Antithrombin III (Systemic)


VA CLASSIFICATION
Primary: BL119

Commonly used brand name(s): ATnativ; Thrombate III.

Other commonly used names are
ATIII and heparin cofactor I .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Anticoagulant—

antithrombotic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Thromboembolism associated with hereditary antithrombin III deficiency (prophylaxis)—Antithrombin III is indicated as prophylaxis against the development of thrombotic complications in patients with hereditary antithrombin III deficiency in situations in which the risk of thromboembolism is increased, such as surgery {01} {02} {04} {11} {17}, delivery {01} {04} {07} {17} (including spontaneous or induced abortion {07}), [pregnancy] {02} {04} {10} {11} {17}, [trauma] {02} {11}, and [prolonged (> 24 hours) immobilization] {02}. Heparin enhances the effects of antithrombin III (and vice versa) and may be given concurrently, using a full-dose, adjusted-dose, or low-dose heparin regimen as determined by the clinical circumstances {01} {02} {04} {07} {10}.
—Although long-term prophylaxis may be required in patients with hereditary antithrombin III deficiency, antithrombin III is usually not used, whether or not a high-risk situation, such as those listed above, exists {02} {10} {11}. A coumarin- or indandione-derivative anticoagulant is usually used for this purpose {02} {10} {11}. However, these anticoagulants should not be administered during the first trimester of pregnancy, and some clinicians recommend that they not be used at all during pregnancy {04} {10}. Heparin is usually used instead, but may be ineffective when concentrations of endogenous antithrombin III are low {04} {07} {10}. Long-term prophylactic use of antithrombin III may therefore be required if heparin alone fails to produce adequate anticoagulation {02} {07} {10}.

Thromboembolism associated with hereditary antithrombin III deficiency (treatment adjunct)—Antithrombin III is indicated as an adjunct to heparin therapy for the treatment of thromboembolism in patients with hereditary antithrombin III deficiency {01} {02} {04} {19}.
—[The safety and efficacy of antithrombin III as an adjunct to heparin for the treatment of thromboembolism associated with acquired antithrombin III deficiency have not been established. However, use of antithrombin III may be considered for individual patients in whom heparin alone is ineffective.]{15}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Pooled human plasma {01} {17}.

Chemical group—
    An alpha-2-globulin {02} {17}.
Molecular weight—
    58,000 daltons {01} {02} {12} {17}


Description
    A glycoprotein consisting of 425 amino acids in a single polypeptide chain cross-linked by three disulfide bridges {01}.


pH (after reconstitution with 10 mL of sterile water for injection)
    6.5–7.5 {01}

Mechanism of action/Effect:

Antithrombin III, which is synthesized in the liver {02} {03} and endothelial cells {03}, is an endogenous inhibitor of blood coagulation {03} {04}, providing approximately 75% of the antithrombin activity of the blood {18}. It combines in a 1:1 molar ratio {02} {12} {17} with the activated serine proteases of the intrinsic coagulation pathway (primarily thrombin [factor IIa] and factor Xa, and, to a lesser extent, factors IXa, XIa, and XIIa) {01} {02} {04} {11} {12} {17} {20} to form inactive {02} complexes {02} {12} {17}. The active binding center is at the Arg 384–Ser 385 peptide bond {02} {12}. Hereditary antithrombin III deficiency has been shown to increase the risk of thromboembolism in some individuals {01} {02} {04} {10} {11} {17}; initial episodes in these patients have occurred most often between 15 {10} {11} and 30 {10} years of age. Administration of exogenous antithrombin III corrects the deficiency, thus normalizing the patient's coagulation-inhibiting capability {01} {02} {04} {07} {08} and inhibiting formation of thromboemboli.

Note: Antithrombin III also has lysine binding sites to which heparin binds in a 1:1 molar ratio {02}. Formation of the antithrombin III–heparin complex produces a conformational change in the antithrombin III molecule that results in more rapid binding with and inactivation of the clotting factors than can be achieved by antithrombin III alone {02} {04} {11}. Because heparin produces its anticoagulant effect only through its cofactors (the primary cofactor being antithrombin III) {02} {12}, the efficacy of heparin is substantially reduced in antithrombin III deficiency {02} {04} {07} {17}. A reduction in the plasma activity of antithrombin III to 70% of the normal value may decrease the efficacy of heparin to 45%, and a reduction to 50% of the normal antithrombin III value may decrease the efficacy of heparin to 20%, of that achieved in the presence of normal antithrombin III activity {02}. Administration of antithrombin III augments or restores the efficacy of heparin {02} {04} {07} {12}.



Other actions/effects:

Antithrombin III also inactivates the fibrinolytic enzyme plasmin, but to a lesser extent than it inactivates the clotting factors {04} {11}.

Distribution:

Antithrombin III is removed from the blood by binding to the epithelium and by redistribution into the extravascular compartment {13}.

Antithrombin III–clotting factor complexes are removed rapidly from the circulation by binding to a specific receptor present on hepatocytes {13}.

Half-life:

Elimination—2 {04} to 3 {01} days; may be decreased by concurrent use of heparin {01} {17}, following surgery {02} {17}, and in patients with disseminated intravascular coagulation {02}.

Therapeutic plasma concentration

Therapeutic benefit requires an antithrombin III activity of 80% or more of the normal value, which ranges between 100 and 200 mcg per mL (100 to 200 mg per L) in individuals 3 months of age and older {01} {11}.

Note: Plasma antithrombin III activity in patients with a hereditary deficiency is generally 25 to 60% of that present in normal adult plasma {01} {11}.
Plasma antithrombin III activity is normally reduced in neonates {11} {14} {17}. Healthy, full-term neonates exhibit 40 to 85% of the antithrombin III activity present in normal adults; gradual increases occur until adult values are reached, generally at about 3 months of age {11}. Antithrombin III activity is even lower in premature neonates {03} {14} {17}.



Precautions to Consider

Pregnancy/Reproduction

Note: Transmission of hereditary antithrombin III deficiency is autosomal-dominant {02} {04} {10} {11} {17}; a deficiency state may occur in the child if either parent is affected {01} {02} {04} {10} {11}. Homozygous fetuses often do not survive (depending on the specific type of antithrombin III deficiency) {02} {11}. Patients with hereditary antithrombin III deficiency should be counseled about the potential risk to a child {01}. Also, female patients with diagnosed hereditary antithrombin III deficiency and their spouses should be informed of {01} {17} the very high risk of thrombosis in antithrombin III–deficient women during pregnancy {01} {02} {04} {10} {11} and delivery {01} {04} {07}.


Pregnancy—
Antithrombin III is effective in preventing thrombotic complications during pregnancy in women with hereditary antithrombin III deficiency {04} {07} {10}, including women with a prior history of thrombosis {04}, and women who are heparin-resistant {04} {07} {10}. Studies in pregnant women have not shown that antithrombin III increases the risk of fetal abnormalities when administered during the third trimester of pregnancy {01}. Antithrombin III has also been administered to a few women during the first 2 trimesters of pregnancy. No adverse effects on the fetus attributable to antithrombin III were reported {04} {09}.

Studies have not been done in animals {01} {17}.

FDA Pregnancy Category C {01} {17}.


Labor and delivery—

Administration of a coumarin- or indandione-derivative anticoagulant or heparin during pregnancy increases the risk of hemorrhage during and following delivery; heparin should be discontinued 12 hours, and coumarin- or indandione-derivative anticoagulants several days, prior to delivery or therapeutic abortion {07} {10} {16}. Antithrombin III therapy, when instituted or continued after another anticoagulant has been discontinued, is effective in preventing thromboembolic complications during and following delivery or therapeutic abortion, even in women who had previously had such complications {01} {04} {07}. Such use of antithrombin III has not been reported to cause problems in the neonate {01} {04} {07}.

Breast-feeding

Problems in nursing infants have not been reported. Distribution of antithrombin III into breast milk is highly unlikely because of antithrombin III's large molecule size {05}.

Pediatrics

Appropriate studies on the relationship of age to the effects of antithrombin III have not been performed in the pediatric population. However, the medication has been administered to a limited number of neonates and children {01} {14} {17}.

Because hereditary antithrombin III deficiency is transmitted in an autosomal-dominant manner {02} {04} {10} {11}, neonates born to a parent with hereditary antithrombin III deficiency should be tested at birth. Fatal thromboemboli have occurred in these neonates {01} {07} {17}. However, even healthy, full-term neonates normally have low antithrombin III activity (compared to adults) {11} {14} {17}, and antithrombin III activity is even further reduced in preterm infants (especially if they are ill with respiratory distress syndrome, necrotizing enterocolitis, sepsis, or disseminated intravascular coagulation) {14}. Therefore, identification of infants at risk for thrombotic complications associated with hereditary antithrombin III deficiency may be difficult, and the advice of an expert should be sought before any prophylactic measure, including antithrombin III administration, is instituted {01} {17}.


Geriatrics


Appropriate studies on the relationship of age to the effects of antithrombin III have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Heparin    (concurrent administration of heparin and antithrombin III increases the anticoagulant effect of both medications, and usually decreases heparin dosage requirements {01} {17}, because antithrombin III is the primary cofactor required for heparin to exert an anticoagulant effect {02} {12}; in some patients [especially patients in whom disseminated intravascular coagulation caused by multiple trauma has produced an acquired antithrombin III deficiency] concurrent use may also increase the risk of bleeding, even with very low doses of heparin {02})

    (heparin decreases the half-life of antithrombin III {01})


Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Antithrombin III activity    (monitoring is essential as a guide to dosage requirements and patient response {01} {02} {03} {11}; for patients with hereditary antithrombin III deficiency, it is recommended that determinations be performed twice a day until the dosage requirement has stabilized {01}, after which determinations may be performed once daily {01}, immediately prior to a dose {01} {04} {17}; however, under certain circumstances, more frequent determinations may be needed {02})


Note: Antithrombin III may be measured quantitatively, using immunoassays, or qualitatively, using procedures that determine functional activity (e.g., measurement of the thrombin-inhibiting or factor Xa–inhibiting ability of the blood) {01} {02} {03} {11}. Functional assays are preferred {02} {03} because, in some forms of antithrombin III deficiency, functional antithrombin III activity may be decreased despite normal immunologic (quantitative) test results {01} {02} {03} {10} {11}.




Side/Adverse Effects

Note: All products derived from human blood or plasma have the potential to transmit viral diseases, including acquired immunodeficiency syndrome (AIDS) and non-A, non-B hepatitis. Plasma used for preparation of antithrombin III for injection has been tested and found nonreactive for hepatitis B surface antigen and for antibody to the human immunodeficiency virus (HIV). In addition, prior to freeze-drying, the product is heat-treated (60 °C for not less than 10 hours). These measures may not be completely effective in eliminating the risk of viral transmission, but no documented cases of hepatitis resulting from administration of antithrombin III to patients with hereditary deficiencies have been reported to date. {01} {17}
Diuretic and vasodilatory effects leading to a fall in blood pressure were reported in 2 of 65 patients receiving antithrombin III for an acquired deficiency caused by severe disseminated intravascular coagulation {01}. In addition, dyspnea and increased blood pressure occurred in one patient who received the medication at a too-rapid rate of administration (1500 IU in 5 minutes) {01}.
Chest pain or tightness, fever, hematoma, hives, oozing, and shortness of breath were also reported in a small number of patients. However, it was not clearly indicated that the symptoms were caused by the medication and were not related to the disease states of the patients. If these side/adverse effects should occur secondary to the infusion of antithrombin III, they may be abated by slowing or temporarily discontinuing the infusion. {17}




General Dosing Information
The potency of antithrombin III is expressed in international units (IU) and is determined using a standard calibrated against a World Health Organization (WHO) antithrombin III reference standard {01} {17}. One IU is equivalent to the quantity of endogenous antithrombin III present in 1 mL of normal human plasma {01}.


Parenteral Dosage Forms

ANTITHROMBIN III(HUMAN)FOR INJECTION

Usual adult and adolescent dose
Thromboembolism associated with hereditary antithrombin III deficiency
Intravenous, administered at a rate of 50 to 100 IU (not to exceed 100 IU) per minute {01}:

Initial—A sufficient quantity to increase the antithrombin III activity, determined 30 minutes after administration, to 120% of the normal activity {01} {17}.

Maintenance—A sufficient quantity to increase the antithrombin III activity to 80% or more of the normal activity. Maintenance doses are generally administered at twenty-four-hour intervals. {01} {17}


Note: Initial dosage is calculated according to the following formula, based on an anticipated 1% increase in plasma antithrombin III (ATIII) activity for each 1 IU per kg of body weight:
Dose = [desired ATIII activity (as % of normal) - baseline ATIII activity (as % of normal)] × body weight (in kg) ÷ 1%.
Maintenance dosage is also calculated using the formula shown above for calculating initial dosage, but the actual increase in ATIII activity (in %) produced by 1 IU per kg of body weight, determined 30 minutes after administration of the initial dose, should be substituted for the 1% (the divisor) in the formula.
Increasing the antithrombin III activity to 120% (rather than 100%) of the normal value with the initial dose prolongs the interval before a second dose is required {04}. However, dosage requirements may be increased in some patients. More frequent monitoring of antithrombin III activity may be required, with the dosage and frequency of administration being adjusted accordingly. {02}
The duration of therapy depends on the indication for antithrombin III administration, the patient's condition and history, and the judgment of the physician. Treatment is usually continued for 2 to 8 days {01}. In some circumstances (e.g., during pregnancy), more prolonged administration may be needed {02} {07} {10}. Also, when treatment is given in conjunction with surgery or during prolonged immobilization, it is recommended that antithrombin III therapy be continued until the patient is fully mobilized {02}.


Usual pediatric dose
See Usual adult and adolescent dose . The target percentage of normal human antithrombin III activity to be achieved for pediatric patients, is the same as for other patients {06}.

Size(s) usually available:
U.S.—


500 IU (Rx) [ATnativ (human albumin 100 mg) (sodium chloride 90 mg)] [Thrombate III (sodium chloride 110 to 210 mEq per L) (alanine 0.075 to 0.125M) (heparin £0.004 USP units per IU antithrombin III)]


1000 IU (Rx) [Thrombate III (sodium chloride 110 to 210 mEq per L) (alanine 0.075 to 0.125M) (heparin £0.004 USP units per IU antithrombin III)]

Canada—
Not commercially available.

Packaging and storage:
Store at 2 to 8 °C (36 and 46 °F) {17}, unless otherwise specified by manufacturer.

Preparation of dosage form:
Antithrombin III for injection is reconstituted using 10 mL of sterile water for injection (provided by the manufacturer) {01} {17} or an alternate solution, such as 0.9% sodium chloride injection or 5% dextrose injection {01}. Do not shake the vial while reconstituting. The solution should then be brought to room temperature before administration. {01} {17} If desired, the reconstituted injection may be further diluted, using the same diluent {01}.

Caution—Use of diluents containing benzyl alcohol is not recommended for preparation of medications for use in neonates. A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Stability:
After reconstitution, the solution must be used within 3 hours {01} {17}.

Because antithrombin III for injection contains no preservative, any unused solution should be discarded.



Revised: 02/23/94



References
  1. ATnativ package insert (KabiVitrum AB—US), Rev 4/90, Rec 10/12/90.
  1. Vinazzer H. Clinical use of antithrombin III concentrates. Vox Sang 1987; 53: 193-8.
  1. Büller HR, tenCate JW. Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate. Am J Med 1989; 87 (3B Suppl): 44S-48S.
  1. Schwartz RS, Bauer KA, Rosenberg RD, Kavanaugh EJ, Davies DC, Bodganoff DA. Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin. Am J Med 1989; 87 (3B Suppl): 53S-60S.
  1. Briggs GG, Freeman RK, Yaffe SJ. A reference guide to fetal and neonatal risk. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams & Wilkins, 1990: 293.
  1. Panel comment, 3/91.
  1. Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 1982; 14: 127-41.
  1. Wisecarver JL, Haire WD. Disseminated intravascular coagulation with multiple arterial thromboses responding to antithrombin-III concentrate infusion. Thromb Res 1989 Jun 25; 54: 809-17.
  1. Panel comment, 3/91.
  1. Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency. Am J Med 1989; 87 (3B Suppl): 34S-38S.
  1. Tollefsen DM. Laboratory diagnosis of antithrombin and heparin cofactor II deficiency. Semin Thromb Hemost 1990; 16: 162-8.
  1. Rosenberg RD. Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism. Am J Med 1989; 87 (3B Suppl): 2S-9S.
  1. Pizzo SV. Serpin receptor 1: a hepatic receptor that mediates the clearance of antithrombin III-proteinase complexes. Am J Med 1989; 87 (3B Suppl): 10S-14S.
  1. Manco-Johnson MJ. Neonatal antithrombin III deficiency. Am J Med 1989; 87 (3B Suppl): 49S-52S.
  1. Panel comment, 3/91.
  1. Panel comment, 4/91.
  1. Thrombate III package insert (Miles—US), Rev 10/92, Rec 5/15/93.
  1. Carvalho ACA, DeMarinis SM, Lynch K, Zapol WM. Antithrombin III in critically ill patients. J Crit Care 1989; 4: 283-93.
  1. Panel comment, 3/91.
  1. Panel comment, 3/91.
  1. Rosenberg RD, editor. Role of antithrombin III in coagulation disorders: state-of-the-art review. Am J Med 1989; 87 (3B Suppl): 1S-67S.
Hide
(web2)