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THROMBATE III^® is an effective choice for patients with hereditary antithrombin deficiency (hATd), which carries the highest risk of VTE

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THROMBATE III is an effective choice for patients with hereditary antithrombin deficiency

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

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.¹

Why THROMBATE III?

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

THROMBATE III has no known contraindications¹

THROMBATE III has a low risk of major bleeding complications, even in the presence of heparin (enoxaparin)¹

THROMBATE III is effective in high-risk situations, including surgery, pregnancy, and childbirth¹

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.

Efficacy

THROMBATE III is an effective choice in high-risk situations¹

In clinical studies, THROMBATE III was proven effective for patients with hereditary antithrombin deficiency (hATd) for the treatment and prevention of thromboembolism, including before, during, and after surgery and childbirth.¹

THROMBATE III is indicated in patients with hereditary antithrombin deficiency for treatment and prevention of thromboembolism and for prevention of perioperative and peripartum thromboembolism.¹

In patients with hATd, THROMBATE III is effective in preventing the expansion of a formed thrombus (clot) and formation of additional clots.¹

No reports of thrombotic complications during obstetrical and surgical procedures¹

Clinical Situation

Childbirth/Surgery

# of Procedures*: N = 13

Outcome: No thrombosis or pulmonary embolism*

*Data included 13 patients with a history of thromboembolism, who were administered THROMBATE III on 16 separate occasions (11 surgeries and 5 pregnancies). One patient was treated on separate occasions for surgery and childbirth. Heparin was administered in 3 of 11 surgical procedures.

*Data included 13 patients with a history of thromboembolism, who were administered THROMBATE III on 16 separate occasions (11 surgeries and 5 pregnancies). One patient was treated on separate occasions for surgery and childbirth. Heparin was administered in 3 of 11 surgical procedures.
Clinical Situation	# of Procedures*	Outcome
Childbirth/Surgery	N = 13	No thrombosis or pulmonary embolism*

Patients diagnosed with hATd are at especially high risk for blood clots in certain situations such as: surgery, pregnancy, and childbirth, and when they already have a blood clot.²

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.

Safety and convenience

THROMBATE III can provide predictable amounts of AT at the point of care¹

Has one dosing formula¹

Bolus intravenous infusion*
Loading dose on day 1

Provides for convenient storage and reconstitution¹

No refrigeration required
- Store at room temperature (not to exceed 25ºC, 77ºF)
- No need to thaw
Single-use vial (500 IU potency)
Sterile water for injection (10 mL), transfer needle, and filter needle provided

Can be used before, during, and after surgery

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

*Rate of administration adapted to the response of the individual patient, but administration of the entire dose in 10 to 20 minutes is generally well tolerated.

^†Expressed as a percent of normal level based on functional AT assay. If laboratory testing is available, monitor plasma AT levels every 12 hours following the initial loading dose. THROMBATE III may be infused intravenously over 10 to 20 minutes.

Use THROMBATE III to replace what is normally present in the body¹

Low risk of major bleeding complications, even in the presence of heparin¹

The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hATd. 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

No known contraindications¹

MOA: At levels and heparin

The role of antithrombin in thrombosis

80% of the natural anticoagulant effect against thrombin is dependent on antithrombin^2,3
AT activity inhibits many clotting factors in the coagulation cascade^2-6

Cofactor Relationship Between Antithrombin and Heparin

Antithrombin inactivates multiple clotting factors in the coagulation cascade^2,4
- Binds irreversibly/inhibits prothrombotic actions of factor Xa and thrombin
The anticoagulant effects of heparin rely on its interaction with antithrombin
- Heparin depends on antithrombin as a cofactor⁷
- Heparin is ineffective in the absence or near absence of antithrombin⁴
- The anticoagulant activity of antithrombin is accelerated >1000X when bound to administered heparin⁴
When antithrombin levels are deficient, activated procoagulant proteins circulate longer, increasing the risk of thrombosis⁸
Signs of heparin (enoxaparin) resistance could suggest an inherited clotting disorder, such as hereditary AT deficiency^2,3,9,10

Impact of Hereditary Antithrombin Deficiency on Heparin Action

Reduced concentrations of antithrombin as a cofactor for heparin action require increased doses of heparin^2,9
- Some patients may be heparin resistant
- Heparin resistance/need for higher doses may provide diagnostic clue to hereditary antithrombin deficiency

Increasing heparin doses without considering the possibility of hereditary antithrombin deficiency can have deleterious effects¹¹
- Inadequate anticoagulation despite large intraoperative heparin doses
- Excessive heparin dosing can lead to increased postoperative bleeding

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.

Heparin response issues

Antithrombin deficiency is the most common cause of low heparin response^7,9

Dr. Stephen Bader discusses important considerations for before, during, and after surgery

Heparin resistance, or responsiveness issues, can occur in heparin-requiring surgeries, and administering additional heparin to overcome resistance could lead to bleeding at the end of the procedure
Low heparin response is commonly defined as needing a daily dose in excess of 35,000 units/day
Options to diagnose low heparin response in the operating room are limited, but interventions should be utilized to achieve the targeted ACT
After the surgery, physicians may consider hematologic workup to make sure that a patient with low heparin response does not have hereditary antithrombin deficiency
Patients with hereditary antithrombin deficiency need to be identified for appropriate management postoperatively and during future surgeries and life events, such as childbirth, which further increase their risk of thrombosis

Mitigating VTE Risk: Functional Evaluation of AT

The risks of hereditary antithrombin deficiency can be mitigated with functional evaluation of antithrombin activity, including laboratory testing, as well as with long-term management to address and reduce risks during future procedures or other high-risk life events⁵

Mitigating VTE Risk

Whom to Test¹²

Unexplained VTE at a younger age (<50 years)
Recurrent spontaneous or unusually extensive spontaneous VTE
Unexplained arterial thromboembolism in a younger patient
Unexplained VTE at an unusual site
Recurrence of VTE while adequatedly anticoagulated
Family history of spontaneous VTE
Family history of known thrombophilia, even if patient is asymptomatic

How to Test: Functional Antithrombin Assays

Functional anththrombin assays are most commonly used and are recommended for initial testing for antithrombin deficiency⁷
Initial testing should be completed a few weeks after thrombotic event—heparin use may decrease antithrombin levels by 30%¹²
High specificity and sensitivity; positive predictive value = 96%⁷

Management¹²

Asymptomatic individuals with antithrombin deficiency typically are not started on long-term anticoagulation; however they need to receive DVT prophylaxis in high-risk situations, such as surgery, pregnancy, or childbirth
Patients with antithrombin deficiency who have had a VTE event should be considered for long-term anticoagulation

Mitigating VTE Risk
Whom to Test¹²	Unexplained VTE at a younger age (<50 years) Recurrent spontaneous or unusually extensive spontaneous VTE Unexplained arterial thromboembolism in a younger patient Unexplained VTE at an unusual site Recurrence of VTE while adequatedly anticoagulated Family history of spontaneous VTE Family history of known thrombophilia, even if patient is asymptomatic
How to Test: Functional Antithrombin Assays	Functional anththrombin assays are most commonly used and are recommended for initial testing for antithrombin deficiency⁷ Initial testing should be completed a few weeks after thrombotic event—heparin use may decrease antithrombin levels by 30%¹² High specificity and sensitivity; positive predictive value = 96%⁷
Management¹²	Asymptomatic individuals with antithrombin deficiency typically are not started on long-term anticoagulation; however they need to receive DVT prophylaxis in high-risk situations, such as surgery, pregnancy, or childbirth Patients with antithrombin deficiency who have had a VTE event should be considered for long-term anticoagulation

The effect of drugs that use antithrombin to exert their anticoagulation may be altered when THROMBATE III is added or withdrawn. Regularly perform coagulation tests suitable for the anticoagulant used (eg, aPTT and anti-Factor Xa activity) to avoid excessive or insufficient anticoagulation. Additionally, monitor the patients for the occurrence of bleeding or thrombosis.

THROMBATE III reduces VTE Risk

Dr. Bader talks about surgery in patients with hATd

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thrombate III vs frozen plasma

THROMBATE III delivers 50x more antithrombin (AT) than the same amount of fresh frozen plasma (FFP)

A vial of THROMBATE III contains concentrated AT factor, while a bag of FFP contains AT as well as varying amounts of other plasma components.^1,13

Properties of antithrombin (AT) concentrate and fresh frozen plasma (FFP)

Indication

THROMBATE III¹: Indicated in patients with hereditary antithrombin deficiency (hATd) for treatment and prevention of thromboembolism and for prevention of perioperative and peripartum thromboembolism

FFP¹³: Indicated in the management of patients with selected coagulation factor deficiencies, congenital or acquired, for which no specific coagulation concentrates are available

How supplied/volume

THROMBATE III¹: Single-use 10-mL vial (500-IU potency)

FFP¹³: Supplied in 200- to 250-mL bags (on average)

Concentration

THROMBATE III¹: 50 IU/mL AT concentration (after reconstitution with 10 mL sterile water for injection)

FFP¹³: ~1 IU/mL AT concentration

Use

THROMBATE III¹: Intravenous bolus infusion, regardless of ABO status. Can be readily available at the point of care

FFP¹³: Needs to be thawed prior to use. Intravenous infusion. Plasma must be ABO compatible with the recipient's red blood cells

Content

THROMBATE III¹: THROMBATE III provides predictable amounts of AT

FFP¹³: Contains AT plus other plasma components in varying levels

Half-life

THROMBATE III¹: The half-life of THROMBATE III is similar to endogenous AT^1,14

FFP¹³: The components of FFP have varying half-lives

Storage

THROMBATE III¹: THROMBATE III can be stored at room temperature (up to 77°F) for up to 36 months. Do not freeze

FFP¹³: FFP should be stored at −18°C (0°F) or colder. Infuse immediately after thawing or store at 1-6°C (34-43°F)

Process

THROMBATE III¹: THROMBATE III is produced from human plasma— it is fractionated and purified to yield concentrated antithrombin

FFP¹³: Centrifuged, separated, and frozen solid at −18°C (0°F) within 8 hours of collection

Dosing

THROMBATE III¹: The loading dose for Thrombate III is calculated with a clear formula:
Units required (IU) = 120% - baseline % x body weight (kg)/1.4%

FFP¹³: The volume of FFP transfused depends on various factors, including the clinical situation and patient weight, and may be guided by laboratory assays of coagulation function

	THROMBATE III¹	FFP¹³
Indication	Indicated in patients with hereditary antithrombin deficiency (hATd) for treatment and prevention of thromboembolism and for prevention of perioperative and peripartum thromboembolism	Indicated in the management of patients with selected coagulation factor deficiencies, congenital or acquired, for which no specific coagulation concentrates are available
How supplied/volume	Single-use 10-mL vial (500-IU potency)	Supplied in 200- to 250-mL bags (on average)
Concentration	50 IU/mL AT concentration (after reconstitution with 10 mL sterile water for injection)	~1 IU/mL AT concentration
Use	Intravenous bolus infusion, regardless of ABO status. Can be readily available at the point of care	Needs to be thawed prior to use. Intravenous infusion. Plasma must be ABO compatible with the recipient's red blood cells
Content	THROMBATE III provides predictable amounts of AT	Contains AT plus other plasma components in varying levels
Half-life	The half-life of THROMBATE III is similar to endogenous AT^1,14	The components of FFP have varying half-lives
Storage	THROMBATE III can be stored at room temperature (up to 77°F) for up to 36 months. Do not freeze	FFP should be stored at −18°C (0°F) or colder. Infuse immediately after thawing or store at 1-6°C (34-43°F)
Process	THROMBATE III is produced from human plasma— it is fractionated and purified to yield concentrated antithrombin	Centrifuged, separated, and frozen solid at −18°C (0°F) within 8 hours of collection
Dosing	The loading dose for Thrombate III is calculated with a clear formula: Units required (IU) = 120% - baseline % x body weight (kg)/1.4%	The volume of FFP transfused depends on various factors, including the clinical situation and patient weight, and may be guided by laboratory assays of coagulation function

Predictable dosing that directly replaces the missing antithrombin (AT)
Concentrated amounts of AT to minimize additional volume load
Rapid preparation at the point of care—no thawing needed
Convenient vial storage for up to 36 months at room temperature

The half-life of AT has been reported to be shortened following surgery, hemorrhage or acute thrombosis, and during intravenous heparin (or low molecular weight heparin) administration. In such conditions, monitor plasma AT levels more frequently, and administer THROMBATE III as necessary.

THROMBATE III provides a direct approach to managing hereditary AT deficiency in high-risk situations¹

The loading dose volume for THROMBATE III is calculated with a clear formula so each dose is precise and accurate
Healthcare professionals have been successfully treating hereditary AT deficiency with THROMBATE III for more than 25 years

Learn more about THROMBATE III

The Risks of Low AT

See how THROMBATE III replaces missing AT

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Causes of Heparin Resistance

Hear Dr. Bader talk about inherited clotting disorders

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THROMBATE III Tools and Resources

Downloadable resources, and much more

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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

THROMBATE III [Prescribing Information]. Research Triangle Park, NC: Grifols Therapeutics LLC
Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis, and treatment options. Drugs. 2007;67(10):1429-1440
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
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
Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev. 2007;21(3):131-142
Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357(24): 2482-2494
Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med. 2002;126(11):1326-1336
Mitton BA, Steineck A. Antithrombin deficiency. eMedicine from WebMD. http://emedicine.medscape.com/article/198573-overview. Updated July 22, 2022. Accessed November 28, 2022
Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. 2008;14(6):1229-1239
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
Ranucci M. Antithrombin III: key factor in extracorporeal circulation. Minerva Anestesiol. 2002;68(5):454-457
Foy P, Moll S. Thrombophilia: 2009 update. Curr Treat Options Cardiovasc Med. 2009;11(2):114-128
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

Achieve Balance

THROMBATE III is an effective choice for patients with hereditary antithrombin deficiency

Why THROMBATE III?

THROMBATE III is an effective choice in high-risk situations1

No reports of thrombotic complications during obstetrical and surgical procedures¹

THROMBATE III can provide predictable amounts of AT at the point of care¹

Provides for convenient storage and reconstitution1

Can be used before, during, and after surgery

Use THROMBATE III to replace what is normally present in the body1

The role of antithrombin in thrombosis

Cofactor Relationship Between Antithrombin and Heparin

Impact of Hereditary Antithrombin Deficiency on Heparin Action

Antithrombin deficiency is the most common cause of low heparin response7,9

Mitigating VTE Risk: Functional Evaluation of AT

THROMBATE III reduces VTE Risk

THROMBATE III delivers 50x more antithrombin (AT) than the same amount of fresh frozen plasma (FFP)

Properties of antithrombin (AT) concentrate and fresh frozen plasma (FFP)

THROMBATE III provides a direct approach to managing hereditary AT deficiency in high-risk situations1

Learn more about THROMBATE III

Have a question about THROMBATE III?

THROMBATE III is an effective choice in high-risk situations¹

Provides for convenient storage and reconstitution¹

Use THROMBATE III to replace what is normally present in the body¹

Antithrombin deficiency is the most common cause of low heparin response^7,9

THROMBATE III provides a direct approach to managing hereditary AT deficiency in high-risk situations¹