AUTHOR INFORMATION

Section 1 of 11

Authored by James L Harper, MD, Associate Chair for Medical Education in Pediatrics, Associate Professor of Pediatric Hematology-Oncology, University of Nebraska Medical Center

James L Harper, MD, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Hematology, and Nebraska Medical Association

Edited by Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Associate Professor, Department of Pediatrics, Uniformed Services University of the Health Sciences; David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	James L Harper, MD
Editor's Email:	Gary R Jones, MD

eMedicine Journal, May 16 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

Background: Antithrombin (antithrombin III, ATIII) is a potent inhibitor of the coagulation cascade. It is a nonvitamin K-dependent protease that inhibits the action of thrombin as well as other procoagulant factors (eg, factor Xa). ATIII activity is markedly potentiated by heparin; potentiation of its activity is the principle mechanism by which both heparin and low molecular weight heparin produce anticoagulation.

Congenital ATIII deficiency is an autosomal dominant disorder in which an individual inherits 1 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. Severe congenital ATIII deficiency, in which the individual inherits 2 defective genes, is an autosomal recessive condition associated with increased thrombogenesis, typically noted in infancy.

Acquired ATIII deficiency is most commonly seen in situations in which activation of the coagulation system is inappropriate. Common conditions that result in acquired ATIII 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 transplant.

Pathophysiology: Heterozygous ATIII deficiency results in venous thrombosis, most commonly starting in the third decade of life. The defect is autosomal dominant, and several different genetic abnormalities have been identified in separate kindreds. The defects are most commonly translational or postprocessing errors, resulting in decreased functional ATIII. 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), while others in nonpolar–amino acid substitutions result in less severe decreases. Clinically, the Wibble gene is associated with a greater risk of thrombosis early in life (second decade).

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

Race: Congenital ATIII deficiency is recognized in all racial and ethnic groups.

Sex: No sex-related difference exists in terms of the prevalence of congenital ATIII deficiency. Women of childbearing age are of special concern.

• ATIII 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 ATIII deficiency, along with protein C or protein S deficiency and AP antibody syndrome.

CLINICAL

Section 3 of 11

History:

• ATIII deficiency is most commonly associated with venous thrombosis. 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.



• Other risk factors include the following:


• • Presence of a central line currently or in the past (an especially common risk factor for thrombosis in infants and small children where 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)
  
  
  
  • 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 ATIII 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, so 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 ATIII 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), while others have yet to be studied.



• Acquired ATIII deficiency is usually due to abnormal activation of a coagulation pathway or synthetic defect, often from medication (eg, L-asparaginase) or liver disease.



• ATIII may be lost in third spaces when it redistributes into edematous tissues. ATIII may also be lost as part of increased protein losses seen in nephrotic syndrome, and this should be suspected if clotting occurs.

DIFFERENTIALS

Section 4 of 11

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

WORKUP

Section 5 of 11

Lab Studies:

• Specific laboratory workup for suspected ATIII deficiency depends on the clinical setting.



• ATIII test


• • ATIII measurement should be the first test performed.
  
  
  
  • This test directly measures the ATIII level.
  
  
  
• 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 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 ATIII.

  • In the newborn, protein S activity must be measured (in addition to total) because, while 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 ATIII 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.



• Anticardiolipin antibodies (both IgG and IgM class) should be measured by ELISA or other physical means to rule out coexisting thrombotic risk from this source.

Imaging Studies:

• Echocardiography should be carried out on all patients with ATIII deficiency, especially if they have evidence of arterial thrombus.


• • Arterial thrombosis due to ATIII deficiency is uncommon.
  
  
  
  • Venous clots may migrate to arterial circulation through a patent foramen ovale or other communicating congenital heart defect (eg, ASD, VSD, truncus arteriosis).
  
  
  
• Venography of the affected limb: Given difficulties in performing and interpreting duplex Doppler ultrasound in children, the venogram is considered to be the criterion standard for the imaging of suspected thrombosis in pediatric populations.



• 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 ATIII deficiency, those children known to have a congenital ATIII deficiency should have CVLs placed only if significant need outweighs increased potential risk of a clinically significant clot.

TREATMENT

Section 6 of 11

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

ATIII deficiency may be congenital but may also be acquired. ATIII replacement in patients with acquired ATIII 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 ATIII using ATIII concentrates or fresh frozen plasma is recommended. In patients undergoing surgery, whether they are homozygote or heterozygote deficient, ATIII replacement may be used during the perioperative period.

  Enoxaparin (Lovenox), a low molecular weight heparin (LMWH), is frequently used to prevent thrombi as well as treating thrombi that have already occurred. Given the ATIII deficiency, the activity of LMWH is not as reliable as in an otherwise normal person. Careful monitoring of the anti-Xa activity in the patient should be undertaken.




• Once a patient with congenital ATIII deficiency has developed thrombosis, anticoagulation is 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. Initially, therapy with low molecular weight heparin or standard heparin may be undertaken 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.

  • ATIII concentrates or fresh frozen plasma (FFP) supplementation may be necessary to achieve the desired therapeutic effect with either heparin product. The duration of warfarin therapy in children experiencing their first clot is controversial, but therapy is generally continued for at least 3-6 months before stopping anticoagulation is considered.



• ATIII-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 ATIII deficiency is due to decreased production or increased consumption. In either case, treatment of the underlying disease and replacement of ATIII using ATIII concentrates is the common approach used. Some evidence indicates that using a supranormal target (140%) is necessary in pediatric trauma patients. In cases of VOD, a target of 120% is used, and treatment is initiated once ATIII level is subnormal ( <80%).



• Low Molecular Weight Heparin (LMWH) has been used to treat heterozygote patients; however, as LMWH is dependent on ATIII for activity, anti-Xa activity levels should be monitored closely and doses adjusted to maintain anti-Xa activity levels in the 0.5-1.0 international units/ml.

Surgical Care:

• ATIII concentrates have been used in the perioperative period for surgical prophylaxis in patients with a known deficiency.

  Should ATIII concentrates not be available, Fresh Frozen Plasma at a dose of 20 ml/kg will be expected to raise the Antithrombin III level by approximately 20%.




• Take care to determine whether risks of a given vascularly invasive procedure (ie, CVL placement) outweigh increased risk of thrombosis.

Consultations: Consult with a hematologist experienced in thrombotic disorders in the event of newly diagnosed ATIII 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

Section 7 of 11

ATIII deficiency may be quickly corrected with infusions of ATIII 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.

Drug Category: Antithrombin-III concentrates -- ATIII 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.

Drug Name	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%.
Pediatric Dose	Limited data exist 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
Contraindications	Documented hypersensitivity
Interactions	Antithrombin III increases anticoagulation effects of heparin
Pregnancy	C - Safety for use during pregnancy has not been established.
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

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

Drug Name	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.
Pediatric Dose	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
Contraindications	Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Interactions	Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, OCs, and sucralfate; medications that may increase anticoagulant effects of warfarin include oral 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
Pregnancy	D - Unsafe in pregnancy
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)

Drug Name	Enoxaparin (Lovenox) -- Produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). Binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III 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.
Adult Dose	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 Dose	Not established; suggested dose: <2 months: 0.75 mg/kg/dose SC bid >2 months: 0.5 mg/kg/dose SC bid
Contraindications	Documented hypersensitivity; major bleeding, thrombocytopenia
Interactions	Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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 low-molecular-weight heparins; 1.0 mg of protamine sulfate will reverse effect of approximately 1.0 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

Section 8 of 11

Complications:

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



• In children more than in adults, 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 ATIII 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.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Complications of undertreated 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 INR for comparison of the 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.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A 13-year-old girl is placed on heparin postoperatively, following repair of a right subclavian vein occlusion. She is found to have a persistently normal activated partial thromboplastin time (aPTT) despite therapeutic levels of heparin. Which of the following conditions is the most likely cause of her laboratory findings?

A: Protein C deficiency
B: Protein S deficiency
C: Factor V Leiden syndrome
D: Antithrombin III (ATIII) deficiency
E: Plasminogen activator deficiency

The correct answer is D: All of the other coagulation proteins are unaffected by heparin (directly). ATIII is the enzyme that is markedly potentiated heparin, and heparin exerts its anticoagulant effect through a massive increase in ATIII activity.

CME Question 2: A 3-year-old child is found to have edema around her labia and eyelids. Her history shows that she has gained several kilograms over the last 2 weeks. Physical examination reveals that she has edema with abdominal distention and an obvious succussion wave. She is found to have a clot in her left popliteal vein. Her prothrombin time (PT) is 15 seconds, and her activated partial thromboplastin time (aPTT) is 40 seconds. The antithrombin (ATIII) level is 50. What is the most likely cause of her ATIII deficiency?

A: Liver failure
B: Disseminated intravascular coagulation (DIC)
C: Third-spacing in the abdomen
D: Renal loss due to nephrotic syndrome
E: Both C and D

The correct answer is E: ATIII may be lost in third spaces when it redistributes into edematous tissues. ATIII may also be lost as part of increased protein losses seen in nephrotic syndrome, and this should be suspected if clotting occurs.

Pearl Question 1 (T/F): A child is receiving a bone marrow transplant. He gains 2 kg, and his liver functions are increased. Doppler ultrasound of his liver reveals reversal of flow in the hepatic vein. His antithrombin III (ATIII) level is 60%. He weighs 20 kg. To correct his deficit to 120%, the dose of ATIII given should be 857 units.

The correct answer is True: According to the 1999 edition Physician’s Desk Reference, dosage is calculated according to this formula: Dose (in units) = [(desired level - observed level) X (body weight in kg)] / 1.4.

Pearl Question 2 (T/F): Heparin is the common anticoagulant that is dependent on normal levels of antithrombin III (ATIII).

The correct answer is True: ATIII activity is markedly potentiated by heparin; potentiation of its activity is the principle mechanism by which both heparin and low molecular weight heparin produce anticoagulation.

Pearl Question 3 (T/F): A patient is placed on warfarin and develops cutaneous thrombosis. Antithrombin III (ATIII) is probably involved.

The correct answer is True: Previously undiagnosed ATIII deficiency in a patient starting warfarin therapy leaves the patient temporarily exposed to thrombosis because the level of protein C is depleted more quickly than levels of other procoagulant factors once therapy has begun. ATIII activity is necessary to avoid this.

Pearl Question 4 (T/F): Antithrombin III (ATIII) levels are low in a patient with fulminant liver failure and ascites. Three potential causes are liver failure (loss of production), third-space loss into ascites, and consumption.

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

BIBLIOGRAPHY

Section 11 of 11

• Andrews M, Monagale PT, Brooker L: Thromboembolic Complications During Infancy and Childhood. BC Decker, Inc. Hamilton, London; 2000: 321-60.
• 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 Oct 15; 92(8): 2696-706[Medline].
• Bucur SZ, Levy JH, Despotis GJ, et al: Uses of antithrombin III concentrate in congenital and acquired deficiency states. Transfusion 1998 May; 38(5): 481-98[Medline].
• de Galan-Roosen AE, Kuijpers JC, Rosendaal FR, et al: Maternal and paternal thrombophilia: risk factors for perinatal mortality. BJOG 2005; 112(3): 306-11[Medline].
• Haire WD: Antithrombin III in hematopoietic stem cell transplantation. Semin Thromb Hemost 1997; 23(6): 591-601[Medline].
• 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].
• Hayek S, Kenet G, Lubetsky A, et al: Does thrombophilia play an aetiological role in Legg-Calve-Perthes disease? J Bone Joint Surg Br 1999 Jul; 81(4): 686-90[Medline].
• Medical Economics, ed: Physicians' Desk Reference. 54th ed. Thomson PDR; 2000: 735-36[Full Text].
• Medical Economics, ed: Physicians' Desk Reference. 55th ed. Thomson PDR; 2001: 899.
• Nagaraja D, Christopher R, Tripathi M: Plasma antithrombin III deficiency in ischaemic stroke in the young. Neurol India 1999 Jun; 47(2): 155-6[Medline].
• 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 2003 Aug; 18(8): 1623-30[Medline].
• Schinzel H, Weilemann LS: Antithrombin substitution therapy. Blood Coagul Fibrinolysis 1998 Nov; 9 Suppl 3: S17-21; discussion S21-2[Medline].
• 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 Haemostat 2005; 3(3): 459-64[Medline].

eMedicine Journals > Pediatrics > Hematology > Antithrombin III Deficiency

Please email us with any comments you have on our new chapter format.

Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Bibliography