL TRIAL REGISTRATION: NCT02352090. RESULTS: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. CONCLUSIONS: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.
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Anticonceptivos Orales Combinados , Nandrolona , Adolescente , Adulto , Anticonceptivos Orales Combinados/farmacología , Estradiol , Estrógenos , Etinilestradiol/farmacología , Femenino , Fibrina , Humanos , Levonorgestrel , Nandrolona/farmacología , Progestinas , Trombina , Tromboplastina , Adulto JovenRESUMEN
INTRODUCTION: Predicting the bleeding phenotype is crucial for the management of patients with moderate haemophilia. Global coagulation assays evaluate haemostasis more comprehensively than conventional methods. AIM: To explore global coagulation assays and the bleeding phenotype of patients with moderate haemophilia A (MHA) and B (MHB). METHODS: The MoHem study is a cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Thromboelastometry in whole blood and thrombin generation (TG) in platelet-poor plasma (1, 2.5 and 5 pM tissue factor (TF)) were compared with joint health (Haemophilia Joint Health Score (HJHS)) and treatment modality. RESULTS: We report on 61 patients from Oslo and Helsinki: 24 MHA and 37 MHB. By TG (2.5 pM TF), patients who had been without replacement therapy during the previous 12 months depicted higher endogenous thrombin potential (P = .03). In contrast, those who had low ETP (< median) captured higher HJHS (P = .02). Patients who had undergone orthopaedic surgery generated least thrombin (P = .02). By thromboelastometry, those without the need of factor consumption had short clotting times, and quick times to maximum velocity (< median values) (P = .03). Factor VIII/factor IX activity (FVIII/FIX:C) did not align with the bleeding phenotype, but FIX:C ≤ 3 IU/dL was associated with lower peak thrombin (P = .03). CONCLUSION: TG differentiated patients with moderate haemophilia according to HJHS, annual factor consumption, and whether orthopaedic surgery had been performed. Thromboelastometry differentiated according to factor consumption only. Global coagulation assays may assist predicting the bleeding phenotype in moderate haemophilia.
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Hemofilia A , Hemofilia B , Estudios Transversales , Factor VIII , Hemofilia A/diagnóstico , Hemofilia B/diagnóstico , Humanos , Fenotipo , Tromboelastografía , TrombinaRESUMEN
INTRODUCTION: Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). AIM: To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. METHODS: PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). RESULTS: Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. CONCLUSION: The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.
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Hemofilia A , Hemofilia B , Adolescente , Adulto , Anciano , Niño , Preescolar , Hemartrosis/etiología , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Hemofilia B/complicaciones , Hemofilia B/tratamiento farmacológico , Humanos , Lactante , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Ultrasonografía , Adulto JovenRESUMEN
INTRODUCTION: Characterisation of outcomes and costs of haemophilia care in common practice settings is essential for evaluation of new treatment options and for developing clinical practices. In Finland, haemophilia care is mostly centralised to University Hospitals, but treatment practices and costs in adult patients have not been systematically evaluated. AIM: This study was designed to characterise healthcare resource utilisation and treatment costs of adult inhibitor-negative haemophilia patients managed in Finnish University Hospitals. METHODS: The study was based on a nationwide cohort, which consists of all adult haemophilia A (HA; n = 120) and B (HB; n = 35) patients treated in University Hospitals from 2012 to 2016. Patient characteristics and data on healthcare utilisation and factor replacement use were collected from medical records. Direct costs of care were evaluated based on wholesale drug prices and healthcare service utilisation with standard unit costs. RESULTS: Most of HA (79%, n = 96) and HB (84%, n = 31) patients received factor replacement therapy. The median annual bleeding rate (ABR) was low, at 0.8 for HA and 0.5 for HB, also among the patients with on-demand therapy. Over 94% (n = 149) of the patients had outpatient visits during the follow-up period. The mean total annual costs of treatment ranged from 2520 to 176,330. The highest individual cost was factor replacement therapy. CONCLUSION: The outcomes of centralising the management of care to University Hospital Treatment Centres show low ABR and lower treatment costs compared with earlier reports from other high-income European populations. Management strategies, including choosing the right therapy between prophylaxis and on-demand, has been successful in Finland.
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Hemofilia A , Adulto , Finlandia , Estudios de Seguimiento , Costos de la Atención en Salud , Hemofilia A/tratamiento farmacológico , Humanos , Aceptación de la Atención de SaludRESUMEN
ABSTRACT: Vascular intervention-induced platelet and coagulation activation is often managed with a combination of antiplatelets and anticoagulants, with evident benefits, but with a risk of systemic bleeding. Antiplatelet and anticoagulant (APAC) is a dual antiplatelet and anticoagulant heparin bioconjugate, which targets vascular injury sites to act as a local antithrombotic. We assessed the nonclinical safety and exposure of intravenously infused APAC in rats and cynomolgus monkeys by using single-day and 14-day repeat dose toxicology and pharmacodynamic markers. Activated partial thromboplastin time (APTT) was used as a functional surrogate of anticoagulant exposure of APAC. Routine clinical in-life observations were followed by clinical pathology and necropsy. The no-observed-adverse-effect level (NOAEL) in rats for the single APAC dose was 20 mg/kg and for the repeated administration was 10 mg/kg/d. Monkeys tolerated a single APAC dose of 10 mg/kg, although the red blood cell count reduced 16%-19% correlating with tissue hemorrhage at vein puncture and affected muscle sites during handling of the animals. However, after 2-week recovery, all clinical signs were normal. The single dose NOAEL exceeded 3 mg/kg. The repeat administration of 3-6 mg/kg/d of APAC was tolerated, but some clinical signs were observed. The NOAEL for repeated dosing was 0.5 mg/kg/d. APAC prolonged APTT dose-dependently in both species, returning to baseline after 1.5 (<10 mg/kg) or essentially by 6 hours also under repetitive dosing. The toxicology profile supports the safety of an intravenous APAC dose of 0.5 mg/kg/d for possible clinical applications. APTT is an acceptable indicator of the immediate systemic anticoagulation effect of APAC.
Asunto(s)
Anticoagulantes/farmacocinética , Coagulación Sanguínea/efectos de los fármacos , Heparina/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Animales , Anticoagulantes/administración & dosificación , Anticoagulantes/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Heparina/administración & dosificación , Heparina/análogos & derivados , Heparina/toxicidad , Infusiones Intravenosas , Macaca fascicularis , Masculino , Nivel sin Efectos Adversos Observados , Tiempo de Tromboplastina Parcial , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/toxicidad , Tiempo de Protrombina , Ratas WistarRESUMEN
INTRODUCTION: Standard subcutaneous low-molecular-weight heparin (LMWH) thromboprophylaxis yields low anti-factor Xa activity in patients in the intensive care unit (ICU). The aim of the study was to assess coagulation status in ICU patients randomized to receive enoxaparin thromboprophylaxis either as a standard subcutaneous bolus (SCB) or continuous intravenous infusion (CII) for 3 consecutive days after the initiation of LMWH thromboprophylaxis. MATERIALS AND METHODS: Thirty-eight patients were studied by conventional coagulation variables: prothrombin fragment F 1+2 (F 1+2) representing FXa inhibition and antithrombin (AT). Additionally, 18 patients were analyzed by the thrombin generation assay-calibrated automated thrombogram (TGA-CAT). Blood samples were collected before the initiation of the LMWH thromboprophylaxis (ie, baseline), at 51 h, and at 72 h. RESULTS: At beginning, no differences in coagulation biomarkers were observed. The levels of F 1+2 were significantly lower at 51 and 72 h in the CII group than in the SCB group. AT levels increased during the follow-up in the CII group, unlike in the SCB group. TGA-CAT was poor in some patients overall. In a subset of patients at 51 h lag time (4.3 vs 7.5 min, respectively, P < 0.05) and time to peak (7.7 vs 14.3 min, respectively, P < 0.05) were prolonged in the SCB group. At 72 h, however, peak thrombin was lower in the CII than in the SCB group: 271 vs 356 nM, respectively (P < 0.05). CONCLUSIONS: Enoxaparin thromboprophylaxis administered by CII inhibited more prominently FXa and preserved better the AT level, compared with standard subcutaneous care.