Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options.
ABSTRACT Antithrombin is a glycoprotein critical to the regulation of coagulation. Its primary action is the inhibition of the activated coagulation factors IIa (thrombin) and Xa. In addition there is growing evidence to suggest that antithrombin also plays a role in the inhibition of inflammation within the environment of the vascular endothelium. Reduced plasma antithrombin may result from congenital deficiency or arise secondarily from a range of disorders such as liver dysfunction, premature infancy and sepsis, or as a result of interventions such as major surgery or cardiopulmonary bypass. Congenital antithrombin deficiency is the most clinically important of the inherited thrombophilias resulting in thrombosis in the majority of those affected. The challenge in managing these patients is preventing potentially life-threatening thrombosis, while minimising the equally significant risk of haemorrhage associated with long-term anticoagulation. This is achieved in the first instance by identifying high-risk episodes such as surgery, immobility and pregnancy for which prophylactic anticoagulation can be used in the short term. Prophylaxis for such periods is best provided by the use of low molecular weight heparin (LMWH) with substitution by or addition of antithrombin concentrate in particularly high-risk circumstances. In the case of pregnancy, antithrombin concentrate is often used around the time of birth when LMWH may increase the risk of post-partum haemorrhage. As patients with congenital antithrombin deficiency get older so their thrombotic risk gradually increases and for many patients long-term anticoagulation becomes unavoidable because of recurrent episodes of venous thromboembolism. There has been much interest in the role of antithrombin deficiency in the setting of sepsis and the critically ill patient where there is a clear correlation between severity of illness and degree of antithrombin reduction. It is not clear yet, however, to what extent the depletion of antithrombin affects the clinical condition of such patients. A number of trials have investigated the use of antithrombin as a treatment in the intensive care setting with the overall conclusion being that there is some benefit to its use but only if large supra-physiological doses are used. It has also become clear that the concurrent use of any form of heparin removes whatever benefit may be derived from antithrombin treatment in this setting. Until recently, antithrombin replacement was only available as a pooled plasma-derived product, which despite effective viral inactivation still carries an uncertain risk of transfusion transmitted infection. A recombinant antithrombin product now under investigation, and recently licensed in Europe, may provide a useful alternative treatment option.
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- "Developmentally, neonates and young infants have lower physiologic levels of circulating plasma AT that reach adult levels by about 6 months of age. AT levels can also decline with acquired conditions such as active thrombosis, sepsis, liver dysfunction, and cardiopulmonary bypass . In addition, pharmacokinetic distribution of LMWH such as dalteparin in infants as a result of binding to non-AT proteins, although lower than UFH, may lead to underestimation of measured anti- Xa activity achieved per dose of heparin . "
ABSTRACT: Dalteparin is a commonly used low molecular weight heparin (LMWH) with extensive safety data in adults. With distinct advantages of once daily dosing and relative safety in renal impairment, it has been used off-label in pediatric practice; however, age-based dosing guidelines, safety and efficacy data in children are evolving. To report our institutional experience with the use of dalteparin in the treatment and prophylaxis of venous thromboembolism (VTE) in pediatric patients. Retrospective chart review of all children (0-18years) that received dalteparin from December 1, 2000 through December 31, 2011. Doses per unit body weight per day (units/kg/day) were calculated for age-based group comparisons. Of 166 patients identified, 116 (70%) received prophylactic doses while 50 (30%) received therapeutic doses of dalteparin. Infants (<1year) required significantly higher weight-based dosing to achieve therapeutic anti-Xa levels compared to children (1-10years) or adolescents (>10-18years) (mean dose units/kg/day; 396.6 versus 236.7 and 178.8 respectively, p<0.0001). Overall response rate, including complete and partial thrombus resolution, was 83%. Bleeding complications were minor and the rates were similar in therapeutic and prophylaxis patients. No significant differences in dosing or bleeding events were noted based on obesity or malignancy. In our experience, dalteparin is effective for prophylaxis and therapy of VTE in pediatric patients. Dosing should be customized in an age-based manner with close monitoring of anti-Xa activity in order to achieve optimal levels, prevent bleeding complications, and to allow full benefit of prevention or therapy of thrombotic complications. Copyright © 2015. Published by Elsevier Ltd.Thrombosis Research 05/2015; DOI:10.1016/j.thromres.2015.05.017 · 2.43 Impact Factor
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ABSTRACT: Objective: To determine the antigenic concentration and percent functional activity of antithrombin in healthy Pakistani males. Methodology: Over a period of one year, 50 healthy male volunteers divided into two age groups were tested for antithrombin levels by radial immunodiffusion(RID), at the Departments of Pathology King Edward Medical College and Postgraduate Medical Institute, Lahore. None of them were suffering from any acute or chronic disease, nor were taking any medications. Plasma samples were used to determine the antigenic and derived percent activity from NOR-Partigen* plates supplied by Dade Behring. Results: The younger group of healthy male volunteers (n=25), mean age 23.5 years showed a higher antithrombin concentration 46.7mg/dl or 155% functional activity: while the older volunteers (n=25), with mean age 44.0 years, showed 42.4 mg/dl concentration or 142% functional activity. The p value was insignificant between the groups (p> 0.05). Conclusions: The younger healthy individuals in our population show higher antithrombin concentration and functional activity, which tends to decrease insignificantly with age.
Conference Paper: Generalized coherence [signal detection][Show abstract] [Hide abstract]
ABSTRACT: The authors introduce a test for detecting the presence of a common signal on M noisy channels that generalizes a popular technique using the magnitude-squared coherence (MSC) estimate for detecting a common signal on two channels. The basis of this test is the generalized coherence estimate, a statistic involving the normalized M × M Gram matrix determinant, which reduces to the MSC estimate for M =2. The distribution of the generalized coherence estimate is derived under the assumptions of independent noise and no common signal on the M channelsAcoustics, Speech, and Signal Processing, 1988. ICASSP-88., 1988 International Conference on; 05/1988