Version May 2024
Hereditary antithrombin deficiency:
Thrombate III: Prophylaxis of thrombosis during surgical or obstetrical procedures or treatment of thromboembolism:
IV:
Initial loading dose: Dosing is individualized based on pretherapy antithrombin (AT) levels. The initial dose should raise AT levels to 120% and may be calculated based on the following formula:
[(desired AT level % - baseline AT level %) x body weight (kg)] divided by 1.4 = units of antithrombin required
For example, if a 70 kg adult patient had a baseline AT level of 57%, the initial dose would be:
[(120% - 57%) x 70] divided by 1.4 = 3150 units
Maintenance dose: In general, subsequent dosing should be targeted to keep levels between 80% to 120%, which may be achieved by administering 60% of the initial loading dose every 24 hours. Adjustments may be made by adjusting dose or interval. Maintain level within normal range for 2 to 8 days depending on type of procedure/situation.
Intraoperative heparin resistance during cardiopulmonary bypass (off-label use):
Thrombate III: IV: Initial: 500 units once (dose can be rounded to the nearest vial size); a repeat dose of 500 units may be considered if activated clotting time remains subtherapeutic after the initial dose (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
Refer to adult dosing.
(For additional information see "Antithrombin, concentrate from human plasma and recombinant human: Pediatric drug information")
Acquired antithrombin III deficiency, replacement (in combination with standard anticoagulation [Heparin]) : Very limited data available: Ideal dose-response not established:
Note: Experts suggest using in combination with standard anticoagulation in patients with deep vein thrombosis, cerebral sinovenous thrombosis (CSVT), or pulmonary embolism who fail to respond clinically to standard anticoagulation treatment and who have low antithrombin (AT) levels based on age-appropriate reference ranges; there is no evidence to suggest that AT replacement improves outcomes (Ref):
Patients receiving extracorporeal membrane oxygenation (ECMO): Infants, Children, and Adolescents:
Lab-directed dosing (Ref): Note: Individualize dosing; calculate dose using the following formula: IV:
Antithrombin dose required (units) = [(desired AT level % − baseline AT level %) x body weight (kg)] divided by 1.4
Desired AT level % is 120% or an appropriate level for age and/or clinical indication (refer to institutional policy).
Baseline AT level % is based on pretherapy AT levels (refer to institutional policy).
Weight-directed dosing: IV: 50 units/kg/dose as a single dose, may repeat to achieve therapeutic anticoagulation and/or appropriate serum antithrombin III level; dosing based on 2 retrospective studies. One retrospective, observational study evaluated pediatric patients on ECMO (n=35, median age: 6 months [range: 0.33 to 144 months]) who failed to achieve adequate anticoagulation despite increasing heparin doses and subsequently received AT supplementation (median dose: 50 units/kg [range: 20 to 92.6 units/kg]). AT supplementation increased AT levels and heparin anti-Xa levels; a single dose of AT was associated with a therapeutic heparin anti-Xa level for at least 48 hours. Only 10 patients required an additional dose due to falling heparin anti-Xa levels and AT levels (Ref). In another retrospective review of 77 patients on ECMO (n=36, mean age: 1.7 years ± 9.8 years), 50 units/kg as a single dose was administered to patients receiving heparin when AT level was <80% as part of the anticoagulation protocol. No association was shown between AT level and bleeding, thrombosis, or heparin dose (Ref). Note: High doses of AT (mean dose: 241 units/kg [range: 199 to 283 units/kg]) in infants have been reported with favorable outcomes (Ref).
Patients NOT receiving ECMO (Ref): Infants, Children, and Adolescents:
Lab-directed dosing: Note: Individualize dosing; calculate dose using the following formula: IV:
Antithrombin dose required (units) = [(desired AT level % − baseline AT level %) x body weight (kg)] divided by 1.4
Desired AT level % is 120% or an appropriate level for age and/or clinical indication (refer to institutional policy).
Baseline AT level % is based on pretherapy AT levels (refer to institutional policy).
Weight-directed dosing: IV: 50 units/kg/dose, may repeat to maintain goal AT level; Note: Dosing reported anecdotally based on reports from various institutions.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Cardiovascular: Chest pain (≤2%)
Central nervous system: Dizziness (2%)
Gastrointestinal: Liver enzyme abnormalities (≤2%)
Genitourinary: Hematuria (≤2%)
Hematologic & oncologic: Hemorrhage (≥5%), hematoma (≤2%)
Local: Infusion site reaction (≥5%)
Neuromuscular & skeletal: Hemarthrosis (≤2%)
<1%, postmarketing, and/or case reports: Blurred vision, chest tightness, chills, dizziness, dyspnea, fever, gastrointestinal fullness, muscle cramps, nausea, unpleasant taste, urticaria
Thrombate III: There are no contraindications listed in manufacturer's labeling.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to antithrombin, other anticoagulants, or any component of the formulation.
Concerns related to adverse effects:
• Hypersensitivity reactions: Hypersensitivity reactions, including severe hypersensitivity reactions (eg, anaphylaxis), may occur; monitor closely during infusions. If hypersensitivity symptoms occur, discontinue immediately and institute supportive emergency care.
• Infections: Thrombate III: Thrombate III is AT collected from pooled human plasma (hpAT). A product of human plasma, it may potentially contain infectious agents which could transmit disease, including the Creutzfeldt-Jakob Disease (CJD) agent; screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces this risk. Infections suspected to be transmitted by this product should be reported to the manufacturer.
Other warnings/precautions:
• Pharmacokinetic differences: Half-life and clearance differ significantly (~7 to 9 times) between the plasma-derived and the recombinant-derived product.
Vial potency may vary; exact potency is labeled on each vial.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Thrombate III: 500 units (1 ea); 1000 units (1 ea)
No
Solution (reconstituted) (Thrombate III Intravenous)
500 unit (Price provided is per AHF Unit): $5.20
1000 unit (Price provided is per AHF Unit): $4.38
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Generic: 550 units (1 ea); 1100 units (1 ea)
IV: Thrombate III: Infuse over 10 to 20 minutes.
IV: Thrombate III: Infuse over 10 to 20 minutes (Ref).
Hereditary antithrombin deficiency: Thrombate III: Treatment and prevention of thromboembolism and prevention of perioperative and peripartum thromboembolism in patients with hereditary antithrombin deficiency.
Intraoperative heparin resistance during cardiopulmonary bypass
Sound-alike/look-alike issues:
Antithrombin may be confused with thrombin (topical)
Thrombate III may be confused with thrombin (topical)
ATIII (abbreviation for Antithrombin) may be confused with ATII (abbreviation for Angiotensin II)
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Heparin: Antithrombin may enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy
Heparins (Low Molecular Weight): Antithrombin may enhance the anticoagulant effect of Heparins (Low Molecular Weight). Risk C: Monitor therapy
The risk of thromboembolic events such as venous thromboembolism (VTE) is increased in patients with hereditary antithrombin (AT) deficiency. Pregnancy-induced physiologic changes also increase this risk; risk is dependent upon maternal antithrombin levels and personal or family history of thromboembolism (ACOG 197 2018). Thrombate III is approved for use in pregnant women with hereditary AT deficiency to replace endogenous antithrombin and reduce the risk of peripartum thromboembolism. Antithrombin replacement can be used in pregnant patients with hereditary AT deficiency in high-risk settings (eg, childbirth, miscarriage, surgery) when other anticoagulant therapy (eg, low molecular weight heparin [LMWH]) is withheld or as adjunctive therapy to LMWH in pregnant women at high risk for VTE (Bauer 2016; Ilonczai 2015; James 2017; Rogenhofer 2014).
The antithrombin in Thrombate III is obtained from human donors; antithrombin is endogenous to human plasma.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Some products may contain sodium.
Hereditary antithrombin deficiency:
Thrombate III: Initially, monitor antithrombin (AT) at baseline, 20 minutes postinfusion (peak), 12 hours postinfusion, then preceding next infusion (trough level). Measure peak and trough AT levels with each subsequent dose until predictable levels achieved (between 80% and 120%). Some situations (eg, following surgery, hemorrhage or acute thrombosis, concurrent IV heparin administration), may require more frequent AT monitoring.
AT concentrations in neonates of parents with hereditary AT deficiency should be measured immediately after birth.
Intraoperative heparin resistance during cardiopulmonary bypass (off-label use):
Due to laboratory turn-around times, routine monitoring of AT levels before or after Thrombate III administration is not feasible in the intraoperative setting. Therefore, therapeutic response should be monitored with activated clotting time (Lemmer 2002).
Normal AT activity: ~1 unit/mL (healthy adults) (Rodgers, 2009). Treatment is used to maintain AT concentrations in plasma >80% of normal; plasma AT concentrations are ~60% lower than normal in near term infants than levels observed in adults; premature infants may have AT concentrations lower than other neonates.
Antithrombin is the primary physiologic inhibitor of in vivo coagulation. It is an alpha2-globulin. Its principal actions are the inactivation of thrombin, plasmin, and other active serine proteases of coagulation, including factors IXa, Xa, XIa, and XIIa. The inactivation of proteases is a major step in the normal clotting process. The strong activation of clotting enzymes at the site of every bleeding injury facilitates fibrin formation and maintains normal hemostasis. Thrombosis in the circulation would be caused by active serine proteases if they were not inhibited by antithrombin after the localized clotting process (Schwartz, 1989).
In patients with hereditary antithrombin (AT) deficiency, spontaneous thrombosis may occur due to decreased AT concentrations; therapy with human or recombinant AT restores functional AT activity.
Plasma derived (Thrombate III):
Half-life elimination: Biologic: 2.5 days (immunologic assay); 3.8 days (functional AT assay). Half-life may be decreased following surgery, with hemorrhage, acute thrombosis, and/or during heparin administration.
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