eMedicine Specialties > Pediatrics: General Medicine > Hematology
Antithrombin III Deficiency: Treatment & Medication
Updated: Jul 10, 2009
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Treatment
Medical Care
Treatment of patients with antithrombin III (ATIII) deficiency depends on the clinical setting. Three congenital conditions are discussed: homozygous antithrombin III deficiency discovered in neonates, heterozygous antithrombin III deficiency in patients with their first thrombosis, and heterozygous antithrombin III deficiency in patients with previous thrombosis.
Antithrombin III deficiency may be congenital but may also be acquired. Antithrombin III replacement in patients with acquired antithrombin III deficiency is also addressed.
- In neonates who are homozygote deficient, both arterial and venous thrombosis is seen, particularly if vascularly invasive procedures (eg, extracorporeal membrane oxygenation [ECMO], umbilical vessel catheterization) are performed. In these patients, replacement of antithrombin III using antithrombin III concentrates or fresh frozen plasma is recommended.
- Replacement of antithrombin in neonates with antithrombin III deficiency to treat lung disease has been studied and found to have no benefit. Antithrombin infusion in otherwise asymptomatic neonates found to be deficient is not recommended.
- Enoxaparin (Lovenox), a low molecular weight heparin (LMWH), is frequently used to prevent thrombi as well as to prevent thrombi that have already occurred from propagating. In antithrombin III deficiency, the activity of LMWH is not as reliable as in an otherwise healthy person. Careful monitoring of the anti-Xa activity in the patient should be performed. Consider alternative anticoagulation medications (eg, warfarin) because the effectiveness of LMWH is likely reduced.
- Once a patient with congenital antithrombin III deficiency has developed thrombosis, anticoagulation is indicated. Replacement with recombinant antithrombin is not indicated for the treatment of thrombi.
- Warfarin (Coumadin) is the principal anticoagulant used. This vitamin K antagonist is administered at a dose to maintain an international normal ratio (INR) on PT of 1.5-2.5. Initially, therapy with LMWH or standard heparin may be administered to decrease the risk of warfarin-associated thrombosis (warfarin-induced skin necrosis) resulting from the inhibition of protein C production, which may occur before inhibition of the synthesis of vitamin K–dependent procoagulant factors (II, VII, IX, X) is reduced adequately for anticoagulation.
- The duration of warfarin therapy in children with acquired or heterozygous congenital antithrombin III deficiency experiencing their first clot is controversial, but therapy is generally continued for at least 3-6 months before cessation of anticoagulation. If the underlying triggering event cannot be removed, indefinite anticoagulation should be considered.
- Antithrombin III–deficient heterozygotes experiencing a second clot, particularly in mesenteric or splanchnic beds, are at significant risk of further life-threatening or organ-threatening thrombosis. These patients are candidates for indefinite warfarin therapy.
- Acquired antithrombin III deficiency is due to decreased production or increased consumption. In either case, treatment of the underlying disease and replacement of antithrombin III using antithrombin III concentrates is the common approach used. Some evidence indicates that using a supranormal target (140%) is necessary in pediatric trauma patients. In cases of venoocclusive disease, a target of 120% is used, and treatment is initiated once antithrombin III level is subnormal (<80%).
- LMWH has been used to treat heterozygote patients; however, as LMWH depends on antithrombin III for activity, anti-Xa activity levels should be closely monitored and doses should be adjusted to maintain anti-Xa activity levels in the 0.5-1 international units/mL.
- Asymptomatic carriers should not receive anticoagulation therapy because the risk of thrombosis does not exceed the bleeding risk associated with anticoagulation therapy.5,5,6
Surgical Care
- Antithrombin III concentrates have been used in the perioperative period for surgical prophylaxis in patients with a known deficiency. Carefully determine the specific agent used, because the dosing of plasma-derived antithrombin widely differs from recombinant antithrombin.
- Should antithrombin III concentrates not be available, fresh frozen plasma at a dose of 20 mL/kg can raise the antithrombin III level by approximately 20%.
- Take care to determine whether risks of a given vascularly invasive procedure (ie, central venous line [CVL] placement) outweigh increased risk of thrombosis.
- Any foreign body stimulates clot formation, and the risk of an occlusive clot significantly increases if the size of the foreign body is such that laminar flow through the vessel is disturbed. For example, neonates commonly have venous obstruction due to central lines, which leads to disturbance of flow in the vein and the development of small vessels that bypass the obstructed vein. The vein becomes obstructed due to the presence of the central line. If an indwelling catheter is needed in a high-risk patient, it should be a small flexible catheter and should remain in only as long as is absolutely necessary. Consider using peripheral intravenous lines or peripherally inserted central catheter (PICC) lines rather than large bore central lines when practical.
Consultations
- Consult with a hematologist experienced in thrombotic disorders in the event of newly diagnosed antithrombin III deficiency.
- In North America, the Canadian Children's Thrombophilia Society (1-800-NO-CLOTS) is available for consultation. In the United States and other countries, regional hemophilia treatment centers are available.
Activity
- Activity should not be restricted unless the patient is receiving anticoagulants.
Medication
Antithrombin III (ATIII) deficiency may be quickly corrected with infusions of antithrombin III concentrates. Long-term therapy for congenital deficiency is generally not indicated, as an asymptomatic period may last decades. Once thrombosis has occurred, warfarin therapy is generally undertaken.
Antithrombin-III concentrates
Antithrombin III concentrate (Thrombate III [Bayer Corporation]) is used for replacement therapy. This product is a plasma-derived concentrate made from pooled human plasma using modified Cohn ethanol separation and heat-treated for viral inactivation. The vials have no preservatives and are labeled in international units calibrated against a World Health Organization (WHO) standard.
Antithrombin, recombinant (ATryn)
Recombinant AT made in goats. AT regulates hemostasis by inhibiting thrombin and factor Xa, key proteases for blood coagulation. Indicated for prevention of perioperative and peripartum thromboembolic events in patients with hereditary AT deficiency. Not indicated for treatment of thromboembolic events. Available as a lyophilized powder that is reconstitution for IV infusion. Normally administered as a continuous IV infusion medication.
Adult
Infusion should begin 24 hours prior to surgery or prior to delivery in pregnant women; pregnant women who require caesarean delivery should be treated per the dosing guidelines for pregnant women
Administer IV using infusion set with 0.22 micron inline filter; administer loading dose over 15 min, then immediately follow with continuous infusion
Target level is to restore and maintain AT activity levels at 80-120% of normal (0.8-1.2 IU/mL); initiate 24 before surgery for surgical patients
Surgical patients:
Loading dose: IU = [(100 - baseline AT activity) divided by 2.3] X body weight (kg)
Maintenance dose: IU/h = [(100 - baseline AT activity) divided by 10.2] X body weight (kg)
Pregnant women:
Loading dose: IU = [(100 - baseline AT activity) divided by 1.3] X body weight (kg)
Maintenance dose: IU/h = [(100 - baseline AT activity) divided by 5.4] X body weight (kg)
Monitor AT activity 2 h after treatment initiation and adjust dose:
AT level <80%: Increase dose by 30% and recheck AT level 2 h after each dose adjustment
AT level 80-120%: No dose adjustment; recheck AT level 6 h after treatment initiation
AT level >120%: Decrease dose by 30% and recheck AT level 2 h after each dose adjustment
Pediatric
Not established
Coadministration with heparin or LMWH increases anticoagulant effect; anticoagulants that use AT to exert their anticoagulant effect may alter half-life of recombinant AT (monitor aPPT and antiFactor Xa level)
Documented hypersensitivity to goat and goat milk proteins
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Do not shake following reconstitution; common adverse events include hemorrhage and infusion site reaction; monitor for hypersensitivity; coagulation tests required to monitor and adjust dose
Antithrombin III (Thrombate III)
Alpha2-globulin that inactivates thrombin; plasmin; and other serine proteases of coagulation including factors IXa, Xa, XIa, XIIa, and VIIa, which, in turn, inhibits coagulation.
Mean recovery in healthy patients is 1.6% activity/U/kg infused (ie, 160% activity when 100 U/kg is infused) based on immunologic ATIII assays. Recovery based on functional assays is 1.4% activity/U/kg (ie, 140% activity when 100 U/kg is infused). Functional assay results are most commonly used to calculate dose. Half-life of ATIII is approximately 22 h. This number should be considered in light of patient's underlying clinical problems, as the rate of ATIII consumption may be increased, which would affect extent of recovery and half-life.
A target of 120% is the upper limit of the reference range for ATIII and is chosen as a target value to allow for maximum amount of time to elapse before clearance and consumption of ATIII drops the level in patient's plasma to <80%.
Adult
Pediatric
Limited data available
Calculate pediatric dose as follows:
Units required = [(the difference between observed and desired levels) X (body weight in kg)] / 1.4
For example, take a 20-kg child with an ATIII level measured at 40%
Desired level = 120%
[(120 - 40) X (20)] / 1.4 = 1143 U
Administer by continuous IV infusion
Antithrombin III increases anticoagulation effects of heparin
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Despite measures taken to delete infectious agents from human product, may transmit disease or contain unknown infectious agents; administer within 3 h after reconstitution; administer only IV; give alone, without mixing with other agents or diluting solutions
Adverse reactions occurred in 17 of 340 infusions and include dizziness (7), chest tightness (3), nausea (3), foul taste in mouth (3), chills (2), cramps (2), shortness of breath (1), chest pain (1), film over eye (1), light-headedness (1), bowel fullness (1), hives (1), fever (1), and oozing and hematoma formation (1); if adverse reaction occurs, decrease infusion rate or, if indicated, discontinue infusion until symptoms abate
Anticoagulants
In patients with congenital ATIII deficiency, anticoagulation reduces the incidence of thrombosis. The duration of therapy is likely to be indefinite.
Warfarin (Coumadin)
Inhibits vitamin K–dependent gamma carboxylation of procoagulant proteins factor II, VII, IX, X, as well as the anticoagulant factor, protein C. Tailor dose to maintain an INR in the range of 2-2.5. The length of time to achieve target INR is age dependent. In infants, the median time to achieve the target INR is 5 d and in adolescents, 3 d.
Adult
Pediatric
Loading dose: 0.2 mg/kg/d PO for 3-5 d; may need to modify loading dose each day to achieve target INR
Maintenance dose:
Infants: 0.32 mg/kg/d PO; adjust dose according to desired INR
Adolescents: 0.09 mg/kg/d PO; adjust dose according to desired INR
Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; medications that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenytoin, propoxyphene, gemfibrozil, acetaminophen, and sulindac
Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; caution in hepatic dysfunction (decrease dose and adjust to target INR)
Enoxaparin (Lovenox)
Produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). Binds to ATIII, enhancing its therapeutic effect. The heparin-ATIII complex binds to and inactivates activated factor X (Xa) and factor II (thrombin).
Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.
Advantages include intermittent dosing and decreased requirement for monitoring. Heparin antifactor Xa levels may be obtained if needed to establish adequate dosing.
LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared with UFH.
Prevents DVT, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Used for prevention in hip replacement surgery (during and following hospitalization), knee replacement surgery, or abdominal surgery in those at risk of thromboembolic complications, or in nonsurgical patients at risk of thromboembolic complications secondary to severely restricted mobility during acute illness.
Used for the treatment of DVT or PE in conjunction with warfarin, for the inpatient treatment of acute DVT with or without PE, or for the outpatient treatment of acute DVT without PE.
No use in checking aPTT (drug has wide therapeutic window and aPTT does not correlate with anticoagulant effect). Average duration of treatment is 7-14 d.
Adult
DVT prophylaxis:
Hip or knee surgery: 30 mg SC q12h
Abdominal surgery: 40 mg SC qd
Restricted mobility: 40 mg SC qd
CrCl <30 mL/min for above indications: 30 mg SC qd
DVT/PE treatment: 1 mg/kg SC q12h; alternatively, 1.5 mg/kg SC qd; CrCl <30 mL/min: 1 mg/kg SC qd
Pediatric
Not established; suggested dose:
<2 months: 0.75 mg/kg/dose SC bid
>2 months: 0.5 mg/kg/dose SC bid
Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
Documented hypersensitivity; major bleeding, thrombocytopenia
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Decrease dose if CrCl <30 mL/min; if thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop; cases of epidural/spinal hematomas have been reported in adults that receive spinal or epidural anesthesia (holding 2 doses prior to LP or surgery is recommended)
More on Antithrombin III Deficiency |
| Overview: Antithrombin III Deficiency |
| Differential Diagnoses & Workup: Antithrombin III Deficiency |
 Treatment & Medication: Antithrombin III Deficiency |
| Follow-up: Antithrombin III Deficiency |
| Multimedia: Antithrombin III Deficiency |
| References |
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References
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Further Reading
Keywords
antithrombin III deficiency, acquired antithrombin deficiency, congenital antithrombin deficiency, AT-III deficiency, ATIII deficiency, AT III deficiency, heterozygous antithrombin deficiency, heparin, low molecular weight heparin, thrombin disorder, anticoagulation, anti-coagulation, venous thrombosis, arterial thrombosis, clotting disorder, blood clots, hematologic disorder, increased thrombogenesis, inappropriate activation of the clotting system, inappropriate coagulation, coagulopathy, disseminated intravascular coagulation, DIC, microangiopathic hemolytic anemias due to endothelial damage, hemolytic-uremic syndrome, veno-occlusive disease, venoocclusive disease, VOD, protein C deficiency, protein S deficiency, liver disease, nephrotic syndrome, bone marrow transplantation, treatment, diagnosis
