651276

review-article2016
AOPXXX10.1177/1060028016651276Annals of PharmacotherapyBauer et al

Review Article
Annals of Pharmacotherapy

Issues in the Diagnosis and Management

1­–10
© The Author(s) 2016
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of Hereditary Antithrombin Deficiency: sagepub.com/journalsPermissions.nav
DOI: 10.1177/1060028016651276

A Review aop.sagepub.com

Kenneth A. Bauer, MD1, Tam M. Nguyen-Cao, PhD2,

and Jeffrey B. Spears, PharmD2

Abstract
Objective: To review insights gained in the past several years about hereditary antithrombin (AT) deficiency and to
outline approaches to the management of patients with AT deficiency in the acute and chronic settings. Data Sources:
An extensive literature search of Scopus (January 2008-April 2016) was performed for the terms congenital antithrombin
deficiency, inherited antithrombin deficiency, or hereditary antithrombin deficiency. Additional references were identified by
reviewing literature citations. Study Selection: All relevant English-language case reports, reviews, clinical studies,
meeting abstracts, and book chapters assessing hereditary AT deficiency were included. Data Synthesis: AT deficiency
significantly increases the risk of venous thromboembolism (VTE). The risk of VTE is particularly high during pregnancy, the
postpartum period, and following major surgery. Effective clinical management includes determination of the appropriate
type and duration of antithrombotic therapy (ie, AT replacement for acute situations) while minimizing the risk of bleeding.
For persons newly diagnosed with AT deficiency, age, lifestyle, concurrent medical conditions, family history, and personal
treatment preferences can be used to individualize patient management. Patients should be informed of the risks associated
with hormonal therapy, pregnancy, surgical procedures, and immobility, which further increase the risk of VTE in patients
with AT deficiency. Conclusion: AT deficiency poses the highest risk for VTE among the hereditary thrombophilias, often
requiring long-term anticoagulation. Undertaking an evaluation for hereditary thrombophilia is controversial; however, a
diagnosis of VTE in association with AT deficiency can have management implications. An important treatment option for
patients with this disorder in high-risk situations is AT concentrate.

Keywords
hereditary antithrombin deficiency, inherited antithrombin deficiency, antithrombin, treatment management, congenital
antithrombin deficiency

Hereditary antithrombin (AT) deficiency is a rare autoso- Data Sources/Study Selection

mal-dominant disorder that was first described in 1965 by
Egeberg,1 who demonstrated an association between low
plasma AT levels and familial thrombosis. Antithrombin is a
natural anticoagulant that inhibits many of the enzymes gen-
erated by the coagulation cascade. Establishing a diagnosis
of AT deficiency may affect future management regarding
antithrombotic treatment, testing of other family members,
and measures to mitigate other risk factors for thrombosis.
The objective of this review is to discuss insights gained in
the past several years about hereditary AT deficiency and
outline approaches to the management of patients with the
disorder in acute and chronic settings. We will also describe
the history of hereditary AT deficiency; its pathophysiology,
genetics, clinical manifestations, and laboratory diagnosis;
and the associated risk of venous thromboembolism (VTE).
For simplicity, hereditary AT deficiency will be referred to
as AT deficiency throughout the remainder of this article.
A literature search of Scopus (January 2008 to April 2016)
was performed for the terms congenital antithrombin defi-
ciency, inherited antithrombin deficiency, or hereditary
antithrombin deficiency. Additional references were identi-
fied from a review of the literature citations. All English-
language case reports, reviews, clinical studies, meeting
abstracts, and book chapters were included and reviewed
for relevance.
1
Harvard Medical School, Boston, MA, USA
2
Grifols, Research Triangle Park, NC, USA
Corresponding Author:
Kenneth A. Bauer, Department of Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston,
MA 02215-5400, USA.
Email: kbauer@bidmc.harvard.edu

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2 Annals of Pharmacotherapy 
Figure 1.  The coagulation cascade.
Abbreviation: AT, antithrombin.
Mechanism of Action of AT
AT—a natural anticoagulant—is a serine protease inhibitor
(SERPIN) that primarily inactivates multiple enzymes gener-
ated by the coagulation cascade, including factors IIa (throm-
bin), Xa, and IXa and, to a lesser extent, factors XIa and XIIa
as well as kallikrein and plasmin (Figure 1).2,3 Antithrombin
has also been shown to have a subsidiary role to tissue factor
pathway inhibitor in the inactivation of factor VIIa-tissue fac-
tor.4 Antithrombin is synthesized by the liver and also indi-
rectly prevents the activation of protein C by inhibiting
thrombin. Activated protein C forms a complex with free pro-
tein S in the presence of calcium on the activated platelet sur-
face to inhibit factors VIIIa and Va. The proteolysis of factors
VIIIa and Va prevents the activation of factor X and prothrom-
bin, respectively, thereby limiting the generation of thrombin.
The mechanism by which AT functions primarily involves
2 distinct domains on the molecule: an active reactive center
and a heparin-binding site.3,5 The arginine-reactive center of
AT interacts with the active serine site of coagulation prote-
ases. In the absence of heparin or heparan sulfate, AT inhibits
the serine proteases of the coagulation cascade at a relatively
slow rate. When heparin or other heparin-like glycosamino-
glycans (eg, heparan sulfate) bind to the heparin-binding site,
AT undergoes a conformational change that enhances its
inhibitory activity by >1000 fold. This conformational
change, forming a ternary bridging complex, increases the
rate of interaction between AT and thrombin, factor Xa, fac-
tor IXa, and to a lesser extent factor XIa and factor XIIa.
Genetics of AT Deficiency
More than 250 mutations in the AT gene have been reported.6
The AT gene (SERPINC1) is located on chromosome
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1q23–25. It has 7 exons spanning 13.4 kb of DNA. Type I
AT deficiency affects quantitative levels of AT activity3; it is
most commonly caused by missense mutations, frameshift
deletions, nonsense mutations, small (less than 30 base
pairs) insertions and deletions, as well as larger and whole
gene deletions.6 Type II AT is divided into 3 subtypes (IIa,
IIb, and IIc) and is characterized by mutations that affect the
reactive site of AT (type IIa), the heparin-binding domain
(type IIb), and a pleiotropic group of mutations near the
reactive loop that result in decreased AT activity levels
(type IIc).3,6
Risks of Thrombosis With AT
Deficiency
Thrombosis can occur in arterial or venous vessels and is a
complex condition influenced by many factors.7 Arterial
thrombosis occurs rarely in patients with AT deficiency,
because most occlusive events in arteries occur in the set-
ting of underlying arteriosclerosis. It is VTE that is primar-
ily associated with AT deficiency.8,9 VTE is a major health
care burden in the United States. The projected number of
adults with VTE is estimated to increase by >2 fold, from
0.95 million in 2006 to 1.82 million in 2050.10 Based on the
National Hospital Discharge Survey that the Centers for
Disease Control analyzed between 2007 and 2009, the esti-
mated average number of hospitalizations for adult patients
with VTE was 547 596 per year in the United States.11
Antithrombin deficiency significantly increases the risk of
VTE, typically deep-vein thrombosis in the legs or pulmo-
nary embolism.3,12 The estimated prevalence of AT defi-
ciency varies widely, with estimates between 1:500 and
1:5000.13-15 This broad range typifies the difficulties in ascer-
taining the true prevalence of a relatively uncommon disor-
der in the general population with different subtypes. The risk
profile for patients with inherited thrombophilia for VTE is
summarized in Table 1. In the general population, the preva-
lence of AT deficiency13,16 appeared to be lower than that of
protein C deficiency,16-18 protein S deficiency,16,19 factor V
Leiden mutation,20-23 and prothrombin G20210A muta-
tion.24-26 Of the various inherited thrombophilic defects, AT
deficiency poses the strongest risk for the development of
VTE in adults27 and children.28 In an Italian cohort family
study in 723 relatives of 150 index patients with various
thrombophilic defects, Martinelli et al29 found higher risks
for VTE in individuals with AT (conditional risk ratio = 42.8;
95% CI = 10.2–180.3), protein C (31.3; 7.0–138.8) or pro-
tein S deficiency (35.7; 7.9–160.1), and factor V Leiden
mutation (10.1; 2.3–43.7) compared with the normal
population.
Martinelli et al29 also found that for the relatives of
patients with AT, protein S or protein C deficiency, and a
strong family history of VTE (ie, multiple symptomatic
first-degree relatives), the lifelong incidence of VTE is high
Bauer et al 3
Table 1.  Risk Profile of VTE in Patients With Hereditary Thrombophilia.
Protein C
AT Deficiency Deficiency
Prevalence in general 0.02–0.20 0.2–1.5
population (%)13,16-26
Prevalence of VTE (%)16,23,25 1.1 2.7
Risk of VTE, RR (95% CI)29,b 42.8 (10.2–180.3) 31.3 (7.0–138.8)
Abbreviations: AT, antithrombin; DVT, deep-vein thrombosis; NA, data not available; RR, conditional risk ratio adjusted for sex and family status; VTE,
venous thromboembolism.
a
The prevalence of factor V Leiden and prothrombin mutations is dependent on the ethnicity of the population, with relatively higher frequency in
Caucasians but much lower frequency or absent in those of Asian and African descents.
b
VTE data included DVT with or without pulmonary embolism.
at 76.5% versus 3.6% in those without inherited thrombo-
philia, and the annual incidence is 2.82% (95% CI = 1.63–
4.80) compared with 0.10% (0.06–0.17), respectively. The
probability of relatives of AT-deficient patients experienc-
ing their first thrombotic episode can be as high as 50% by
age 50 years.29
In another Italian cohort family study with at least 2 fam-
ily members who were carriers of AT, protein C, and/or pro-
tein S deficiency, Bucciarelli et al30 reported that the
incidence of VTE was associated with age but not with sex.
The mean age at onset was 30 to 40 years for all inherited
thrombophilia defects, and the risk for VTE increased with
age after 20 years but appeared to level off in those older
than 40 years of age. For high-risk situations, VTE occurred
following surgery in 29% of cases, postpartum in 21%,
pregnancy in 18%, immobilization in 11%, and oral contra-
ceptive use in 11%.
A third cohort study, from Amsterdam,31 reported the
annual incidence of an unprovoked VTE in asymptomatic
adults with AT, protein C, or protein S deficiency to be
approximately 10-fold higher than in those with no defi-
ciency (0.40% versus 0.04%, respectively).
The risk of VTE varies by the type of AT deficiency, as
individuals with a defect in heparin-binding site (type IIb)
had been shown to have a lower risk of thrombosis than
those with other variants.32 Interestingly, a recent study sug-
gested that type IIb AT deficiency may be more prevalent
than previously thought, because it may be difficult to
detect.33 In the next sections, we discuss the risks of VTE
associated with pregnancy and those undergoing surgery.
The treatment of children with known AT deficiency and
their long-term management will also be reviewed.
Pregnancy and AT Deficiency
Virchow, in 1856, first postulated 3 main factors that
increase the risk of thrombosis: vessel wall injury, static
blood flow, and hypercoagulability.34 All elements of
Virchow’s triad are associated with pregnancy.35 Blood
flow alterations during pregnancy may result in venous
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Protein S Prothrombin
Deficiency Factor V Leiden Mutation
0.03–1.3 Up to 7a Up to4a
1.1 11.6a 6.2
35.7 (7.9–160.1) 10.1 (2.3–43.7) NA
stasis, and vessel wall injury can occur during childbirth.
All of these factors contribute to an increased risk for mater-
nal thromboembolism.
Thrombosis has been reported to complicate approxi-
mately 37% of pregnancies and deliveries in women with
AT deficiency, with most events occurring postpartum.36 A
recent single-center study in Hungary found a high risk of
maternal VTE and frequent pregnancy complications with
adverse neonatal outcomes in those with AT defects at the
heparin-binding site (type IIb).37 This study suggested that
the type of AT deficiency may play a crucial role in deter-
mining the clinical phenotype of pregnant women.
For pregnant women with no prior VTE who do not have
a positive family history, the 2012 American College of
Chest Physicians Guidelines suggested careful antepartum
and postpartum monitoring rather than anticoagulant pro-
phylaxis.38 However, it was reported that in AT-deficient
patients with recent or recurrent thrombosis, AT administra-
tion during labor was successful in preventing thrombotic
recurrences2; this is a period during which anticoagulation
cannot be safely administered. It has, therefore, been rec-
ommended that women with known AT deficiency receive
AT concentrate prior to delivery and postpartum if they
have recently experienced acute VTE or have a history of
VTE.
A retrospective, multicenter analysis was performed in
Germany, in which >1000 patients with pregnancy-associ-
ated VTE or severe pregnancy complications were screened
for hereditary or acquired thrombophilia.39 A total of 7
patients with AT deficiency were identified with 18 preg-
nancies total, including 11 healthy newborns at ≥37 weeks
of gestation, 1 newborn at 25 weeks of gestation, 2 losses at
21 and 28 weeks of gestation, and 4 early miscarriages.
Three VTE events occurred in these patients during preg-
nancy, and 1 occurred postpartum despite treatment with
low-molecular-weight heparin (LMWH). However, the
study found fewer maternal complications as well as better
neonatal outcomes during pregnancy, delivery, and the
postpartum period when LMWH was used in combination
with AT concentrate administration.
4 Annals of Pharmacotherapy 
Surgery and AT Deficiency
Patients with AT deficiency undergoing surgery have an
increased risk of VTE and other complications, such as
graft failure following vascular surgery.40,41 There are
studies of patients undergoing orthopedic,42,43 bariatric,44
cardiac,40,45-47 and vascular surgery48-50 with regard to the
prevalence and management of AT deficiency, including
recommendations for screening prior to surgery. Although
many of these are case reports, it is important to highlight a
few of these scenarios.
Having AT deficiency does not necessarily exclude patients
from receiving AT concentrate as part of a perioperative anti-
coagulation regimen during neuraxial anesthesia. A recent
case report43 described the successful use of neuraxial anes-
thesia for 2 different total hip arthroplasties in a patient with
AT deficiency. The patient had AT activity levels between
37% and 66% for 12 months before surgery, was taken off
warfarin therapy 4 days prior to surgery, and treated periop-
eratively with enoxaparin and human-derived AT concentrate.
The dosing of AT concentrate was targeted at elevating and
maintaining AT levels at 80% to 120% until long-term antico-
agulation with warfarin was reinstated aiming for an interna-
tional normalized ratio (INR) >2.0, at which time enoxaparin
and AT concentrate were discontinued. In both surgeries, the
patient experienced no VTE or major bleeding events.
With the increase in obesity in the United States, there
has been a rise in bariatric surgery. As with most surgeries,
patients undergoing bariatric surgery are at increased risk of
VTE. One institution investigated routine thrombophilia
screening to develop a more rational approach to risk strati-
fication for VTE in bariatric surgery.44 Whereas the preva-
lence of patients with AT deficiency undergoing bariatric
surgery was 1% to 3% compared with 0.02% to 0.17% in
the general population, the investigators also found that
other clotting analytes, such as factor VIII, factor IX, factor
XI, D-dimer, and fibrinogen, were significantly elevated.
Therefore, patients with abnormal screening coagulation
tests were recommended for presurgery VTE screening in
addition to follow-up thrombophilia evaluation.
Clark et al46 reported on 3 cases of AT deficiency in
patients undergoing coronary artery bypass surgery that were
managed successfully with a preoperative AT loading dose of
([120 − initial AT activity] × 0.6 × kg body weight) IU of AT
concentrate on the evening before surgery, followed by 50%
to 60% of the loading dose to maintain AT activity between
80 IU/dL and 120 IU/dL for 5 to 7 days postoperatively. In
addition to AT therapy, all 3 patients received postoperative
heparin as part of a prophylaxis protocol, and none experi-
enced thromboembolic complications.
Pediatrics and AT Deficiency
Given the risk of VTE in relatives of patients with heredi-
tary thrombophilia, including AT deficiency, Holzhauer
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et al51 suggested that screening for hereditary thrombophilia
should be done in children with VTE and their first-degree
relatives. Based on their findings, the authors concluded
that appropriate prophylactic measures should be under-
taken with either long-term anticoagulation with vitamin K
antagonists or intermittent anticoagulation during high-risk
periods; they acknowledged that future studies are needed
to evaluate the efficacy and safety of prophylaxis in this
population. In 2008, Young et al28 also demonstrated that
the evaluation for inherited thrombophilia was warranted in
the pediatric population with or at risk for VTE. Their sys-
tematic review and meta-analysis of 35 observational stud-
ies published between 1970 and 2007 showed that the odds
ratio of first VTE in children with AT deficiency was 9.44
(95% CI = 3.34–26.66, P < 0.0001) and that for a recurrent
VTE was 3.01 (1.43–6.33, P = 0.003). Based on these find-
ings, it is appropriate to investigate the cause of unexpected
thrombosis in the pediatric population.
Diagnosis of AT Deficiency
Diagnosis of AT deficiency is usually suspected if one has
a family history of VTE and decreased plasma AT levels.
With decreased levels of AT, a patient can become heparin
resistant, meaning that they will not respond as expected
to heparin, even at high doses. Heparin resistance may be
a sign that a patient who has experienced a VTE may have
underlying AT deficiency. Acquired AT deficiency should
be ruled out by ensuring that there is no condition present
associated with AT deficiency. Causes of potential
acquired AT deficiency include the following clinical
scenarios3,52:
1. Decreased synthesis of AT (eg, liver disease, malnu-
trition, neonatal status)
2. Increased AT excretion (eg, nephrotic syndrome,
irritable bowel syndrome, protein-losing enteropa-
thy, diabetes)
3. Accelerated AT consumption (eg, disseminated
intravascular coagulation, surgery, burns, pre-
eclampsia, hemolytic-uremic syndrome)
4. Drug-induced depletion of AT (eg, heparin, l-aspar-
aginase, monomethoxypolyethylene glycol aspara-
ginase, oral contraceptives)
5. Extracorporeal circulation (eg, plasmapheresis,
hemodialysis, cardiopulmonary bypass, extracor-
poreal membrane oxygenation, systemic lupus ery-
thematosus, Behçet vasculitis, after prothrombin
complex concentrate infusion, malignancy, aging)
Individuals with AT deficiency may have decreased hep-
arin sensitivity if AT levels drop sufficiently, requiring
AT replacement for a sufficient anticoagulant effect of
heparin.14,53 When individuals with AT deficiency become
resistant to heparin therapy, they often require higher doses
Bauer et al 5
of heparin and may also require AT supplementation to achieve
a level of anticoagulation that is protective from developing
progressive thrombosis or a new thromboembolic event.
Functional assays to diagnose AT deficiency include
chromogenic activity assays, in which patient plasma is
incubated in the presence of heparin with excess thrombin
or factor Xa. Antithrombin in the plasma, catalyzed by the
heparin, reacts with and neutralizes thrombin or factor Xa.
The amount of thrombin or factor Xa that is not neutralized
is inversely proportional to the patient’s AT activity level,
which is quantified using an automated chromogenic detec-
tion system.3 These types of functional assays may not dis-
tinguish type IIa from type IIb AT deficiency, which is
characterized by impaired binding of AT and heparin.
Detection of type IIb involves an AT activity assay per-
formed in the absence of heparin or mutation analysis with
gene sequencing. Antigenic assays are a quantitative mea-
sure of the amount of AT present in an individual’s plasma
and are useful once a functional assay has been performed
to define the type of AT deficiency.
Genetic analysis is useful to further classify AT defi-
ciency. In a comparison of activity assays and direct genetic
analysis to identify individuals with AT deficiency, a study
identified 16 patients who had decreased AT activity and
confirmed 13 mutations in 14 patients.54
In 2010, Khor and Van Cott55 as well as Margetic56
developed diagnostic algorithms for thrombophilia screen-
ing in patients presenting with VTE. Khor and Van Cott’s
algorithm was based on AT activity and other factors, such
as whether there was a direct thrombin inhibitor, heparin
therapy, or evidence of acquired AT deficiency.55 Their
algorithm recommends repeated testing at a later date if a
patient is diagnosed with type I or type II AT deficiency
and to consider testing relatives. Margetic’s algorithm
involves performing a series of steps that consider a
patient’s age, recurrent thrombosis, family history, unusual
site of thrombosis, and environmental risk factors for
VTE.56 It then follows 2 diagnostic steps based on the
negative or positive response to the test. Algorithms such
as these determine the utility of screening patients present-
ing with VTE who have a higher probability of having
hereditary thrombophilia.
Controversy in Testing for AT
Deficiency
There is no consensus as to which patients should be
assessed for hereditary thrombophilia.57 AT deficiency is an
important, albeit uncommon, genetic risk factor for VTE,
and the decision whether to test should be made judiciously.
The clinical presentation of each individual as well as risk
factors for VTE must be considered and/or assessed when
determining if a patient should be tested for AT deficiency.
Controversy exists with regard to routine testing for the
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presence of hereditary thrombophilia. Additional informa-
tion detailing the controversy can be found in the literature,
including recommendations for9,51,55,58-60 and against61-64 as
well as a middle-ground approach.65 Many experts suggest
that testing be performed in patients with certain character-
istics, such as in a first-degree family member with AT defi-
ciency. Because AT deficiency is uncommon (<1%) in the
general population, the chance of misdiagnosing AT defi-
ciency has been postulated to be higher than the chance of
detecting a true inherited deficiency because of issues
related to laboratory testing and the chance of a laboratory
false positive.62,66 Other considerations include acquired
deficiencies in which low levels of AT may also occur.52,61,67
Reduced levels of AT can also occur postoperatively and
during the postpartum period.68 Plasma levels of AT are
physiologically low in healthy newborns, increase rapidly
over the first 6 months of life, and appear to reach “normal”
levels at about 1 year of age.61,69,70
Benefits of testing include finding a major risk factor for
thrombosis, use of anticoagulant treatment to prevent recur-
rent thrombosis, implementation of preventive strategies in
high-risk situations, and the possibility of testing and find-
ing family members who may be at risk.59,61 The potential
downsides of testing include potential diagnostic errors that
may lead to false-positive or false-negative test results;
adverse effects, including increased bleeding risk associ-
ated with the use of primary prophylactic anticoagulation
therapy in patients with incorrect diagnoses; and the psy-
chosocial burden of disease.61
There are additional issues surrounding testing for AT
deficiency in asymptomatic children identified through
screening of families with an affected proband. In children,
prophylactic anticoagulation is not always administered in
high-risk situations, such as immobilization or following
major surgery or trauma, because the overall risk of recur-
rent thrombosis is lower in children than in adults.61 Also,
as noted previously, plasma levels of AT are naturally low in
healthy neonates after birth and increase to normal levels
over the first year or so of life; age-related pediatric normal
ranges for AT are not widely available or validated. As in
adults, low levels of AT may occur in children during hepa-
rin therapy, liver disease, nephrotic syndrome, and several
other conditions.
Timing of thrombophilia testing is an important factor
to consider. Patients should not undergo thrombophilia
testing in acute settings (eg, during an acute VTE or while
anticoagulant therapy is being administered), because
these can lead to abnormal test results.57,71 Therefore,
additional tests need to be repeated at a later time to con-
firm a diagnosis of thrombophilia. Moreover, the manage-
ment of an acute thrombosis, especially if the event
follows a major surgery, does not change within the short
term (ie, first 3 months), regardless of the presence or
absence of thrombophilia.
6 Annals of Pharmacotherapy 

Table 2.  Administration and Pharmacokinetics of AT Concentrates.a,73,75,76

pdAT rhAT
Administration IV infusion over 10 to 20 minutes IV infusion over 15 minutes immediately followed
by continuous infusion of the maintenance dose
Pregnancy Dosing
  Loading (IU) ([Desired (%) − Baseline AT (%)] × kg ([100 − Baseline AT (%)]/1.3) × kg BW
BW)/1.4
  Maintenance (IU) Approximately 60% of initial dose given ([100 − Baseline AT (%)]/5.4) × kg BW given per
every 24 hours hour
 Adjustments Based on maintaining AT activity levels of Based on AT activity level 2 hours after initial
80% to 120%, with initial monitoring done treatment
at least every 12 hours and before the • If <80%, increase dose by 30% and recheck 2
next infusion hours after each adjustment
• If 80% to 120%, do not adjust and recheck 6
hours after initial treatment or dose adjustment
• If >120%, decrease dose by 30% and recheck 2
hours after each adjustment
Perioperative Dosing
  Loading (IU) Same as for pregnancy ([100 − Baseline AT %]/2.3) × kg BW
  Maintenance (IU) Same as for pregnancy ([100 − Baseline AT]/10.2) × kg BW given per hour
 Adjustments Same as for pregnancy Same as for pregnancy
Duration of treatment 2 to 8 days Until adequate follow-on anticoagulation can be
established
Half-life 92 hours (3.8 days) 11.6 to 17.7 hours
Excretion  
Kidney clearance <10% NA
Total body clearance NA 7.2 to 9.6 mL/h/kg

Abbreviations: AT, antithrombin; BW, body weight; IU, international unit; NA, not available; pdAT, plasma-derived AT; rhAT, recombinant human AT.
a
Baseline percentage AT levels are expressed as percentage of normal AT activity level based on functional AT assay.

Management of Patients With AT Each product exhibits distinct pharmacokinetic proper-

Deficiency
Surgery, immobilization, and pregnancy are some of the
additional risk factors for thrombosis that warrant consid-
eration of prophylaxis with AT concentrate in patients
with AT deficiency and prior VTE or a family history of
VTE.72 Additionally, in the event of acute VTE and/or
heparin resistance, AT replacement therapy can be used
along with heparin in the hospital.73,74 In rare circum-
stances, a patient with AT deficiency may need AT supple-
mentation as an ambulatory patient while also receiving
LMWH.
Food and Drug Administration-approved AT replace-
ment products include a human plasma-derived AT (pdAT;
Thrombate III, Grifols)75 and a recombinant human AT
(rhAT; ATryn, rEVO Biologics)76 produced from the milk of
genetically engineered goats (Table 2). Antithrombin con-
centrates are indicated to prevent thrombotic complications
during or following pregnancy and surgical procedures.
Additionally, Thrombate III is also approved for use in
treating or preventing thromboembolism in patients with
AT deficiency.75 In these situations, the goal is to raise the
AT activity level to normal (80%–120%).73-76
ties (Table 2), which should be considered when choosing
the appropriate treatment option.75,76 Plasma-derived AT
concentrate is given intravenously at an initial dose calcu-
lated based on pretherapy plasma AT activity level.75 The
initial dose is given over 10 to 20 minutes, and AT activity
should be initially monitored at 12 hours after the initial
dose and before the next infusion. The dosing interval is
once daily to maintain trough AT activity of at least 80%,
which is made possible as a result of the long half-life of
pdAT. Maintenance doses can be adjusted depending on the
AT levels of each individual.
Recombinant human AT is indicated for the prevention,
not treatment, of perioperative and peripartum thromboem-
bolic events in AT-deficient patients.76 Unlike pdAT, the
half-life of rhAT is much shorter and requires administra-
tion via continuous infusion (Table 2). The difference in
half-life between the 2 products is likely a result of post-
translational glycosylation differences. Antithrombin activ-
ity should be monitored and the dose adjusted accordingly.
The decision to treat with either pdAT or rhAT should be
made on a case-by-case basis, with careful consideration of
the duration and total dosage of therapy.77 Table 3 presents
2 hypothetical scenarios illustrating the recommended

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Bauer et al 7

Table 3.  Hypothetical Case Scenarios Illustrating Recommended Doses of pdAT Versus rhAT Concentrates.75,76

pdAT rhAT
a
Pregnancy case
  Loading dose ([120% − 49%] × 79 kg)/1.4 = 4006 IU ([100% − 49%]/1.3) × 79 kg = 3099 IU
  Maintenance dose 4006 IU × 60% = 2404 IU ([100% − 49%]/5.4) × 79 kg = 746 IU per hour
  Total first 24 hours 4006 IU 21 003 IU
  Total 3 days 8814 IU 56 811 IUb
Perioperative casec
  Loading dose ([120% − 53%] × 84 kg)/1.4 = 4020 IU ([100% − 53%]/2.3) × 84 kg = 1717 IU
  Maintenance dose 4020 IU × 60% = 2412 IU ([100% − 53%]/10.2) × 84 kg = 387 IU per hour
  Total first 24 hours 4020 IU 11 005 IU
  Total 3 days 8844 IU 29 581 IU

Abbreviation: AT, antithrombin; DVT, deep-vein thrombosis; IU, international unit; pdAT, plasma-derived AT; rhAT, recombinant human AT.
a
A 28-year-old pregnant woman admitted for full-term labor and delivery; the patient was diagnosed with inherited AT deficiency after DVT at age 22
years. AT activity level was 49%, and body weight at admission was 79 kg.
b
Total 3-day dosages for the pregnancy case assume that the same regimen is required postpartum as during pregnancy or delivery.
c
A 54-year-old man with mitral valve insufficiency and documented inherited AT deficiency undergoing mitral valve replacement; preadmission AT
activity level was 53%, and body weight at admission was 84 kg.

doses of pdAT and rhAT concentrates used to treat a periop-
erative case and a pregnancy case. The total recommended
doses required of each AT concentrate (in IU) are shown for
the first 24 hours and for 3 days of treatment.
For pregnant women with AT deficiency who develop
thromboembolism, LMWH and/or unfractionated heparin
administered subcutaneously is typically administered for
the duration of the pregnancy. For pregnant women who
have a high-risk profile for VTE (ie, prior VTE or very
compelling family history) with AT level <60% and those
with very low AT levels <40%,2 AT concentrate should be
given immediately before and during (if rhAT is used)
childbirth when other anticoagulants cannot be given.
As mentioned previously, surgery is associated with a tran-
sient decrease in AT activity level and increased thrombotic
risk. Antithrombin replacement in patients with AT deficiency
provides sufficient thromboprophylaxis in concert with a pro-
phylactic heparin regimen when warfarin is halted for
surgery.3,78
Disease Management Issues in AT
Deficiency
Anticoagulant therapy is required for AT-deficient patients
who have thromboembolic events. Long-term clinical man-
agement of patients with AT deficiency involves consider-
ation of a number of factors, including the optimal regimen
and duration of treatment, along with balancing the associ-
ated risk of bleeding.68
The ultimate goal for a patient with AT deficiency is to
maintain a near-normal life without the threat of VTE. For
the person newly diagnosed with AT deficiency who experi-
ences an acute event, treatment decisions for long-term man-
agement to prevent recurrence are typically based on medical
history, prior VTE history, number and type of thrombophilic
genetic defects, and patient preference. The risk of VTE
recurrence can vary among patients. Antithrombin concen-
trate is rarely given in the outpatient setting but may be nec-
essary during pregnancy when a patient is not responding to
LMWH. It may also be necessary if an ambulatory patient is
intolerant of oral therapy and is not responding well to
LMWH.
Warfarin (targeting an INR of 2-3) is generally effective
for preventing recurrent unprovoked VTE. Patients who toler-
ate warfarin tend to stay on warfarin, given the current lack of
experience with direct oral anticoagulants (DOACs) in highly
prothrombotic patient populations. Warfarin is, thus, the pre-
ferred agent for long-term management of AT deficiency
because of the extensive experience with warfarin in this pop-
ulation and the ability to reliably monitor anticoagulant ther-
apy. One issue to keep in mind when administering warfarin,
however, is the risk of major hemorrhage if warfarin therapy
is not well controlled. Poor disease control on warfarin may
indicate nonadherence with therapy. One might presume that
these nonadherent patients may be candidates for DOACs;
however, in reality, the lack of mandatory laboratory follow-
up with DOACs as opposed to warfarin may actually lead to
worse disease control. Until data in patients with AT defi-
ciency become available, warfarin is the best option for high-
risk patients. The use of warfarin and INR monitoring works
well in outpatient settings, particularly in difficult-to-treat
patients. Antithrombin concentrate can be given in addition to
anticoagulants for the treatment or prevention of acute epi-
sodes in certain difficult-to-manage cases, when the need
arises. An individual treatment plan is needed for every case.
Conclusions
Antithrombin is a natural anticoagulant that inactivates
several activated factors of the coagulation cascade.

Downloaded from aop.sagepub.com at CAMBRIDGE UNIV LIBRARY on June 11, 2016

8 Annals of Pharmacotherapy 
Antithrombin deficiency is a rare but serious genetic con-
dition that can result in a significantly increased risk of
venous thrombosis. Thromboprophylaxis with AT concen-
trate is recommended in high-risk clinical settings, includ-
ing surgery, pregnancy, and the peripartum period.
Acknowledgments
The authors wish to acknowledge Latoya M. Mitchell, PhD,
CMPP, for conducting the initial literature search.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Kenneth A. Bauer has consulted for Instrumentation
Laboratory, Daiichi Sankyo, Bristol-Meyers Squibb, and Janssen
Pharmaceuticals. Tam M. Nguyen-Cao and Jeffrey Spears are
employees of Grifols; Latoya Mitchell was a former employee of
Grifols. Grifols is a manufacturer of antithrombin concentrate.
There are no other relevant conflicts of interest.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
References
1. Egeberg O. Thrombophilia caused by inheritable deficiency
of blood antithrombin. Scand J Clin Lab Invest. 1965;17:92.
2. James AH, Konkle BA, Bauer KA. Prevention and treatment
of venous thromboembolism in pregnancy in patients with
hereditary antithrombin deficiency. Int J Womens Health.
2013;5:233-241.
3. Patnaik MM, Moll S. Inherited antithrombin deficiency: a
review. Haemophilia. 2008;14:1229-1239.
4. Agerso H, Brophy DF, Pelzer H, et al. Recombinant human
factor VIIa (rFVIIa) cleared principally by antithrombin fol-
lowing intravenous administration in hemophilia patients. J
Thromb Haemost. 2011;9:333-338.
5. Tanaka KA, Levy JH. Regulation of thrombin activity—
pharmacologic and structural aspects. Hematol Oncol Clin
North Am. 2007;21:33-50.
6. Bayston T, Lane D. Antithrombin Mutation Database.
London, UK: Imperial College of London; 2013.
7. Foy P, Moll S. Thrombophilia: 2009 update. Curr Treat
Options Cardiovasc Med. 2009;11:114-128.
8. Kim RJ, Becker RC. Association between factor V Leiden,
prothrombin G20210a, and methylenetetrahydrofolate reduc-
tase C677t mutations and events of the arterial circulatory
system: a meta-analysis of published studies. Am Heart J.
2003;146:948-957.
9. Mahmoodi BK, Brouwer JL, Veeger NJ, van der Meer J.
Hereditary deficiency of protein C or protein S confers
increased risk of arterial thromboembolic events at a young
age: results from a large family cohort study. Circulation.
2008;118:1659-1667.
10. Deitelzweig SB, Johnson BH, Lin J, Schulman KL.
Prevalence of clinical venous thromboembolism in the
Downloaded from aop.sagepub.com at CAMBRIDGE UNIV LIBRARY on June 11, 2016
USA: current trends and future projections. Am J Hematol.
2011;86:217-220.
11. Centers for Disease Control and Prevention. Venous throm-
boembolism in adult hospitalizations—United States, 2007-
2009. MMWR Morb Mortal Wkly Rep. 2012;61:401-404.
12. Di Minno MN, Ambrosino P, Ageno W, Rosendaal F, Di
Minno G, Dentali F. Natural anticoagulants deficiency and
the risk of venous thromboembolism: a meta-analysis of
observational studies. Thromb Res. 2015;135:923-932.
13. Tait RC, Walker ID, Perry DJ, et al. Prevalence of antithrom-
bin deficiency in the healthy population. Br J Haematol.
1994;87:106-112.
14. Thaler E, Lechner K. Antithrombin III deficiency and throm-
boembolism. Clin Haematol. 1981;10:369-390.
15. Wells PS, Blajchman MA, Henderson P, et al. Prevalence
of antithrombin deficiency in healthy blood donors: a cross-
sectional study. Am J Hematol. 1994;45:321-324.
16. Koster T, Rosendaal FR, Briet E, et al. Protein C deficiency in
a controlled series of unselected outpatients: an infrequent but
clear risk factor for venous thrombosis (Leiden thrombophilia
study). Blood. 1995;85:2756-2761.
17. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of pro-
tein C deficiency in the healthy population. Thromb Haemost.
1995;73:87-93.
18. Miletich J, Sherman L, Broze G Jr. Absence of thrombosis
in subjects with heterozygous protein C deficiency. N Engl J
Med. 1987;317:991-996.
19. Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. A
study of protein S antigen levels in 3788 healthy volunteers:
influence of age, sex and hormone use, and estimate for prev-
alence of deficiency state. Br J Haematol. 2001;113:636-641.
20. Rees DC. The population genetics of factor V Leiden
(Arg506gln). Br J Haematol. 1996;95:579-586.
21. Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke
JP, Bertina RM. Venous thrombosis due to poor anticoagulant
response to activated protein C: Leiden thrombophilia study.
Lancet. 1993;342:1503-1506.
22. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood
coagulation factor V associated with resistance to activated
protein C. Nature. 1994;369:64-67.
23. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ,
Eisenberg PR, Miletich JP. Mutation in the gene coding for
coagulation factor V and the risk of myocardial infarction,
stroke, and venous thrombosis in apparently healthy men. N
Engl J Med. 1995;332:912-917.
24. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic dis-
tribution of the 20210 G to a prothrombin variant. Thromb
Haemost. 1998;79:706-708.
25. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common
genetic variation in the 3’-untranslated region of the prothrombin
gene is associated with elevated plasma prothrombin levels and
an increase in venous thrombosis. Blood. 1996;88:3698-3703.
26. Ridker PM, Hennekens CH, Miletich JP. G20210a muta-
tion in prothrombin gene and risk of myocardial infarction,
stroke, and venous thrombosis in a large cohort of US men.
Circulation. 1999;99:999-1004.
27. Coppola A, Tufano A, Cerbone AM, Di Minno G. Inherited
thrombophilia: implications for prevention and treatment
Bauer et al 9
of venous thromboembolism. Semin Thromb Hemost.
2009;35:683-694.
28. Young G, Albisetti M, Bonduel M, et al. Impact of inherited
thrombophilia on venous thromboembolism in children: a
systematic review and meta-analysis of observational studies.
Circulation. 2008;118:1373-1382.
29. Martinelli I, Mannucci PM, De Stefano V, et al. Different
risks of thrombosis in four coagulation defects associated
with inherited thrombophilia: a study of 150 families. Blood.
1998;92:2353-2358.
30. Bucciarelli P, Rosendaal FR, Tripodi A, et al. Risk of venous
thromboembolism and clinical manifestations in carriers of
antithrombin, protein C, protein S deficiency, or activated
protein C resistance: a multicenter collaborative family study.
Arterioscler Thromb Vasc Biol. 1999;19:1026-1033.
31. Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous
thromboembolism in families with inherited thrombophilia.
Thromb Haemost. 1999;81:198-202.
32. Finazzi G, Caccia R, Barbui T. Different prevalence of
thromboembolism in the subtypes of congenital antithrom-
bin III deficiency: review of 404 cases. Thromb Haemost.
1987;58:1094.
33. Orlando C, Heylen O, Lissens W, Jochmans K. Antithrombin
heparin binding site deficiency: a challenging diagnosis of a not
so benign thrombophilia. Thromb Res. 2015;135:1179-1185.
34. Virchow R. Phlogose und Thrombose in Gefasssystem.
In: Virchow R, ed. Gesammelte Abhandlungen Zur
Wissenschaftlichen Medizin. Frankfurt, Germany: Von
Meidinger Sohn; 1856:458-636.
35. Carbone JF, Rampersad R. Prenatal screening for throm-
bophilias: indications and controversies. Clin Lab Med.
2010;30:747-760.
36. De Stefano V, Leone G, Mastrangelo S, et al. Thrombosis
during pregnancy and surgery in patients with congenital
deficiency of antithrombin III, protein C, protein S. Thromb
Haemost. 1994;71:799-800.
37. Ilonczai P, Olah Z, Selmeczi A, et al. Management and out-
come of pregnancies in women with antithrombin deficiency:
a single-center experience and review of literature. Blood
Coagul Fibrinolysis. 2015;26:798-804.
38. Guyatt GH, Akl EA, Crowther M, et al. Executive summary:
antithrombotic therapy and prevention of thrombosis, 9th ed:
American College of Chest Physicians evidence-based clini-
cal practice guidelines. Chest. 2012;141:7S-47S.
39. Rogenhofer N, Bohlmann MK, Beuter-Winkler P, et al.
Prevention, management and extent of adverse pregnancy
outcomes in women with hereditary antithrombin deficiency.
Ann Hematol. 2014;93:385-392.
40. Kfoury E, Taher A, Saghieh S, Otrock ZK, Mahfouz R. The
impact of inherited thrombophilia on surgery: a factor to con-
sider before transplantation? Mol Biol Rep. 2009;36:1041-1051.
41. Flinn WR, McDaniel MD, Yao JS, Fahey VA, Green D.
Antithrombin III deficiency as a reflection of dynamic protein
metabolism in patients undergoing vascular reconstruction. J
Vasc Surg. 1984;1:888-895.
42. Salvati EA, Della Valle AG, Westrich GH, et al. The John
Charnley Award: heritable thrombophilia and development
of thromboembolic disease after total hip arthroplasty. Clin
Orthop Relat Res. 2005;441:40-55.
Downloaded from aop.sagepub.com at CAMBRIDGE UNIV LIBRARY on June 11, 2016
43. Piper BJ, Farrell PT. Hereditary antithrombin III defi-
ciency and neuraxial anaesthesia. Anaesth Intensive Care.
2015;43:782-785.
44. Overby DW, Kohn GP, Cahan MA, et al. Prevalence of
thrombophilias in patients presenting for bariatric surgery.
Obes Surg. 2009;19:1278-1285.
45. Kitahara H, Kudo M, Okamoto K, Inaba Y, Sasaki A, Shimizu
H. Management of right atrial hemangioma in a patient with
antithrombin deficiency. Ann Thorac Surg. 2015;99:e53-e55.
46. Clark P, Walker ID, Neilson RF. Coronary artery bypass sur-
gery in patients with inherited antithrombin deficiency. Br J
Haematol. 1995;90:479-482.
47. Wang YQ, Chen QL, Zhu D, Dong L. Portal vein thrombosis
after aortic valve replacement surgery in a patient with anti-
thrombin III deficiency: case presentation. J Cardiothorac
Surg. 2014;9:73.
48. Jackson MR, Olsen SB, Gomez ER, Alving BM. Use of anti-
thrombin III concentrates to correct antithrombin III deficiency
during vascular surgery. J Vasc Surg. 1995;22:804-807.
49. Kelly MD, Rosenfeld D, Leslie GJ. Venous surgery in patients
with congenital antithrombin III deficiency. Aust N Z J Surg.
1994;64:865-868.
50. Tengborn L, Bergqvist D. Surgery in patients with congeni-
tal antithrombin III deficiency. Acta Chir Scand. 1988;154:
179-183.
51. Holzhauer S, Goldenberg NA, Junker R, et al. Inherited
thrombophilia in children with venous thromboembolism and
the familial risk of thromboembolism: an observational study.
Blood. 2012;120:1510-1515.
52. Maclean PS, Tait RC. Hereditary and acquired antithrom-
bin deficiency: epidemiology, pathogenesis and treatment
options. Drugs. 2007;67:1429-1440.
53. Marciniak E, Farley CH, DeSimone PA. Familial thrombosis
due to antithrombin 3 deficiency. Blood. 1974;43:219-231.
54. Zeng W, Tang L, Jian XR, et al. Genetic analysis should be
included in clinical practice when screening for antithrombin
deficiency. Thromb Haemost. 2015;113:262-271.
55. Khor B, Van Cott EM. Laboratory tests for antithrombin defi-
ciency. Am J Hematol. 2010;85:947-950.
56. Margetic S. Diagnostic algorithm for thrombophilia screen-
ing. Clin Chem Lab Med. 2010;48:S27-S39.
57. Moll S. Thrombophilia: clinical-practical aspects. J Thromb
Thrombolysis. 2015;39:367-378.
58. Franchini M. The utility of thrombophilia testing. Clin Chem
Lab Med. 2014;52:495-497.
59. Whitlatch NL, Ortel TL. Thrombophilias: when should we
test and how does it help? Semin Respir Crit Care Med.
2008;29:25-39.
60. Muszbek L, Bereczky Z, Kovács B, Komáromi I. Antithrombin
deficiency and its laboratory diagnosis. Clin Chem Lab Med.
2010;48:S67-S78.
61. Heleen Van Ommen C, Middeldorp S. Thrombophilia
in childhood: to test or not to test. Semin Thromb Hemost.
2011;37:794-801.
62. Favaloro EJ, McDonald D, Lippi G. Laboratory investiga-
tion of thrombophilia: the good, the bad, and the ugly. Semin
Thromb Hemost. 2009;35:695-710.
63. Favaloro EJ. The futility of thrombophilia testing. Clin Chem
Lab Med. 2014;52:499-503.
10 Annals of Pharmacotherapy 
64. Tientadakul P, Chinthammitr Y, Sanpakit K, Wongwanit C,
Nilanont Y. Inappropriate use of protein C, protein S, and
antithrombin testing for hereditary thrombophilia screen-
ing: an experience from a large university hospital. Int J Lab
Hematol. 2011;33:593-600.
65. Lijfering WM, Brouwer JLP, Veeger NJGM, et al.
Selective testing for thrombophilia in patients with first
venous thrombosis: results from a retrospective family
cohort study on absolute thrombotic risk for currently
known thrombophilic defects in 2479 relatives. Blood.
2009;113:5314-5322.
66. Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton
L. Laboratory identification of familial thrombophilia: do
the pitfalls exceed the benefits? A reassessment of ABO-
blood group, gender, age, and other laboratory param-
eters on the potential influence on a diagnosis of protein
C, protein S, and antithrombin deficiency and the poten-
tial high risk of a false positive diagnosis. Lab Hematol.
2005;11:174-184.
67. Kottke-Marchant K, Duncan A. Antithrombin deficiency:
issues in laboratory diagnosis. Arch Pathol Lab Med.
2002;126:1326-1336.
68. Kearon C, Crowther M, Hirsh J. Management of patients
with hereditary hypercoagulable disorders. Annu Rev Med.
2000;51:169-185.
69. Monagle P, Barnes C, Ignjatovic V, et al. Developmental
haemostasis. impact for clinical haemostasis laboratories.
Thromb Haemost. 2006;95:362-372.
Downloaded from aop.sagepub.com at CAMBRIDGE UNIV LIBRARY on June 11, 2016
70. Raffini L, Thornburg C. Testing children for inherited throm-
bophilia: more questions than answers. Br J Haematol.
2009;147:277-288.
71. Lim MY, Moll S. Thrombophilia. Vasc Med. 2015;20:193-196.
72. Vossen CY, Conard J, Fontcuberta J, et al. Risk of a first
venous thrombotic event in carriers of a familial thrombophilic
defect. The European Prospective Cohort on Thrombophilia
(EPCOT). J Thromb Haemost. 2005;3:459-464.
73. Schwartz RS, Bauer KA, Rosenberg RD, Kavanaugh EJ,
Davies DC, Bogdanoff DA. Clinical experience with anti-
thrombin III concentrate in treatment of congenital and
acquired deficiency of antithrombin. The Antithrombin III
Study Group. Am J Med. 1989;87:53S-60S.
74. Tiede A, Tait RC, Shaffer DW, et al. Antithrombin alfa in
hereditary antithrombin deficient patients: a phase 3 study
of prophylactic intravenous administration in high risk situ-
ations. Thromb Haemost. 2008;99:616-622.
75. Thrombate III. Antithrombin III (human) [prescribing infor-
mation]. Research Triangle Park, NC: Grifols; 2016.
76. Atryn. Antithrombin (recombinant) [prescribing informa-
tion]. Framingham, MA: Revo Biologics; 2013.
77. Salas CM, Miyares MA. Antithrombin III utilization in a
large teaching hospital. P T. 2013;38:764-779.
78. Paidas MJ, Forsyth C, Quéré I, Rodger M, Frieling JTM,
Tait RC. Perioperative and peripartum prevention of venous
thromboembolism in patients with hereditary antithrombin
deficiency using recombinant antithrombin therapy. Blood
Coagul Fibrinolysis. 2014;25:444-450.