EXPLORING THE ROLE OF ANTITHROMBIN REPLACEMENT FOR THE

TREATMENT OF PREECLAMPSIA

By:
Dr. Indra

PPDS 1 Obstetry and Gynaecology

Medical Faculty of Sebelas Maret University / dr. Moewardi Hospital Surakarta
2015

CHAPTER I
INTRODUCTION

Antithrombin III (henceforth referred to as antithrombin or AT) is a 58-kDa molecule

belonging to the serine protease inhibitor (serpin) superfamily that plays a central role in
anticoagulation and in regulating appropriate wound healing in mammalian circulation
systems. It blocks our blood clotting mechanism by inactivating the major clotting protein
thrombin. It is, therefore, called anti-thrombin. While antithrombin III was the original
name given to this protein, the correct name now is just antithrombin, with the III dropped.
Common names and abbreviations for the same protein are antithrombin, antithrombin III,
AT, ATIII, and heparin cofactor I. As its name implies, antithrombin was first characterized as
an inhibitor of thrombin. Antithrombin also affects other serine proteases of the coagulation
cascade.[3, 4, 5, 6] A diagrammatic representation of the serine proteases with which antithrombin
interacts is shown in the image below. Recent studies have shown that antithrombin also has
anti-inflammatory

actions

that

are

independent

of

its

effect

on

regulating

coagulation.Antithrombin deficiency, which may be congenital or acquired, results in

increased risk for venous thrombosis and, far less commonly, arterial thrombosis.
Pre-eclampsia is a multisystem disorder that complicates 3%8% of pregnancies
in Western countries and constitutes a major source of morbidity and mortality
worldwide. The criteria that defne pre-eclampsia have not changed over the past decade.
These are: onset at >20 weeks gestational age of 24-hour proteinuria 30 mg/day or, if not
available, a protein concentration 30 mg (1+ on dipstick) in a minimum of two random
urine samples collected at least 46 hours but no more than 7 days apart, a systolic blood
pressure >140 mmHg or diastolic blood pressure 90 mmHg as measured twice, using an
appropriate cuff, 46 hours and less than 7 days apart, and disappearance of all these
abnormalities before the end of the 6th week postpartum. Nonetheless, some presentations of
pregnancy-related hypertension combined with clinical or laboratory abnormalities or
intrauterine growth restriction should also be considered as potential pre-eclampsia. Overall,
10%15% of maternal deaths are directly associated with pre-eclampsia and eclampsia.
Some epidemiological fndings support the hypothesis of a genetic and immunological
etiology. The risk of pre-eclampsia is 2-fold to 5-fold higher in pregnant women with a
maternal history of this disorder. Depending on ethnicity, the incidence of pre-eclampsia
ranges from 3% to 7% in healthy nulliparas and 1% to 3%. in multiparas. Moreover,

nulliparity and a new partner have been shown to be important risk factors (Table 1). Other
risk factors have been identified, including a medical history of chronic hypertension,
kidney

disease, diabetes, obesity, birthplace in Africa, age 35 years, and pregnancy

characteristics, such as twin or molar pregnancy, previous pre-eclampsia, or fetal congenital

abnormality. High altitude has also been shown to increase the incidence of pre-eclampsia,
and is attributed to greater placental hypoxia, smaller uterine artery diameter, and lower
uterine artery blood fow. Pre-eclampsia may be life-threatening for both mother and child,
increasing both fetal and maternal morbidity and mortality. In the mother, pre-eclampsia may
cause premature cardiovascular disease, such as chronic

hypertension, ischemic heart

disease, and stroke, later in life, while children born after pre-eclamptic pregnancies and
who are

relatively small at birth, have an increased risk of stroke, coronary heart disease,

and metabolic syndrome in adult life. The sole curative treatment being delivery,
management must continuously balance the riskbeneft ratio of induced preterm delivery and
maternalfetal complications.

Screening women at high risk and preventing recurrences are

also key issues in the management of pre-eclampsia.

Figure 1 Algorithm for antihypertensive treatment of pre-eclampsia.

Note: MBP = [systolic BP + 2 diastolic BP]/3. Abbreviations: MBP, mean blood pressure;
Ci, contraindication; SBP, systolic blood pressure; DBP, diastolic blood pressure.
Women with AT deficiency are at particularly high risk for developing clots during
pregnancy and after delivery. The exact risk of developing blood clots during pregnancy is
impossible to determine accurately. One study showed that only 3 % of pregnancies will be
complicated by a blood clot if no concomitant prophylactic blood thinners are given.
However, other studies have shown that blood clots occur in up to 50 % of pregnancies.
Treatment with heparin injections underneath the skin (subcutaneously) during pregnancy
should strongly be considered to prevent blood clots. However, no well designed clinical
studies exist that allow strong recommendations as to how exactly to treat pregnant women
(dose of heparin; treatment with antithrombin concentrate, etc.). Some physicians recommend
antithrombin replacement therapy during delivery, when heparin may be contraindicated,
since heparin might lead to an increased risk of bleeding. AT concentrate may also be given
for a few days after delivery, together with heparin. Warfarin is not used during pregnancy
because it may cause birth defects. However, for 6-12 weeks postpartum, warfarin should be
considered, because there is a high risk for blood clots in the post-delivery period. A
summary of 45 cases of pregnancy in women with AT deficiency with detailed information
concerning prophylactic therapy with heparin and/or antithrombin has recently been
published. However, no treatment guidelines can be derived from that publication, since
many different regimens were used. Women with AT deficiency also have an increased risk
for pregnancy loss, either early (miscarriage) or late (stillbirth) in the pregnancy. This is
probably due to blood clots forming in the placenta, leading to blockage of blood flow and
oxygen delivery to the fetus. Approximately 1 of 6 pregnancies in women with antithrombin
deficiency (17 %) will end with an early fetal loss, and 1 in 40 pregnancies (2.3 %) will end
with a stillbirth if no blood thinners are given. Therapy with heparin with or without
antithrombin throughout the pregnancy likely decreases that risk.
There have been limited case reports and studies using antithrombin replacement in
the setting of preeclampsia. Buller administered a dose of 2,000 Units of antithrombin
(plasma) concentrate to an antithrombin deficient patient with severe preeclampsia and found
that the antithrombin infusion improved blood pressure, proteinuria and coagulation
parameters. The patient had an uneventful Cesarean delivery. Terao et al (1989) considered
that there was a 40% efcacy in the treated group vs 0% in the untreated group They also
found a correlation between GI and antithrombin activity. Nakabayashi and colleagues
evaluated antithrombin (plasma) replacement vs heparin in early onset severe preeclampsia

with intrauterine fetal growth restriction under 32 weeks and concluded that antithrombin
replacement therapy was useful for improving maternal hypertension and fetal weight in
severe preeclampsia. Kobayashi and colleagues (2005) on a late Phase II study reported
improved uteroplacental circulation found with administration of antithrombin replacement
The optimal dose of antithrombin replacement was 3000 units/ day, which was efcacious and
safe for both mother and fetus. Maki and colleagues (2000) performed that antithrombin
replacement in addition to conventional therapy improved maternal symptoms, improved the
biophysical profle score, prolonged pregnancy and decreased prevalence of very low birth
weight infants

Paternoster (2004)

concluded that the Standard dose of antithrombin

replacement corrects the hemostatic abnormality, while the High dose also corrects
infammatory state

In summary, there is preliminary evidence suggesting a beneft to

antithrombin replacement in the setting of preeclampsia.

CHAPTER II
ANTITHROMBIN
Antithrombin is a complex glycoprotein with multiple pharmacologically important
activities in both the coagulation and infammatory cascades Normal serum AT levels range
between 12 5 15 mg/dL (Murano et al 1980) It is the most critical modulator of coagulation
(Figure 1) and has potent anti-infammatory properties (Figure 2) independent of its efects on
coagulation (reviewed in Roemisch et al 2002)

Antithrombin (AT) concentrates can be therapeutically useful in cases of primary and

acquired AT deficiency; their use, to be reserved to clinical conditions in which low levels of
functional AT are associated with a thrombotic imbalance in haemostasis, has yet to be
supported by clear scientific evidence.
A. Notions of physiology
AT is a glycoprotein synthesised by the liver. Its molecular weight is 58,000 Da
and it circulates in the plasma at a concentration of 150 mg/mL. Belonging to the family
of serpins or inhibitors of serine proteases, it inhibits proteases. AT is the most potent
naturally occurring inhibitor of coagulation and plays a fundamental role in maintaining
haemostatic balance. Furthermore, it has anti-inflammatory and anti-aggregant properties
mediated through the release of prostacyclins from endothelial cells. Normal values of
AT activity in the plasma range from 80% to 120%. In normal conditions its biological
half-life is 1.5-2.5 days; in conditions of acquired deficiency and in the presence of
heparin, the half- life of AT can be notably shorter, being reduced to even a few hours.
B. Preparations of AT
AT concentrates, like all other plasma derivates, are prepared from pools of
human plasma, made from at least 1,000 different donors. Various companies have been
licensed to manufacture this product for clinical use. AT preparations undergo microbial
inactivation by pasteurisation, sometimes followed by nanofiltration. Vials containing
500, 1,000, 1,500 and 2,000 UI are available.
C. Mechanism of action
AT is used as replacement therapy in conditions of acquired or inherited
deficiency, in particular circumstances. Its anticoagulant activity is mainly due to the
inhibition of thrombin, activated factor X (FXa) and, to a lesser degree, also other
activated clotting factors (FIXa, FXIa, FXIIa). The rate of formation of the thrombinantithrombin complex is very greatly increased by heparan sulphate, present on the
surface of endothelial cells. Subjects lacking AT have an increased risk of thrombosis,
particularly in the presence of other thrombophilic conditions.
D. Congenital AT deficiency
The estimated prevalence is 1/2,000-5,000 in the general population and 2-3% in
a selected population of patients with thrombotic event. There are two different types of
congenital deficiency of AT, which are inherited in an autosomal dominant manner:
- TYPE I (quantitative defect), in which there are proportional decreases in the
concentration and, therefore, functional activity of the AT.

- TYPE II (qualitative defect), characterised by normal levels of protein, but a reduction

in its functional activity.
E. Acquired AT deficiency
Various clinical conditions are associated with acquired AT deficiency:
1) Reduced production:
- acute and chronic liver disorders;
- premature neonates;
- treatment with L-asparaginase.
2) Increased excretion/loss:
- protein-losing enteropathy;
- nephrotic syndrome;
- burns.
3) Dilution:
- massive transfusion;
- plasma exchange;
- extracorporeal circulation.
4) Increased consumption:
- disseminated intravascular coagulation (DIC);
- major surgery;
- heparin infusion;
- multiple trauma;
- severe sepsis/septic shock;
- severe thromboembolism;
- haemolytic-uraemic syndrome;
- pre-eclampsia.
F. Indications
The use of AT concentrates, to be reserved to clinical conditions in which low
levels of functional AT are associated with a thrombotic imbalance in haemostasis, has
yet to be supported by clear scientificevidence.
1. Patients with congenital AT deficiency
In the absence of symptoms or risk factors, congenital AT deficiency is not an
indication for replacement therapy with AT concentrates, which should be reserved,
on a temporary basis and in association with heparin therapy, to the following
circumstances (Grade of Recommendation: 2C):

- prophylaxis of deep vein thrombosis and thromboembolism in high-risk conditions:

major surgery, obstetric procedures (such as delivery or abortion), trauma,
immobilisation;
- treatment of ongoing thrombosis, until the indicated level of oral anticoagulation is
reached.
Patients

with

congenital AT deficiency and

repeated

episodes

thromboembolism must receive life-long oral anticoagulant therapy

of

(Grade of

Recommendation: 2C+) (Table I).

2. Patients with acquired AT deficiency
There is little evidence concerning treatment with AT in conditions of acquired
deficiency; replacement therapy with AT may be useful, although the levels of
evidence are not high, in DIC associated with severe sepsis, in which the use of high
doses, not associated with heparin, could improve the survival of patients (Grade of
Recommendation: 2C+).
Further studies are needed on the use of AT concentrates in the case of:
- DIC associated with trauma, burns, pregnancy;
- neonates of mothers with AT deficiency or a family history of severe venous
thromboembolism;
- ongoing thrombosis with low levels of AT and resistance to heparin;
- acute thromboembolism during treatment with L-asparaginase;
- extracorporeal circulation;
- thrombosis of the hepatic artery following orthotopic liver transplantation;
- veno-occlusive disease following bone marrow transplantation;
Furthermore, the use of AT is not generally indicated (given the lack of proof of
clinical efficacy), even when AT levels are considerably below normal, in the following
conditions of chronic, not decompensated deficiency: acute or chronic liver disease,
nephrotic syndrome, protein-losing enteropathy, pre-eclampsia, neonatal respiratory
distress syndrome, multiple trauma and post-operatively in the absence of DIC (Table I).
G. Calculation of the dose of AT to administer
There is no evidence that higher than normal levels of AT provide greater
protection than physiological levels, just as an overdose does not imply an increased risk
of bleeding. Before starting replacement therapy with a specific concentrate, it is
advisable to assay AT functional activity. Given that the administration of 1UI/kg of body

weight increases plasma AT activity by 1.5%, the dose to administered is calculated as

follows:
units of AT = body weight (kg) x [desired level assayed activity(%)]/1.5.
For example:
60 kg x (100 38%)/1.5 = 2,480 UI.
The dose and timing of subsequent administrations are based on the results of
monitoring plasma AT activity every 12-48 h.
H. Monitoring indices for clinical auditing
Use of AT treatment in the following conditions:
- congenital AT deficiency in the absence of symptoms or risk factors and/or with AT
values >70%.
I. Side effects and adverse reactions
AT infusions are generally well tolerated; allergic-type reactions are, however,
possible. The use of AT concentrates contemporaneously with heparin increases the risk
of bleeding and careful clinical and laboratory monitoring is, therefore, necessary,
particularly in patients at high haemorrhagic risk.
J. Recommendations
It is recommended that all the details of the product infused, including its batch
number, are recorded in the clinical records.

CHAPTER III
PREECLAMPSIA
Preeclampsia is most commonly defned by new-onset proteinuria and, potentially,
other end-organ dysfunction. Hypertension and proteinuria are discussed above under
Diagnosis of Hypertension and Management of Proteinuria. Women with preeclampsia
may have a diminished, or no, nocturnal BP decrease. Maternal end-organ dysfunction and
fetal manifestations of preeclampsia illustrated in the Figure are all non-specifc. In this
model of

its origins we describe preeclampsia that arises primarily through imperfect

placentation (early-onset or placental preeclampsia [pink]) or through either a lowered

maternal threshold or excessive physiological placentation (late-onset or maternal
preeclampsia [blue]). Some aspects of the preeclampsia process are specifc to it, while
others are shared with normotensive IUGR. A lowered maternal threshold may also
infuence the development of

early-onset preeclampsia through direct endothelial cell

activation. The consequences of endothelial cell activation that appear consistent between all
women with preeclampsia include a variable impact on multiple vulnerable organ systems.
Disease severity generally correlates with the degree and number of organ dysfunctions.
Fetal manifestations may occur before, with, or in the absence of maternal manifestations.
Table below outlines the end-organ dysfunctions of preeclampsia: adverse conditions
and severe complications. Adverse conditions consist of maternal symptoms, signs, and
abnormal laboratory results, and abnormal fetal monitoring results that may herald the
development of severe maternal or fetal complications (including stillbirth). The adverse
conditions are those that we wait for and respond to (e.g., low oxygen saturation) in an effort
to avoid entirely the severe complications (e.g., pulmonary edema). That response could be
more intensive maternal or fetal monitoring, specifc treatment, or delivery. Severe
maternal complications of preeclampsia warrant delivery.
The adverse conditions are manifestations of preeclampsia that increase the risk of
adverse maternal or perinatal outcomes. Table 3 lists the adverse conditions by maternal
organ system. Of particular importance are preterm preeclampsia, chest pain or dyspnea, and
abnormality of one or more of oxygen saturation by pulse oximetry, platelet count, serum
creatinine, or aspartate transaminase. Proteinuria predicts neither short-term adverse
outcomes nor long-term maternal renal prognosis. HELLP syndrome is represented by its
component parts (hemolysis, elevated liver enzymes, and low platelets), to which we react to
by initiating delivery.

How maternal adverse conditions may predict fetal or neonatal outcomes in

preeclampsia is unclear. The perinatal literature suggests that abnormal fetal monitoring of
various types may identify increased fetal risk. The biophysical profle has unproven utility in
high risk women, and may falsely reassure with early-onset IUGR or preeclampsia.
Currently, there is no single fetal monitoring test to accurately predict fetal
compromise in women with preeclampsia. Most experts suggest a combination of tests, with
emphasis on umbilical artery Doppler when there is IUGR.
Other non-specifc risk factors for severe complications of preeclampsia are
immigrant status, young maternal age, nulliparity, lower maternal weight, and in the index
pregnancy, multiple pregnancy and early-onset preeclampsia.
Defnitions of severe preeclampsia vary, but most include multi-organ involvement.
We modifed our defnition of severe preeclampsia to preeclampsia associated with one or
more severe complications. Severe preeclampsia now warrants delivery regardless of
gestational age. Our defnition excludes heavy proteinuria and HELLP syndrome, which

are not absolute indications for delivery, and includes stroke and pulmonary edema, which
are leading causes of maternal death in preeclampsia.

A transient hypertensive effect is not associated with an increased risk of adverse

outcomes. White-coat effect in early pregnancy (~30%) is common. Forty percent of women
progress to persistent hypertension at 20 weeks (i.e., gestational hypertension) and 8% to
preeclampsia. Women with white-coat effect have risks (e.g., severe hypertension, preterm
delivery, and NICU admission) intermediate between normotension and either pre-existing or
gestational hypertension.
Masked hypertension in early pregnancy (~30%) is also common, but associated
perinatal risks are unknown. Outcomes with masked hypertension at 20 weeks (~10%)
equate to those of gestational hypertension. Masked hypertension could be considered (and
ambulatory or home BP monitoring performed) if there are unexplained maternal or perinatal
complications typically associated with the HDPs.

CHAPTER IV
EXPLORING THE ROLE OF ANTITHROMBIN REPLACEMENT FOR THE
TREATMENT OF PREECLAMPSIA

From the medical research described in the literature, it is clear that preeclampsia is a
multifactorial disorder that involves both the cardiovascular and infammatory systems Due
to its pleiotropic nature as an anticoagulant and anti-infammatory agent, AT has been
suggested as a potential treatment to ameliorate this disorder. Antithrombin (AT) replacement
has been described in patients with hereditary AT deciency undergoing delivery; however,
the kinetics of AT replacement in preeclampsia is not adequately understood. If one considers
the various features of the preeclamptic state and the potential impact that AT treatment might
provide on these features (Table 1), it is clear that the anti-infammatory properties of AT
would most likely provide the most beneft in this disorder

However, one cannot

underestimate the damage that thrombin and microthrombi play in placental damage and
maternal cardiovascular damage.

Women with AT deficiency are at particularly high risk for developing clots during
pregnancy and after delivery. The exact risk of developing blood clots during pregnancy is
impossible to determine accurately. One study showed that only 3 % of pregnancies will be
complicated by a blood clot if no concomitant prophylactic blood thinners are given.
However, other studies have shown that blood clots occur in up to 50 % of pregnancies.
Treatment with heparin injections underneath the skin (subcutaneously) during pregnancy
should strongly be considered to prevent blood clots. However, no well designed clinical
studies exist that allow strong recommendations as to how exactly to treat pregnant women
(dose of heparin; treatment with antithrombin concentrate, etc.). Some physicians recommend
antithrombin replacement therapy during delivery, when heparin may be contraindicated,
since heparin might lead to an increased risk of bleeding. AT concentrate may also be given
for a few days after delivery, together with heparin. Warfarin is not used during pregnancy
because it may cause birth defects. However, for 6-12 weeks postpartum, warfarin should be
considered, because there is a high risk for blood clots in the post-delivery period. A
summary of 45 cases of pregnancy in women with AT deficiency with detailed information
concerning prophylactic therapy with heparin and/or antithrombin has recently been
published. However, no treatment guidelines can be derived from that publication, since
many different regimens were used. Women with AT deficiency also have an increased risk
for pregnancy loss, either early (miscarriage) or late (stillbirth) in the pregnancy. This is
probably due to blood clots forming in the placenta, leading to blockage of blood flow and
oxygen delivery to the fetus. Approximately 1 of 6 pregnancies in women with antithrombin
deficiency (17 %) will end with an early fetal loss, and 1 in 40 pregnancies (2.3 %) will end
with a stillbirth if no blood thinners are given. Therapy with heparin with or without
antithrombin throughout the pregnancy likely decreases that risk.
Hallmarks of preeclampsia include aberrant trophoblast invasion, endothelial cell
dysfunction, and activation of the coagulation cascade; decreased AT levels have also been
noted. Weiner et al. measured AT levels near term in hypertensive patients (i.e., those with
chronic hypertensive preeclampsia or chronic hypertension with superimposed preeclampsia)
and reported that mean S.E. AT activity level was 60 15% in preeclamptic patients, 68
16% in patients with superimposed preeclampsia, and 85 15%in control patients.With a
cutoff of 70%, the negative predictive value for preeclampsia was 89%, andwith a cutoff of
<70%, the positive predictive value for preeclampsiawas 80%. Antithrombin possesses a
number of properties that make it a potentially attractive therapy for pre-eclampsia. As a
therapeutic agent, it has potent anti-coagulant and anti-inammatory properties.

Plasma-derived AT (e.g., Thrombate and Talecris Grifols, Research Triangle Park,

NC, USA) and recombinant AT (ATryn; GTC Biotherapeutics, Framingham, MA, USA) are
available for consideration in future clinical trials, given their approval by the United States
Food and Drug Administration for other indications in pregnancy. Plasma-derived AT has
been administered as a treatment for preeclampsia in several small clinical trials, with success
in improving both perinatal and maternal outcomes. There are no studies of recombinant
human antithrombin (rhAT) in the treatment of preeclampsia.
Antithrombin III (Human) Dosage and Administration
General

Monitor antithrombin III concentrations periodically to individualize dosage and

assess response to therapy.1 (See Laboratory Monitoring under Cautions.)

Suggested dosage recommendations are general guidelines.1

Individualize dosage and duration of therapy based on clinical situation (e.g.,

indication for treatment, patients clinical condition and past history, type and extent
of surgery or obstetrical procedure), clinical judgment, response to therapy, actual
antithrombin III plasma concentrations achieved, and desired plasma concentrations.1

Administration
IV Administration
For solution and drug compatibility information, see Compatibility under
Stability. Prior to administration, allow reconstituted solution to warm to room
temperature.Administer by IV infusion over 1020 minutes.
Reconstitution
Prior to reconstitution, allow manufacturer-supplied diluent to warm to room
temperature. Reconstitute lyophilized powder with diluent provided by manufacturer.
Use strict aseptic technique since drug contains no preservative. Reconstitute single-use
vials of lyophilized powder by adding 10 or 20 mL of sterile water for injection without
preservatives to vial containing approximately 500 or 1000 units of drug, respectively,
using transfer needle provided by manufacturer.1 Direct stream of diluent at 45-degree
angle against side of vial to minimize foaming. Gently swirl to avoid foam formation and
dissolve powder completely. Withdraw reconstituted solution from vial(s) using filter
needle provided by manufacturer.1 Before administration, remove filter needle and attach
injection or butterfly needle.

Rate of Administration
Individualize infusion rates based on patient response. Administration of entire
dose in 1020 minutes usually well tolerated.
Dosage
Potency expressed in international units (units) as tested against activity of WHO
reference standard. One unit approximately equivalent to amount of antithrombin III (mg) in
1 mL of pooled human plasma from healthy donors. Specific activity of antithrombin III is
6.99 units of antithrombin III per mg of protein.
Number of units of antithrombin III indicated on label of each vial.
Use clinical response and laboratory tests to guide dosage calculations. (See
Laboratory Monitoring under Cautions.)
Determine preinfusion (baseline) antithrombin III concentration and calculate initial
(loading) dosage using following formula:
Initial Dose (units) = (desired antithrombin III concentration - baseline antithrombin
III concentration [% of normal] wt (in kg) 1.4
Formula based on expected incremental in vivo recovery (increase) of antithrombin
III concentrations above baseline values of 1.4% for each unit/kg administered (functional
activity).
For example, to increase antithrombin III plasma concentrations to 120% of normal
from a baseline antithrombin III plasma concentration of 57% of normal, the total initial dose
of antithrombin III for a 70-kg adult would be 3150 units.
Following initial dose, subsequent dose based on recovery (increase) of antithrombin
III plasma concentrations resulting from initial dose. Base adjustments of maintenance
dosage and/or dosage interval on actual antithrombin III plasma concentrations achieved.
Adults
IV Infusion
Initial (loading) dose: Administer appropriate dose to increase plasma antithrombin III
concentration to a suggested level of 120% of normal using above formula.
Following initial dose, determine plasma antithrombin III concentrations 20 minutes
postinfusion (peak concentration), 12 hours after administration, and before next infusion
(trough concentration) to ensure plasma antithrombin III concentrations >80% of normal. If
plasma antithrombin III concentration at 12 hours <80% of normal, administer additional

antithrombin III (using the same formula used to calculate the initial dose) to achieve plasma
concentration >80% of normal.
Maintenance dosage: Determine preinfusion (trough) and peak postinfusion
antithrombin III concentrations and administer additional doses of antithrombin III at
appropriate intervals (e.g., every 24 hours) until peak and trough concentrations are
maintained within therapeutic range (i.e., steady state), generally 80120% of normal.
In general, approximately 60% of initial loading dose every 24 hours required to
maintain steady-state plasma antithrombin III concentrations within 80120% of normal.
(See Laboratory Monitoring under Cautions.)
Continue therapy for 28 days following thromboembolism or surgical or obstetric
procedure, depending on clinical situation. (See General under Dosage and Administration.)

CHAPTER V
SUMMARY
Pre-eclampsia is a rare pregnancy-related disease with an unpredictable course
that can have serious consequences for both the mother and the fetus. The treatment is
simple, ie, delivery. Nonetheless, induced preterm delivery requires careful weighing of
both maternal and fetal risk-beneft. Accordingly, identifying delivery criteria in case of preeclampsia is crucial to optimal

management. Current research focuses on the prediction

of onset of pre-eclampsia or even severe pre-eclampsia so as to allow early management and

improve the morbidity and mortality associated with this disease. Specifc tools for
secondary prevention must also be developed for recurrent pre-eclampsia.In summary, it is
clear that AT, in addition to its central role in the coagulation cascade, has potent antiinfammatory activities Since the anti-infammatory properties of AT are mediated through its
interaction with heparin-like receptors such as syndecan-4, located on endothelial surfaces
and leukocytes, supra-physiological doses are necessary to achieve a signifcant efect.
A signifcant body of research, both non-clinical and clinical, has demonstrated the
signifcant anticoagulant and potent
limited

anti-infammatory properties of antithrombin

non-clinical and clinical studies have shown the potential for

More

AT therapeutic

treatment of women with preeclampsia As suggested in a number of the clinical studies cited
above, the next step is the use of antithrombin in a well-controlled, randomized clinical study
in women with preeclampsia.
The published studies do suggest a beneft to antithrombin replacement in
preeclampsia. A high quality trial is needed to address the many questions raised by these
provocative preliminary studies.

REFERENCES