Antithrombin III Deficiency

I. Review: Antithrombin III (AT):

Synthesized in liver and endothelial cells
Acts as an anticoagulant by directly binding and inactivating the serine proteases (Factors XIa, IXa, Xa, and Thrombin.
The presence of heparin increases the activity of AT by 10⁴- 10⁵.

II. Mechanisms of deficiency:

A. Defect in synthesis of AT

1. Congenital (See section III below)

2. Acquired (See section IV below)

B. Increased consumption of AT due to higher levels of serine proteases, which is often seen in:

1. Disseminated intravascular coagulation (DIC)

2. Extensive deep venous thrombosis (DVT)

3. Pulmonary embolus

C. Loss of AT - i.e. nephrotic syndrome

D. Increased protein catabolism

III. Congenital AT deficiency

A. Inheritance - usually autosomal dominant. Most patients with hereditary AT deficiency are heterozygous.

B. There are two types of hereditary AT deficiency:

1. Type 1 - Classic - There is reduced synthesis of the AT molecule. A gene deletion or frameshift mutation results in a truncated protein which is unstable.

2. Type 2 - The level of AT produced is normal, but the protein is dysfunctional.

3. Type 3 - The quantity and quality of AT is normal but it lacks the receptor for heparin; therefore, it cannot be acclerated.

C. Clinical features of congenital AT deficiency:

Increased risk of venous thrombosis and pulmonary embolism. Venous thrombosis occurs most frequently in the deep veins of the lower extremities.
Thrombotic events begin in mid-late teenage years.
Mesenteric veins, inferior vena cava, renal veins are all susceptible.
Cerebral vein thrombosis can occur.
Events occur with AT activity at 40-60% of normal. Homozygosity is fatal in utero.
May be precipitated by provocations such as surgery, trauma, pregnancy, oral contraceptive (OCP) use, or infection.
Arterial thrombotic events are not increased.

IV. Acquired AT deficiency

A. Causes include acute thrombosis, DIC, liver disease, nephrotic syndrome, oral contraceptive use.

1. 70% of individuals with DVT or PE have decreased AT levels before treatment of underlying cause. The AT level corrects to normal after treatment.

2. In liver disease, there is decreased AT levels, but this is not associated with any increased risk of thrombosis.

3. In AT deficiency secondary to nephrotic syndrome, treatment of the nephrotic syndrome with glucocorticoids will enhance AT levels. This is either because of steroid-induced stimulation of AT synthesis or from decreased protein loss.

B. Clinical features - same as congenital AT deficiency.

V. Treatment of AT deficiency

A. Anticoagulation with either heparin or warfarin is the mainstay of treatment.

B. AT concentrates are available. The amount need can be calculated by:

{desired level - initial level} x 0.6 x kg. body weight

C. In patients with recurrent thrombotic episodes, anticoagulation is required indefinitely.

D. In pregnancy, maintain the mother on subcutaneous heparin throughout the pregnancy. If used, AT concentrates are most useful during labor, delivery, or obstetric complications.

E. DIC - may use AT concentrates

F. In acquired AT deficiency, treatment of the underlying disease will often correct the AT levels to normal.