Interpretation of Antithrombin
III Activity
C/E
Update: by Mary Ann McGann, MT(ASCP), and
Hematology I Douglas A. Triplett, MD
Antithrombin III (AT III) is the primary in-
hibitor of the physiologic anticoagulation
system and thus serves a crucial role in main-
taining hemostatic balance and control. An-
tithrombin III levels appear to correlate well
when assessing an individual's predisposi-
tion to thrombosis, thereby providing the
physician with a vital tool in assessing a po-
tential prethrombotic state. The function of
AT III, its role in a variety of clinical situa-
tions, and its place in the diagnosis and man-
agement of patients prior to or during
thrombotic episodes are discussed. Various
methods for measuring AT III, including re-
cent developments in substrate assays, are
summarized.
Importance of Antithrombin III
(AT III)
Despite the fact that antithrombin ac-
tivity was first observed more than 80
years ago, the role of inhibitors in blood
coagulation has not been well appre-
ciated. If there were no inhibitors to
modulate the amplification system of
blood coagulation, it w o u l d be virtually
impossible to maintain the fluidity of
blood in vivo. Consequently, there are
several defense systems designed to i n -
hibit activated serine proteases and to
confine the coagulation response to the
site of injury. Normal plasma contains an
intricate system of inhibitors capable of
inhibiting activated serine proteases of
the coagulation, fibrinolytic, c o m p l e -
ment, and kinin systems (Table I). The
most important of these protease inhib-
From the itors is AT III.
Department of
Hematology, Ball
Memorial Hospital,
Physiology of AT III
Muncie, Indiana.
AT III is an alpha-2 globulin w i t h
a molecular weight of approximately
742 0007-5027/82/1200/742 $01.20 © American Society of Clinical Pathologists
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65,000 daltons and a half-life of 96 hours
in the circulation. It is a glycoprotein
containing approximately 15% carbo-
hydrate. AT III appears to be synthesized
in the liver, although recent w o r k sug-
gests that endothelial cells may be a
source of AT III as well. 1
In normal plasma, AT III is present in
concentrations of 23-40 m g / d L , al-
though this varies w i t h age and sex.
W o m e n between the ages of 19 and 60
years, for example, have slightly lower
AT 111 levels than younger or older
w o m e n . In men, AT III levels have been
found to decrease slightly w i t h age,
especially after the age of 60. 2 AT III
forms an inactive complex by binding
irreversibly in a 1:1 ratio w i t h an activated
enzyme (thrombin, Xa, etc). Therefore,
the functional activity of AT III is deter-
mined by the amount of t h r o m b i n i n -
hibited by a plasma or serum sample. The
value for functional AT 111 activity is ex-
pressed as a percentage based on a stan-
dard plasma pool considered to have
100% activity. The normal functional
range varies from laboratory to labora-
tory due to various collection proce-
dures and sample-handling techniques,
but is generally considered to be ap-
proximately 75-125%. 3 The serum AT III
activity is approximately 3 5 % less than
that of plasma.4 Although there are no
definitive guidelines, it appears that lev-
els between 50 and 7 5 % indicate a m o d -
erate risk for thrombosis, and levels less
than 50% indicate a significant risk.
The biochemistry of AT III is important
not only in terms of normal physiology,
but also in understanding the pharma-
cology of heparin. In addition to t h r o m -
 added, heparin has little or no an-
Table 1—Major Inhibitors of Plasma Proteolysis
ticoagulant effect.
Plasma Inhibitor of
Concen- Congenital Deficiency of AT III
tration Fibrin- Comple-
(mg/dL) Clotting olysis Kinins ment Familial AT III deficiency was
first described in 1965 by Ege-
a 1 Antitrypsin 250 ± + +
a 2 Macroglobulin 250 berg. 5 Several generations of
+* +* +* —
C esterase inhibitor 25 + + + + a family w i t h recurrent ve-
AT III 20 + + + — nous thromboembolism were d e -
a 2 Antiplasmin 5 ? ++ ? ? scribed in conjunction with a
plasma antithrombin concentra-
* Partial inhibitor.
tion that averaged 4 0 % of normal.

AT III deficiency is inherited as

an autosomal dominant trait with
(I) SERINE PROTEASE-ANTiTHROMBIN III incomplete penetrance. 6 Fagerhol
and Abildgaard have estimated
that the prevalence of AT III d e -
ficiency in the Norwegian p o p u -
lation approaches one in 2,000,
while Rosenburg suggests f r o m
clinical experience that the prev-
HEPARIN
alence of this disorder in the Mas-
sachusetts population is compa-
rable. 7 It has been estimated that
as many as 2 % of clinical p u l m o -
nary emboli may be due to AT III
III) INACTIVATION OF SERINE PROTEASE
deficiency. Affected individuals
HEPARIN frequently experience the onset
of clinical t h r o m b o t i c disease at
a relatively early age; there have
been reports of t h r o m b o t i c epi-
sodes in the pediatric age range. 8,9

Individuals with hereditary AT

III deficiency have activity levels
ranging from 35 to 6 0 % of normal,
with decreased or normal antigen
levels. 10 Because these individuals
have deficient quantities of this
major physiologic inhibitor, any
Fig 1. The effect of heparin on AT III. Heparin will accelerate the inactivation
stress situation that increases
of active serine proteases by antithrombin III. t h r o m b i n generation, such as sur-
gery, pregnancy, trauma, or infec-
center, containing arginine, more t i o n , may precipitate a t h r o m b o t i c
bin, AT III inhibits all of the acti-
available to the active serine site episode. Clinically, hereditary AT
vated serine proteases of the co-
of t h r o m b i n and the other active III deficiency is characterized by
agulation system: factors Xlla, Xla,
serine proteases of the coagula- an increased thromboembolic risk.
IXa, Xa, and possibly factor Vila.
tion system. Thus, heparin admin- The sites of thrombosis have been
Normally, AT III is a weak inhibi-
istered even in small doses c o n - located mostly in the veins of the
tor, but as illustrated in Fig 1, h e p -
verts AT III f r o m a relatively in- lower half of the body, such as the
arin, which is a highly negatively
effective inhibitor into a fast and iliofemoral vein, the deep veins of
charged mucopolysaccharide, i n -
efficient one (Fig 2). AT III is also the leg, the inferior vena cava, and
teracts with a domain in the AT
known as heparin cofactor, and as the mesenteric vein, often w i t h
III molecule containing a high
the name implies, it is essential for complicating pulmonary emboli. 1 1
concentration of the basic amino
heparin activity both in vivo and Other families have since been
acid lysine. As a result, confor-
in vitro. If AT III is selectively re- reported to exhibit both venous
mational changes occur in the AT
moved from plasma and heparin and arterial t h r o m b o t i c episodes
III molecule, making its active

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 in association w i t h partial d e f i -
ciencies of AT III.
In addition to the quantitative
abnormalities of AT III, sev-
eral qualitative abnormalities have
been reported. Individuals in a
Hungarian family had normal an-
tigenic amounts of AT III, but the
activity was markedly decreased. 12
This abnormal molecule was
named " a n t i t h r o m b i n 111 Buda-
pest." Family members w i t h this
protein exhibited the same symp-
toms as other persons w i t h both
decreased AT III activity and a n -
tigen.
Because this deficiency is p r o b -
ably far more c o m m o n than is
generally realized by practicing
physicians, many cases are missed.
This is an unfortunate c i r c u m -
stance, since the diagnosis can be
readily made on the basis of rel-
atively simple tests in the labora-
tory. Early recognition is impor-
tant in order to institute appro-
priate treatment. Warfarin ther-
apy appears to increase the AT III
activity to normal or near-normal
levels, and is the preferred treat-
ment for patients w i t h recurrent
thrombosis and pulmonary e m -
bolism.
Acquired States with Altered
AT III Activity
Clinical conditions associated
w i t h acquired AT III deficiencies
can be divided into deficiencies
due to decreased p r o d u c t i o n and
those due to increased use of AT
III. Certain drugs also lower AT III
levels. Table II provides a list of
acquired disorders in which d e -
creased AT III levels have been
found.
Since one site of AT III synthesis
appears to be the liver, decreased
levels of both AT III antigen and
activity have been measured in
hepatic diseases such as cirrhosis,
hepatitis, and hepatoma. 13 De-
creased AT III p r o d u c t i o n has also
been observed in arteriovascular
disorders and is often associated
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XII — • X l l a *
/
XI — * - x i a # „
/
IX — » H X a *
V I I I + C a + + + PF
ANTITHROMBIN III
H E PARIN
/
i +4
a
I THROMBIN
FIBRINOGEN — • FIBRIN MONOMER
1 XIII+C a +
STABLE FIBRIN CLOT
Fig 2. Heparin's mode of action (intrinsic system). Antithrombin III will
inhibit all of the serine proteases in a time-dependent manner. The presence
of heparin will significantly accelerate AT Ill's ability to neutralize activated
coagulation enzymes.
with maturity-onset diabetes m e l - ducted on w o m e n receiving these
Iitus. 14 preparations indicated that AT 111
Consumption of AT III is i n - levels decreased f r o m the baseline
creased in disseminated intravas- AT III level by approximately 2 0 -
cular dissemination (DIC), and 30%. 1 6 Subsequently, manufac-
turers reduced the estrogen c o n -
during and after surgery, and p u l -
tent and, in some instances, the
monary embolism, leading to low
AT III levels in these conditions. 1 5 progesterone content as well.
The consumption of AT III is ap- However, it has been suggested
parently secondary to the binding that in w o m e n w h o are older than
of t h r o m b i n and the other p r o - the age of 30 years or w h o have
teases to a n t i t h r o m b i n , with the a positive family history of deep
removal of the complex by the vein thrombosis and pulmonary
reticuloendothelial system. O t h e r embolism, the AT III level should
conditions in which clearance of be evaluated before oral contra-
AT III exceeds p r o d u c t i o n include ceptives are prescribed, and then
protein-losing enteropathy and periodically at three- and six-
massive proteinuria, such as that m o n t h intervals following institu-
observed in nephrotic syndrome. tion of such medication.
Certain drugs are also capable Another important cause of
of decreasing AT III activity, n o - drug-induced AT III depletion is
tably birth control pills containing the use of heparin. Since heparin
estrogen. Initially, the oral contra- accelerates the binding of AT III
ceptives that were available c o n - with coagulation proteases, plasma
tained relatively high concentra- AT III levels may be depleted in
tions of estrogen. Studies c o n - patients treated with continuous
 Dicumarol inhibits the normal
Table II—Decreased Antithrombin III Levels
synthesis of the vitamin I n d e p e n -
Activity Antigen dent factors (II, VII, IX, and X), it
has been proposed that the p r o -
Acquired duction of activated proteases is
Decreased synthesis
reduced and that less AT III is
Cirrhosis D D
Chronic hepatitis D D
used in the formation of anti-
Arteriosclerosis D N thrombin-protease complexes.
Cardiovascular disease D — Consequently, AT III levels may
Maturity-onset diabetes mellitus D — increase up to 4 0 % above normal
Increased utilization but quickly return to pretherapy
Disseminated intravascular coagulation (DIC) D D levels after therapy has been dis-
Pulmonary embolism D D or N continued. Penner et al noted that
Postoperative, postpartum D — patients whose antithrombin lev-
Stroke D — els did not increase following ini-
Protein-losing enteropathy D D
Nephrotic syndrome (massive proteinuria) D D tiation of Dicumarol therapy ap-
Homocystinuria D — pear to be subject to recurrent
thromboembolic complications,
Drug induced
Oral contraceptives (estrogens) D D or N
despite being maintained in an
Heparin D D acceptable anticoagulant range by
Fibrinolysin D D the usual parameters, ie, p r o -
L-asparginase D D t h r o m b i n time results. 18 Thus, in
Miscellaneous disorders these instances, failure t o elevate
Malignancies D N the AT III level may be more
Burns D D meaningful than the standard as-
say for oral anticoagulant activity.
D = Decreased; N = Normal.
Recently, however, it has been
reported that plasma AT III activity
levels remain unchanged in war-
farin-treated patients. 19 Bull et al
Table III—Increased Antithrombin III Levels
suggest that the increase observed
Activity Antigen in patients receiving oral antico-
agulants is probably due to the
Congenital hemorrhagic deficiencies
Hemophilia A and B 1 1 effects of age and underlying dis-
Factor V and factor VIII deficiency 1 1 ease, rather than to the antico-
agulant treatment itself.
Drug induced
Oral anticoagulants 1 N
Progesterones 1 — Increased AT III levels are also
Androgens 1 — noted in congenital hemorrhagic
Renal disease
disorders, such as hemophilia A
Renal transplantation 1 and B, and factors V and VIM d e -
ficiencies. In addition, increased
1 = Increased; N = Normal. AT III levels have been reported
in patients w i t h acute hepatitis,
and following renal transplanta-
tion and administration of p r o -
To date, patients with bleeding gesterone and androgens.
infusion or repeated injections of
heparin during a period of several tendencies due to increased AT
days. Loss of AT III activity has not III activity have not been re- Methodology
been observed in those patients ported. However, increased levels
receiving heparin at infrequent of AT III have been described in Laboratory evaluation of AT III
intervals, eg, hemodialysis pa- several clinical conditions (Ta- levels may aid in the diagnosis,
tients. Other drugs associated with ble III). treatment, or prophylaxis of a
decreased AT III levels include number of conditions. Generally,
therapeutic fibrinolytic agents, as Increased AT III activity was first AT III assays should be performed
well as L-asparginase used in the associated w i t h the administration on any patient w h o presents w i t h
of Dicumarol (Abbott Laborato- a history of recurrent t h r o m -
treatment of acute lymphoblastic
ries, North Chicago, IL).17 Since boembolic episodes. Table IV lists
leukemia.

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 titation of AT III. 20 Crossed I m -
Table IV—When to Measure Antithrombin III
munoelectrophoresis in the pres-
Any patient presenting with a recurrent history of thromboembolic episodes ence of heparin may be used to
Any patient with a strong family history of thrombosis identify antigenically abnormal
Diagnosis and monitoring of disseminated intravascular coagulation (DIC) or deep vein molecules.
thrombosis (DVT)
Patients receiving oral anticoagulant therapy in whom classic prothrombin time monitoring is The biologic assays are all based
not effective on the fact that AT III inhibits ac-
Patients undergoing heparin therapy to determine; 1) if even increased heparin tivated serine proteases. T h r o m -
administration may result in inadequate anticoagulation (low initial AT III); 2) the effect of
bin, or factor Xa, is added in excess
the heparin administration (increasing or decreasing AT III); and 3) decreasing AT III
levels. to the patient's plasma, and the
Women with a positive history of thrombosis and all women older than 30 years of age amount not inactivated by AT III
before prescription of estrogen-containing oral contraceptives is quantitated by a fibrin clot end
Part of a complete preoperative and postoperative screen to test for patients presurgically point or by a synthetic substrate
who are at high risk for thrombosis due to 'ow AT III levels and patients who are at high procedure. In procedures using
risk for thrombosis due to high consumption during surgery (large difference between
the fibrin clot as the end point, a
presurgical and postsurgical plasma AT III levels)
linear relationship exists between
the logarithm of the coagulation
other clinical indications for mea- of hereditary AT III deficiency time (in seconds) and the amount
suring AT III. there is a normal antigen level, but of t h r o m b i n remaining after it has
the antigen is functionally defec- been neutralized by the anti-
As evidenced by Table V, there
tive. t h r o m b i n in the patient's plasma.
are a number of laboratory p r o -
cedures for evaluating AT III. The Immunologic methods are The methods based on the fibrin
t w o major categories of AT III as- based on an antigen-antibody re- clot as an end point have not been
says are those that quantitate the action between the AT III mole- practical for screening large n u m -
immunologically reactive protein cule and a specific antibody. I m - bers of specimens due to the
and those that evaluate the bio- munologic assays include radial time-consuming process of defi-
logic activity in the presence or immunodiffusion (RID), rocket brination. The elimination of the
absence of heparin. It is important Immunoelectrophoresis (Laurell), defibrination step by a dilution
to perform both types of assays, and radioimmunoassay (RIA). Re- technique reduces the fibrinogen
because antigenic activity does cently, laser nephelometric e n d - level, adds convenience, and per-
not necessarily coincide w i t h point methodologies have been mits assays t o be performed rap-
functional activity. In some cases introduced for more rapid quan- idly. 21

Table V—Laboratory Procedures for Evaluating Antithrombin III

Procedure Principle Special Equipment Advantages Disadvantages

Immunologic
Radial immuno- Plasma sample diffuses None required Technically simple; No results for 48
diffusion through agar-containing requires little hours; lacks sensi-
(RID) antibody to AT III, caus- technician time; tivity; requires high
ing formation of precipi- specific; avail- antibody concentra-
tant able in kits tion
Immunoelectro- Plasma is electro- Electrophoresis cham- Specific: more sen- Technically more
phoresis phoresed through aga- ber and power sitive than RID; complex than RID;
(Laurell) rose-containing antibody source crossed Immu- not practical for
to AT III noelectropho- screening large
resis identifies numbers; no result
abnormal mole- until following day;
cules requires high anti-
body concen-
tration
Radioimmu- Plasma incubated with Gamma scintillation Specific: very sen- Requires gamma
noassay (125l) AT III and antibody; counter sitive; same-day counter; involves
antibody-bound AT III is results: practical use of potentially
counted on gamma for large volume hazardous radioac-
counter screening; avail- tive materials; re-
able in kits quires meticulous
technique

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 Table V—Continued
Procedure Principle Special Equipment Advantages Disadvantages

Laser nephelo- Plasma sample incubated Laser nephelometer Specific; same-day Expense; not com-
metric proce- with AT III human antise- results; very mercially available;
dure rum; relative light scatter sensitive limited by natural
units are measured in light-scattering
the laser nephelometer properties of bio-
logic fluids
Functional
Antithrombin Two stages: Waterbath; semiauto- Inexpensive; avail- Defibrination is time-
clotting assay 1) Neutralization of throm- mated coagulation able in commer- consuming and dif-
bin by plasma instrument (op- cially prepared ficult to standard-
2) Clotting of fibrinogen tional) kits ize; nonspecific for
AT III; elevated fi-
brin split products
(FSP) interfere by
inhibiting fibrin poly-
merization
Anti-Xa clotting Two stages: Waterbath; semiauto- More specific than Elevated FSP may in-
assay 1) Neutralization of Xa by mated coagulation antithrombin terfere*
plasma instrument (op- clotting assay; Source of Xa
2) Clotting of substrate tional) available in kits;
plasma by remaining plasma need not
Xa be defibrinated
Amidolytic anti- Two stages: Waterbath; spectro- FSP do not inter- More expensive than
thrombin as- 1) Neutralization of throm- photometer fere; plasma clotting assay
say bin by plasma need not be de-
2) Digestion of synthetic fibrinated; more
substrate by remaining specific than
thrombin (color devel- clotting assay;
opment read at 405 adaptable to
nm) laboratories not
otherwise suited
for coagulation
procedures;
available in kits;
adaptable to au-
tomation
Abbott Quan- Two stages: Quantum I® or other Calculates stan- Expense
tichrom® AT 1) Neutralization of throm- spectrophotometer dard curve;
III bin by plasma plots graphs;
2) Digestion of synthetic computes aver-
substrate by remaining ages; flags ab-
thrombin (color devel- normais; prepro-
opment read at 405 grammed; can
nm) be modified
Fluorometric Two stages: Protopath® Preprogrammed Expense; cannot be
1) Neutralization of throm- modified
bin by plasma
2) Digestion of synthetic
substrate by remaining
thrombin (read fluoro-
metrically)
DuPont Two stages: "aca" Automated; rapid Requires "aca"
"aca" AT III 1) Inactivation of thrombin turnaround;
by plasma STAT capability
2) Hydrolysis of synthetic
ester substrate by re-
sidual thrombin (chro-
mophore absorbs at
452 nm)

* FSP interfere in comprehensive assay, but are diluted out in specific assay.

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 Recently, automated methods
have been made available for test-
ing AT III, employing synthetic
substrates and the "aca" instru-
ment (DuPont, W i l m i n g t o n , DE).22
In the "aca" AT III reaction, hep-
arin combines w i t h AT III, forming
a complex that rapidly inactivates
a proportional amount of human
t h r o m b i n , which has been added
in excess. The residual t h r o m b i n
activity catalyzes the hydrolysis of
a synthetic substrate, a-N-carbo-
benzoxy-L-lysine thiobenzlester
(Z-lys-SBzl). The hydrolysis p r o d -
uct, a-tholuenethiol (SBzl) reacts
further w i t h DTNB [5,5' dithiobis-
(2-nitrobenzoic acid)], producing
a c h r o m o p h o r e . The reaction in
the sequence is:
AT III + Thrombin + Heparin —»
(excess) (excess)
T h r o m b i n - A T lll-Heparin
(inactive complex)
Residual Thrombin
Z-Lys-SBzl -> Z-Lys + SBzl
SBzl + DTNB -> C h r o m o p h o r e
The rate of c h r o m o p h o r e forma-
tion is directly proportional to re-
sidual t h r o m b i n and inversely
proportional to the patient's AT
III level. The synthetic substrate
assays are generally preferred to
the fibrin clot e n d - p o i n t proce-
dures for a number of reasons, i n -
cluding the highly reproducible
results and accuracy relative to
coagulation methodologies.
Therapy
The physician has several o p -
tions, depending on the patient
and clinical setting, when pre-
sented with a patient with d e -
creased AT III levels. Heparin is a
relatively ineffective anticoagu-
lant in the patient w i t h acute
thrombophlebitis; such a patient
should receive an oral anticoagu-
lant. Conversely, in such situations
as the nephrotic syndrome, the
physician might consider the ad-
ministration of fresh frozen plasma
as a source of AT III. In the future,
transfusion with AT III c o n c e n -
trates may be the preferred
7 4 8 LABORATORY
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m e t h o d of treatment, especially boembolic disease. Thus, the d e -
in surgical procedures. Patients termination of AT III is f u n d a m e n -
w i t h DIC have recently been tal to both the evaluation of
treated successfully w i t h AT III t h r o m b o t i c risk and the m o n i t o r -
concentrates that were activated ing of coagulation factor c o n -
in vitro by low doses of heparin. 2 3 sumption in a variety of disease
In a number of the initial patients states leading to t h r o m b o t i c c o m -
so treated, dramatic cessation of plications. W i t h the recognition
the ongoing intravascular coagu- of the role of inhibitors in blood
lation and an improvement to a coagulation and the increased
near normal hemostatic state have availability of AT III concentrates,
been demonstrated. This therapy the measurement of AT III is tak-
is preferred in patients w i t h only ing its place in the clinical labo-
moderately low AT III levels, since ratory among the many proce-
heparin therapy alone may be i n - dures that today are c o m m o n -
effective in the presence of d e - place but only yesterday were
creased AT III levels. regarded as mere research tools.
Summary
References
Thrombotic disease is the most 1. Chan TK, Chan V. Antithrombin III, the major mod-
c o m m o n cause of death in the ulator of intravascular coagulation, is synthesized
western w o r l d . Consequently, re- by human endothelial cell. Thromb Haemost
1981;46:504-506.
searchers have sought to identify
2. Odegard OR, Fagerhol MK, Lie M. Heparin cofac-
certain risk factors in the patient tor activity and antithrombin III concentration in
population that w o u l d allow phy- plasma related to age and sex. Scand J Haematol
sicians to institute prophylactic 1976;17:258-262.
3. Hedner U, Nilsson IM. Antithrombin III in a clinical
measures in patients w h o have an material, 7th European Conference Microcircula-
increased risk of thrombosis. To tion, Aberdeen, Part II. Bibl Anat 1972;12:267-271.
date, AT III deficiency has d e m - 4. Refven O, Fagerhol MK, Abildgaard U. Changes
in antithrombin III following cessation of antico-
onstrated a significant correlation agulant therapy. Acta Med Scand 1973;193:307-
with an increased risk of t h r o m - 309.
Review Questions
Hematology I
• What clinical manifestations might be anticipated in a patient
with hereditary AT III deficiency?
• Patients with nephrotic syndrome may be refractory to the an-
ticoagulant effect of heparin. Explain one possible mechanism.
• Indicate whether AT III activity levels are increased or decreased
for each of the following conditions and the mechanisms in-
volved:
A. Continuous infusion heparin therapy
B. Warfarin therapy
C. Liver disease
D. Protein-losing enteropathy
E. Hemophilia
• In patients with AT III Budapest, would it be more appropriate
to perform immunologic or biologic assays for AT III? Why?
• What is the rationale for administering heparin-activated AT III
concentrates in certain patients with DIC?
• What are the advantages of synthetic substrate assays over assays
based on fibrin clot endpoints for quantitating AT III levels?
 5. Egeberg 0. Inherited antithrombin deficiency
causing thrombophilia. Thrombosis Diathesis Hae-
morrhagia 1965;13:516-530.
6. Barrowcliffe TWA, Johnson EA, Thomas D. Anti-
thrombin III and heparin. Br Med Bull 1978;34:143-
150.
7. Rosenburg RD. Actions and interactions of anti-
thrombin. N Engl J Med 1975;292:146-151.
8. Bjarke B, Herin P, Blomback M. Neonatal aortic
thrombosis. A possible clinical manifestation of
congenital antithrombin III deficiency. Acta Pae-
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