Antithrombin III (Human)

Anticoagulant; naturally occurring plasma thrombin inhibitor.1 4 6 9 14 16 17 18

Contraindications

• None known.1

Warnings/Precautions

Warnings

Potential vehicle for transmission of human viruses (e.g., hepatitis C virus [HCV], hepatitis B virus [HBV], HIV) or other infectious agents.1 5 9

Despite application of a number of viral elimination/reduction steps (e.g., heat treatment in solution, Cohn cold ethanol precipitation, screening for certain viruses) to prevent transmission of infectious agents, risk of transmission still remains.1 5

Weigh risk of viral infection against benefits of therapy.1 5

Report all infections thought possibly to have been transmitted by antithrombin III preparation to manufacturer at 800-520-2807.1

May carry a risk of transmitting causative agent of Creutzfeldt-Jakob disease (CJD).1

Fractionation procedure decreases infectivity of intentionally added, experimental agent of transmissible spongiform encephalopathy (TSE), a model for CJD and variant CJD (vCJD) agents.1 Provides reasonable assurance of removal of low concentrations of CJD or vCJD agents during manufacturing process.1

Enhanced anticoagulant effect with concurrent heparin; reduced heparin dosage recommended during concurrent therapy.1 (See Interactions.)

General Precautions

Prior to therapy, confirm congenital antithrombin III deficiency based on clear family history of venous thrombosis and decreased endogenous plasma antithrombin III concentrations determined by amidolytic assays with chromogenic substrates, clotting assays, or immunoassays (e.g., crossed immunoelectrophoresis).1 9 10 17 Immunoassays may not detect all congenital antithrombin III deficiencies.1 12

Investigations to determine possible thrombophilia should not be performed after a recent thromboembolic event or during anticoagulant therapy since antithrombin III concentrations are reduced in these circumstances.6 (See Special Populations under Pharmacokinetics.)

Monitoring of antithrombin III concentrations critical for adjusting dosage and ensuring adequate therapeutic response.1 18 (See Antithrombin III Deficiency under Dosage and Administration.)

More frequent monitoring necessary in patients with increased clearance of antithrombin III (e.g., hemorrhage, acute thrombosis, concurrent IV heparin therapy, surgery).1 5 (See Special Populations under Pharmacokinetics.)

Determination of antithrombin III concentrations immediately after birth recommended in neonates of parents with congenital antithrombin III deficiency.1 (See Pediatric Use under Cautions.)

Specific Populations

Category B.1

Safety and efficacy of antithrombin III not established in pediatric patients younger than 16 years of age.1 23

Fatal thromboembolism (e.g., aortic thrombi) reported in neonates born to women with congenital antithrombin III deficiency.1 5 Determine antithrombin III concentrations immediately after birth in neonates of parents with congenital antithrombin III deficiency.1

Plasma antithrombin III concentrations in healthy full-term neonates or healthy premature neonates average approximately 60 or 35%, respectively, of those in healthy adults.1 5 23 Low antithrombin III plasma concentrations, especially in premature neonates, do not necessarily indicate congenital deficiency.1

Manufacturer and some clinicians recommend consultation with an expert on coagulation disorders regarding testing and treatment of neonates with suspected congenital antithrombin III deficiency.1

Common Adverse Effects

Dizziness,1 4 chest tightness,1 4 nausea,1 foul taste,1 4 chills,1 cramps,1 4 shortness of breath,1 4 chest pain,1 film over eye,1 lightheadedness,1 3 4 bowel fullness,1 hives,1 4 fever,1 4 oozing,1 hematoma formation.1

Specific Drugs

Absorption

Plasma Concentrations

Therapeutic target plasma concentrations in patients with congenital antithrombin III deficiency range from 80–120% of values in healthy adults.1 18 23 (See Dosage under Dosage and Administration.) At plasma concentrations ≤70% of normal, increased thrombin generation.4 Supraphysiologic plasma concentrations (e.g., 150–200% of normal) have increased bleeding risk in patients with sepsis and disseminated intravascular coagulation†;11 not known whether supraphysiologic concentrations increase bleeding risk in patients with congenital antithrombin III deficiency.11 23

Distribution

Extent

Distributed into plasma (39%), extravascular space (49%), and vascular endothelial cells (11%).9 11 16

Elimination

Metabolism

<5% metabolized to low molecular weight breakdown products.16

Elimination Route

Complexes of antithrombin III with thrombin or other proteinases cleared principally by liver6 9 and excreted in urine.15 16

Half-life

Biphasic; terminal half-life is approximately 2.5–4.8 days.1 3 4 5 9 11 16 18

Special Populations

Decreased half-life associated with hemorrhage, acute thrombosis, pregnancy, surgery, or concurrent IV heparin therapy.1 4 5 9 16 18 (See Special Populations under Dosage and Administration.)

Storage

Parenteral

2–8°C; protect from freezing as diluent vial may break.1

Reconstituted solutions contain no preservative; use ≤3 hours after reconstitution and do not refrigerate.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Once reconstituted, do not mix with other agents or diluents.1