- Antithrombin III (ATIII) deficiency is a rare inherited or acquired thrombophilic disorder characterized by reduced levels or impaired function of antithrombin, a crucial natural anticoagulant protein. This condition significantly increases the risk of venous thromboembolism, as antithrombin plays a primary role in inhibiting several activated coagulation factors, particularly thrombin and factor Xa.
- The inherited form of ATIII deficiency follows an autosomal dominant inheritance pattern, caused by mutations in the SERPINC1 gene. There are two main types of hereditary antithrombin deficiency: Type I, characterized by reduced antithrombin levels, and Type II, where antithrombin levels are normal but the protein functions abnormally. Type II is further subdivided based on whether the defect affects the reactive site or the heparin-binding site.
- Antithrombin functions as a potent inhibitor of multiple activated coagulation factors, including factors IXa, Xa, XIa, XIIa, and thrombin. Its inhibitory activity is dramatically enhanced by heparin, which serves as a cofactor. This interaction is particularly important clinically, as it forms the basis for heparin’s anticoagulant effect. Patients with antithrombin deficiency may show relative resistance to heparin therapy.
- Clinical manifestations typically include venous thromboembolism, with deep vein thrombosis and pulmonary embolism being the most common presentations. The first thrombotic event often occurs in early adulthood, frequently before age 30, and may be spontaneous or triggered by additional risk factors such as surgery, trauma, pregnancy, or immobilization. The risk of thrombosis is particularly high during pregnancy and the postpartum period.
- Homozygous antithrombin deficiency is extremely rare and typically incompatible with life, resulting in severe thrombosis in utero or shortly after birth. The heterozygous form is more common and has variable expressivity, with some individuals remaining asymptomatic while others experience recurrent thrombotic events.
- Diagnosis involves both clinical assessment and laboratory testing. Initial testing includes measurement of antithrombin activity (functional assay) and antigen levels. If abnormal results are found, specific assays can determine whether the defect affects the reactive site or heparin-binding site. Genetic testing may be performed to identify specific mutations in the SERPINC1 gene.
- Treatment approaches depend on the clinical situation and severity of the deficiency. Acute thrombotic events require anticoagulation, typically with heparin or low molecular weight heparin, followed by oral anticoagulants. Some patients may require antithrombin concentrate during acute events or high-risk situations, particularly when heparin resistance is encountered.
- Long-term management often involves extended or lifelong anticoagulation, especially for patients with unprovoked thrombosis or recurrent events. Prophylactic anticoagulation is typically recommended during high-risk periods such as surgery, pregnancy, or prolonged immobilization. Regular monitoring of anticoagulation therapy is essential to maintain therapeutic levels.
- Pregnancy management requires special attention due to the high risk of thrombotic complications. Pregnant women with antithrombin deficiency typically require prophylactic anticoagulation throughout pregnancy and the postpartum period. Some may need antithrombin concentrate during delivery or other high-risk periods.
- Prevention strategies focus on minimizing additional risk factors for thrombosis. This includes maintaining a healthy weight, regular physical activity, avoiding prolonged immobility, and careful consideration of prothrombotic medications such as oral contraceptives. Patient education about thrombosis symptoms is crucial for early recognition and treatment.
- The prognosis varies depending on the severity of the deficiency and the effectiveness of preventive measures. With appropriate management and careful attention to risk factors, many individuals with antithrombin deficiency can lead relatively normal lives, although they require ongoing medical supervision.
- Family screening is important when antithrombin deficiency is diagnosed, as early identification of affected family members allows for appropriate preventive measures. Genetic counseling may be beneficial, particularly for individuals planning pregnancy or considering family planning options.
- Research continues in understanding the complex interactions between antithrombin and the coagulation system, as well as developing new therapeutic approaches. Novel antithrombin concentrates and targeted therapies are under investigation to improve treatment options for affected individuals.
- Quality of life considerations include the impact of long-term anticoagulation, the need for regular medical monitoring, and lifestyle modifications. Support systems and patient education programs can help individuals cope with the chronic nature of the condition and maintain adherence to treatment regimens.
