Inherited Antithrombin III Deficiency in the Neonate

Seguin, John; Weatherstone, Kathleen; Nankervis, Craig A.

doi:10.1001/archpedi.1994.02170040055009

Cited by 20 publications

(10 citation statements)

References 18 publications

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“…Thrombotic disease in patients with homozygous type II HBS AT deficiency includes deep vein thrombosis, disseminated intravascular coagulation, cerebral or peripheral arterial thrombosis, fetal loss, and pulmonary embolism [17,18]. Thrombosis in the heart atrium or ventricle has been described in neonates with proved or suspected AT deficiency [19]. The thrombotic phenotype of the AT m/m mice differs somewhat from the human findings, in that no obvious thrombi were found in the larger vessels, whereas it was marked by severe thrombotic eye disease, liver pathology consistent with portal hypertension, placental thrombosis, and priapism in sexually active males.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice

Dewerchin

Elst

Singh

et al. 2004

Journal of Thrombosis and Haemostasis

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Summary. Venous thromboembolic disease is a major cause of morbidity and mortality, necessitating antithrombotic therapy. A human monoclonal anti-factor (F)VIII antibody, LCL-mAb-LE2E9, produced by a lymphoblastoid cell line derived from a hemophilia A patient with inhibitor to wild-type but not mutant self FVIII, was previously reported to achieve ef®cient inhibition of thrombosis in an experimental vena cava thrombosis model in mice. Here, the antithrombotic ef®cacy of a recombinant DNAderived version of this anti-FVIII antibody (rec-mAb-LE2E9) was tested in mice which carry a type II heparin binding site antithrombin de®ciency mutation and display spontaneous chronic thrombosis in several sites including the penile vein of sexually active males. The recombinant anti-FVIII antibody (100 mg, repeated after 3 days) prevented thrombotic priapism in all treated males, whereas all control animals treated with saline (group of four animals) developed priapism within 6 days after mating (P < 0.05 for treated vs. saline). The rec-mAb-LE2E9 and the original LCL-mAb-LE2E9 were equally effective (®ve and seven males/group, respectively). These results con®rm that FVIII inhibition represents a potent antithrombotic strategy, and show that both LCL-mAb-LE2E9 and rec-mAb-LE2E9 ef®-ciently prevent thrombosis in a physiological model representative of thrombosis in patients with a severe prothrombotic risk.

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Section: Introductionmentioning

confidence: 99%

Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice

Dewerchin

Elst

Singh

et al. 2004

Journal of Thrombosis and Haemostasis

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“…However, ocular vein occlusion, portal vein thrombosis, placental thrombosis, and although rarely, priapism are observed in patients with Factor V Leiden, prothrombin mutation, or decreased protein S, protein C, or AT levels. [32][33][34][35][36] Thrombosis in the heart has been described in neonates with proved or suspected AT deficiency, in addition to thrombus formation in the large vessels and intracranial venous sinus (see review 37 ).…”

Section: Discussionmentioning

confidence: 99%

Life-Threatening Thrombosis in Mice With Targeted Arg48-to-Cys Mutation of the Heparin-Binding Domain of Antithrombin

Dewerchin

Hérault

Wallays

et al. 2003

Circulation Research

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Abstract-Antithrombin (AT) inhibits thrombin and some other coagulation factors in a reaction that is dramatically accelerated by binding of a pentasaccharide sequence present in heparin/heparan-sulfate to a heparin-binding site on AT.Based on the involvement of R47 in the heparin/AT interaction and the frequent occurrence of R47 mutations in AT deficiency patients, targeted knock-in of the corresponding R48C substitution in AT in mice was performed to generate a murine model of spontaneous thrombosis. The mutation efficiently abolished the effect of heparin-like molecules on coagulation inhibition in vitro and in vivo. Mice homozygous for the mutation (AT m/m mice) developed spontaneous, life-threatening thrombosis, occurring as early as the day of birth. Only 60% of the AT m/m offspring reached weaning age, with further loss at different ages. Thrombotic events in adult homozygotes were most prominent in the heart, liver, and in ocular, placental, and penile vessels. In the neonate, spontaneous death invariably was associated with major thrombosis in the heart. This severe thrombotic phenotype underlines a critical function of the heparin-binding site of antithrombin and its interaction with heparin/heparan-sulfate moieties in health, reproduction, and survival, and represents an in vivo model for comparative analysis of heparin-derived and other antithrombotic molecules.

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“…the potentiation of antithrombin inhibition of thrombin and factor Xa. Neonates usually require higher doses of heparin than paediatric or adult patients because of a short half-life, secondary to an increased clearance, [82] and because of physiologically low ATIII plasma concentrations; [83] however, no clinical trials of heparin therapy for thrombosis are available in neonates, although successful thrombolysis has been described repeatedly in small case series. [6,26,82,84] Major disadvantages of heparin therapy are the increased risk of bleeding complications, the requirement for frequent and careful monitoring, significant but nonspecific protein binding and the risk of inducing thrombocytopenia.…”

Section: Unfractionated Heparinmentioning

confidence: 99%

Management of Preterm Infants with Intracardiac Thrombi

2001

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Improvement in neonatal care has led to improvements in survival and patient outcome in preterm infants; however, this improved survival has been associated with the development of secondary complications, such as catheter-associated intravascular and intracardiac thrombus formation with a non-negligible morbidity and mortality. The sick preterm infant is at high risk of catheter-related thrombus formation because of the combination of a high prothrombotic activity, low levels of natural anticoagulants, and various imbalances in the fibrinolytic systems. Based on clinical experience in adults and children, and several neonatal case reports demonstrating the efficacy and tolerability of specific thrombolytic treatment, this approach should be recommended as a first choice treatment in the premature infant with intracardiac or intravascular thrombosis. The thrombolytic agents of choice are urokinase or tissue plasminogen activator (tPA); however, none of them have proven to be superior to the other in terms of efficacy or tolerability, either in adult patients or premature infants. In the past, it has been suggested that newborn infants may require higher doses of thrombolytic agents than adults for effective systemic thrombolysis; however, based on more recent in vitro studies, it seems unlikely that this is true. Nevertheless, systemic (high dose) fibrinolysis is of concern as premature neonates present an increased risk of cerebral haemorrhage during the first weeks of life; therefore, low dose treatment has been proposed with, if possible, direct infusion of the fibrinolytic agent into, or close to, the thrombus. This approach has proven to be efficient and well tolerated in several small case series of newborn and preterm infants. Recommended doses are 1000 to 3000 U/kg/h for urokinase or 0.01 to 0.05 mg/kg/h for tPA. A systemic proteolytic state will not be induced by this low dose; however, specific monitoring of fibrinogen plasma levels has to be recommended. Fibrinogen levels should remain above 100 mg/dL during low dose treatment. Lower levels of fibrinogen will indicate the presence of an unwanted systemic fibrinolytic state. After successful thrombolysis, a follow-up treatment, preferentially with low-molecular-weight heparin for neonates at adjusted doses, should be instituted for at least 6 weeks in the absence of any persisting thrombophilic factor. A longer course (3 to 6 months) of anticoagulation therapy is recommended when thrombophilic factors (i.e. hereditary thrombophilia or central venous catheter still in place) are present. Furthermore, it is recommended that any neonate with thrombosis should be evaluated for hereditary thrombophilia later in life.

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Inherited Antithrombin III Deficiency in the Neonate

Cited by 20 publications

References 18 publications

Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice

Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice

Life-Threatening Thrombosis in Mice With Targeted Arg48-to-Cys Mutation of the Heparin-Binding Domain of Antithrombin

Management of Preterm Infants with Intracardiac Thrombi

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