Antithrombin III Deficiency Treatment & Management

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]}

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.

• 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.

Diet manipulations have no direct effect on antithrombin activity. If warfarin is used for thromboprophylaxis, then standard warfarin diet instructions should be used.

Obesity is an independent risk factor for thrombosis. Diet manipulation to encourage a healthy lifestyle should be undertaken in children with a congenital procoagulant disorder to avoid additional risks later in life.

• Activity should not be restricted unless the patient is receiving anticoagulants.