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Coagulant Activity (coagulant + activity)
Selected AbstractsEffect of two oral doses of 17,-estradiol associated with dydrogesterone on thrombin generation in healthy menopausal women: a randomized double-blind placebo-controlled studyFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2010Alexandra Rousseau Abstract Oral hormone therapy is associated with an increased risk of venous thrombosis. Drug agencies recommend the use of the lowest efficient dose to treat menopausal symptoms for a better risk/ratio profile, although this profile has not been totally investigated yet. The aim of the study was to compare the effect of the standard dose of 17,-estradiol to a lower one on thrombin generation (TG). In a 2-month study, healthy menopausal women were randomized to receive daily 1mg or 2 mg of 17,-estradiol (E1, n = 24 and E2, n = 26; respectively) with 10 mg dydrogesterone or placebo (PL, n = 22). Plasma levels factors VII, X, VIII and II were assessed before and after treatment as well as Tissue factor triggered TG, which allows the investigation of the different phases of coagulation process. The peak of thrombin was higher in hormone therapy groups (E1: 42.39 ± 50.23 nm, E2: 31.08 ± 85.86 nm vs. 10.52 ± 40.63 nm in PL, P = 0.002 and P = 0.01). Time to reach the peak was also shortened (PL: 0.26 ± 0.69 min vs. E1: ,0.26 ± 0.80 min, E2: ,0.55 ± 0.79 min, P <10,3 for both comparisons) and mean rate index of the propagation phase of TG was significantly increased. Among the studied clotting factors, only the levels of FVII were significantly increased after treatment administration. The two doses of 17,-estradiol induced in a similar degree an acceleration of the initiation and propagation phase of tissue factor triggered thrombin generation and a significant increase of FVII coagulant activity. [source] Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C,T mutationHAEMOPHILIA, Issue 1 2009A. SHARATHKUMAR Summary., The aim of this study was to characterize the variability of bleeding phenotype and its association with plasma factor IX coagulant activity (FIX:C) in haemophilia B carriers in a large Amish pedigree with a unifying genetic mutation, C-to-T transition at base 31008 of the factor IX gene (Xq27.1,27.2). A cross-sectional survey of haemophilia B carriers included a multiple choice questionnaire evaluating symptoms of mucocutaneous bleeding, joint bleeding and bleeding after haemostatic stress [menstruation, postpartum haemorrhage (PPH), dental extractions and invasive surgeries]. Severity of bleeding was graded as 0 to 4, 0 being no bleeding whereas 4 being severe bleeding. Association between total bleeding scores and the FIX:C was evaluated. Sixty-four haemophilia B carriers participated in this study. Median age: 18 years (range 1,70 years); median bleeding score: 1 (range 0,8). Besides PPH, isolated symptoms of bruising, epistaxis, menorrhagia and postsurgical bleeding including dental extraction were not associated with lower FIX:C. Bleeding score ,3 was associated with involvement of at least two bleeding sites and a lower mean FIX:C of 42 ± 10.3% (95% CI 36.4,47.7) while a score >3 had involvement of ,2 sites and higher mean FIX:C of 54.9 ± 21.5% (95% CI 49,61), P = 0.005. Subcutaneous haematoma formation and bleeding after haemostatic stress requiring treatment were associated with bleeding scores ,3. Phenotypic variability existed among the carriers of haemophilia B who belonged to a single pedigree carrying a single unifying mutation. The utility of bleeding scores to define bleeding phenotype precisely in haemophilia B carriers needs further evaluation. [source] The impact of joint bleeding and synovitis on physical ability and joint function in a murine model of haemophilic synovitisHAEMOPHILIA, Issue 1 2008C. MEJIA-CARVAJAL Summary., Haemophilia is a congenital disorder that commonly results in musculoskeletal bleeding and orthopaedic complications. After an acute joint haemorrhage, an increase in intra-articular pressure and inflammation cause pain, swelling and limited motion. Blood in the joint space provokes a proliferative disorder known as haemophilic synovitis. Overgrowth of the synovial membrane causes mechanical dysfunction. Eventually, there is destruction of the articular surface and underlying bone. The aim of this project was to test the hypothesis that a minimum number of haemarthroses negatively impacts on joint function and that this would be reflected by decreased physical performance of experimental animals. Mice deficient in factor VIII coagulant activity were trained to ambulate on a rotating rod then injured three times at weekly intervals. Their ability to walk was then compared to a group of uninjured mice. Cohorts of mice were killed after 1, 2 or 3 months and the knee joints examined by gross and histological methods. The results supported the following conclusions: (i) haemophilic mice can be trained to ambulate on a rotating rod; (ii) acute hemarthrosis temporarily impairs their ability to ambulate and (iii) following recovery from acute injury, mice developing synovitis demonstrated inferior physical ability compared to mice not developing synovitis. This is the first description of a quantitative assay to monitor joint function in experimental animals and should be useful to evaluate the efficacy of new therapies developed to prevent and treat bleeding and to test strategies to counter the devastating effects of synovitis. [source] Efficacy and safety of a factor VIII,von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experienceHAEMOPHILIA, Issue 5 2002A. Lubetsky Summary., The present study was undertaken to evaluate stability, pharmacokinetic profile and efficacy of continuous infusion of 8Y in patients with different types of von Willebrand disease (vWD). Following reconstitution, 8Y levels of von Willebrand factor ristocetin cofactor (vWF:Rco), vWF antigen and factor VIII coagulant activity (FVIII:C) decreased to about 80% of the baseline levels; addition of low molecular weight heparin decreased the level of FVIII:C even further. Reconstituted 8Y was found to be sterile for up to 6 days postreconstitution. Ten vWD patients (four with type 2A, three with type 3, two with type 1 and one with 2N) underwent pharmacokinetic analysis. The recovery of vWF: RCo was significantly lower in patients with type 3 vWD (1.4 ± 0.05% U,1 kg,1) compared withthat of the patients with types 1 (2.3 ± 0.52% U,1 kg,1) or 2A (2.0 ± 0.06% U,1 kg,1) vWD (P = 0.015). Type 3 vWD patients exhibited significantly higher vWF:RCo clearance (5.1 ± 1.1 mL kg,1 h,1) compared with that of patients with type 2A (2.8 ± 0.7 mL kg,1 h,1) and type 1 (2.6 ± 1.0 mL kg,1 h,1) vWD (P = 0.028). Accordingly, terminal half-life was lower in patients with type 3 vWD (8.0 ± 0.6 h,1) compared with type 2A (12.7 ± 5.9 h,1) or type 1 (14 ± 1.2 h,1) vWD patients. Multimeric pattern of vWF from patients' plasma was similar to that of 8Y. In two patients treated with 8Y by continuous infusion for prevention or treatment of bleeding haemostasis was achieved. Thus, 8Y is suitable and haemostatically effective for continuous infusion treatment in patients with vWD. [source] Effect of lyophilisation, refrigerated storage and frozen storage on the coagulant activity and microbiological quality of Cynara cardunculus L. extractsJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 8 2008Luis Tejada Abstract BACKGROUND:Cheese-makers have traditionally kept vegetable coagulants refrigerated until use, even though little was known of their microbiological quality or coagulant activity during storage. This study aimed to assess the efficacy of lyophilisation, refrigerated storage and frozen storage of fresh vegetable extract as a means of standardising coagulant activity in terms of coagulation times, pH and microbiological quality. RESULTS:Neither the pH nor the coagulation time of lyophilised extracts was significantly modified during 1 year; however, changes were observed following frozen storage, and more notable following refrigerated storage. Lyophilisation of aqueous extracts prompted the destruction of most micro-organisms; low counts initially noted for total mesophiles, lactic acid bacteria and yeasts disappeared during the first few days of storage, due to low water activity. There was a generalised decrease in micro-organism counts during frozen storage. Refrigeration was found to be unsuitable for storing of cardoon extract; an increase of roughly 2 log unit counts was recorded in total mesophile, lactic acid bacteria, yeast and mould counts after 1 year of refrigerated storage. CONCLUSION:Refrigerated storage cannot be considered a suitable method for prolonged conservation of aqueous cardoon extract. Both lyophilisation and frozen storage of aqueous extracts proved ideal for prolonged storage of vegetable coagulant. Lyophilisation additionally had certain advantages over frozen storage. Copyright © 2008 Society of Chemical Industry [source] Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover studyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2010P. COLLINS Summary.,Background: Hemarthroses in severe hemophilia precipitate physical, psychosocial and financial difficulties. Objective: To compare the effects of secondary prophylaxis with on-demand sucrose-formulated recombinant factor VIII (rFVIII-FS) therapy in severe hemophilia A. Patients and methods: This open-label study included patients aged 30,45 years with factor VIII (FVIII) coagulant activity < 1 IU dL,1 who were using on-demand FVIII treatment. Patients were treated with rFVIII-FS on demand for 6 months, followed by 7 months prophylaxis (20,40 IU kg,1, three times per week, with the first month considered a run-in). The primary endpoint was the number of hemarthroses. Results: Twenty patients were enrolled (n = 19 completed); the mean age was 36.4 years, and 16 had target joints. The median (25,75%) number of joint bleeds decreased significantly with prophylaxis [0 (0,3)] vs. on-demand [15 (11,26); P < 0.001] therapy. The number of all bleeds was 0 (0,3) vs. 20.5 (14,37; P < 0.001), respectively. Median (range) total Gilbert scores improved after prophylaxis [18 (3,39)] compared with on-demand [25 (4,46)] therapy, predominantly reflecting the improved bleeding score. Median time from last prophylactic infusion to bleed was 2 days; 82.5% of bleeds occurred 2,3 days after the last infusion. Median 48-h and 72-h FVIII trough levels measured during months 10 and 13 were consistently > 6 and > 4 IU dL,1, respectively. Treatment was well tolerated, and no inhibitor formation was observed. Conclusion: Secondary prophylaxis with rFVIII-FS significantly reduced the frequency of hemarthroses compared with on-demand therapy in adult patients with severe hemophilia A. [source] Six novel mutations including triple heterozygosity for Phe31Ser, 514delT and 516T,G factor X gene mutations are responsible for congenital factor X deficiency in patients of Nepali and Indian originJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2005G. JAYANDHARAN Summary., Factor X (FX) deficiency is a rare (1 : 100000) autosomal recessive disorder caused by heterogeneous mutations in FX gene. We have studied the molecular basis this disease in six Indian and one Nepali patients. Diagnosis was confirmed by measuring the FX coagulant activity (FX: C) using a PT based assay. Six of them had a FX: C of < 1% and one patient had 24% coagulant activity. Mutations were identified in all the seven patients. These included eight (88.8%) missense and one frame-shift (11.2%) mutations of which six were novel. Three of the novel mutations, a Phe31Ser affecting ,Gla' domain and 514delT and 516T,G mutations affecting Cys132 in ,connecting region' were identified in a triple compound heterozygous state in a Nepali patient presenting with a severe phenotype. Two other novel mutations, Gly133Arg, may affect the disulphide bridge between Cys132-Cys302 in the connecting region while Gly223Arg may perturb the catalytic triad (His236, Asp282 and Ser379). The other novel mutation, Ser354Arg, involves the replacement of a small-buried residue by a large basic aminoacid and is likely to have steric or electrostatic effects in the pocket involving Lys351-Arg347-Lys414 that contributes to the core epitope of FXa for binding to FVa. Three previously reported mutations, Thr318Met; Gly323Ser; Gly366Ser were also identified. This is the first report of the molecular basis of FX deficiency in patients from the Indian subcontinent. [source] A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiencyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2004P. H. B. Bolton-Maggs Summary., Factor XI (FXI) deficiency is a mild bleeding disorder that is particularly common in Ashkenazi Jews, but has been reported in all populations. In Jews, two FXI gene (F11) mutations (a stop codon in exon 5, E117X, type II, and a point mutation in exon 9, F283L, type III) are particularly common, but in other populations a variety of different mutations have been described. In the Basque region of France one mutation, C38R in exon 3, was found in eight of 12 families studied, haplotype analysis suggesting a founder effect. In the course of screening 78 unrelated individuals (including 15 Jewish and 12 Asian) we have found 10 Caucasian non-Jewish patients with the mutation C128X in exon 5. Individuals were investigated because of a personal or family history of bleeding, or finding a prolonged activated partial thromboplastin time. Individuals negative for the type II and type III mutations were screened by a combination of SSCP and heteroduplex analysis. The C128X mutation was found in 10 families (one previously described). Among three individuals with severe FXI deficiency, one was homozygous for the C128X mutation, and two were compound heterozygotes for the C128X and another mutation; other individuals were carriers of the C128X mutation. This is a nonsense mutation producing a truncated protein; individuals have FXI antigen levels concordant with FXI coagulant activity. Haplotype analysis of 11 families, including a further kindred previously reported from the USA, but which originally came from the UK (in which the index patient was homozygous for C128X), suggests a founder effect. [source] Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogram characteristicsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2004K. Vanschoonbeek Summary., The hemostatic activity of plasma is determined by platelet activation and coagulation, which processes are mutually stimulatory. We studied this interaction by measuring the cleavage of fluorescent thrombin substrate in platelet-rich plasma (PRP), using the calibrated thrombogram method. In freshly isolated human plasma, thrombin formation triggered by tissue factor was fully dependent on the presence of platelets. It was abolished by annexin A5, indicating dependence on phosphatidylserine (PS) exposure at activated platelets. Comparison of plasmas from various subjects showed considerable interindividual variation in total amount of thrombin generation, regardless of whether platelets or PS-containing phospholipids were present. Integrin ,IIb,3 antagonists and ADP receptor blockage, but not aspirin, decreased the rate of thrombin generation (thrombin peak level) and extended the time of onset. Platelet inhibition with cAMP-elevating agents decreased the thrombin-forming rate, but surprisingly shortened the onset time. Stimulation of platelets with agonists of Gi/q-coupled receptors and, to a larger extent, with collagen or Ca2+ -ionophore increased the rate of thrombin generation and shortened its onset. In PRP from donors with low and high generation, platelet inhibitors and activators were similarly effective. Taken together, these results indicate that, in tissue factor-triggered PRP, PS exposure on activated platelets regulates both onset and rate of thrombin generation. However, coagulant activity rather than platelet activation determines the total amount of thrombin formed, i.e. the endogenous thrombin potential. Thus, kinetics of thrombin generation in PRP are controlled by platelet inhibitors and agonists, but the process is restricted in amount by the subject-dependent variation in coagulation. [source] Atorvastatin and omega-3 fatty acids protect against activation of the coagulation system in patients with combined hyperlipemiaJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2003A. Nordøy Summary., Activation of factor (F)VII by tissue factor may represent a critical event during plaque rupture in acute coronary syndromes. Patients with combined hyperlipemia are at high risk for developing coronary heart disease and their tendency to thrombosis may be accelerated during postprandial hyperlipemia. In the present double-blind, placebo-controlled parallel study, 42 patients with combined hyperlipemia and serum triglycerides between 2.0 and 15.0 mmol L,1 and serum cholesterol >5.3 mmol L,1 at the end of a 3-month dietary run-in period were treated with atorvastatin at 10 mg day,1 for at least 10 weeks. During the last 5 weeks the patients were randomized into two groups receiving 1.68 g day,1 omega-3 fatty acids (,-3 FA) or placebo (corn oil). The fasting levels of FVII antigen (FVII-Ag) and FVII coagulant activity (FVII:C) were high compared with healthy males. The fasting levels of activated FVII (FVIIa) and FVII-Ag correlated both to serum triglycerides and apolipoprotein A1 (apoA1). FVIIa and FVII:C increased during postprandial hyperlipemia. This increase of FVIIa correlated to the fasting triglyceride and apoA1 levels, but not to the degree of postprandial hypertriglyceridemia. The concentrations of fasting FVIIa in these patients were reduced in parallel with a reduction of fasting triglycerides by treatment with atorvastatin + placebo. This treatment also reduced the postprandial level of FVIIa. ,-3 FA in addition to atorvastatin further reduced FVIIa concentrations, fasting and postprandially, and also significantly reduced FVII:C and FVII-Ag during postprandial hyperlipemia. Prothrombin fragment 1 + 2 (F1 + 2) increased during postprandial hyperlipemia. This increase was significantly reduced after treatment with atorvastatin plus ,-3 FA. The increase of F1 + 2 measured as incremental area under the curve (iAUC) during postprandial hyperlipemia correlated to the fasting levels of FVIIa, FVII:C and FVII-Ag and also to the levels of these factors during postprandial lipemia. In conclusion, patients with combined hyperlipemia are at risk for activation of the coagulation system, particularly during postprandial lipemia. This activation may be significantly reduced by statins and ,-3 FA. [source] Cosegregation of a Factor VIII Microsatellite Marker with Mild Hemophilia A in Golden Retriever DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2005Marjory B. Brooks Mild hemophilia A (factor VIII deficiency) was diagnosed in Golden Retrievers and pedigree studies were undertaken to test the cosegregation of an intragenic factor VIII marker with the disease phenotype. The study population consisted of 30 client-owned dogs (22 males and 8 females). Hemophilic males (n = 12) typically demonstrated prolonged bleeding after trauma or surgery rather than spontaneous hemorrhagic events. The affected males had a proportionate reduction in factor VIII coagulant activity (mean FVIII:C = 4%) and factor VIII protein concentration (mean FVIII:Ag = 3%). Twenty-five dogs (10 affected males, 8 clear males, 2 obligate carrier dams, and 5 suspect carrier daughters) were genotyped for a factor VIII microsatellite marker, with allele size assigned by an automated capillary electrophoresis system. Five distinct marker alleles were present in the study pedigree and a 300-base pair allele was found to segregate with the hemophilia A phenotype. The inheritance of the hemophilia-associated allele defined carrier status for 5 suspect daughters of obligate carrier dams. The limitations inherent to linkage analyses (ie, lack of access to key family members and homozygosity at the marker locus) did not preclude carrier detection in this pedigree. We conclude that genotype analysis for the intragenic factor VIII marker can aid in control of canine hemophilia A through enhanced carrier detection. [source] | ||||||||||