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.

Physical exam

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.

• Pain

  Patients with pulmonary embolism will develop dyspnea, pain with inspiration, chest pain, and cough. Additionally, the vital signs may feature tachycardia and other abnormalities. [symptoma.com]

  A common place is the lung, where the clot can cause a cough, shortness of breath, pain while taking deep breaths, chest pain, and even death. Blood clots that travel to the brain can cause a stroke. [medlineplus.gov]

  SIDE EFFECTS In clinical studies, the most common adverse reactions (≥ 5% of subjects) were dizziness, chest discomfort, nausea, dysgeusia, and pain (cramps). [rxlist.com]

• Swelling

  Symptoms of a blood clot due to hereditary antithrombin deficiency include coughing up blood, fainting, shortness of breath, and swelling of one leg. A physician can diagnose hereditary antithrombin deficiency with a physical exam and blood tests. [diseaseinfosearch.org]

  Symptoms Patients will usually have symptoms of a blood clot, including: Coughing up blood Fainting Shortness of breath and pain when taking deep breaths Swelling of one leg Signs and tests A physical examination may show: Abnormal lung sounds Fast breathing [coordinatedhealth.com]

  Symptoms People will usually have symptoms of a blood clot, including: Coughing up blood Fainting Shortness of breath and pain when taking deep breaths Swelling of one leg Exams and Tests A physical exam may show: Abnormal lung sounds Fast breathing Fast [nicklauschildrens.org]

  Physical exam 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. [symptoma.com]

• Sepsis

  Sepsis Interest in the role of antithrombin deficiency in the setting of sepsis and the critically ill patient has been growing. [emedicine.medscape.com]

  Acquired: Present after birth and can occur in: Neonates Pregnancy Liver disease Kidney disease Bone marrow transplantation Sepsis (infection spread in blood) Drug-induced reduction in Antithrombin levels The Genetics behind Antithrombin III deficiency [inrtracker.com]

  DIC, Inflammation, Sepsis And Activated Protein C (APC). Transfusion Medicine Update, Issue #3 [On-line information]. Available online at http://www.annals.org/issues/v135n5/full/200109040-00013.html through http://www.annals.org. [labtestsonline.it]

  "Clinical Experience With Antithrombin III Concentrates in Critically Ill Patients With Sepsis and Multiple Organ Failure," Semin Thromb Hemost, 1998, 24:(1)71-80. [mghlabtest.partners.org]

  Accelerated consumption can be seen in acute thrombotic conditions such as disseminated intravascular coagulation, sepsis and following major surgery. [jscimedcentral.com]

• Fever

  Reported adverse reactions include: dizziness 7, nausea 3, foul taste 3, chest tightness 3, abdominal cramps 2, chills 2, fever 1, hives 1, chest pain 1, shortness of breath 1, bowel fullness 1, oozing and hematoma formation 1, film over eye 1 and lightheadedness [rxmed.com]

  Included were dizziness (7), chest tightness (3), nausea (3), foul taste in mouth (3), chills (2), cramps (2), shortness of breath (1), chest pain (1), film over eye (1), light-headedness (1), bowel fullness (1), hives (1), fever (1), and oozing and hematoma [drugs.com]

  Interestingly, fevers can trigger conformational stress on the Antithrombin-Wobble protein and favor thrombosis. [emedicine.medscape.com]

• Pathologist

  College of American Pathologists, Newspath V 17 (2). Available online at http://www.cap.org/apps/docs/newspath/spring_2003/clinical.html through http://www.cap.org (© 2004) Antithrombin, Antigen. [labtestsonline.org.tr]

  College of American Pathologists, Newspath V 17 (2).Available online at http://www.cap.org/apps/docs/newspath/spring_2003/clinical.html. (© 2004) Antithrombin, Antigen.ARUP's Guide to Clinical Laboratory Testing [On-line information].Available online [labtestsonline.it]

• Cough

  Symptoms of a blood clot due to hereditary antithrombin deficiency include coughing up blood, fainting, shortness of breath, and swelling of one leg. A physician can diagnose hereditary antithrombin deficiency with a physical exam and blood tests. [diseaseinfosearch.org]

  Symptoms Patients will usually have symptoms of a blood clot, including: Coughing up blood Fainting Shortness of breath and pain when taking deep breaths Swelling of one leg Signs and tests A physical examination may show: Abnormal lung sounds Fast breathing [coordinatedhealth.com]

  Symptoms People will usually have symptoms of a blood clot, including: Coughing up blood Fainting Shortness of breath and pain when taking deep breaths Swelling of one leg Exams and Tests A physical exam may show: Abnormal lung sounds Fast breathing Fast [nicklauschildrens.org]

  Patients with pulmonary embolism will develop dyspnea, pain with inspiration, chest pain, and cough. Additionally, the vital signs may feature tachycardia and other abnormalities. [symptoma.com]

• Dyspnea

  7.5) Dizziness 4 (12) 8 (2.1) Chest discomfort 3 (9) 3 (0.8) Nausea 3 (9) 3 (0.8) Dysgeusia 2 (6) 3 (0.8) Pain (cramps) 2 (6) 2 (0.5) Chills 1 (3) 2 (0.5) Wound secretion and hematoma 1 (3) 2 (0.5) Vision blurred 1 (3) 1 (0.3) Chest pain 1 (3) 1 (0.3) Dyspnea [rxlist.com]

  Patients with pulmonary embolism will develop dyspnea, pain with inspiration, chest pain, and cough. Additionally, the vital signs may feature tachycardia and other abnormalities. [symptoma.com]

• Abdominal Pain

  要約・抄録 An 81-year-old man visited our outpatient department with a chief complaint of lower abdominal pain. Detailed diagnostic examination revealed circumferential sigmoid colon cancer. [iss.ndl.go.jp]

• Chest Pain

  Patients with pulmonary embolism will develop dyspnea, pain with inspiration, chest pain, and cough. Additionally, the vital signs may feature tachycardia and other abnormalities. [symptoma.com]

  A common place is the lung, where the clot can cause a cough, shortness of breath, pain while taking deep breaths, chest pain, and even death. Blood clots that travel to the brain can cause a stroke. [medlineplus.gov]

  SIDE EFFECTS In clinical studies, the most common adverse reactions (≥ 5% of subjects) were dizziness, chest discomfort, nausea, dysgeusia, and pain (cramps). [rxlist.com]

• Venous Insufficiency

  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. [symptoma.com]

• Tachycardia

  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. [symptoma.com]

• Hypotension

  Potential hypersensitivity reactions (e.g., anaphylaxis, hives, urticaria, chest tightness, wheezing, and hypotension) should be monitored during infusions. [ptcommunity.com]

  These reductions are not only due to impaired synthesis, but also to an element of increased consumption, particularly when additional risk factors, such as sepsis, surgery, and hypotension, are present in patients with chronic liver disease. [emedicine.medscape.com]

• Skin Discoloration

  Know the symptoms of blood clots in the legs (deep vein thrombosis = DVT: Swelling, usually in one leg; Leg pain or tenderness; Reddish or bluish skin discoloration; Leg warm to touch) or lung (pulmonary embolism = PE: Sudden shortness of breath; Chest [stoptheclot.org]

• Flushing

  Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. [webmd.com]

• Stroke

  Blood clots that travel to the brain can cause a stroke. [medlineplus.gov]

  Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a prospective follow-up study. Stroke. 2003 Dec. 34(12):2887-92. [Medline]. Langlois NJ, Wells PS. [emedicine.medscape.com]

  It can create serious damage in the body and on some situations it can cause heart attack or stroke if left untreated. [thrombocyte.com]

  Arterial thrombosis (eg, stroke, myocardial infarction) has occasionally been reported in association with hereditary antithrombin deficiency. [mayomedicallaboratories.com]

  Clots in the arteries of the heart may lead to heart attack (myocardial infarction) and clots in the arteries of the brain to stroke. However, arterial clots are rare in antithrombin deficiency. [rarediseases.org]

• Confusion

  Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances Antithrombin antigen results are potentially affected by: -Heparin (unfractionated [mayomedicallaboratories.com]

  Confusing Coagulation Test Names. UAB Coagulation Service, Univ of Alabama at Birmingham [Online information]. [labtestsonline.it]

The clinical assessment is comprised of the patient and family history, physical exam, and the appropriate studies.

Laboratory tests

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.

Other

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 [11]. Experts recommend higher doses of heparin since patients with this coagulation disorder exhibit resistance to the drug [11]. Greater doses are usually required to achieve therapeutic levels of aPTT and anticoagulation. Fondaparinux may present as an alternative [12].

Pregnancy

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.

Contraindications

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.

Special considerations

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 [8] [9]. Additionally, women with this disorder are at an elevated risk for fetal loss [10]. 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 [2] [3]. 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 [4] [5] 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 [6].

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 [7]; 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) [1] 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:

• Pain
• Swelling
• Redness

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:

• Shortness of breath
• Chest pain
• Pain when taking a deep breath
• Cough

The following groups are at risk:

• Pregnant women
• Patients who recently underwent surgery
• Patients who are on bed rest

How is it diagnosed?

When an individual presents with repetitive episodes of blood clots or fetal deaths, the clinician will obtain the patient and family history, perform a physical exam, and order the following tests:

• Specialized tests known as assays are performed to measure the activity and quantity of antithrombin III.
• Clotting tests such as activated partial thromboplastin time (aPTT) and prothrombin time (PT): these tests measure the time it takes for a blood clot to form.
• Doppler ultrasound is used to diagnose blood clots in the legs.
• CT scan or other imaging tests of the lungs can be done if needed.

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.

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