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Antithrombin III
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Dosage can be calculated from the following formula: Units required (International Units) = [desired concentration - baseline AT III concentration] x weight (kg)/1.4% (International Units/kg). In general, calculate initial loading dose to elevate the plasma AT III concentration to 120%, assuming an expected rise over the baseline AT III concentration of 1.4% (functional activity) per International Unit/kg of AT III administered. If the in vivo recovery differs from an anticipated rise of 1.4% for each International Units/kg administered, modify the formula accordingly. Plasma concentrations between 80% to 120% may be maintained with maintenance doses of 60% of the initial loading dose given approximately every 24 hours as needed. However, adjustments in the maintenance dose and/or interval between doses should be made based on actual plasma AT III concentrations achieved. In many cases, it is desirable to raise the AT III concentration to normal and maintain this concentration for 2 to 8 days, depending on the indication for treatment, type and extensiveness of surgery, the patient's medical condition and history, and the clinician's judgment.
Dosage can be calculated from the following formula: Units required (International Units) = [desired concentration - baseline AT III concentration] x weight (kg)/1.4% (International Units/kg). In general, calculate initial loading dose to elevate the plasma AT III concentration to 120%, assuming an expected rise over the baseline AT III concentration of 1.4% (functional activity) per International Unit/kg of AT III administered. If the in vivo recovery differs from an anticipated rise of 1.4% for each International Units/kg administered, modify the formula accordingly. Plasma concentrations of 80% to 120% may be maintained with maintenance doses of 60% of the initial loading dose, given approximately every 24 hours as needed. However, adjustments in the maintenance dose and/or interval between doses should be made based on actual plasma AT III concentrations achieved. In many cases, it is desirable to raise the AT III concentration to normal and maintain this concentration for 2 to 8 days, depending on the indication for treatment, type and extensiveness of surgery, the patient's medical condition and history, and the clinician's judgment.
Give a loading dose over 15 minutes starting 24 hours before the procedure, then, immediately start a continuous infusion of the maintenance dose. The loading dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/2.3] X Body Weight (kg). The maintenance dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/10.2] X Body Weight (kg). The treatment goal is to restore and maintain functional antithrombin activity concentrations of 80% to 120% of normal (0.8 to 1.2 International Units/mL). Continue treatment continue anticoagulation is established.
Give a loading dose over 15 minutes starting 24 hours before the procedure, then, immediately start a continuous infusion of the maintenance dose. The loading dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/1.3] X Body Weight (kg). The maintenance dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/5.4] X Body Weight (kg). The treatment goal is to restore and maintain functional antithrombin activity concentrations of 80% to 120% of normal (0.8 to 1.2 International Units/mL). Continue treatment continue anticoagulation is established.
Plasma-derived antithrombin (Thrombate III):
The baseline antithrombin III (AT III) concentration is usually expressed as a percentage of a reference plasma. To calculate the in vivo recovery, plasma AT III concentrations should be measured prior to the infusion and 20 minutes after the infusion (peak). Plasma concentrations of AT III should also be measured at least every 12 hours and immediately before the next infusion to maintain plasma AT III concentrations more than 80% (range: 80% to 120%). Plasma AT III concentrations should be monitored more frequently if the half-life of AT III is shortened, such as after surgery, with hemorrhage or acute thrombosis, and during intravenous heparin administration. Antithrombin III concentrations should be measured before and 20 minutes after each infusion until predictable peak and trough concentrations have been achieved. Do not use immunoassays to measure AT III concentrations; immunoassays do not detect all hereditary AT deficiencies. Measure AT III concentrations by amidolytic assays using chromogenic substrates or by clotting assays.[30131]
Recombinant antithrombin III (ATryn):
The AT III activity concentration should be obtained 2 hours after initiation of treatment. If the AT III concentration is less than 80%, increase the maintenance infusion by 30% and recheck the AT III activity concentration in 2 hours. If the AT III concentration is 80% to 120%, no dose adjustment is needed, and the AT III activity concentration should be checked again in 6 hours. If the AT III activity concentration is more than 120%, decrease the maintenance infusion by 30%, and recheck the AT III activity concentration in 2 hours. The AT III activity concentration should be checked immediately after surgery or delivery as a rapid decrease in AT III activity concentration may occur during these procedures. If the AT III activity concentration is less than 80%, give an additional loading dose utilizing the last available AT III activity concentration in the formula. Thereafter, restart the maintenance dose at the same rate of infusion as before the bolus.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
† Off-label indicationAntithrombin, or Antithrombin III (AT III), is another name for heparin cofactor I, a factor in plasma necessary for heparin to exert its anticoagulant activity. AT III is a natural anticoagulant synthesized in the liver. It plays a major role in the regulation of hemostasis by inhibiting thrombin; factors IXa, Xa, XIa, and XIIa; kallikrein; and plasmin. AT III deficiency predisposes patients to venous thromboembolic events by impairing the clearance of activated coagulation factors. Thrombate III is AT III concentrate produced from pooled human plasma and indicated in patients with hereditary antithrombin III deficiency for treatment and prevention of thromboembolism, including peri-operative and peri-partum thromboembolism. Another product, ATryn, is the first biological agent produced by genetically engineered animals (goats) and the first recombinant human antithrombin. ATryn is produced utilizing recombinant DNA technology in which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland-specific DNA sequence that directs the expression of antithrombin into the milk of goats. ATryn is indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.
For storage information, see the specific product information within the How Supplied section.
Reconstitution of human antithrombin III (Thrombate III):
Reconstitution of recombinant antithrombin III (ATryn):
Intravenous infusion:
Human antithrombin III (Thrombate III):
Recombinant antithrombin III (ATryn):
Human antithrombin III (Thrombate III) is well tolerated. Only occasional, mild, and transient reactions have been noted. Although manufacturing practices are designed to reduce the risk of transmitting viral infection, human antithrombin III is prepared from pooled human plasma, which may contain the causative agents of hepatitis and other viral diseases. However, no cases of HIV seroconversion have been described with the use of human antithrombin III.[30131]
In clinical studies involving human antithrombin III (Thrombate III), dizziness (12%), chest pain (unspecified) (3%), chest discomfort (9%), and dyspnea (3%) were reported. Non-cardiac chest pain was reported in 2% of patients treated with recombinant antithrombin III (ATryn).[30131] [34885]
Bleeding has been reported in patients receiving antithrombin III. In clinical trials involving recombinant antithrombin III (ATryn), the most common adverse event reported was bleeding (5% or more); GI bleeding (reported as intra-abdominal hemorrhage), hemarthrosis, hematoma, and hematuria were each reported in 2% of patients. Hematoma and wound secretion were reported in 3% (n = 1) of patients receiving human antithrombin III (Thrombate III) and described as severe.[30131] [34885]
In clinical trials involving human antithrombin III (Thrombate III), chills and fever occurred in 3% of patients and pain (cramps) in 6% of patients.[30131]
Injection site reaction (5% or more) was among the most common adverse reactions reported with recombinant antithrombin III (ATryn); application site pruritus and flushing were reported in 2% of patients.[34885] Urticaria was reported in 3% of patients during clinical trials of human antithrombin III (Thrombate III).[30131]
In clinical trials, elevated hepatic enzymes occurred in 2% of patients receiving recombinant antithrombin III (ATryn).[34885] Nausea (9%), dysgeusia (6%), and intestinal dilatation (3%) were reported in patients receiving human antithrombin III (Thrombate III).[30131]
During human antithrombin III (Thrombate III) clinical trials, blurred vision was reported in 3% of patients.[30131]
Human antithrombin III (Thrombate III) is derived from pooled human plasma. As with other products derived from or purified with human blood components, the remote possibility of contamination with bacterial or viral infection, including hepatitis, or Creutzfeldt-Jakob disease (CJD) exists in patients receiving human antithrombin III. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents are present in the pooled product. All infections thought to have been transmitted by human antithrombin III should be reported to the manufacturer.[30131]
ATryn is contraindicated in patients with known goat and goat milk protein hypersensitivity. ATryn is a recombinant human product derived from genetically engineered goats in which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland specific DNA sequence, directing the expression of antithrombin into the milk. The goats that produce recombinant antithrombin are contained in a closed, USDA certified scrapie-free herd and are controlled for specific pathogens. Immunological reactions to the recombinant protein, goat antithrombin, or goat-milk proteins are possible. Assays have been developed to detect antibodies to these proteins. No confirmed immunological reactions were seen in clinical trials. The manufacturer has developed a post-marketing patient registry to collect additional data on the immunogenetic potential of recombinant antithrombin III. Healthcare providers are encouraged to call Ovation Pharmaceuticals (1—800—455—1141) for further instruction on this registry. ATryn is not formulated with human plasma proteins and therefore not associated with the risks of human plasma-derived products (e.g., viral or bacterial contamination).
Use antithrombin III during pregnancy only if clearly needed.[30131] [34885] There are no data in pregnant women to determine a drug-associated risk with plasma-derived antithrombin III (Thrombate). It is not known whether plasma-derived antithrombin III can cause fetal harm when administered to a pregnant woman or if can affect reproductive capacity. Reproduction studies in rats and rabbits at doses up to 4 times the human dose have revealed no evidence of impaired fertility or harm to the fetus due to plasma-derived antithrombin III. During labor and obstetric delivery, suspend heparin or low molecular weight heparin and continue plasma-derived antithrombin III administration.[30131] Recombinant antithrombin III (ATryn) is classified as pregnancy category C. There are no adequate and well-controlled studies in pregnant women. In clinical trials of hereditary antithrombin III deficient patients, 22 pregnant women were treated with recombinant antithrombin III around parturition; no adverse reactions were reported in infants born to these women.[34885]
It is not known whether plasma-derived antithrombin III (Thrombate III) is excreted in human milk, the effects on the breast-fed infant, or the effects on milk production. Recombinant antithrombin III (ATryn) is present in breast milk at concentrations 1/50 to 1/100 of that found in blood, which is estimated to be equivalent to that found in normal lactating women and is not thought to be harmful to breast-fed infants. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for antithrombin III and any potential adverse effects on the breast-fed infant from antithrombin III or the mother's underlying condition.[30131] [34885]
Antithrombin III (AT III) belongs to the serpine family of serine protease inhibitors and plays a major role in the regulation of hemostasis by inhibiting thrombin; factors IXa, Xa, XIa, and XIIa; kallikrein; and plasmin. The activity of AT III results from the interaction between its active arginine site and the active serine residue on thrombin that forms a covalent bond with 1:1 stoichiometry. The binding of heparin to a lysine residue on AT III induces a conformational change at the arginine-reactive center of AT III, thereby enhancing the rate of thrombin:AT III complex formation 1000-fold. Thus, AT III is important in mediating the major antithrombotic effect of heparin. AT III also neutralizes Factor Xa by forming a complex that is rapidly removed from the circulation.
In clinical situations that reduce AT III activity levels (e.g., DIC, sepsis, trauma, surgery), heparin may become less effective. In most cases, the decrease in AT III activity associated with heparin administration (about 15%) is negligible. However, it has been shown that, in cases of disseminated intravascular coagulation, heparin responsiveness depends on AT III activity and that normalization of AT III activity level reduces the amount of heparin required for adequate anticoagulation. The ability of AT III to bind thrombin and Factor Xa is increased 300—1000 fold when it is concurrently bound to heparin. Therefore, in patients with suspected heparin resistance, it may be desirable to raise the AT III activity level to 80—100% prior to and during heparin therapy. Although controlled trials are lacking, use of AT III concentrate in conjunction with extracorporeal circulation may improve the coagulation profile and reduce the amount of heparin necessary for anticoagulation.[25406]
Hereditary AT III deficiency results in an increased risk of thromboembolism in affected individuals, particularly during high-risk procedures such as surgery, trauma, and during the peri-partum period. The administration of plasma-derived and recombinant AT III to patients with AT III deficiency results in normalization of AT III activity levels.
Revision Date: 11/20/2024, 01:31:00 AMAntithrombin III is administered intravenously. Surgical procedures, bleeding, and concomitant heparin administration may influence the pharmacokinetic properties of AT III; therefore, AT III monitoring should be performed for all patients receiving therapy to ensure adequate AT III levels are obtained.
Use antithrombin III during pregnancy only if clearly needed.[30131] [34885] There are no data in pregnant women to determine a drug-associated risk with plasma-derived antithrombin III (Thrombate). It is not known whether plasma-derived antithrombin III can cause fetal harm when administered to a pregnant woman or if can affect reproductive capacity. Reproduction studies in rats and rabbits at doses up to 4 times the human dose have revealed no evidence of impaired fertility or harm to the fetus due to plasma-derived antithrombin III. During labor and obstetric delivery, suspend heparin or low molecular weight heparin and continue plasma-derived antithrombin III administration.[30131] Recombinant antithrombin III (ATryn) is classified as pregnancy category C. There are no adequate and well-controlled studies in pregnant women. In clinical trials of hereditary antithrombin III deficient patients, 22 pregnant women were treated with recombinant antithrombin III around parturition; no adverse reactions were reported in infants born to these women.[34885]
It is not known whether plasma-derived antithrombin III (Thrombate III) is excreted in human milk, the effects on the breast-fed infant, or the effects on milk production. Recombinant antithrombin III (ATryn) is present in breast milk at concentrations 1/50 to 1/100 of that found in blood, which is estimated to be equivalent to that found in normal lactating women and is not thought to be harmful to breast-fed infants. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for antithrombin III and any potential adverse effects on the breast-fed infant from antithrombin III or the mother's underlying condition.[30131] [34885]
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