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Hereditary Deficiency of Antithrombin

Antithrombin III Deficiency Familial

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.

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Presentation

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]
  • 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]
  • 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
  • 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]
  • 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]
  • Blood clots in the arms or legs usually cause swelling, redness, and pain. When a blood clot breaks off from where it formed and travels to another part of the body, it is called a thromboembolism. Symptoms depend on where the blood clot travels to.[medlineplus.gov]
  • 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]
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]
Leg Swelling
  • Approximately 50% of symptomatic patients complained of leg swelling and 30% of pain, and 20% had had a varicose ulcer at least once.[atvb.ahajournals.org]
Cough
  • 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]
  • 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]
  • 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]
  • 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]
Dyspnea
  • 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]
  • 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]
Decreased Breath Sounds
  • A physical exam may show: A swollen leg or arm Decreased breath sounds in the lungs A rapid heart rate The health care provider can also order a blood test to check if you have a low level of antithrombin III.[medlineplus.gov]
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]
  • pain 1 (3) 1 (0.3) Dyspnea 1 (3) 1 (0.3) Intestinal dilatation 1 (3) 1 (0.3) Pyrexia 1 (3) 1 (0.3) Urticaria 1 (3) 1 (0.3) *MedDRA Preferred Term; an adverse reaction is defined as any adverse event where either a) the event was related, or possibly[rxlist.com]
  • These include: Coughing up blood Shortness of breath Fainting Chest pain when asked to take deep breaths Swelling of one of the legs 3 Other less common findings include: Neurological symptoms like headaches Rash Cardiovascular disease Bleeding 3 Diagnosing[inrtracker.com]
  • Chest pain. Leg pain. Diagnosis: 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.[medigoo.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
  • ., anaphylaxis, hives, urticaria, chest tightness, wheezing, and hypotension) should be monitored during infusions.[ptcommunity.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]
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]
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 pain-sharp[stoptheclot.org]
Suggestibility
  • In the remaining 15 kindreds, two copies of the ATIII gene are present and appear to be grossly normal at the level of whole genome Southern blotting, suggesting that small deletions, insertions or limited nucleotide substitution(s) in the antithrombin[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
  • The genetic basis of antithrombin deficiency is heterogeneous: there may be normal antigenic levels of the protein, in which case there is a functional defect in the antithrombin reduced antigenic levels of antithrombin suggest a defect in the synthesis[gpnotebook.co.uk]
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]
  • AT deficiency does not appear to be a risk factor for clots in arteries (strokes or heart attacks).[stoptheclot.org]

Workup

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.

Treatment

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.

Prognosis

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.

Etiology

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.

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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.

Patient Information

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:

  • 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.

References

Article

  1. Diseases of the Placenta : Blaustein's Pathology of the Female Genital Tract. Robert J Kurman, ed. Fifth Edition; 2002:1136-7.
  2. Beauchamp NJ, Pike RN, Daly M, et al. Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation. Blood. 1998;15. 92(8):2696-706.
  3. Kuhle S, Lane DA, Jochmanns K, et al. Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism. Thrombosis and Haemostasis. 2001; 86(4):1007-11.
  4. Tait RC, Walker ID, Perry DJ et al. Prevalence of antithrombin deficiency in the healthy population. British Journal of Haematology. 1994; 87(1): 106–12.
  5. Wells PS, Blajchman MA, Henderson P, et al. Prevalence of antithrombin deficiency in healthy blood donors: a cross-sectional study. American Journal of Hematology. 1994; 45(4): 321–4.
  6. Melissari E,Monte G,Lindo VS, et al. Congenital thrombophilia among patients with venous thromboembolism. Blood Coagulation and Fibrinolysis 1992; 3(6): 749–758.
  7. Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in the subtypes of congenital antithrombin III deficiency: review of 404 cases. Thrombosis and Haemostasis. 1987; 58(4): 1094.
  8. Robertson L, Wu O, Langhorne P et al. Thrombophilia in pregnancy: a systematic review. British Journal of Haematology. 2006;132(2): 171–96.
  9. Vicente V, Rodriguez C, Soto I, Fernandez M, Moraleda JM. Risk of thrombosis during pregnancy and post-partum in hereditary thrombophilia. American Journal of Hematology. 1994; 46(2): 151–2.
  10. Preston FE, Rosendaal FR, Walker ID et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996; 348(9032): 913–6.
  11. Vossen CY, Conard J, Fontcuberta J et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). Journal of Thrombosis and Haemostasis. 2005; 3(3):459–64.
  12. Bauersachs R, Alban S. Perioperative bridging with fondaparinux in a woman with antithrombin deficiency. Thrombosis and Haemostasis. 2007; 97(3): 498–9.

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Last updated: 2019-07-11 19:57