Antithrombin III deficiency
Antithrombin III deficiency - Description, Causes and Risk Factors:
Antithrombin III deficiency is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism. Inheritance is usually autosomal dominant, though a few recessive cases have been noted.
Antithrombin III (ATIII) is a potent inhibitor of the coagulation cascade. It is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. Antithrombin III activity is markedly potentiated by heparin; potentiation of its activity is the principle mechanism by which both heparin and low molecular weight heparin result in anticoagulation.
Deficiency may be due to several different genetic defects associated with differing degrees of enzyme production, enzymatic activity, and chemical stability. Certain abnormal alleles have been associated with specific clinical features (Wibble and Wobble, mutations in the "shutter" region of the enzyme), and others have yet to be studied. Acquired antithrombin III deficiency is usually due to abnormal activation of a coagulation pathway or synthetic defect, often from medication (eg, L-asparaginase) or liver disease. Antithrombin III may be lost in third spaces when it redistributes into edematous tissues. Antithrombin III may also be lost as part of increased protein losses seen in nephrotic syndrome, and this should be suspected if clotting occurs.
Congenital antithrombin III deficiency is an autosomal dominant disorder in which an individual inherits one copy of a defective gene. This condition leads to increased risk of venous and arterial thrombosis, with an onset of clinical manifestations typically appearing in young adulthood. This form is commonly diagnosed during childhood by screening after an affected family member has been identified or after a child has had a thrombotic event. Severe congenital antithrombin III deficiency, in which the individual inherits 2 defective genes, is a rare autosomal recessive condition associated with increased thrombogenesis, typically noted in the neonatal period or early infancy. This condition is rarely compatible with life. Most neonates have heterozygous antithrombin III deficiency.
- Acquired antithrombin III deficiency is a deficiency of antithrombin primarily due to consumption. It is observed in situations in which activation of the coagulation system is inappropriate. Common conditions that result in acquired antithrombin III deficiency include disseminated intravascular coagulation (DIC), microangiopathic hemolytic anemias due to endothelial damage (i.e., hemolytic-uremic syndrome), and venoocclusive disease (VOD) in patients undergoing bone marrow transplantation.
The prevalence of the hereditary deficiency of ATIII is estimated to be one per 2000 to 5000 in the general population. The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with ATIII levels of 40-60% of normal. These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary antithrombin III deficiency during pregnancy has been reported to be 70%, and several studies of the beneficial use of antithrombin III concentrates during pregnancy in women with hereditary deficiency have been reported. In many cases, however, no precipitating factors can be identified for venous thrombosis or pulmonary embolism. Greater than 85% of individuals with hereditary ATIII deficiency have had at least one thrombotic episodes by the age of 50 years. In about 60% of patients thrombosis is recurrent.
Patients will usually have symptoms of a blood clot, including:
- Coughing up blood.
- Shortness of breath and pain when taking deep breaths.
- Swelling of one leg.
- Recurrent miscarriages.
- Chest pain.
- Leg pain.
A physical examination may show:
- Abnormal lung sounds.
- Fast breathing.
- Fast heart rate.
- Swollen foot or leg.
The diagnosis is made by checking for low levels of antithrombin III in the patient's blood. There are several techniques for checking these levels. Specific laboratory workup for suspected antithrombin III (ATIII) deficiency depends on the clinical setting, which may include:
Antithrombin assays: Antithrombin III activity should be measured first. If low, then antithrombin antigen is measured to look for mutations consistent with type II disease.
- Prothrombin time (PT) and activated partial thromboplastin time (aPTT): These studies allow evaluation of the presence of inappropriate activation of the coagulation system. aPTT is a useful screen for antiphospholipid (AP) antibody syndrome. APTT-mixing study may distinguish between AP antibody syndrome and disseminated intravascular coagulation (DIC). Advanced DIC may present with a persistently prolonged aPTT if fibrin degradation products inhibit fibrin generation or acquired deficiencies of coagulation factors are severe.
- Protein C (antigen and activity tests) and protein S (total and free tests): Protein C or protein S deficiencies are both associated with venous thrombosis and are important exclusions in evaluating congenital deficiency of antithrombin III. In the newborn, protein S activity must be measured (in addition to total) because, whereas total antigen levels are lower in neonates than in adults, protein S activity is usually normal because of the lack of expression of C4-binding protein in the neonate. (C4 acts to bind protein S in children and adults.) These tests may also be important in the acquired state to determine the extent of a given patient's thrombotic risk.
- Factor V Leiden testing: The most common congenital procoagulant disorder, factor V Leiden, occurs in about 5% of patients and needs to be documented when attempting to make the diagnosis of congenital antithrombin III deficiency. Knowing what this level is also helps to define a given patient's procoagulant risk. Although factor V Leiden does not commonly produce thrombosis during childhood, it may contribute to thrombosis started by other etiologies (eg, central venous catheters). Physicians should note that this is not a measurement of factor V activity but rather a determination of a specific mutation of factor V that leads to a decreased sensitivity to the inhibitory effects of protein C.
- Homocysteine level: Increased levels of homocysteine are associated with an increased risk of thrombosis in adults, but this is rarely seen in children. In a child with elevated homocysteine levels, MTHFR gene analysis should be performed. Anticardiolipin antibodies (both immunoglobulin G [IgG] and immunoglobulin M [IgM] class). These should be measured by enzyme-linked immunoabsorbent assay (ELISA) or other physical means to rule out coexisting thrombotic risk from this source.
Echocardiography: This should be performed in all patients with antithrombin III deficiency, especially if they have evidence of arterial thrombus. Arterial thrombosis due to antithrombin III deficiency is uncommon. Venous clots may migrate to arterial circulation through a patent foramen ovale or other communicating congenital heart defect (eg, atrial septal defect, ventricular septal defect, truncus arteriosus).
- Doppler ultrasonography: Doppler ultrasonography of the affected extremity with compression should be performed at diagnosis and then used in follow-up to determine resolution of an acute thrombus.
- Ventilation-perfusion scanning: Pulmonary thrombosis can be imaged with ventilation-perfusion scan. Thin-cut spiral CT scanning has also been used for this, but small lesions may be missed.
Personal history of thrombosis is particularly important in terms of treatment. Patients with congenital antithrombin III deficiency who have had one unprovoked thrombotic event (particularly in the mesenteric or splanchnic systems) are much more likely to have recurrent clots. These patients are usually treated with indefinite anticoagulant therapy; thus, careful review of this area is wise. Asymptomatic carriers should not receive anticoagulation therapy because the risk of thrombosis does not exceed the bleeding risk associated with anticoagulation therapy. 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 (low molecular weight heparin) 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.
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.
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 veno-occlusive disease, a target of 120% is used, and treatment is initiated once antithrombin III level is subnormal (< 80%).
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
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