Hereditary deficiency of antithrombin III is the most significant thrombophilia since it poses a serious thrombogenic risk in most affected individuals. This disorder arises from genetic mutations.
A primary manifestation of this disease is its tendency to cause thromboembolism. It poses a greater risk for VTE formation than the other inherited blood disorders. These patients can develop VTEs in the limbs and lungs. Moreover, clots can form in the cerebral, mesenteric, retinal, hepatic, and portal veins. Since most thrombotic events affect the venous circulation, this can lead to venous insufficiency. This disease may lead to arterial occlusion and ischemic events, which are more common in the pediatric population.
Findings consistent with blood clots in the legs or arms are tenderness, swelling, and redness at the affected site(s). Patients with pulmonary embolism will develop dyspnea, pain with inspiration, chest pain, and cough. Additionally, the vital signs may feature tachycardia and other abnormalities.
The clinical assessment is comprised of the patient and family history, physical exam, and the appropriate studies.
The initial screening test for these patients is a functional assay of ATIII, which measures the activity. If the function is reduced, then an antigen assay can be utilized to quantify ATIII, thereby differentiating between type 1 and type 2. The antigen levels in type 1 are low, but normal in the second type. This test should be repeated later again to confirm the results.
Coagulation studies such as prothrombin time (PT) and activated partial thromboplastin time (PTT) are also performed to evaluate the integrity of the coagulation pathways and to clarify the diagnosis. Furthermore, the activity of protein S and protein C should also be performed to exclude other disorders.
Patients who are suspected to have a VTE and/or PE warrant imaging studies. Extremity blood clots are diagnosed by doppler ultrasonography. Pulmonary clots are diagnosed by ventilation-perfusion scan, spiral computed tomography (CT) scanning, or magnetic resonance (MR) angiography.
Additionally, all patients should undergo echocardiography.
The management of patients with hereditary ATIII deficiency involves a balance between prophylaxis and the risk of bleeding that may occur secondary to chronic anticoagulation therapy. The thrombotic risk increases with the patient's age, and therefore long-term anticoagulation is warranted to prevent further episodes of VTE.
The high-risk groups that are candidates for short-term prophylaxis include surgical, pregnant, and immobile patients. Low molecular weight heparin (LMWH) is the optimal option for these individuals. Some patients may be treated with antithrombin concentrate as well. Currently, there is plasma-derived antithrombin, but this has the risk of viral transmission. A recombinant form is under investigation.
Surgery and immobility
The clinician should be vigilant of risk factors that predispose patients to thrombotic events. Prophylaxis is paramount for patients with ATIII deficiency as 42% of VTEs in this population develop in high-risk settings . Experts recommend higher doses of heparin since patients with this coagulation disorder exhibit resistance to the drug . Greater doses are usually required to achieve therapeutic levels of aPTT and anticoagulation. Fondaparinux may present as an alternative .
Managing women during pregnancy can be challenging. One standard regimen is treatment with subcutaneous LMWH throughout the pregnancy and for a short period of time in the postpartum period. The patient is then switched to warfarin, which should not be used in pregnancy due to its teratogenicity. Antithrombin concentrate may replace or be used adjunctively with LMWH at the time of childbirth.
Women with ATIII deficiency must avoid taking estrogen-based medications such as certain contraceptives since this hormone affects the concentration of ATIII.
Additionally, warfarin has a drug interaction with numerous medications and therefore, the clinician should be aware of any drug that may increase or decrease its effect. Also, this anticoagulant is contraindicated in numerous conditions such as pregnancy, peptic ulcer disease, etc.
The are several prognostic factors for hereditary ATIII deficiency, which include the severity of the disease, as well as the number and site(s) of clots.
The location of the clot is a significant variable in determining the prognosis. For example, clots in the mesenteric vein can be fatal, and therefore should be treated with life-long warfarin treatment. Since recurring episodes are likely, appropriate management is necessary as further occurrences of thrombosis can lead to ominous outcomes and complications.
Heterozygotes typically exhibit a higher risk for thrombosis in the third or fourth decade. However, as stated earlier, homozygous patients have fatal outcomes in utero or as neonates.
This disease is of particular concern during pregnancy since this population is associated with a high-risk for VTE. Therefore, anticoagulation prophylaxis is essential in pregnant women  . Additionally, women with this disorder are at an elevated risk for fetal loss . However, data on the relationship between this thrombophilia and obstetric complications such as pre-eclampsia, eclampsia, intrauterine growth restriction, and placental abruption have been insufficient.
This autosomal dominant disorder is caused by genetic defects in the AT3 (also referred to as SERPINC1) gene located on chromosome 1q25.1. Specifically, multiple point mutations have been isolated  . Two specific mutations known as wibble and wobble have been identified. These are described as amino acid substitutions which consequently lead to reduced activity of ATIII.
There is also a rare autosomal recessive form which clinically manifests as a serious life-threatening disorder.
The prevalence of this disease ranges from 1 in 500 to 1 in 5000   without any gender, racial, or ethnic preference. The distinct types of AT deficiency vary in prevalence as type I accounts for the majority of symptomatic patients while type II is more common in the general population. Furthermore, hereditary ATIII deficiency may be found in up to 5% of individuals with VTE .
There are various genetic defects that affect ATIII, of which many involve the steps of translation. This glycoprotein is pivotal for the regulation of the coagulation system as it neutralizes thrombin. Hence, lower levels or activity of ATIII leads to thrombogenesis.
Hereditary ATIII deficiency is divided into two types. Type I, which is a quantitative disorder, is caused by reduced synthesis of ATIII. The qualitative, type II deficiency is further classified into IIA and IIb. The former results from a defective thrombin-binding site and the latter occurs due to an abnormal heparin binding site. Of all the types of AT deficiencies, IIb exhibits a much smaller risk for thrombosis ; it is more prevalent than IIa. There is also type IIc.
There is no prevention. However, genetic counseling is offered to patients and family members in order to provide them with information about the disease, its mode of inheritance, expectations, and other important details.
Hereditary deficiency of antithrombin III (ATIII) is an autosomal dominant thrombophilic disorder. It results from mutations in the AT3 gene, which encodes ATIII. The latter is among the essential proteins that play a key role in the coagulation system. Specifically, it inhibits clotting factors IIa and Xa. Therefore, a deficiency or impairment of ATIII results in thrombosis. This rare congenital disease mostly manifests in the heterozygous form while homozygotes typically die in utero or in the neonatal period. The disease either occurs due to insufficient levels of ATIII (type I) or secondary to structural defects of the protein (type II).
Hereditary ATIII deficiency is usually recognized in patients who experience recurrent episodes of venous thromboembolism (VTE) and pulmonary embolism (PE). Affected individuals may also develop clots in mesenteric, cerebral, or other veins. Women who suffer from obstetric complications such as intrauterine fetal death (IUFD)  also raise suspicion for this disease.
Patients with the above findings and/or a positive family history should be assessed with a detailed account of the personal and family history, a physical exam, and laboratory tests. The latter includes an antithrombin functional assay, radioimmunoassay, coagulation panel, and other specialized tests as well. The assays are repeated for confirmation. Patients with a clinical picture suggestive of a thrombotic event will undergo imaging for detection of the blood clot.
The management of these patients is challenging as it is centered on the prophylactic approach. Specifically, individuals with known deficiency should be treated with short-term anticoagulation therapy in high-risk circumstances such as surgery, pregnancy, and immobility. Overall, the clinician will consider variables such as the age of the patient, the location(s) and recurrence of blood clots, as well as present risk factors in order to determine the duration of prophylaxis therapy (short-term versus indefinite) and the best anticoagulant.
What is hereditary deficiency of antithrombin III?
This is an inherited disorder in which the patients develop blood coagulation defects since the levels of antithrombin III are low. Antithrombin III is an important protein that prevents the abnormal development of blood clots.
What are the causes?
This is caused by mutations in a gene found on chromosome 1. The mutations lead to impaired function of ATIII or the necessary quantity of ATIII may not be formed. Because the structure of the antithrombin molecule is abnormal, it cannot function effectively.
This disease is inherited in an autosomal dominant pattern. This means that one of the parents has the disease and passes it on to the offspring. An affected parent has a 50% chance of passing it to each child.
What are the signs and symptoms?
The main concern in patients with this disorder is the development of blood clots. Many patients will form blood clots in the legs or arms, which will present as:
Blood clots in the legs or arms can break off and travel to the lungs and develop a condition called pulmonary embolism. These patients will develop:
The following groups are at risk:
How is it diagnosed?
How is it treated?
The clinician will treat the patients to prevent the formation of blood clots. However, patients at high risk should receive short-term prophylaxis (prevention) with low molecular weight heparin (LMWH). Patients with repetitive episodes of blood clots are usually treated with life-long warfarin.
Can it be prevented?
Since this is a hereditary disorder, it cannot be prevented. However, genetic counseling is offered to patients and their family members to spread awareness about the disease.
What is the prognosis?
With the appropriate treatment and management, these patients can have a good prognosis.