Antithrombin III: Difference between revisions

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{{Infobox_Disease |
{{DrugProjectFormSinglePage
  Name          = {{PAGENAME}} |
|authorTag={{AL}}
  Image          = |
|genericName=Antithrombin III
  Caption        = |
|aOrAn=a
  DiseasesDB    = |
|drugClass=[[anti-coagulant]]
  ICD10          = |
|indication=[[hereditary antithrombin III deficiency]]
  ICD9          = |
|adverseReactions=[[dizziness]], [[chest discomfort]], [[nausea]], [[dysgeusia]], [[chills]]
  ICDO          = |
|blackBoxWarningTitle=Warning Title
  OMIM          = |
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
  MedlinePlus    = |
|fdaLIADAdult======Hereditary Antithrombin III Deficiency=====
  eMedicineSubj = |
* Dosage should be determined on an individual basis based on the pre-therapy plasma ATIII level, in order to increase plasma ATIII levels to the level found in normal human plasma (80-120%).
  eMedicineTopic = |
* Dosage of antithrombin III can be calculated from the following formula:
  MeshID        = |
[[Image:ATIII Dosing Formula.png|450px|left]]
}}
{{clr}}
{{SI}}
* The recommendations for dosing are provided as a general guideline for therapy only. The exact loading and maintenance dosages and dosing intervals should be individualized for each subject, based on the individual clinical conditions, response to therapy, and actual plasma ATIII levels achieved.
{{WikiDoc Cardiology Network Infobox}}
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Antithrombin III in adult patients.
{{CMG}}
|offLabelAdultNoGuideSupport======Acquired Antithrombin III Deficiency=====
* Severe Sepsis<ref>{{Cite journal
| author = [[B. Eisele]], [[M. Lamy]], [[L. G. Thijs]], [[H. O. Keinecke]], [[H. P. Schuster]], [[F. R. Matthias]], [[F. Fourrier]], [[H. Heinrichs]] & [[U. Delvos]]
| title = Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis
| journal = [[Intensive care medicine]]
| volume = 24
| issue = 7
| pages = 663–672
  | year = 1998
| month = July
| pmid = 9722035
}}</ref>
:* Loading dose: '''3000 IU''' (in 1 hour)
:* Maintenance dose: '''1500 IU q12h''' for 5 days.


{{Editor Join}}
*Shock and DIC
:* Dose was based in the following formula: (100 - antithrombin III activity in %) x body weight (kg).
:* Repeat dose if antithrombin III activity fell below 80%.


==Overview==
=====Heparin Resistance=====
'''Antithrombin''' (AT) is a small protein molecule that inactivates several enzymes of the [[coagulation]] system. It is a [[glycoprotein]] produced by the [[liver]] and consists of 432 amino acids. It contains three [[disulfide bond]]s and a total of four possible [[glycosylation]] sites. α-antithrombin is the dominant form of antithrombin found in [[blood plasma]] and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin.<ref>{{cite book |last = Bjork | first = I | coauthors = Olson, JE | title = Antithrombin, A bloody important serpin (in Chemistry and Biology of Serpins) | publisher = Plenum Press | date = 1997 | pages=17-33 | id=ISBN 0-306-45698-2}}</ref>
* In patients with unstable angina:<ref>{{Cite journal
| author = [[M. Rossi]], [[L. Martinelli]], [[S. Storti]], [[M. Corrado]], [[R. Marra]], [[C. Varano]] & [[R. Schiavello]]
| title = The role of antithrombin III in the perioperative management of the patient with unstable angina
| journal = [[The Annals of thoracic surgery]]
| volume = 68
| issue = 6
| pages = 2231–2236
| year = 1999
| month = December
| pmid = 10617008
}}</ref>
:* '''3000 IU + [[heparin]] 300 U/kg'''
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Antithrombin III in pediatric patients.
|offLabelPedNoGuideSupport======Disseminated Intravascular Coagulation=====


==== Reference Range ====
* Dosing Information
{|
|-style="background:silver; color:black"
| '''Level''' ||  '''0.14-0.39 g/l''' 
|-style="background:silver; color:black"
| '''Activity''' || '''70-120% of Normal Activity'''
|}


== Nomenclature ==
:* Children (1 month to 5 years): '''250 units IV q8h''', with or without [[heparin]]. <ref>{{Cite journal
Antithrombin is officially termed '''antithrombin III''' (AT III) and it is a member of a larger family of antithrombins, numbered antithrombin I (AT I) through to antithrombin VI (AT VI). All antithrombins are [[serine protease inhibitor|serpin]]s, however only AT III and possibly AT I are medically significant. AT III is generally referred to solely as ''antithrombin'' and it is antithrombin III that is discussed in this article.
| author = [[T. Hanada]], [[T. Abe]] & [[H. Takita]]
| title = Antithrombin III concentrates for treatment of disseminated intravascular coagulation in children
| journal = [[The American journal of pediatric hematology/oncology]]
| volume = 7
| issue = 1
| pages = 3–8
| year = 1985
| month = Spring
| pmid = 4037242
}}</ref>
:* Newborn infants: '''40 units/kg/day + [[heparin]] 200 units/kg/day'''<ref>{{Cite journal
| author = [[R. von Kries]], [[H. Stannigel]] & [[U. Gobel]]
| title = Anticoagulant therapy by continuous [[heparin]]-antithrombin III infusion in newborns with disseminated intravascular coagulation
| journal = [[European journal of pediatrics]]
| volume = 144
| issue = 2
| pages = 191–194
| year = 1985
| month = July
| pmid = 4043133
}}</ref>
|contraindications=*Antithrombin III is contraindicated in patients with hypersensitivity to antithrombin III.
|warnings=*Because antithrombin III is made from human [[plasma]], it may carry a risk of transmitting infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
*No cases of transmission of viral diseases or CJD have ever been identified for antithrombin III.
*Inform patients that antithrombin III is made from human [[plasma]] and may contain infectious agents that can cause disease.  
*While the risk that antithrombin III can transmit an infectious agent has been reduced by screening [[plasma]] donors for prior exposure, testing donated [[plasma]], and by inactivating or removing pathogens during manufacturing, patients should report any symptoms that concern them.
*All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider.
* The [[anticoagulant]] effect of [[heparin]] is enhanced by concurrent treatment with antithrombin III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of [[heparin]] is recommended during treatment with antithrombin III.
|clinicalTrials=In clinical studies involving antithrombin III, adverse reactions were reported in association with 17 of the 340 infusions during the clinical studies. Included were:
* [[Dizziness]]
*[[Chest discomfort]]
*[[Nausea]]
*[[Dysgeusia]]
*[[Chills]]
*[[Abdominal pain]]
*[[Dyspnea]]
*[[Chest pain]]
*[[Blurred vision]]
*[[Intestinal dilatation]]
*[[Urticaria]]
*[[Pyrexia]]
*Wound secretion and [[hematoma]]


==Structure==
If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate.
Antithrombin has a [[half life]] in [[blood plasma]] of around 3 days.<ref>{{cite journal | author = Collen DJ, Schetz F. ''et al''. | title = Metabolism of antithrombin III (heparin cofactor) in man: Effects of venous thrombosis of heparin administration | journal = Eur. J. Clin. Invest | year=1977 | volume=7 | pages=27-35 | id = PMID 65284 }}</ref>
|drugInteractions=*The [[anticoagulant]] effect of [[heparin]] is enhanced by concurrent treatment with antithrombin III in patients with hereditary ATIII deficiency.  
The normal antithrombin concentration in human [[blood plasma]] is high at approximately 0.12 mg/ml, which is equivalent to a [[Concentration#Molarity|molar]] concentration of 2.3 μM.<ref>{{cite journal | author = Conrad J, Brosstad M. ''et al.'' | title = Molar antithrombin concentration in normal human plasma | journal = Haemostasis | year=1983 | volume=13 | pages=363-368 | id = PMID 6667903 }}</ref>
*Thus, in order to avoid bleeding, reduced dosage of [[heparin]] is recommended during treatment with antithrombin III.
Antithrombin has been isolated from the plasma of a large number of species additional to humans.<ref>{{cite journal | author = Jordan RE. | title = Antithrombin in vertebrate species: Conservation of the heparin-dependent anticoagulant mechanism | journal = Arch. Biochem. Biophys | year=1983 | volume=227 | pages=587-595 | id = PMID 6607710 }}</ref>
|FDAPregCat=B
As deduced from protein and [[cDNA]] sequencing, cow, sheep, rabbit and mouse antithrombins are all 433 amino acids in length, which is one amino acid longer than human antithrombin III. The extra amino acid is thought to occur at amino acid position 6. Cow, sheep, rabbit, mouse and human antithrombins share between 84 and 89% amino acid sequence identity.<ref name=olson>{{cite journal | author = Olson ST, Bjork I. | title = Regulation of thrombin activity by antithrombin and heparin | journal = Sem. Thromb. Hemost. | year=1994 | volume=20 | issue=4 | pages=373-409 | id = PMID 7899869 }}</ref>
|useInPregnancyFDA=Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to antithrombin III. It is not known whether antithrombin III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
They all have four potential [[N-glycosylation]] sites. These occur at [[asparagine]] (Asn) amino acid numbers 96, 135, 155 and 192 in humans and at similar amino acid numbers in other species. All these sites are occupied by covalently attached oligosaccharide side chains in the predominant form of human antithrombin, α-antithrombin. The potential glycosylation site at asparagine 135 is not occupied in a minor form of antithrombin, β-antithrombin.<ref>{{cite journal | author = Brennan SO, George PM, Jordan, RE. | title = Physiological variant of antithrombin-III lacks carbohydrate side chain at Asn 135 | journal = FEBS Lett | year=1987 | volume=219 | pages=431-436 | id = PMID 3609301 }}</ref>
|useInPed=Safety and effectiveness in the pediatric population have not been established. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal [[thromboembolism]], such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.)
Shown below are the location of the four potential glycosylation sites within the [[tertiary structure]] of an antithrombin [[monomer]], as taken from the [[protein data bank]] file [http://www.pdb.org/pdb/explore/explore.do?structureId=2ANT 2ANT]. In this structure only Asn 155 is glycosylated by the addition of a single [[N-Acetylglucosamine|''N''-acetylglucosamine]] residue. 
[[Image:antithrombin 1.jpeg|500px]]


== Function ==
[[Plasma]] levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower.  Low [[plasma]] ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with antithrombin III of neonates be discussed with an expert on coagulation.
Antithrombin is a [[serine protease inhibitor|serpin]] (serine protease inhibitor). The physiological target [[protease]]s of antithrombin are those of the [[Coagulation#Contact activation pathway|''contact activation pathway'']] (formerly known as the intrinsic pathway), namely the activated forms of [[Factor X]] (Xa), [[Factor IX]] (IXa), [[Factor XI]] (XIa), [[Factor XII]] (XIIa) and [[Factor II]] (thrombin) (IIa) and also the activated form of [[Factor VII]] (VIIa) from the [[Coagulation#Tissue factor pathway|''tissue factor pathway'']] (formerly known as the extrinsic pathway).<ref>{{cite journal | author = Persson E, Bak H and Olsen OH. | title = Substitution of valine for leucine 305 in factor VIIa increases the intrinsic enzymatic activity | journal = J. Biol. Chem. | year=2001 | volume=276 | issue=31 | pages=29195-29199 | id = PMID 11389142}}</ref> Protease inactivation results as a consequence of the trapping the protease in an equimolar complex with antithrombin in which the active site of the protease enzyme is inaccessible to its usual [[substrate]].<ref name=olson/> The formation of an antithrombin-protease complex involves an interaction between the protease and a specific reactive [[peptide bond]] within antithrombin. In human antithrombin this bond is between [[arginine]] (arg) 393 and [[serine]] (ser) 394.<ref name=olson/> As shown below the reactive arg 393 - ser 394 bond is located on an exposed loop at the surface of the molecule. This loop is termed the reactive site loop.
|administration=*Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.
*Administer only by the intravenous route.
*Antithrombin III, once reconstituted, should be given alone, without mixing with other agents or diluting solutions.
*Product administration and handling of the needles must be done with caution. [[Percutaneous]] puncture with a needle contaminated with blood can transmit infectious virus including [[HIV]] ([[AIDS]]) and [[hepatitis]]. Obtain immediate medical attention if injury occurs.


[[Image:antithrombin 2.jpeg|300px]]
=====Reconstitution=====
Vacuum Transfer<br>
Note: Aseptic technique should be carefully followed. All needles and vial tops that will come into contact with the product to be administered via the intravenous route should not come in contact with any nonsterile surface. Any contaminated needles should be discarded by placing in a puncture-proof container and new equipment should be used.


It is thought the trapping of protease enzymes in inactive antithrombin-protease complexes results as a consequence of their attack of the reactive bond. Where the attack of a similar bond within their normal substrate results in its rapid [[proteolytic]] cleavage, on initiating an attack on the antithrombin reactive bond the antithrombin inhibitor is activated to trap the enzyme at an intermediate stage during the proteolytic process. Given time thrombin is able to cleave the reactive bond within antithrombin and an inactive thrombin-antithrombin complex will dissociate, however the time it takes for this to occur may be greater than 3 days.<ref>{{cite journal | author = Danielsson A and Bjork, I | title = Slow, spontaneous dissociation of the antithrombin-thrombin complex produces a proteolytically modified form of the inhibitor | journal = FEBS Lett | year=1980 | volume=119 | pages=241-244 | id = PMID 7428936}}</ref> 
# Antithrombin III and diluent should be at room temperature before reconstitution.
# Remove shrink band from product vial. '''If the shrink band is absent or shows signs of tampering, do not use the product and notify Grifols Therapeutics Inc. immediately.'''
# Remove the plastic flip tops from each vial (Fig. A). Cleanse vial tops (grey stoppers) with alcohol swab and allow surface to dry. After cleaning, do not allow anything to touch the stopper.
# Carefully remove the plastic sheath from the short end of the transfer needle. Insert the exposed needle into the diluent vial to the hub (Fig. B).
# Carefully grip the sheath of the other end of the transfer needle and twist to remove it.
# Invert the diluent vial and insert the attached needle into the antithrombin III vial at a 45° angle (Fig. C). This will direct the stream of diluent against the wall of the vial and minimize foaming. The vacuum will draw the diluent into the antithrombin III vial.*
# When diluent transfer is complete, remove the diluent vial and transfer needle (Fig. D).
# Immediately after adding the diluent, swirl continuously until completely dissolved (Fig. E). Some foaming may occur, but attempt to avoid excessive foaming. The vial should then be visually inspected for particulate matter and discoloration prior to administration.
# Clean the top of the vial of reconstituted antithrombin III again with alcohol swab and let surface dry.
# Attach the filter needle (from the package) to sterile syringe. Withdraw the antithrombin III solution into the syringe through the filter needle (Fig. F).
# Remove the filter needle from the [[syringe]] and replace with an appropriate injection or [[butterfly needle]] for administration. Discard filter needle into a puncture-proof container.
# If the same patient is using more than one vial of antithrombin III, the contents of multiple vials may be drawn into the same syringe through the filter needles provided.


The rate of antithrombin's inhibition of protease activity is greatly enhanced by its additional binding to [[heparin]].
*If vacuum is lost in the antithrombin III vial during reconstitution, use a sterile syringe to remove the sterile water from the diluent vial and inject it into the antithrombin III vial, directing the stream of fluid against the wall of the vial.


==Antithrombin and heparin==
[[File:Antithrombin_III_03.png|thumb|600px|left]]
AT-III binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer
{{clr}}


GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S)
=====Rate of Administration=====
The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 10 to 20 minutes is generally well tolerated.
|monitoring=*It is recommended that following an initial dose of Antithrombin III, plasma levels of ATIII be initially monitored at least every 12 hours and before the next infusion of Antithrombin IIII to maintain plasma ATIII levels greater than 80%.
*Measure preinfusion and 20 minutes postinfusion (peak) [[plasma]] ATIII levels following the initial loading dose, [[plasma]] ATIII level after 12 hours, then preceding the next infusion (trough level).
*Subsequently measure ATIII levels preceding and 20 minutes after each infusion until predictable peak and trough levels have been achieved, generally between 80%–120%.
* [[Plasma]] levels between 80%–120% may be maintained by administration of maintenance doses of 60% of the initial loading dose, administered every 24 hours.
* Adjustments in the maintenance dose and/or interval between doses should be made based on actual [[plasma]] ATIII levels achieved.
*In some situations, e.g., following surgery, hemorrhage or acute thrombosis, and during intravenous [[heparin]] administration, the half-life of antithrombin III (Human) has been reported to be shortened. In such conditions, [[plasma]] ATIII levels should be monitored more frequently, and antithrombin III administered as necessary.
|overdose=There is limited information regarding overdose of antithrombin III in the drug label.
|mechAction=Antithrombin III, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human [[plasma]] at a concentration of approximately 12.5 mg/dL and is the major [[plasma]] inhibitor of [[thrombin]].
|structure=There is limited information regarding the structure of antithrombin III in the drug label.
|PD=Inactivation of [[thrombin]] by ATIII occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active [[serine]] of [[thrombin]] and an [[arginine]] reactive site on ATIII.  ATIII is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin.
|PK=There is limited information regarding pharmacokinetics of antithrombin III in the drug label.
|nonClinToxic=There is limited information regarding nonclinical toxicology of antithrombin III in the drug label.
|clinicalStudies=In clinical studies of antithrombin III conducted in 10 asymptomatic subjects with hereditary deficiency of ATIII, the mean in vivo recovery of ATIII was 1.6% per unit per kg administered based on immunologic ATIII assays, and 1.4% per unit per kg administered based on functional ATIII assays. The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of ATIII.  These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8–4.8 days.


Upon binding to this pentasaccharide sequence, inhibition of protease activity is increased by heparin as a result of two distinct mechanisms.<ref>{{cite journal | author = Johnson DJ, Langdown J, ''et al''. | title = Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation | journal =  J. Biol. Chem. | year=2006 | volume=281 | issue=46 | pages=35478-35486 | id = PMID 16973611}}</ref> In one mechanism heparin stimulation of Factor IXa and Xa inhibition depends on a conformational change within antithrombin involving the reactive site loop and is thus [[allosteric]]. This conformational change results in an approximate 300 fold increase in Factor IXa and Xa inhibitory activity.<ref name=Langdown>{{cite journal | author = Langdown J, Johnson DJ. ''et al''. | title = Allosteric activation of antithrombin critically depends upon hinge region extension | journal =  J. Biol. Chem. | year=2004 | volume=279 | issue=45 | pages=47288-47297 | id = PMID 15326167}}</ref> In another mechanism stimulation of thrombin inhibition depends on the formation of a [[ternary complex]] between AT-III, thrombin, and heparin. Formation of this complex results in an approximate 4 fold increase in antithrombin inhibitory activity.<ref name=Langdown/>
In clinical studies of antithrombin III, none of the 13 patients with hereditary ATIII deficiency and histories of [[thromboembolism]] treated prophylactically on 16 separate occasions with antithrombin III for high [[thrombotic]] risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. [[Heparin]] was also administered in 3 of the 11 surgical procedures. Eight patients with hereditary ATIII deficiency were treated therapeutically with antithrombin III as well as [[heparin]] for major thrombotic or [[thromboembolic]] complications, with seven patients recovering. Treatment with antithrombin III reversed [[heparin]] resistance in two patients with hereditary ATIII deficiency being treated for [[thrombosis]] or [[thromboembolism]].


===Allosteric activation===
During clinical investigation of antithrombin III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving antithrombin III became antibody positive to [[human immunodeficiency virus]] ([[HIV]]-1). None of 14 subjects monitored for ≥ 3 months demonstrated any evidence of [[hepatitis]], either non-A, non-B [[hepatitis]] or [[hepatitis B]].
Increased Factor IXa and Xa inhibition requires the minimal heparin pentasaccharide sequence. The conformational changes that occur within antithrombin in response to pentasaccharide binding are well documented.<ref>{{cite journal | author = Schreuder HA, de Boer B. ''et al''. | title = The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions | journal = Nat. Struct. Biol. | year=1994 | volume=1 | issue=1 | pages=48-54 | id = PMID 7656006}}</ref><ref>{{cite journal | author = Carrell RW, Stein PE.''et al''. | title = Biological implications of a 3 A structure of dimeric antithrombin | journal = Structure | year=1994 | volume=2 | issue=4 | pages=257-270 | id = PMID 8087553}}</ref><ref>{{cite journal | author = Whisstock JC, Pike RN. ''et al''. | title = Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparindagger | journal = J. Mol. Biol. | year=2000 | volume=301 | issue=5 | pages=1287-1305 | id = PMID 10966821}}</ref> Shown below are two [[X-ray crystallography|crystal structure]]s for antithrombin. Model '''A''' is taken from the [[Protein Data Bank|pdb]] file [http://www.pdb.org/pdb/explore/explore.do?structureId=2ANT 2ANT] and model '''B''' from pdb file [http://www.pdb.org/pdb/explore/explore.do?structureId=1AZX 1AZX]. Model '''B''' is complexed with a pentasaccharide while model '''A''' is uncomplexed.
|howSupplied=Antithrombin III is supplied in a kit containing one single use vial of Antithrombin III lyophilized powder, one vial of Sterile Water for Injection, USP, one sterile double-ended transfer needle, and one sterile filter needle. The total activity of ATIII in International Units is stated on the label of the Antithrombin III vial.


[[Image:Antithrom+heparin.jpeg|center|300px]]
[[image:Antithrombin III 04.png|500px|left]]
{{clr}}
|storage=Antithrombin III should be stored at temperatures not to exceed 25°C (77°F). Freezing should be avoided as breakage of the diluent bottle might occur.
|alcohol=Alcohol-Antithrombin III interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=


The conformational change most relevant for Factor IXa and Xa inhibition occurs within the [[N-terminus|N-terminal]] portion of the reactive site loop and is circled in model '''B''' above. This region has been termed the hinge region and it has been shown that by preventing the normal extension of this region in response to heparin binding, increased Factor IXa and Xa inhibition does not occur.<ref name=Langdown/> It is thought that the increased flexibility given to the reactive site loop as a result of the hinge region conformational change is a key factor in influencing increased Factor IXa and Xa inhibition.
Thrombate III


===Non-allosteric activation===
|nlmPatientInfo=(Link to patient information page)
Increased thrombin inhibition requires the minimal heparin pentasaccharide plus at least an additional 13 monomeric units.<ref>{{cite journal | author = Petitou M, Herault JP, Bernat A, Driguez PA, ''et al''. | title= Synthesis of Thrombin inhibiting Heparin mimetics without side effects | journal= Nature | year=1999 | volume=398 | pages=417-422 | id= PMID 10201371}}</ref> This is thought to be due to a requirement that antithrombin and thrombin must bind to the same heparin chain adjacent to each other. This can be seen in the series of models below taken from the pdb file [http://www.pdb.org/pdb/explore/explore.do?structureId=1TB6 1TB6]
|drugShortage=Drug Shortage
 
}}
[[Image:Throm+anti+hep_complex.jpeg|center|400px]]
{{LabelImage
 
|fileName=Antithrombin III label.jpg
== Role in disease ==
}}
{{details|Antithrombin III deficiency}}
Evidence for the important role antithrombin plays in regulating normal blood coagulation is demonstrated by the correlation between [[inherited disorder|inherited]] or [[acquired disorder|acquired]] antithrombin deficiencies and an increased risk of any affected individual developing thrombotic disease.<ref>{{cite journal | author = van Boven HH and Lane DA.| title = Antithrombin and its inherited deficiency states | journal = Semin. Hematol. | year=1997 | volume=34 | issue=3 | pages=188-204 | id = PMID 9241705}}</ref> [[Antithrombin deficiency]] generally comes to light when a patient suffers recurrent venous [[thrombosis]] and [[pulmonary embolism]]. Variability across patients in the levels of antithrombin III account for some of the variability in patients' response to [[heparin]].
 
===Acquired antithrombin deficiency===
Acquired antithrombin deficiency may result from a range of disorders such as [[Acute liver failure#Coagulopathy |liver dysfunction (coagulopathy)]], [[sepsis]], or [[premature birth]] or as a result of interventions such as [[surgery|major surgery]] or [[cardiopulmonary bypass]].<ref>{{cite journal | author = Maclean PS and Tait RC. | title = Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options | journal = Drugs | year=2007 | volume=67 | issue=10 | pages=1429-1440 | id = PMID 17600391}}</ref> Smoking and oral contraceptives reduce antithrombin III levels.
 
===Inherited antithrombin deficiency===
Inherited deficiencies in blood antithrombin activity may be due to a low circulating level of structurally and functionally normal antithrombin. In this case typically antithrombin levels and therefore activity may be reduced by 50% compared to normal antithrombin levels.<ref name=Lane>{{cite journal | author = Lane DA, Olds RJ and Thein SL. | title = Antithrombin III: summary of first database update | journal = Nucleic Acids Res. | year=1994 | volume=22 | issue=17 | pages=3556-3559 | id = PMID 7937056}}</ref> This type of deficiency is classified as '''type I antithrombin deficiency'''.
 
Inherited deficiencies may also be the result of a structurally and functionally abnormal antithrombin protein circulating in the blood. In this case levels of antithrombin may be normal but the activity produced by this protein again may be reduced by 50% when compared to normal antithrombin activity levels.<ref name=Lane/> This type of deficiency is classified as '''type II antithrombin deficiency'''.
 
Both type I and type II antithrombin deficiency have been shown to be the result of any one of a number of [[frameshift mutation]]s, [[missense mutation]]s or [[nonsense mutation]]s in the gene that encodes antithrombin.<ref name=Lane/><ref>{{cite journal | author = Lane DA, Ireland H. ''et al''. | title = Antithrombin III: a database of mutations | journal = Thromb. Haemost. | year=1991 | volume=66 | issue=6 | pages=657-661 | id = PMID 1796410}}</ref><ref>{{cite journal | author = Picard V, Nowak-Göttl U. ''et al''| title = Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene | journal = Hum. Mutat. | year=2006 | volume=27 | issue=6 | pages=600 | id = PMID 16705712}}</ref>
 
Renal losses of antithrombin account for an increased risk of [[thrombosis]] in patients with [[nephrotic syndrome]].
 
== Complete Differential Diagnosis of Disorders of Antithrombin III==
=== Increased Antithrombin III ===
* [[Cholestasis]]
* [[Warfarin]] therapy
 
=== Decreased Antithrombin III ===
* [[Coronary artery bypass grafting]]
* [[Cirrhosis]]
* Congenital heterozygous familial AT III deficiency
* [[Disseminated intravascular coagulation]] ([[DIC]])
* [[Heparin]] therapy
* Major surgery
* [[Nephrotic syndrome]]
* [[Oral contraceptive]]s
* [[Premature birth]]
* [[Protein-Losing Enteropathy]] or exudative enteropathy
* [[Sepsis]]
* Surgery involving large wound surfaces
* [[Thrombolysis]]
* [[Hepatic failure]]
* [[Trauma]]
 
==References==
{{reflist|2}}
 
==External links==
* {{MeshName|Antithrombin+III}}
 
== Acknowledgements ==
The content on this page was first contributed by {{CMG}}
 
{{Coagulation}}
{{Serpins}}
{{Alpha globulins}}
{{SIB}}
[[Category:Coagulation system]]
[[Category:Serine protease inhibitors]]
 
[[Category:Cardiology]]
[[Category:Blood tests]]
[[Category:Hematology]]
 
[[de:Antithrombin]]
[[es:Antitrombina]]
[[it:Antitrombina]]
[[pl:Antytrombina]]
[[pt:Antitrombina]]


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Latest revision as of 17:40, 18 August 2015

Antithrombin III
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Disclaimer

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Overview

Antithrombin III is a anti-coagulant that is FDA approved for the {{{indicationType}}} of hereditary antithrombin III deficiency. Common adverse reactions include dizziness, chest discomfort, nausea, dysgeusia, chills.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hereditary Antithrombin III Deficiency
  • Dosage should be determined on an individual basis based on the pre-therapy plasma ATIII level, in order to increase plasma ATIII levels to the level found in normal human plasma (80-120%).
  • Dosage of antithrombin III can be calculated from the following formula:
  • The recommendations for dosing are provided as a general guideline for therapy only. The exact loading and maintenance dosages and dosing intervals should be individualized for each subject, based on the individual clinical conditions, response to therapy, and actual plasma ATIII levels achieved.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Antithrombin III in adult patients.

Non–Guideline-Supported Use

Acquired Antithrombin III Deficiency
  • Severe Sepsis[1]
  • Loading dose: 3000 IU (in 1 hour)
  • Maintenance dose: 1500 IU q12h for 5 days.
  • Shock and DIC
  • Dose was based in the following formula: (100 - antithrombin III activity in %) x body weight (kg).
  • Repeat dose if antithrombin III activity fell below 80%.
Heparin Resistance
  • In patients with unstable angina:[2]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Antithrombin III FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Antithrombin III in pediatric patients.

Non–Guideline-Supported Use

Disseminated Intravascular Coagulation
  • Dosing Information
  • Children (1 month to 5 years): 250 units IV q8h, with or without heparin. [3]
  • Newborn infants: 40 units/kg/day + heparin 200 units/kg/day[4]

Contraindications

  • Antithrombin III is contraindicated in patients with hypersensitivity to antithrombin III.

Warnings

  • Because antithrombin III is made from human plasma, it may carry a risk of transmitting infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
  • No cases of transmission of viral diseases or CJD have ever been identified for antithrombin III.
  • Inform patients that antithrombin III is made from human plasma and may contain infectious agents that can cause disease.
  • While the risk that antithrombin III can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing pathogens during manufacturing, patients should report any symptoms that concern them.
  • All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider.
  • The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with antithrombin III.

Adverse Reactions

Clinical Trials Experience

In clinical studies involving antithrombin III, adverse reactions were reported in association with 17 of the 340 infusions during the clinical studies. Included were:

If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate.

Postmarketing Experience

There is limited information regarding Antithrombin III Postmarketing Experience in the drug label.

Drug Interactions

  • The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III in patients with hereditary ATIII deficiency.
  • Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with antithrombin III.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): B Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to antithrombin III. It is not known whether antithrombin III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Antithrombin III in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Antithrombin III during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Antithrombin III in women who are nursing.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.)

Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with antithrombin III of neonates be discussed with an expert on coagulation.

Geriatic Use

There is no FDA guidance on the use of Antithrombin III in geriatric settings.

Gender

There is no FDA guidance on the use of Antithrombin III with respect to specific gender populations.

Race

There is no FDA guidance on the use of Antithrombin III with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Antithrombin III in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Antithrombin III in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Antithrombin III in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Antithrombin III in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.
  • Administer only by the intravenous route.
  • Antithrombin III, once reconstituted, should be given alone, without mixing with other agents or diluting solutions.
  • Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.
Reconstitution

Vacuum Transfer
Note: Aseptic technique should be carefully followed. All needles and vial tops that will come into contact with the product to be administered via the intravenous route should not come in contact with any nonsterile surface. Any contaminated needles should be discarded by placing in a puncture-proof container and new equipment should be used.

  1. Antithrombin III and diluent should be at room temperature before reconstitution.
  2. Remove shrink band from product vial. If the shrink band is absent or shows signs of tampering, do not use the product and notify Grifols Therapeutics Inc. immediately.
  3. Remove the plastic flip tops from each vial (Fig. A). Cleanse vial tops (grey stoppers) with alcohol swab and allow surface to dry. After cleaning, do not allow anything to touch the stopper.
  4. Carefully remove the plastic sheath from the short end of the transfer needle. Insert the exposed needle into the diluent vial to the hub (Fig. B).
  5. Carefully grip the sheath of the other end of the transfer needle and twist to remove it.
  6. Invert the diluent vial and insert the attached needle into the antithrombin III vial at a 45° angle (Fig. C). This will direct the stream of diluent against the wall of the vial and minimize foaming. The vacuum will draw the diluent into the antithrombin III vial.*
  7. When diluent transfer is complete, remove the diluent vial and transfer needle (Fig. D).
  8. Immediately after adding the diluent, swirl continuously until completely dissolved (Fig. E). Some foaming may occur, but attempt to avoid excessive foaming. The vial should then be visually inspected for particulate matter and discoloration prior to administration.
  9. Clean the top of the vial of reconstituted antithrombin III again with alcohol swab and let surface dry.
  10. Attach the filter needle (from the package) to sterile syringe. Withdraw the antithrombin III solution into the syringe through the filter needle (Fig. F).
  11. Remove the filter needle from the syringe and replace with an appropriate injection or butterfly needle for administration. Discard filter needle into a puncture-proof container.
  12. If the same patient is using more than one vial of antithrombin III, the contents of multiple vials may be drawn into the same syringe through the filter needles provided.
  • If vacuum is lost in the antithrombin III vial during reconstitution, use a sterile syringe to remove the sterile water from the diluent vial and inject it into the antithrombin III vial, directing the stream of fluid against the wall of the vial.
Rate of Administration

The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 10 to 20 minutes is generally well tolerated.

Monitoring

  • It is recommended that following an initial dose of Antithrombin III, plasma levels of ATIII be initially monitored at least every 12 hours and before the next infusion of Antithrombin IIII to maintain plasma ATIII levels greater than 80%.
  • Measure preinfusion and 20 minutes postinfusion (peak) plasma ATIII levels following the initial loading dose, plasma ATIII level after 12 hours, then preceding the next infusion (trough level).
  • Subsequently measure ATIII levels preceding and 20 minutes after each infusion until predictable peak and trough levels have been achieved, generally between 80%–120%.
  • Plasma levels between 80%–120% may be maintained by administration of maintenance doses of 60% of the initial loading dose, administered every 24 hours.
  • Adjustments in the maintenance dose and/or interval between doses should be made based on actual plasma ATIII levels achieved.
  • In some situations, e.g., following surgery, hemorrhage or acute thrombosis, and during intravenous heparin administration, the half-life of antithrombin III (Human) has been reported to be shortened. In such conditions, plasma ATIII levels should be monitored more frequently, and antithrombin III administered as necessary.

IV Compatibility

There is limited information regarding the compatibility of Antithrombin III and IV administrations.

Overdosage

There is limited information regarding overdose of antithrombin III in the drug label.

Pharmacology

There is limited information regarding Antithrombin III Pharmacology in the drug label.

Mechanism of Action

Antithrombin III, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin.

Structure

There is limited information regarding the structure of antithrombin III in the drug label.

Pharmacodynamics

Inactivation of thrombin by ATIII occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on ATIII. ATIII is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin.

Pharmacokinetics

There is limited information regarding pharmacokinetics of antithrombin III in the drug label.

Nonclinical Toxicology

There is limited information regarding nonclinical toxicology of antithrombin III in the drug label.

Clinical Studies

In clinical studies of antithrombin III conducted in 10 asymptomatic subjects with hereditary deficiency of ATIII, the mean in vivo recovery of ATIII was 1.6% per unit per kg administered based on immunologic ATIII assays, and 1.4% per unit per kg administered based on functional ATIII assays. The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of ATIII. These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8–4.8 days.

In clinical studies of antithrombin III, none of the 13 patients with hereditary ATIII deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with antithrombin III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures. Eight patients with hereditary ATIII deficiency were treated therapeutically with antithrombin III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with antithrombin III reversed heparin resistance in two patients with hereditary ATIII deficiency being treated for thrombosis or thromboembolism.

During clinical investigation of antithrombin III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving antithrombin III became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored for ≥ 3 months demonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B.

How Supplied

Antithrombin III is supplied in a kit containing one single use vial of Antithrombin III lyophilized powder, one vial of Sterile Water for Injection, USP, one sterile double-ended transfer needle, and one sterile filter needle. The total activity of ATIII in International Units is stated on the label of the Antithrombin III vial.

Storage

Antithrombin III should be stored at temperatures not to exceed 25°C (77°F). Freezing should be avoided as breakage of the diluent bottle might occur.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Antithrombin III Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Antithrombin III interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Thrombate III

Look-Alike Drug Names

There is limited information regarding Antithrombin III Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ B. Eisele, M. Lamy, L. G. Thijs, H. O. Keinecke, H. P. Schuster, F. R. Matthias, F. Fourrier, H. Heinrichs & U. Delvos (1998). "Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis". Intensive care medicine. 24 (7): 663–672. PMID 9722035. Unknown parameter |month= ignored (help)
  2. ↑ M. Rossi, L. Martinelli, S. Storti, M. Corrado, R. Marra, C. Varano & R. Schiavello (1999). "The role of antithrombin III in the perioperative management of the patient with unstable angina". The Annals of thoracic surgery. 68 (6): 2231–2236. PMID 10617008. Unknown parameter |month= ignored (help)
  3. ↑ T. Hanada, T. Abe & H. Takita (1985). "Antithrombin III concentrates for treatment of disseminated intravascular coagulation in children". The American journal of pediatric hematology/oncology. 7 (1): 3–8. PMID 4037242. Unknown parameter |month= ignored (help)
  4. ↑ R. von Kries, H. Stannigel & U. Gobel (1985). "Anticoagulant therapy by continuous heparin-antithrombin III infusion in newborns with disseminated intravascular coagulation". European journal of pediatrics. 144 (2): 191–194. PMID 4043133. Unknown parameter |month= ignored (help)

{{#subobject: 

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