eMedicine Specialties > Pediatrics: General Medicine > Hematology

Antithrombin III Deficiency

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

Updated: Jul 10, 2009

Introduction

Background

Antithrombin III (ATIII) is a potent inhibitor of the coagulation cascade. It is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. Antithrombin III activity is markedly potentiated by heparin; potentiation of its activity is the principle mechanism by which both heparin and low molecular weight heparin result in anticoagulation.

Congenital antithrombin III deficiency is an autosomal dominant disorder in which an individual inherits one copy of a defective gene. 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 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 2 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 neonates have heterozygous antithrombin III deficiency.

Acquired antithrombin III deficiency is a deficiency of antithrombin primarily due to consumption. It is observed in situations in which activation of the coagulation system is inappropriate. 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), and venoocclusive disease (VOD) in patients undergoing bone marrow transplantation.

Pathophysiology

Antithrombin (AT) sites of action.

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 are of special concern. 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, consider antithrombin III deficiency, along with protein C or protein S deficiency and AP antibody syndrome.

Oral contraceptives (OCs) contain large doses of estrogen, which is a stimulator of coagulation. Women who are antithrombin III–deficient heterozygotes are at an increased risk of thrombosis when taking OCs.

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 homozygotes often present in the neonatal period; individuals who are heterozygotes may remain asymptomatic well into middle age. A thrombotic challenge, such as placement of a central venous catheter or other vascular catheter, frequently unmask heterozygotes. 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.

Clinical

History

• Antithrombin III (ATIII) deficiency is most commonly associated with venous thrombosis. Guidelines for venous thromboembolism have been established.³ 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)⁴
  • 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)
• 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, owing 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

• 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 other problems are coexistent.

Causes

• 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.

Differential Diagnoses

Antiphospholipid Antibody Syndrome

Other Problems to Be Considered

Congenital disorders

Protein C or protein S deficiency
Dysfibrinogenemia
Plasminogen activator inhibitor deficiency
Factor V Leiden

Acquired disorders

Disseminated intravascular coagulation (DIC)
Lupus anticoagulant
Endothelial injury
Trauma
Liver disease
Nephrotic syndrome (or protein loss)

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.
• 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. 
• 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.

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 are homozygote deficient, both arterial and venous thrombosis is 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 thrombi that have already occurred from propagating. In antithrombin III deficiency, 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 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 heterozygotes experiencing 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 trauma patients. In cases of venoocclusive disease, a target of 120% is used, and treatment is initiated once antithrombin III level is subnormal (<80%).
• LMWH has been used to treat heterozygote patients; 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.^5,5,6

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 high-risk patient, 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

• 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.

Activity

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

Medication

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

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.

Dosing

Adult

Infusion should begin 24 hours prior to surgery or prior to delivery in pregnant women; pregnant women who require caesarean delivery should be treated per the dosing guidelines for pregnant women

Administer IV using infusion set with 0.22 micron inline filter; administer loading dose over 15 min, then immediately follow with continuous infusion

Target level is to restore and maintain AT activity levels at 80-120% of normal (0.8-1.2 IU/mL); initiate 24 before surgery for surgical patients

Surgical patients:
Loading dose: IU = [(100 - baseline AT activity) divided by 2.3] X body weight (kg)
Maintenance dose: IU/h = [(100 - baseline AT activity) divided by 10.2] X body weight (kg)

Pregnant women:
Loading dose: IU = [(100 - baseline AT activity) divided by 1.3] X body weight (kg)
Maintenance dose: IU/h = [(100 - baseline AT activity) divided by 5.4] X body weight (kg)

Monitor AT activity 2 h after treatment initiation and adjust dose:
AT level <80%: Increase dose by 30% and recheck AT level 2 h after each dose adjustment
AT level 80-120%: No dose adjustment; recheck AT level 6 h after treatment initiation
AT level >120%: Decrease dose by 30% and recheck AT level 2 h after each dose adjustment

Pediatric

Not established

Interactions

Coadministration with heparin or LMWH increases anticoagulant effect; anticoagulants that use AT to exert their anticoagulant effect may alter half-life of recombinant AT (monitor aPPT and antiFactor Xa level)

Contraindications

Documented hypersensitivity to goat and goat milk proteins

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not shake following reconstitution; common adverse events include hemorrhage and infusion site reaction; monitor for hypersensitivity; coagulation tests required to monitor and adjust dose

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%.

Dosing

Adult

Pediatric

Limited data available
Calculate pediatric dose as follows:
Units required = [(the difference between observed and desired levels) X (body weight in kg)] / 1.4
For example, take a 20-kg child with an ATIII level measured at 40%
Desired level = 120%
[(120 - 40) X (20)] / 1.4 = 1143 U
Administer by continuous IV infusion

Interactions

Antithrombin III increases anticoagulation effects of heparin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Despite measures taken to delete infectious agents from human product, may transmit disease or contain unknown infectious agents; administer within 3 h after reconstitution; administer only IV; give alone, without mixing with other agents or diluting solutions
Adverse reactions occurred in 17 of 340 infusions and include 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 formation (1); if adverse reaction occurs, decrease infusion rate or, if indicated, discontinue infusion until symptoms abate

Anticoagulants

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.

Dosing

Adult

Pediatric

Loading dose: 0.2 mg/kg/d PO for 3-5 d; may need to modify loading dose each day to achieve target INR
Maintenance dose:
Infants: 0.32 mg/kg/d PO; adjust dose according to desired INR
Adolescents: 0.09 mg/kg/d PO; adjust dose according to desired INR

Interactions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; medications that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenytoin, propoxyphene, gemfibrozil, acetaminophen, and sulindac

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; caution in hepatic dysfunction (decrease dose and adjust to target INR)

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.

Dosing

Adult

DVT prophylaxis:
Hip or knee surgery: 30 mg SC q12h
Abdominal surgery: 40 mg SC qd
Restricted mobility: 40 mg SC qd
CrCl <30 mL/min for above indications: 30 mg SC qd
DVT/PE treatment: 1 mg/kg SC q12h; alternatively, 1.5 mg/kg SC qd; CrCl <30 mL/min: 1 mg/kg SC qd

Pediatric

Not established; suggested dose:
<2 months: 0.75 mg/kg/dose SC bid
>2 months: 0.5 mg/kg/dose SC bid

Interactions

Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

Contraindications

Documented hypersensitivity; major bleeding, thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Decrease dose if CrCl <30 mL/min; if thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop; cases of epidural/spinal hematomas have been reported in adults that receive spinal or epidural anesthesia (holding 2 doses prior to LP or surgery is recommended)

Follow-up

Complications

• 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

• 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, visit eMedicine's Circulatory Problems Center. Also, see eMedicine's patient education article Blood Clot in the Legs.
• Medlineplus.gov has a continually updated listing of patient information for antithrombin deficiency.

Miscellaneous

Medicolegal Pitfalls

• Complications of undertreated antithrombin III (ATIII) deficiency comprise an important pitfall, as do the complications of warfarin therapy. Careful follow-up care and monitoring of the patient's degree of anticoagulation and general clinical course are important.
• Physicians who practice in rural environments where laboratory studies may be performed at a referring hospital must take care to ensure that data are accurate and reliable. Use of the international normalized ratio (INR) for comparison of the prothrombin time (PT) data is essential to treat patients of these physicians.
• Parents of a newborn that is found to have a congenital anticoagulation factor deficiency or a thrombotic event in the neonatal period are themselves at an increased risk of thrombotic disease and should be referred for evaluation of their own coagulation status.

Special Concerns

• Warfarin is potentially teratogenic. All female patients of childbearing potential, and their parents, should be strongly counseled regarding the importance of avoiding unplanned pregnancies. They should keep their hematologist informed of any pregnancy.
• Lovenox requires daily subcutaneous infusions that may be problematic for families of sick neonates and children. Home health care should be set up prior to discharge to assist families in getting started at home. Home health care should also be available in case families are unable to administer the medication; the short half life of the medication will affect its efficacy, if doses are missed.

Multimedia

Media file 1: Antithrombin (AT) sites of action.

References

1. 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. Oct 15 1998;92(8):2696-706. [Medline].

2. Kuhle S, Lane DA, Jochmanns K, et al. Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism. Thromb Haemost. Oct 2001;86(4):1007-11. [Medline].

3. [Guideline] Institute for Clinical Systems Improvement (ICSI). Venous thromboembolism. ICSI. Jun 2007;[Full Text].

4. Mitchell L, Andrew M, Hanna K, et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost. Aug 2003;90(2):235-44. [Medline].

5. 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). J Thromb Haemost. Mar 2005;3(3):459-64. [Medline].

6. [Best Evidence] Young G, Albisetti M, Bonduel M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. Sep 23 2008;118(13):1373-82. [Medline].

7. Andrews M, Monagale PT, Brooker L. Thromboembolic Complications During Infancy and Childhood. London: BC Decker, Inc. Hamilton; 2000:321-60.

8. ATryn, Antithrombin (recombinant) [package insert]. GTC Biotherapeutics, inc; 2009. [Full Text].

9. Bucur SZ, Levy JH, Despotis GJ, et al. Uses of antithrombin III concentrate in congenital and acquired deficiency states. Transfusion. May 1998;38(5):481-98. [Medline].

10. Corral J, Hernandez-Espinosa D, Soria JM, Gonzalez-Conejero R, Ordonez A, Gonzalez-Porras JR. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood. May 15 2007;109(10):4258-63. [Medline].

11. de Galan-Roosen AE, Kuijpers JC, Rosendaal FR, Steegers EA, van Beers WA, Ponjee GA. Maternal and paternal thrombophilia: risk factors for perinatal mortality. BJOG. Mar 2005;112(3):306-11. [Medline].

12. Feero WG. Genetic thrombophilia. Prim Care. Sep 2004;31(3):685-709, xi. [Medline].

13. Haire WD. Antithrombin III in hematopoietic stem cell transplantation. Semin Thromb Hemost. 1997;23(6):591-601. [Medline].

14. Haire WD, Ruby EI, Stephens LC, et al. A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 1998;4(3):142-50. [Medline].

15. Hayek S, Kenet G, Lubetsky A, et al. Does thrombophilia play an aetiological role in Legg-Calve-Perthes disease?. J Bone Joint Surg Br. Jul 1999;81(4):686-90. [Medline].

16. Kurnik K, Kosch A, Strater R, Schobess R, Heller C, Nowak-Gottl U. Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a prospective follow-up study. Stroke. Dec 2003;34(12):2887-92. [Medline].

17. Langlois NJ, Wells PS. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review. Thromb Haemost. Jul 2003;90(1):17-26. [Medline].

18. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs. 2007;67(10):1429-40. [Medline].

19. Medical Economics, ed. Physicians' Desk Reference. 54^th ed. Thomson PDR; 2000:735-6. [Full Text].

20. Medical Economics, ed. Physicians' Desk Reference. 55^th ed. Thomson PDR; 2001:899.

21. Nagaraja D, Christopher R, Tripathi M. Plasma antithrombin III deficiency in ischaemic stroke in the young. Neurol India. Jun 1999;47(2):155-6. [Medline].

22. Ota K, Akizawa T, Hirasawa Y, et al. Effects of argatroban as an anticoagulant for haemodialysis in patients with antithrombin III deficiency. Nephrol Dial Transplant. Aug 2003;18(8):1623-30. [Medline].

23. Picard V, Nowak-Göttl U, Biron-Andreani C, Fouassier M, Frere C, Goualt-Heilman M. Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene. Hum Mutat. Jun 2006;27(6):600. [Medline].

24. Schinzel H, Weilemann LS. Antithrombin substitution therapy. Blood Coagul Fibrinolysis. Nov 1998;9 Suppl 3:S17-21; discussion S21-2. [Medline].

Keywords

antithrombin III deficiency, acquired antithrombin deficiency, congenital antithrombin deficiency, AT-III deficiency, ATIII deficiency, AT III deficiency, heterozygous antithrombin deficiency, heparin, low molecular weight heparin, thrombin disorder, anticoagulation, anti-coagulation, venous thrombosis, arterial thrombosis, clotting disorder, blood clots, hematologic disorder, increased thrombogenesis, inappropriate activation of the clotting system, inappropriate coagulation, coagulopathy, disseminated intravascular coagulation, DIC, microangiopathic hemolytic anemias due to endothelial damage, hemolytic-uremic syndrome, veno-occlusive disease, venoocclusive disease, VOD, protein C deficiency, protein S deficiency, liver disease, nephrotic syndrome, bone marrow transplantation, treatment, diagnosis

Contributor Information and Disclosures

Author

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

Medical Editor

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)