Antithrombin III Deficiency 

Updated: Feb 10, 2018
Author: James L Harper, MD; Chief Editor: Hassan M Yaish, MD 

Overview

Practice Essentials

Antithrombin III (ATIII) is a nonvitamin K-dependent protease that inhibits coagulation by neutralizing the enzymatic activity of thrombin (factors IIa, IXa, Xa). Antithrombin III activity is markedly potentiated by heparin, the principal mechanism by which both heparin and low–molecular-weight heparin result in anticoagulation.[1]

Congenital antithrombin III deficiency is an autosomal dominant disorder in which an individual inherits one copy of the SERPINC1 (also called AT3) gene on chromosome 1q25.1, which encodes antithrombin III. 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 most 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 two 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 affected neonates, however, have heterozygous antithrombin III deficiency rather than the homozygous state.

Acquired antithrombin III deficiency is a deficiency of antithrombin primarily due to consumption or decreased production. It is observed in situations in which activation of the coagulation system is abnormal. Common conditions that result in acquired antithrombin III deficiency include disseminated intravascular coagulation (DIC), microangiopathic hemolytic anemias due to endothelial damage (ie, hemolytic-uremic syndrome), veno-occlusive disease (VOD) (in patients undergoing bone marrow transplantation), sepsis, liver disease, and nephrotic syndrome. Oral contraceptive use and even heparin administration have also been associated with antithrombin III deficiency.

Diagnosis

Laboratory studies that can be performed in the workup for antithrombin III deficiency include the following:

  • Antithrombin assays
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
  • Protein C (antigen and activity tests) and protein S (total and free tests)
  • Factor V Leiden testing
  • Homocysteine level
  • Anticardiolipin antibodies (immunoglobulin G [IgG] and IgM class)

Imaging studies that can be used in the evaluation of antithrombin III deficiency include the following:

  • Echocardiography: This should be performed in all patients with antithrombin III deficiency, especially if they have evidence of arterial thrombus
  • 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 this modality

Management

In neonates who have AT3 homozygous mutations, arterial and venous thrombosis are 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.

Enoxaparin (Lovenox), a low–molecular-weight heparin (LMWH), is frequently used to prevent thrombi, as well as to prevent the propagation of thrombi that have already occurred. In antithrombin III deficiency, however, the activity of LMWH is not as reliable as in an otherwise healthy person.

Once a patient with congenital antithrombin III deficiency has developed thrombosis, anticoagulation is more strongly indicated. 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.

Pathophysiology

A study by Yilmaz and Gunaydin indicated that in the absence of major acquired risk factors, patients under age 45 years with venous thromboembolism (VTE) commonly have inherited risk factors for the condition. The study involved 58 VTE patients under age 45 years, 45 of whom had at least one inherited risk factor, including 14 with antithrombin III deficiency. (Factor V Leiden mutation was the most common risk factor, occurring in 30 patients.)[2]

See the image below.

Antithrombin (AT) sites of action. Antithrombin (AT) sites of action.

Antithrombin III deficiency is usually inherited in an autosomal dominant fashion.

Several different genetic abnormalities have been identified in separate kindreds. The defects most frequently affect the proteins translation or post-translational processing, which results in decreased functional antithrombin III.

Two types of antithrombin III deficiency have been described. Type I (classic) is the result of decreased synthesis of biologically normal antithrombin III, resulting in quantitative deficiency of the enzyme; thus, both antigen and activity levels are similarly low. Type II (functional) is the result of a discrete molecular defect within the antithrombin III itself, resulting in a normal antigen level associated with a reduction in heparin cofactor activity levels of about 50%.

Two functional assays for antithrombin III deficiency identified two separate subclasses of the type 2 defect. The assays are the antithrombin-heparin cofactor activity and the progressive antithrombin activity. The first measures the ability of heparin to neutralize the enzymatic activity of thrombin and factor Xa and the second measures the ability of antithrombin III to neutralize thrombin in the absence of heparin. Heterozygotes of type 2 antithrombin III deficiency that exhibit diminished levels of both thrombin-heparin cofactor and progressive antithrombin activity level usually carry a mutation near the thrombin binding site (active site), while those with diminished thrombin-heparin cofactor and normal progressive antithrombin activity are carriers of a defect in the heparin binding site. The distinction between the two is clinically important, since the second group of patients rarely develop any symptoms unless they are homozygous for the defect; then they will have significant thrombotic events early in life and their thrombin-heparin cofactor level will be less than 10%. Both parents will be affected.

Numerous discrete point mutations of the antithrombin gene have been identified.[3, 4] The type I deficiency is the most common phenotype however.

Two defects, wibble and wobble, have been characterized as resulting in substitutions of a single amino acid at the beginning of the beta sheet of the peptide. Substitutions that result in polar amino acids in this location result in decreased activity and survival of the enzyme (Wibble), whereas others cause amino acid substitutions and result in less severe decreases. Clinically, the Wibble gene is associated with a greater risk of thrombosis early in life (second decade).

Other regions of the gene (eg, the "shutter" region) are also associated with clinically significant thrombosis. The shutter region of the antithrombin III protein is centrally located near the "A" B sheet and facilitates opening and closing of the enzyme's active site. These examples are all part of the conformational diseases that may occur in all SERPIN class enzymes (see Alpha-1 Antitrypsin Deficiency).

Acquired deficiencies are commonly due to increased coagulation activity secondary to endothelial injury or the presence of antiphospholipid (AP) antibodies (eg, lupus anticoagulant). In both of these situations, antithrombin III is consumed at increased rates because of excessive activation of the coagulation pathway. Other reported mechanisms of acquired antithrombin III deficiency include chronic liver disease, with resultant synthetic failure, and protein loss due to ascites or nephrotic syndrome, as indicated earlier.

A study by Di Minno et al indicated that in patients with unprovoked VTE, even mild antithrombin deficiency significantly increases the risk of VTE recurrence. In the report, which involved 823 patients who had suffered a first VTE, the investigators found that after adjusting for major VTE risk factors and anticoagulation duration, patients with antithrombin levels as high as 80% had a significantly higher risk of VTE recurrence than did those with antithrombin levels above 80%.[5]

A study by Sokol et al further supported evidence that mild antithrombin deficiency can be linked to recurrent VTE. The report found that when patients with antithrombin activity of less than 70% were compared with those with antithrombin activity of over 80%, VTE recurrence in the lower group had a hazard ratio of 3.7.[6]

Epidemiology

Frequency

United States

The prevalence of antithrombin III deficiency has been estimated as approximately 1 per 2,000 individuals.[7] However, in patients who develop thrombosis, the prevalence is increased to between 1 in 20 individuals to 1 in 200 individuals.[8]

International

In some regions, for example Scotland, the frequency of type I antithrombin III deficiency in blood donors has been reported to be about 0.2 per 1,000 population; type II has a frequency of about 2-3 per 1,000 population.[9]

Mortality/Morbidity

The incidence of thrombotic events is increased in patients with antithrombin III deficiency. In the hereditary form, the lifetime risk has been estimated to be 50-85%, whereas in other groups, the risk may be as low as 20%.[10, 8]

A study by Lenz et al in women with pregnancy-related complications and VTE found antithrombin III deficiency in just 3% of the group, although other thrombophilic risk factors were present.[11]

A literature review by Rhéaume et al indicated that women with asymptomatic antithrombin deficiency have a greater risk of pregnancy-associated VTE. The estimated odds ratio for VTE in these women, using pooled results from case-control studies, was 6.09.[12]

Race

Congenital antithrombin III deficiency is recognized in all racial and ethnic groups.

Sex

No sex-related difference is noted in terms of the prevalence of congenital antithrombin III deficiency. Women of childbearing age present special risk factors. Antithrombin III deficiency, like other congenital procoagulant defects, may contribute to an increased risk of spontaneous abortions. Particularly in cases of fetal or umbilical thrombosis as the cause of the miscarriage, it is important to consider antithrombin III deficiency, along with protein C or protein S deficiency and AP antibody syndrome.

Oral contraceptives (OCs) contain estrogen, which is a stimulator of coagulation. Women who are antithrombin III–deficient heterozygotes are at an increased risk of thrombosis when taking OCs, which have also been implicated in causing some decrease in antithrombin III level.

Parents of newborns who have a thrombotic event are at increased risk of having a procoagulant disorder themselves. These individuals should be referred for further assessment of their own risk factors.

Age

Patients who are homozygous for gene defects often present in the neonatal period; individuals who are heterozygous for gene defects may remain asymptomatic well into middle age. A thrombotic challenge, such as placement of a central venous catheter or other vascular catheter, frequently unmask disease due to heterozygotic gene mutations. Individuals who have multiple catheter-related thrombotic events, or life/organ threatening events with no other risk factor, should be evaluated for an underlying procoagulant condition.

 

Presentation

History

Antithrombin III (ATIII) deficiency is most commonly associated with venous thrombosis. Guidelines for VTE have been established.[13] History should focus on current symptoms, defining the patient's personal medical history in terms of thrombosis and thrombotic symptoms, as well as determining if other procoagulant risk factors are present. Often, children with antithrombin III deficiency present with unusual clot locations (eg, mesenteric veins, splenic veins).

Other risk factors include the following:

  • Presence of a central line currently or in the past (This is an especially common risk factor for thrombosis in infants and small children, in whom the lumen of the vessel is small, and blood flow around the catheter is no longer laminar)

  • Medications known to be procoagulant or medications that nonspecifically impair protein synthesis (eg, L-asparaginase)[14]

  • Other diseases associated with procoagulant states (systemic lupus erythematosus [SLE], nephrotic syndrome, bone marrow transplantation, trauma)

  • Communicating heart defects (atrial septal defect [ASD], ventriculoseptal defect [VSD], truncus arteriosus)

  • Presence of a second pro-coagulant disorder (acquired or inherited)

  • Non-O ABO phenotype (This has been associated with increased thrombotic risk in other procoagulant conditions [prothrombin G20210A]; although little is known of the impact of ABO phenotype on more severe procoagulant conditions like antithrombin deficiency, the ABO phenotype should be documented.)

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.

Family history may be helpful. However, due to a late onset of venous thrombosis and a relatively recent development of the ability to accurately screen for specific defects, many patients have family histories that are negative for the condition, even in affected kindreds. Family history topics should include venous thrombosis of the splanchnic system, thrombosis in any vessel without evident cause of local etiology, and recurrent miscarriages.

Physical

See the list below:

  • No physical stigmata are associated with congenital antithrombin III deficiency.

  • Homozygote-deficient newborns may have purpura fulminans-type presentation with embolic lesions in the skin. Heterozygote newborns are typically normal in appearance and do not commonly develop purpura fulminans unless coexisting risk factors are present.

Causes

See the list below:

  • Deficiency may be due to several different genetic defects associated with differing degrees of enzyme production, enzymatic activity, and chemical stability (see Pathophysiology).

  • 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.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Specific laboratory workup for suspected antithrombin III (ATIII) deficiency depends on the clinical setting.

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.

The single most commonly used test for antithrombin III assay is thrombin-heparin cofactor level.

Avoid measuring antithrombin III while the patient is on heparin or even warfarin.

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.

Imaging Studies

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. Venography or MR angiography may be needed for upper extremity thrombi.

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.

MR angiography may be used to detect PE or other intrathoracic thrombi.

Procedures

Given the significant risk of venous thrombosis associated with central venous line (CVL) placement in children without signs of antithrombin III deficiency, those children known to have a congenital antithrombin III deficiency should have CVLs placed only if significant need outweighs increased potential risk of a clinically significant clot.

 

Treatment

Medical Care

Treatment of patients with antithrombin III (ATIII) deficiency depends on the clinical setting. Three congenital conditions are discussed: homozygous antithrombin III deficiency discovered in neonates, heterozygous antithrombin III deficiency in patients with their first thrombosis, and heterozygous antithrombin III deficiency in patients with previous thrombosis.

Antithrombin III deficiency may be congenital but may also be acquired. Antithrombin III replacement in patients with acquired antithrombin III deficiency is also addressed.

In neonates who have AT3 homozygous mutations, arterial and venous thrombosis are 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.

Enoxaparin (Lovenox), a low–molecular-weight heparin (LMWH), is frequently used to prevent thrombi, as well as to prevent the propagation of thrombi that have already occurred. In antithrombin III deficiency, however, the activity of LMWH is not as reliable as in an otherwise healthy person. Careful monitoring of the anti-Xa activity in the patient should be performed. Consider alternative anticoagulation medications (eg, warfarin) because the effectiveness of LMWH is likely reduced.

Once a patient with congenital antithrombin III deficiency has developed thrombosis, anticoagulation is more strongly indicated. Replacement with recombinant antithrombin is not indicated for the treatment of thrombi.

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 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.

The duration of warfarin therapy in children with acquired or heterozygous congenital antithrombin III deficiency experiencing their first clot is controversial, but therapy is generally continued for at least 3-6 months before cessation of anticoagulation. If the underlying triggering event cannot be removed, indefinite anticoagulation should be considered.

Antithrombin III–deficient patients with heterozygotic mutations who experience a second clot, particularly in mesenteric or splanchnic beds, are at significant risk of further life-threatening or organ-threatening thrombosis. These patients are candidates for indefinite warfarin therapy.

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 patients who have experience trauma. In cases of venoocclusive disease, a target of 120% is used, and treatment is initiated once antithrombin III level is subnormal (< 75%).

LMWH has been used to treat patients with heterozygotic gene mutations; however, as LMWH depends on antithrombin III for activity, anti-Xa activity levels should be closely monitored and doses should be adjusted to maintain anti-Xa activity levels in the 0.5-1 international units/mL.

Asymptomatic carriers should not receive anticoagulation therapy, because the risk of thrombosis does not exceed the bleeding risk associated with anticoagulation therapy.[15, 16]

Surgical Care

Antithrombin III concentrates have been used in the perioperative period for surgical prophylaxis in patients with a known deficiency. Carefully determine the specific agent used, because the dosing of plasma-derived antithrombin widely differs from recombinant antithrombin.

Should antithrombin III concentrates not be available, fresh frozen plasma at a dose of 20 mL/kg can raise the antithrombin III level by approximately 20%.

Take care to determine whether risks of a given vascularly invasive procedure (ie, central venous line [CVL] placement) outweigh increased risk of thrombosis.

Any foreign body stimulates clot formation, and the risk of an occlusive clot significantly increases if the size of the foreign body is such that laminar flow through the vessel is disturbed. For example, neonates commonly have venous obstruction due to central lines, which leads to disturbance of flow in the vein and the development of small vessels that bypass the obstructed vein. The vein becomes obstructed due to the presence of the central line. If an indwelling catheter is needed in a patient at high risk for thrombosis, it should be a small flexible catheter and should remain in only as long as is absolutely necessary. Consider using peripheral intravenous lines or peripherally inserted central catheter (PICC) lines rather than large bore central lines when practical.

Consultations

See the list below:

  • Consult with a hematologist experienced in thrombotic disorders in the event of newly diagnosed antithrombin III deficiency.

  • In North America, the Canadian Children's Thrombophilia Society (1-800-NO-CLOTS) is available for consultation. In the United States and other countries, regional hemophilia treatment centers are available.

Diet

Diet manipulations have no direct effect on antithrombin activity. If warfarin is used for thromboprophylaxis, then standard warfarin diet instructions should be used.

Obesity is an independent risk factor for thrombosis. Diet manipulation to encourage a healthy lifestyle should be undertaken in children with a congenital procoagulant disorder to avoid additional risks later in life.

Activity

See the list below:

  • Activity should not be restricted unless the patient is receiving anticoagulants.

 

Medication

Medication Summary

Antithrombin III (ATIII) deficiency may be quickly corrected with infusions of antithrombin III concentrates. Long-term therapy for congenital deficiency is generally not indicated, as an asymptomatic period may last decades. Once thrombosis has occurred, warfarin therapy is generally undertaken.

Antithrombin-III concentrates

Class Summary

Antithrombin III concentrate (Thrombate III [Bayer Corporation]) is used for replacement therapy. This product is a plasma-derived concentrate made from pooled human plasma using modified Cohn ethanol separation and heat-treated for viral inactivation. The vials have no preservatives and are labeled in international units calibrated against a World Health Organization (WHO) standard.

Antithrombin, recombinant (ATryn)

Recombinant AT made in goats. AT regulates hemostasis by inhibiting thrombin and factor Xa, key proteases for blood coagulation. Indicated for prevention of perioperative and peripartum thromboembolic events in patients with hereditary AT deficiency. Not indicated for treatment of thromboembolic events. Available as a lyophilized powder that is reconstitution for IV infusion. Normally administered as a continuous IV infusion medication.

Antithrombin III (Thrombate III)

Alpha2-globulin that inactivates thrombin; plasmin; and other serine proteases of coagulation including factors IXa, Xa, XIa, XIIa, and VIIa, which, in turn, inhibits coagulation.

Mean recovery in healthy patients is 1.6% activity/U/kg infused (ie, 160% activity when 100 U/kg is infused) based on immunologic ATIII assays. Recovery based on functional assays is 1.4% activity/U/kg (ie, 140% activity when 100 U/kg is infused). Functional assay results are most commonly used to calculate dose. Half-life of ATIII is approximately 22 h. This number should be considered in light of patient's underlying clinical problems, as the rate of ATIII consumption may be increased, which would affect extent of recovery and half-life.

A target of 120% is the upper limit of the reference range for ATIII and is chosen as a target value to allow for maximum amount of time to elapse before clearance and consumption of ATIII drops the level in patient's plasma to < 80%.

Anticoagulants

Class Summary

In patients with congenital ATIII deficiency, anticoagulation reduces the incidence of thrombosis. The duration of therapy is likely to be indefinite.

Warfarin (Coumadin)

Inhibits vitamin K–dependent gamma carboxylation of procoagulant proteins factor II, VII, IX, X, as well as the anticoagulant factor, protein C. Tailor dose to maintain an INR in the range of 2-2.5. The length of time to achieve target INR is age dependent. In infants, the median time to achieve the target INR is 5 d and in adolescents, 3 d.

Enoxaparin (Lovenox)

Produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). Binds to ATIII, enhancing its therapeutic effect. The heparin-ATIII complex binds to and inactivates activated factor X (Xa) and factor II (thrombin).

Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.

Advantages include intermittent dosing and decreased requirement for monitoring. Heparin antifactor Xa levels may be obtained if needed to establish adequate dosing.

LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared with UFH.

Prevents DVT, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Used for prevention in hip replacement surgery (during and following hospitalization), knee replacement surgery, or abdominal surgery in those at risk of thromboembolic complications, or in nonsurgical patients at risk of thromboembolic complications secondary to severely restricted mobility during acute illness.

Used for the treatment of DVT or PE in conjunction with warfarin, for the inpatient treatment of acute DVT with or without PE, or for the outpatient treatment of acute DVT without PE.

No use in checking aPTT (drug has wide therapeutic window and aPTT does not correlate with anticoagulant effect). Average duration of treatment is 7-14 d.

 

Follow-up

Further Outpatient Care

Consultation with a coagulation-focused hematologist needs to be done both with the child's parents and the child. Repeat consultation should be undertaken later in adolescence for those children diagnosed early in life.

Complications

See the list below:

  • Most thrombotic complications involve the venous circulation; venous insufficiency is a common complication.

  • In children more than in adults, antithrombin III (ATIII) deficiency may cause arterial occlusion resulting in stroke or other ischemic injury.

Prognosis

Prognosis depends on 3 variables: the degree of the deficiency, the nature of the observed clot, and the number of clots seen.

  • Prognosis for homozygous-deficient antithrombin III deficiency is grim. Typically, severe thrombotic complications arise in neonates. Prognosis for survival into adulthood is good for patients who are heterozygous deficient. The peak risk for thrombotic complications does not arise until the third and fourth decades of life.

  • The nature of the observed clot is an important variable. A clot that occurs in the mesenteric circulation or other central vein carries a more ominous prognosis than clots in the peripheral circulation. Patients with clots in the mesenteric circulation are often best treated with indefinite anticoagulation, even after a single episode.

  • Clots that recur, particularly those that recur either in the central or mesenteric circulation, are of important prognostic significance. Patients with such clots are much more likely to continue to experience thrombotic episodes and eventually to suffer either a life-threatening clot or suffer needlessly from the complications of the thrombi. One thrombotic event may be treated successfully with limited warfarin therapy, particularly if no other prothrombotic condition is present. Patients who experience multiple thrombi are often best treated with indefinite warfarin therapy.

Patient Education

See the list below:

  • Education regarding signs and symptoms of thrombi, as well as the risks associated with warfarin therapy, is the cornerstone of management.

  • Given the teratogenic potential of warfarin, carefully instruct female patients on the importance of avoiding pregnancy. These patients should alert their hematology team regarding any pregnancy or intention to become pregnant so that alternative anticoagulation strategies may be explored in a timely manner.

  • For excellent patient education resources, see eMedicineHealth's patient education article Blood Clot in the Legs.

  • Medlineplus.gov has a continually updated listing of patient information for antithrombin deficiency.

 

Questions & Answers

Overview

What is antithrombin III (ATIII) deficiency?

Which lab tests are performed in the workup of antithrombin III (ATIII) deficiency?

What is the role of imaging studies in the evaluation of antithrombin III (ATIII) deficiency?

How is antithrombin III (ATIII) deficiency treated?

What is the pathophysiology of antithrombin III (ATIII) deficiency?

What is the role of genetics in the pathophysiology of antithrombin III (ATIII) deficiency?

What is pathophysiology of acquired antithrombin III (ATIII) deficiency?

What is the prevalence of antithrombin III (ATIII) deficiency in the US?

What is the global prevalence of antithrombin III (ATIII) deficiency?

What is the morbidity associated with antithrombin III (ATIII) deficiency?

What are the racial predilections of antithrombin III (ATIII) deficiency?

What are the sexual predilections of antithrombin III (ATIII) deficiency?

Which age groups have highest prevalence of antithrombin III (ATIII) deficiency?

Presentation

What is the focus of clinical history for the diagnosis of antithrombin III (ATIII) deficiency?

What the risk factors for antithrombin III (ATIII) deficiency?

Which clinical history findings are characteristic of antithrombin III (ATIII) deficiency?

Which physical findings are characteristic of antithrombin III (ATIII) deficiency?

What causes antithrombin III (ATIII) deficiency?

DDX

What are the differential diagnoses for Antithrombin III Deficiency?

Workup

Which lab studies are performed in the workup of antithrombin III (ATIII) deficiency?

What is the role of antithrombin assays in the workup of antithrombin III (ATIII) deficiency?

What is the role of prothrombin time (PT) and activated partial thromboplastin time (aPTT) testing in the workup of antithrombin III (ATIII) deficiency?

What is the role of protein C and protein S testing in the workup of antithrombin III (ATIII) deficiency?

What is the role of factor V Leiden testing in the workup of antithrombin III (ATIII) deficiency?

What is the role of homocysteine measurement in the workup of antithrombin III (ATIII) deficiency?

What is the role of enzyme-linked immunoabsorbent assay (ELISA) in the workup of antithrombin III (ATIII) deficiency?

What is the role of echocardiography in the workup of antithrombin III (ATIII) deficiency?

What is the role of Doppler ultrasonography in the workup of antithrombin III (ATIII) deficiency?

What is the role of CT scanning and MRA in the workup of antithrombin III (ATIII) deficiency?

When is a central venous line indicated in children with antithrombin III (ATIII) deficiency?

Treatment

When is indefinite warfarin therapy indicated in the treatment of antithrombin III (ATIII) deficiency?

How is antithrombin III (ATIII) deficiency treated?

What is the role of enoxaparin (Lovenox) in the treatment of antithrombin III (ATIII) deficiency?

What is the role of warfarin (Coumadin) in the treatment of antithrombin III (ATIII) deficiency?

How is acquired antithrombin III (ATIII) deficiency treated?

What is the role of LMWH in the treatment of antithrombin III (ATIII) deficiency?

How is asymptomatic antithrombin III (ATIII) deficiency treated?

What surgical prophylaxis is required for patients with antithrombin III (ATIII) deficiency?

What should be considered before central venous line placement in patients with antithrombin III (ATIII) deficiency?

Which specialists should be consulted in the treatment of antithrombin III (ATIII) deficiency?

Which dietary modifications are used in the treatment of antithrombin III (ATIII) deficiency?

Which activity modifications are used in the treatment of antithrombin III (ATIII) deficiency?

Medications

What is the role of medications in the treatment of antithrombin III (ATIII) deficiency?

Which medications in the drug class Anticoagulants are used in the treatment of Antithrombin III Deficiency?

Which medications in the drug class Antithrombin-III concentrates are used in the treatment of Antithrombin III Deficiency?

Follow-up

Which specialist consultations are beneficial to patients with antithrombin III (ATIII) deficiency?

What are the possible complications of antithrombin III (ATIII) deficiency?

What is the prognosis of antithrombin III (ATIII) deficiency?

What should be included in patient education about antithrombin III (ATIII) deficiency?