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A 37-year-old woman developed deep venous thrombosis (DVT) of the left lower extremity at 8 weeks of gestation during her second pregnancy. There was no personal or family history of thrombosis. She received intravenous heparin, but heparin resistance was noted. The plasma antithrombin activity decreased to 45% in the acute phase, and it remained low postpartum. Her mother also had low plasma antithrombin activity (46%), and genetic testing revealed a heterozygous SERPINC1 mutation. Even without a family history of thrombosis, we should suspect hereditary antithrombin deficiency in patients with initial DVT and perform thorough investigation.

Objective: To review insights gained in the past several years about hereditary antithrombin (AT) deficiency and to outline approaches to the management of patients with AT deficiency in the acute and chronic settings. Data Sources: An extensive literature search of Scopus (January 2008-April 2016) was performed for the terms congenital antithrombin deficiency, inherited antithrombin deficiency, or hereditary antithrombin deficiency. Additional references were identified by reviewing literature citations. Study Selection: All relevant English-language case reports, reviews, clinical studies, meeting abstracts, and book chapters assessing hereditary AT deficiency were included. Data Synthesis: AT deficiency significantly increases the risk of venous thromboembolism (VTE). The risk of VTE is particularly high during pregnancy, the postpartum period, and following major surgery. Effective clinical management includes determination of the appropriate type and duration of antithrombotic therapy (ie, AT replacement for acute situations) while minimizing the risk of bleeding. For persons newly diagnosed with AT deficiency, age, lifestyle, concurrent medical conditions, family history, and personal treatment preferences can be used to individualize patient management. Patients should be informed of the risks associated with hormonal therapy, pregnancy, surgical procedures, and immobility, which further increase the risk of VTE in patients with AT deficiency. Conclusion: AT deficiency poses the highest risk for VTE among the hereditary thrombophilias, often requiring long-term anticoagulation. Undertaking an evaluation for hereditary thrombophilia is controversial; however, a diagnosis of VTE in association with AT deficiency can have management implications. An important treatment option for patients with this disorder in high-risk situations is AT concentrate.

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. Despite full anticoagulation during pregnancy and the postpartum period, women with AT deficiency may still be vulnerable to developing venous thromboembolism (VTE), including fatal events. There is limited guidance on the management of AT deficiency in pregnancy, including the role of AT concentrates. Following a comprehensive review of the state of the art with respect to recommendations and guidelines, our expert panel in maternal-fetal medicine, hematology and basic science reached consensus on key issues in the recognition and management of AT deficiency in pregnancy. This paper summarizes the state of the art and summarizes what we believe are best practices with special emphasis on a multidisciplinary approach involving obstetrics and hematology in the care of women with AT deficiency.

The clinical use of recombinant therapeutic proteins has increased significantly during the last few decades. However, therapeutic indications often require large amounts of highly purified product, especially for therapies that call for chronic dosing regimes. The development of very efficient expression systems is essential to the full exploitation of the recombinant technology, so that life-saving medicines will become more readily available. Transgenic production technology is a highly scalable, capital-sparing approach to the manufacturing of complex recombinant proteins. ATryn®, recombinant antithrombin purified from the milk of transgenic goats, the first transgenically-derived therapeutic protein to gain regulatory approval, is currently approved in the United States and the EU for the treatment of Hereditary Antithrombin Deficiency. In addition, production of additional recombinant proteins in the milk of transgenic goats and rabbits is currently being tested for the production of a number of therapeutic antibodies as well as an alternative to plasma fractionation for the manufacture of human plasma proteins. The following review examines the potential of somatic cell nuclear transfer to generate transgenic goats used in the production of human recombinant therapeutics.

Population pharmacokinetic (PK) analyses were conducted to refine dosing recommendations for recombinant human anti-thrombin therapy in surgery and delivery patients with hereditary antithrombin deficiency (HD). Single-dose PK data from patients with HD and nonlinear mixed-effects modeling were used to devise a dosing regimen to target antithrombin (AT) activity levels between 80% and 120% of normal. External validation with data from a phase 3 trial confirmed the correctness of a covariate-free model for surgery patients, but dosing adjustment was necessary for delivery patients. After different covariates were tested, the model was updated to incorporate the influential covariate, delivery. Simulations were used to develop a therapeutic drug-monitoring scenario that results in steady state AT activity levels within the target range as quickly as practically feasible. Data from a second clinical trial provided additional external validation and confirmed the accuracy of the dosing model for both groups of patients.

Thrombate III® is a highly purified antithrombin concentrate that has been used by clinicians worldwide for more than two decades for the treatment of hereditary antithrombin deficiency. The manufacturing process is based on heparin-affinity chromatography and pasteurization. To modernize the process and to further enhance the pathogen safety profile of the final product, despite the absence of infectious disease transmission, a nanofiltration step was added. The biochemical characterization and pathogen safety evaluation of Thrombate III® manufactured using the modernized process are presented. Bioanalytical data demonstrate that the incorporation of nanofiltration has no impact on the antithrombin content, potency, and purity of the product. Scaledown models of the manufacturing process were used to assess virus and prion clearance under manufacturing setpoint conditions. Additionally, robustness of virus clearance was evaluated at or slightly outside the manufacturing operating limits. The results demonstrate that pasteurization inactivated both enveloped and non-enveloped viruses. The addition of nanofiltration substantially increased clearance capacities for both enveloped and non-enveloped viruses by approximately 4–6 log10. In addition, the process achieves 6.0 log10 ID50 prion infectivity clearance. Thus, the introduction of nanofiltration increased the pathogen safety margin of the manufacturing process without impacting the key biochemical characteristics of the product.

Hereditary antithrombin deficiency is a hypercoagulable state associated with an increased risk for venous thrombosis. The recommended initial test for antithrombin is an activity (functional) assay. The advantages and disadvantages of the various testing options are presented. The causes of acquired antithrombin deficiency are much more common than hereditary deficiency. Therefore, this article describes the appropriate steps to take when antithrombin activity is low, in order to confirm or exclude a hereditary deficiency. The causes of falsely normal results are also described, including direct thrombin inhibitors. Am. J. Hematol. 85:947-950, 2010. © 2010 Wiley-Liss, Inc.

Venous thrombosis or thromboembolism in younger people and especially in children or adolescents is in the majority of cases related to one or more inherited defects of naturally occurring antithrombotic proteins.

A recombinant human antithrombin (rhAT; generic name: antithrombin Alfa) has recently been developed. A 37 year-old parturient with hereditary antithrombin deficiency, receiving rhAT infusion therapy, who successfully received an epidural catheter for analgesia and anesthesia during labor and cesarean delivery, is presented.

FDA announced February 6 that it had approved the first biological product made from a genetically engineered animal. The antithrombin recombinant product, which will be marketed as ATryn, is intended to help patients who have hereditary antithrombin deficiency, according to FDA. The anticoagulant

Subcutaneous heparin and plasma infusion were successfully used during an induced abortion in a young woman with familial antithrombin-III deficiency and a history of severe thrombotic episodes.Women with herditary antithrombin-3 deficiency are exposed to a considerable risk of thrombosis during periods of thrombogenic stress, such as labour, delivery or abortion. This study describes treatment with heparin and subcutaneous infusion of plasma in a pregnant 25 year old, AT-3 deficient woman undergoing abortion. The patient belonged to a family in which thrombotic episodes were not uncommon; the patient herself had experienced thrombosis during her first pregnancy. At the 3rd month of gestation it was decided to interrupt pregnancy. Prophylactic treatment with subcutaneous heparin, 5000 IU 3 times a day, began 10 days before abortion. On the day of the abortion, she received 900 ml of fresh plasma as a source of AT-3 over a period of 7 hours, and an additional amount of 5000 IU heparin shortly before the abortion. The abortion and injection of methylergometrin caused a significant reduction of platelet number; changes in plasma AT-3 were minimal. On the 4th day after abortion the platelet number increased to pretreatment level, and heaprin treatment was stopped on the 12th day. This study demonstrates that subcutaneous infusion of fresh plasma is a safe prophylactic treatment for AT-3 deficient patients exposed to thrombogenic stress.