Article

Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options.

Department of Haematology, Glasgow Royal Infirmary, Glasgow, UK.
Drugs (Impact Factor: 4.13). 02/2007; 67(10):1429-40.
Source: PubMed

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.

1 Follower
 · 
98 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study we report the largest descriptive cohort of congenital antithrombin (AT) deficiency in children, its clinical presentation, molecular basis and genotype-phenotype correlation. Paediatric patients diagnosed with AT deficiency at two tertiary care children's hospitals over a 10-year period were retrospectively reviewed. SERPINC1 gene sequencing was offered to subjects who did not already have the test performed. Molecular modelling and stability simulations were performed for the novel mutations identified. Twenty-nine subjects from 18 pedigrees were identified. Mean age (± standard deviation) at diagnosis and mean duration of follow-up were 8·4 (± 6·6) years and 6·6 (± 5·7) years respectively. Most recent mean AT activity and AT antigen levels (n = 20) were 0·53 (± 0·09) iu/ml and 0·60 (± 0·17) iu/ml respectively. Ten subjects were diagnosed secondary to low AT activity measured following venous thrombo-embolism (VTE). All 10 subjects had additional risk factors at the time of VTE. None of the 19 subjects diagnosed with AT deficiency in the setting of positive family history have had VTE with 7·4 (± 5·8) years follow-up. Mutation analysis has been completed on 19 subjects from 16 pedigrees. Nine unique mutations, including 4 novel mutations were identified.
    British Journal of Haematology 03/2014; 166(1). DOI:10.1111/bjh.12842 · 4.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recombinant human antithrombin (rhAT; ATryn), isolated from the milk of transgenic goats, provides an alternative to human plasma-derived antithrombin (AT) concentrate for perioperative and peripartum prophylaxis of venous thromboembolism (VTE) in patients with hereditary AT deficiency. Optimized rhAT dosing algorithms and improved plasma AT monitoring protocol were used in an open-label, single-arm, multinational, pivotal safety and efficacy study that was conducted in patients with hereditary AT deficiency in perioperative and peripartum settings. Loading and maintenance doses were calculated on the basis of pretreatment AT activity levels. Specific dosing regimens were used for pregnant and surgical patients; rhAT was to be given for at least 3 days and for 14 days or less. The primary efficacy end point was the incidence of any thromboembolic event during rhAT therapy or within 7 days of rhAT discontinuation. Safety and AT activity levels were secondary end points. Six surgical and 12 pregnant patients were treated for a median of 3.2 days (range 0.9-14 days). With the optimized dosing regimens, a median of 1 dose adjustment (range 0-6 dose adjustments) was needed to maintain AT activity levels within 80-120% of normal. No confirmed VTEs occurred during treatment or in the subsequent 7 days. Overall, rhAT was well tolerated, but some bleeding complications occurred after rhAT discontinuation and anticoagulation reinstitution. No antibodies to rhAT or goat milk proteins were detected. Perioperative and peripartum prophylactic rhAT therapy in patients with hereditary AT deficiency is well tolerated and effective in preventing VTE.
    Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 03/2014; 25(5). DOI:10.1097/MBC.0000000000000076 · 1.38 Impact Factor
  • Thrombosis Research 06/2014; 133(6). DOI:10.1016/j.thromres.2014.03.025 · 2.43 Impact Factor