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Download these resources to better understand use of THROMBATE III in patients with hATd for management of VTE due to low antithrombin levels

Learn more about THROMBATE III

Find answers about THROMBATE III, hereditary antithrombin deficiency (hATd), risk of venous thromboembolism (VTE), and more:

What is THROMBATE III?1

THROMBATE III is a human antithrombin (AT) indicated in patients with hereditary antithrombin deficiency for:

  • Treatment and prevention of thromboembolism
  • Prevention of peri-operative and peri-partum thromboembolism

What is hereditary antithrombin deficiency (hATd)?

hATd presents the highest risk of thrombosis among inherited thrombophilias18

  • hATd affects 1 in every 500 to 5000 individuals9
  • Those with hATd have a 20-fold greater risk of thrombosis than the general population18

When should THROMBATE III be used?

Clinical studies have shown that THROMBATE III is an effective choice for patients with hATd and for the treatment and prevention of thromboembolism, including before, during, and after surgery and childbirth.1

How is THROMBATE III used?

THROMBATE III is for intravenous use after reconstitution only. THROMBATE III is a sterile lyophilized powder for reconstitution in single use vials. Each vial of THROMBATE III contains the labeled amount of antithrombin in units per vial, typically 500 IU. When reconstituted with 10 mL of Sterile Water for Injection, USP, the final concentration is approximately 50 IU.1

What are the implications of low antithrombin levels?

Even modest decreases in AT levels significantly increase VTE risk.  Low AT can be the reason why surgical patients do not have the expected response to their anticoagulation.* Each year, more than 250,000 patients are hospitalized for VTE in the United States.26 This emphasizes the importance of assessing VTE risk in patients.

*Heparin and enoxaparin.

What is the mechanism of action for THROMBATE III?1

Antithrombin, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by AT occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on AT. AT is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. The neutralization rate of serine proteases by AT proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect of heparin is mediated by AT, heparin in vivo is ineffective in the absence or near absence of AT.

After administration, THROMBATE III temporarily replaces the missing AT in patients with hereditary antithrombin deficiency.

Do heparin and THROMBATE III work differently?

AT activity inhibits many clotting factors in the coagulation cascade. The inhibition of multiple clotting factors by AT helps prevent the expansion of existing clots and the formation of new clots in 3 stages2-4

  1. Procoagulation factors bind to AT
  2. Once bound to AT, procoagulation factors are cleared
  3. This results in arresting the growth of existing clots and helps prevent new clots

The anticoagulation effects of heparin rely entirely on its interaction with AT.2 The administration of heparin increases the anticlotting effects of AT 1000-fold.4

How is THROMBATE III manufactured?1

THROMBATE III is prepared from pooled units of human plasma from normal donors. The capacity of the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties. There are two dedicated virus inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses as small as 18 nm.

The THROMBATE III manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the variant Creutzfeldt-Jakob disease (vCJD) and Creutzfeldt-Jakob disease (CJD) agents. An individual production step in the THROMBATE III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.

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Important Safety Information

THROMBATE III® (antithrombin III [human]) is indicated in patients with hereditary antithrombin deficiency for treatment and prevention of thromboembolism and for prevention of perioperative and peripartum thromboembolism.

Hypersensitivity reactions may occur. Should evidence of an acute hypersensitivity reaction be observed, promptly interrupt the infusion and begin appropriate treatment.

Because THROMBATE III is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in the product.

Perform coagulation tests to avoid excessive or insufficient anticoagulation and monitor for bleeding or thrombosis. Measure functional plasma AT levels with amidolytic or clotting assays; do not use immunoassays.

In clinical studies, the most common adverse reactions (≥ 5% of subjects) were dizziness, chest discomfort, nausea, dysgeusia, and pain (cramps).

The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary AT deficiency. Thus, in order to avoid bleeding, the dosage of heparin (or low molecular weight heparin) may need to be reduced during treatment with THROMBATE III.

Please see full Prescribing Information for THROMBATE III.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch, or call 1-800-FDA-1088.

References

  1. THROMBATE III [Prescribing Information]. Research Triangle Park, NC: Grifols Therapeutics LLC
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  3. Li W, Johnson DJD, Esmon CT, Huntington JA. Structure of the antithrombin–thrombin–heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol. 2004;11(9):857-862
  4. James AH, Konkle BA, Bauer KA. Prevention and treatment of venous thromboembolism in pregnancy and patients with hereditary antithrombin deficiency. Int J Womens Health. 2013;5:233-241
  5. Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev. 2007;21(3):131-142
  6. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357(24): 2482-2494
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  9. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. 2008;14(6):1229-1239
  10. Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III protein C, or protein S deficiency. Arteroscler Thromb Vasc Biol. 1996;16(6):742-748
  11. Ranucci M. Antithrombin III: key factor in extracorporeal circulation. Minerva Anestesiol. 2002;68(5):454-457
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  13. AABB, American Red Cross, America’s Blood Centers, Armed Services Blood Program. Circular of information for the use of human blood and blood components. https://www.aabb.org/docs/default-source/default-document-library/resources/circular-of-information-watermark.pdf?sfvrsn=7f5d28ab_5 December 2021. Accessed November 28, 2022
  14. Tengborn L et al. Scand J Clin Lab Invest. 1981;41(5):469-477
  15. Wells PS, Blajchman MA, Henderson P, et al. Am J Hematol. 1994;45:321-324
  16. US Census Bureau, Population Division. US and World Population Clock. http://www.census.gov/ popclock/. Accessed November 28, 2022
  17. Khawar H, Kelley W,Guzman N. Fresh frozen plasma. In: StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK513347/. Updated September 19, 2022. Accessed November 28, 2022 
  18. Hellgren M, Tengborn T, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest. 1982;14:127-141
  19. Franchini M, Veneri D, Salvagno GL, Manzato F, Lippi G. Inherited thrombophilia. Crit Rev Clin Lab Sci. 2006;43(3):249-290
  20. Rodgers GM. Role of antithrombin concentrate in hereditary antithrombin deficiency: an update. Thromb Haemost. 2009;101(5):806-812
  21. Di Minno MND, Dentali F, Lupoli R, Ageno W. Mild antithrombin deficiency and risk of recurrent venous thromboembolism. Circulation. 2014;129(4):497-503
  22. Bucciarelli P, Passamonti SM, Biguzzi E, et al. Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism. J Thromb Haemost. 2012;10(9):1783-1791
  23. Centers for Disease Control and Prevention. Venous thromboembolism in adult hospitalizations – United States, 2007-2009. MMWR Morb Mortal Wkly Rep. 2012;61(22):401-404
  24. Finley A, Greenberg C. Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg. 2013;116(6):1210-1222
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