PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIPS
Clin. Pharmacokinet. 22 (5): 359-374, 1992
03.12-5963/92/0005-0359/$08.00/0
© Adis International Limited. All rights reserved.
CPK1
Heparin Pharmacokinetics and Pharmacodynamics
Robert J. Kandrotas
Department of Pharmacy Practice, College of Pharmacy, University of Utah,
Salt Lake City, Utah, USA
Contents
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Summary
Summary
I. Physiology and Biochemistry of Heparin
1.1 Unfractionated Heparin
1.2 Low Molecular Weight Heparin
2. Assays
3. Pharmacokinetics
3.1 Administration and Bioavailability
3.2 Distribution
3.3 Clearance
4. Pharmacokinetics and Other Physiological States
4.1 Effects of Age
4.2 Pregnancy
4.3 Thromboembolic Disease
4.4 Renal Disease
4.5 Hepatic Disease
5. Pharmacodynamics
5.1 Anticoagulant Versus Antithrombotic Activity
5.2 Variability of Response
6. Clinical Implications
6.1 Clinical Use of Heparin
6.2 Therapeutic Monitoring
6.3 Adverse Effects
7. Conclusions
Heparin was discovered approximately 75 years ago and has been used extensively for the
last 50 years to treat thromboembolic disorders. An endogenous glycosaminoglycan, heparin is
found largely in the liver, lung and intestine. It is available for exogenous administration both
as unfractionated and low molecular weight heparin. Unfractionated heparin is a heterogenous
mixture of polysaccharide chains of varying length resulting in a range of molecular weights from
3000 to 30 OOOD while low molecular weight heparin ranges from 3000 to 6000D. Heparin produces its anti thrombotic effect by binding to antithrombin III and this complex then binds to
thrombin. In order to accomplish this a total of 18 to 22 monosaccharide units is necessary
including a specific pentasaccharide binding site for antithrombin III. After either subcutaneous
or intravenous injection heparin is distributed primarily within the intravascular space. A short
distribution phase is seen which is thought to correspond to endothelial cell binding and inter-
360
Clin. Pharmacokinet. 22 (5) 1992
nalisation. The disposition curve for unfractionated heparin has a unique concave-convex shape
which is the result of combined saturable and nonsaturable elimination mechanisms. The nonsaturable elimination mechanism is renal and is the primary route of elimination for low molecular weight heparins. For this reason, the concave-convex pattern is not seen with low molecular weight preparations. Both forms of heparin are useful anti thrombotic agents; however,
the correlation between the anti thrombotic effect and an in vitro laboratory test for either type
still needs further clarification.
The discovery of heparin was first reported by
J McLane, a second year medical student at Johns
Hopkins University approximately 75 years ago
(McLane 1916). It was named and further described by WH Howell, in whose laboratory
McLane was working at the time of his discovery
(Howell & Holt 1918). It was not until the 1940s
that heparin began to be used extensively in the
clinical setting. Despite its extensive clinical use
over the past 50 years, very little was known regarding its structure and the mechanism by which
it produces its antithrombotic effect. In fact, it is
only in the past 25 years that our knowledge of the
nature of heparin significantly increased. This is a
result of technological developments in the areas
of biochemistry and pharmacology which have become available during that time.
1. Physiology and Biochemistry
of Heparin
Heparin is one of a number of glycosaminoglycans synthesised endogenously and stored in the
basophilic granules of mast cells, which are found
in most tissues of mammalian species. The greatest
concentrations are found in the liver, lung and intestine (Nader et al. 1980; Straus et al. 1982). Heparin produces its anticoagulant and antithrombotic
effects indirectly by binding to antithrombin III
(also known as AT-III, antithrombin and heparin
cofactor). Heparin accelerates the interaction between AT-III and various serine proteases in the
clotting cascade (fig. 1) [Rosenberg 1975]. Activated factor X (Xa) and thrombin (lIa) are the
principal factors responsible for clot formation.
1.1 Unfractionated Heparin
Commercially available heparin is isolated primarily from bovine lung and porcine intestinal
mucosa and until recently was only available as
unfractionated heparin (UFH). UFH preparations
consist of a heterogenous mixture of polysaccharide chains of varying length ranging in molecular
weight from about 3000 to 30 OOOD. The structure
of the heparin binding site for AT -III is depicted
in figure 2. This pentasaccharide is the minimal
number of monosaccharide units necessary to accomplish the binding of heparin to AT -III (Choay
et al. 1981; Sinay et al. 1984; Thunberg et al. 1982).
Rosenberg and Damus (1973) determined that
the binding of AT-III to thrombin occurs in a 1 : 1
stoichiometric ratio. These investigators found that
adding heparin to their in vitro system resulted in
an accelerated rate of thrombin inhibition without
changing the stoichiometric relationship. They
proposed that the binding of heparin to AT-III results in a conformational change which allows the
heparin/AT-III complex to bind to various clotting
factors including factor Xa and thrombin. AT-III
binds irreversibly to thrombin by a covalent bond
(Owen 1975); once bound to thrombin, its affinity
for heparin decreases (Carlstrom et al. 1977). This
allows heparin to dissociate from the compl~x,
freeing it to bind to another AT-III molecule. A
similar mechanism is likely to be responsible for
the inhibition of factors IXa, XIa and Xlla (Damus et al. 1973; Rosenberg et al. 1975; Stead et al.
1976a,b).
To accelerate the inhibition of thrombin by ATIII, heparin must bind to both molecules. In addition to the pentasaccharide binding site, heparin
needs a polysaccharide chain with a minimum of
Heparin Kinetics and Dynamics
18 to 22 monosaccharide units to facilitate binding
of the heparin/AT-III complex to thrombin by
bringing the 2 molecules into close proximity
(Griffith 1982; Laurent et al. 1978; Pomerantz &
Owen 1978).
UFH is more than a heterogenous mixture of
molecular weights. It can also be separated by affinity chromatography, using matrix-bound AT-III,
'into 2 components based oniheir affinity for ATIII (Andersson et al. 1976; Hook.et al. 1976; Lam
et al. 1976). Approximately one-third of the heparin isolated from UFH in this manner is high affinity heparin (HAH) and the rest is low affinity
heparin (LAH). The HAH fraction results in most
of the activity of commercial preparations of UFH
and this activity is dependent on a 3-0-sulphated
glucosamine residue in the pentasaccharide binding site (Atha et al. 1984; Caranobe et al. 1986;
Lindahl et al. 1980).
1.2 Low Molecular Weight Heparin
The therapeutic use of heparin carries with it
the risk of bleeding. A number of investigators have
361
suggested that the antithrombotic effect (that which
inhibits clot formation) produced by heparin is the
result of factor Xa inhibition, whereas its anticoagulant effect (that which results in prolonged
bleeding times) is the result of the inhibition of
prothrombin activation (Ofosu et al. 1980, 1982).
Thus, if factor Xa could be selectively inhibited,
the risk of bleeding could be reduced while still
maintaining the anti thrombotic effect. Low molecular weight heparin (LMWH) fractions seemed to
provide t~is selectivity and therefore these preparations have been explored as therapeutic alternatives to UFH (Carter et al. 1981, 1982; Chiu et
al. 1977).
LMWH may be synthesised in a variety of ways,
the most common being nitrous acid depolymerisation, hydrolytic cleavage, /3-elimination of heparin esters, enzymatic depolymerisation and fractionation of LMWH that has been generated by
previous depolymerisation (Nielsen & Ostergaard
1988). These processes result in preparations ranging in molecular weight from 4000 to 60000. It has
been suggested the various LMWHs do not proXII -
Xlla
Xla
~
~+
B -- ·~
IX/
/
/
IXa
Villa
+ Ca++
+ PF-3
X- - - - -·Xa
/
/
II - - - - -.lIa
Fibrinogen - -
- - -.. Flbnn
Fig. 1. Steps in the coagulation cascade inhibited by the heparin/antithrombin-III complex. Abbreviations: H = heparin;
AT-III = antithrombin-III; II, IX, X, XI, XII = blood clotting factors; IIa, VIIIa, IXa, Xa, XIa, Xlla = activated blood
clotting factors; PF-3 = platelet factor 3.
Clin. Pharmacokinet. 22 (5) 1992
362
CH20S0)-\
CO)-0~:H20S0)-0\
-6)-{L0---J>--/
OH
NH
I
OH
OH
)-0~:20S0)-\
~O~
~O
OS03" NH
OH OS03"
OH NH
~
H3C 0
I
~
I
~
Fig. 2. Pentasaccharide segment of heparin responsible for binding of antithrombin-III.
duce equivalent pharmacological effects (Fareed et
al. 1989).
LMWHs retain many of the characteristics of
UFH. The main difference appears to be its effect
on the inhibition offactors Xa and IIa. Anti-factor
Xa activity appears to be inversely related to the
molecular weight of the heparin fragments, increasing as molecular weight decreases (Briant et al.
1989). The opposite is true for factor IIa; as molecular weight decreases, anti-factor IIa activity decreases (Briant et al. 1989). As with UFH, approximately one-third ofLMWH possesses high affinity
for AT-III and this is dependent on the critical 3O-sulphated glucosamine residue in the pentasaccharide binding site.
2. Assays
A number of clinical assays is available for
measuring the effectiveness as well as the concentration of heparin in whole blood or plasma (i:able
I). These assays can generally be divided into 2 categories: global assays and specific assays. Global
assays reflect the effect of heparin on the clotting
cascade (intrinsic and common pathways), whereas
specific assays measure the rate of inhibition of
specific factors (e.g. factor Xa and factor IIa).
The most commonly used global assay is the
activated partial thromboplastin time (APTT),
which measures the time required for coagulation
to occur in a blood sample after the addition of an
activating agent such as kaolin (Proctor & Rapaport 1961). The activating agent makes the APTT
a practical test for clinical use by shortening the
usual coagulation time. APTT is not without its
problems. There is a high degree of interpatient
variability in pre-heparin baseline APTT (Bjornsson & Wolfram 1982). Whitfield & Levy (1980)
demonstrated that the interindividual variability
in response to heparin measured by the APTT is
related to the baseline APTT. In addition, there is
a high degree of variability between reagents used
to measure APTT (Bjornsson et al. 1982; Bjornsson & Nash 1986; Brandt & Triplett 1981).
Factor Xa inhibition is the most commonly used
specific assay (Yin et al. 1973). This tests heparinised plasma to which bovine factor Xa is added
in excess. The mixture is then incubated for a
specified period of time at 37°C and the time until
clot formation is determined. A number of investigators have used variations of this method (Denson & Bonnar 1973; Eggleton et al. 1981).
The anti-factor Xa chromogenic substrate assay
is a modification of the factor Xa inhibition assay,
based on the same principle of measuring the rate
Table I. Laboratory assays for monitoring heparin therapy
Name of assay
Type of assay
Lee-White whole blood clotting time
(WBCT)
Thrombin clotting time (TCT)
Activated partial thromboplastin time
(APTI)
Activated coagulation time (ACT)
Polybrene titration
Protamine titration
Anti-factor Xa assay for clot formation
Anti-factor Xa chromogenic substrate
assay
Global
Global
Global
Global
Specific
Specific
Specific
Specific
Heparin Kinetics and Dynamics
of factor Xa inhibition. However, this test uses a
chromogenic substrate as well as excess bovine factor Xa. A chromogen is released and the rate of
change in optical density is determined (Bartle et
al. 1979; Teien et al. 1976). The chromogenic substrate assay is highly specific and may be the
method of choice for clinical determination ofheparin concentration in plasma. An anti-factor Xa
assay is essential when LMWH is used since these
preparations have only minimal effects on the inhibition of prothrombin activation and, therefore,
global assays such as the APTT will only be increased slightly over baseline (Bratt et al. 1986).
3. Pharmacokinetics
The pharmacokinetic properties of both UFH
and LMWH are summarised in table II.
3.1 Administration and Bioavailability
The administration of heparin is generally restricted to either subcutaneous or intravenous injection. The bioavailability of orally administered
heparin is very low at supratherapeutic doses (Larsen et al. 1986) and this route is therefore generally
not used clinically. Intramuscular injection ofheparin is capable of producing a sustained anticoagulant affect in dogs (Perry & Horton 1976), but
because of the significant risk of bleeding into tissues, this route of administration is usually avoided.
Heparin has also been administered by the intrapulmonary route to patients with thromboembolic
disease. This method of administrati.on resulted in
a recurrence rate of thromboembolic disease of 1.4%
per year (Bick & Ross 1985). Specific concentrations or bioavailability data were not reported.
After subcutaneous injection of UFH, approximately 22 to 40% of the administered dose is absorbed systemically when determined by anti-factor
Xa assays (Bara et al. 1985; Emanuele & Fareed
1987) and concentrations reach a plateau between
4 and 10h (Briant et al. 1989; Frydman et al. 1988).
In comparison, subcutaneous administration of
LMWH results in significantly greater absorption
with bioavailability ranging from 65 to 99% when
363
determined by anti-factor Xa assay. The increased
bioavailability is inversely related to molecular
weight (Emanuele & Fareed 1987). Use of an
anti-factor lIa assay reveals a slightly lower bioavailability for LMWH, ranging from 19 to 85%,
compared with the anti-factor Xa determination.
This is slightly greater than UFH (Bara et al. 1985;
Fareed et al. 1989). When APTT was determined
after LMWH administration, the effect ranged from
no change to only a slight increase over baseline
(Fareed et al. 1985).
3.2 Distribution
Endogenous heparin is found in mast cell granules of most tissues throughout the body. Exogenously administered heparin, however, largely remains in the intravascular space. Minor distribution
to other tissues has been measured using radiolabelled heparin (Larsen et al. 1984).
The volume of distribution (Vd) of UFH has
been reported to be the same as the plasma volume
(Estes 1975; Estes & Poulin 1974). Vd determination in these studies was based on global clotting
assays. When specific assays, such as the anti-factor
Xa assay, are used the Vd more closely reflects the
whole blood volume than the plasma volume
(Kandrotas et al. 1989, 1990a). A Vd which is larger
than plasma volume is also seen with LMWH
(Frydman et al. 1988). Endothelial cell binding of
heparin may account for the apparent Vd being
closer to blood volume. Exogenously administered
heparin binds to endothelial cells (Glimelius et al.
1978; Mahadoo et al. 1977) and is internalised
within these cells (Barzu et al. 1987). Endothelial
cell binding is related to molecular weight, with high
molecular weight fractions having a greater affinity
for these cells (Barzu et al. 1985; van Rijn et al.
1987; Vannucci et al. 1988). This appears to be a
function of the charge density, with higher molecular weight fractions having a greater number of
negative charges (Barzu et al. 1986). The degree of
sulphation may also playa role in endothelial cell
binding (Barzu et al. 1986); however, because of
conflicting data, this point is not as well defined
(Vannucci et al. 1988).
364
Clin. Pharmacokinet. 22 (5) 1992
Table II. Mean (± SD) pharmacokinetic parameters after heparin administration
Reference
Population
No. of
MW
subjects (D)
Route
(dose)
tv,
Bara et al. (1985)
HV
8
Bratt et al. (1986)
HV
Bjornsson et al.
(1982)
Esquerre et al.
(1979)
Vd
(L/kg)
UFH
UFH
4000-6000
4000-6000
SC
IV
SC
IV
177
35
275
275
6
4000-6000
IV
119 (17)
HV
4
UFH
UFH
UFH
IV (25 U/kg)
IV (50 U/kg)
IV (75 U/kg)
HV
TE
10
13
UFH
UFH
IV
IV
(min)
CL
(L/h. kg)
Assay
Anti-Xa
27.7 (6.1)
38.9 (2.5)
47.8 (3.1)
3.4 (0.5) La
1.23 (0.15) L/h a
Anti-Xa
0.073 (0.014)
0.072 (0.009)
0.072 (0.005)
0.112 (0.013)
0.077 (0.011)
0.063 (0.002)
HN
99mTc
label
234 (30)
133 (50)
Estes et al. (1969)
HVb
19
UFH
IV
Frydman et al.
(1988)
HV
12
4000-6000
4000-6000
4000-6000
4000-6000
SC
SC
SC
SC
Goudable at al.
(1986)
HV
6
RD
5
UFH
2500
UFH
2500
IV
IV
IV
IV
Hirsh at al. (1976)
DVT
PE
15
4
UFH
UFH
IV
IV
69.8 (16.6)
37.75 (1.5)
0.124 (0.068)
0.141 (0.047)
0.078 (0.034)
0.158 (0.059)
PAT
Kandrotas et al.
(1989)
Lockner et al.
(1986)
HD
21
UFH
IV
108.41 (56.86)
0.066 (0.023)
0.028 (0.013)
Anti-Xa
HV
8
8
8
6
UFH
4000-6000
4000-6000
4000-6000
IV
IV
IV
IV
57
126
139
119
3.13 (.88) La
2.57 (.65) La
2.92 (.78) La
3.4 (.42) La
2.34 (0.84) L/h a
0.900 (0.300) L/h a
0.900 (0.180) L/h a
1.26 (0.180) L/h a
Anti-Xa
McDonald et al.
(1981)
Neonates
25-28 wks
29-32 wks
33-36 wks
Healthy adults
10
7
8
8
UFH
UFH
UFH
UFH
IV
IV
IV
IV
41.6
35.5
35.5
63.3
0.081
0.073
0.058
0.037
0.089
0.086
0.082
0.026
Anti-Xa
Parry et al. (1974)
HV
RD
10
13
UFH
UFH
IV
IV
36.8 (4.6)
47.5 (16.6)
Psuja (1988)
MI
10
Simon et al. (1978)
HV
RD
LD
DVT
PE
12
12
7
14
11
UFH
4000-6000
3000-5000
UFH
UFH
UFH
UFH
UFH
IV
IV
IV
IV
IV
IV
IV
IV
12.9 (3.6)
13.6 (4.8)
13.1 (4)
106.8 (16.8)
109.8 (18)
79.8 (21)
106.2 (28.2)
79.8 (19.2)
Teien at al. (1977)
LD
6
UFH
IV
117.8 (30.77)
PBT
Teien & Bjornsson
(1976)
BN
RD
HV
5
6
6
UFH
UFH
UFH
IV
IV
IV
118.6 (7.83)
97.8 (19.13)
74.7 (7.53)
PBT
87.48 (31.5)
(20mg)
(40mg)
(60mg)
(80mg)
250.8 (132.6)
261.6 (62.2)
222 (49.2)
207.6 (15)
57
129
55
247
(40 U/kg)
(40 U/kg
(60 U/kg)
(120 U/kg)
a
Results not normalised for weight and weight not reported.
b
Retrospective review of previously published studies.
0.057 (0.001)
9.30
8.49
6.59
5.83
(3.67)
(3.37)
(1.33)
(1.78)
La
La
La
La
0.0271
1.86
1.33
1.25
1.18
GC
(0.63)
(1.15)
(0.21)
(0.25)
L/h a
L/h a
L/h a
L/h a
(14)
(26)
(11)
(35)
(12)
(21)
(28)
(17)
(14.3)
(6.8)
(6.8)
(15.6)
Anti-Xa
Anti-Xa
(0.041)
(0.025)
(0.032)
(0.007)
(0.052)
(0.023)
(0.028)
(0.005)
GC
324 (85)
337 (89)
306 (54)
0.070 (0.007)
0.071 (0.012)
0.078 (0.012)
0.062 (0.011)
0.068 (0.015)
B.11La
8.10La
7.31 La
0.038 (0.007)
0.036 (0.008)
0.052 (0.002)
0.033 (0.011)
0.048 (0.014)
99mTc
label
PBT
= molecular weight; tv, = elimination half-life; Vd = volume of distribution; CL = total body clearance;
= healthy volunteers; TE = thromboembolism; RD = renal disease; HD = haemodialysis; DVT = deep venous thrombosis;
PE = pulmonary embolism; MI = myocardial infarction; LD = liver disease; BN = bilateral nephrectomy; UFH = unfractionated heparin,
MW 3000-30000D; SC = subcutaneous; IV = intravenous; HN = hexodimethrine bromide neutralisation; GC = global coagulation;
PAT = protamine titration; PBT = polybrene titration.
Abbreviations: MW
HV
Heparin Kinetics and Dynamics
365
3.3 Clearance
The disposition of heparin is unique. Early investigations with UFH seemed to indicate that
heparin is eliminated by a first-order exponential
process (Estes et al. 1969; Olsson et al. 1963; Perry
et al. 1974). These studies used global assays such
as whole blood clotting time or APTT to measure
heparin concentration. Pharmacokinetic determinations were based on the assumption that the decline in effect paralleled the decline in heparin concentration. Thus, a first-order elimination process
was assumed since the clotting assay declined in a
log-linear fashion. This assumption has been found
to be invalid since there are a number of endogenous substances in the blood which contribute
to the anticoagulant effect (Godal 1974). Subsequent studies using radiolabelled heparin (Dawes
& Pepper 1979) or anti-factor Xa assays (de Swart
et al. 1982) show that the pharmacokinetics ofheparin are more complex. The declines in heparin
concentration and effect were recently compared
(Kandrotas et al. 1991a). The effect was determined by the activated coagulation time (ACT), a
global clotting assay, and heparin concentration was
measured by an anti-factor Xa assay. The study
demonstrated a lack of parallelism indicating the
2 measurements were not equivalent.
When anti-factor Xa assays or radiolabelling are
used, a characteristic concave-convex elimination
curve is noted (Boneu et al. 1989; de Swart et al.
1982). This type of elimination curve suggests that
there is a rapid distribution phase followed by a
saturable, zero-order elimination phase (fig. 3). The
half-life (tV2) of heparin is both dose- and timedependent, increasing if either the dose or duration
of administration is increased (Bjornsson & Levy
1979a,b). This increase in tlj, is the result of a dosedependent decrease in total heparin clearance
(Bjornsson et al. 1982).
There are 2 separate mechanisms by which heparin is eliminated. At lower doses, a saturable
mechanism appears to be the primary route of
elimination. With higher doses, when the primary
elimination mechanism is saturated, the drug is
cleared by a nonsaturable mechanism (Boneu et al.
10.0
5.0
2.0
E
2:
i=-
1.0
0.5
:~
0
"'
"'
~
'E
«
0.2
0.1
0.05
o
2
3
4
Time (h)
Fig. 3. Characteristic concave-convex elimination curve
demonstrating saturation of the primary mechanism ofelimination at higher doses of heparin. From left to right, lines
depict the results after 10, 25, 50, 100,250,375 and 500 antiXa U/kg (Boneu et al. 1987; with permission).
1987). This phenomenon is generally not seen
clinically since therapeutic doses are lower than
those used in studies. In certain therapeutic situations such as haemodialysis and cardiopulmonary
bypass surgery, higher UFH doses are used and saturation of the primary elimination mechanism occurs. The zero-order component appears to be of
minimal clinical significance within the usual therapeutic range and a first-order process can be assumed (Kandrotas et al. 1989) [fig. 4]. In addition,
it appears that AT-III affinity plays a role in the
clearance of UFH. When the clearance of UFH
fractions, separated on the basis of AT-III affinity,
is examined using radiolabelling, HAH is cleared
more slowly than either LAH or the parent UFH
(Caranobe et al. 1986).
366
Clin. Pharmacokinet. 22 (5) 1992
1.0
,,
E 0.5
:2c
,,
.g
c
~
\
8
\
8c
,
"
·c
.,l1
I
-
First-order eliminatIon
... Zero-order elimi nation
0.1+-- - - r - - - - . - -.,---...,.....---.-----,--.,90
120
150
180
210
60
o 30
Time (min)
Fig. 4. When bolus therapeutic doses of heparin are injected
during haemodialysis, zero-order elimination is minimal and
may be approximated by a first-order elimination process
(after Kandrotas et al. 1989).
After UFH is bound to endothelial cells it is
internalised by the cells (Hiebert & McDuffie 1989;
Vannucci et al. 1988). Once it is endocytosed, depolymerisation occurs creating smaller heparin
fragments (Barzu et al. 1987; Vannucci et al. 1988).
The exact mechanism of depolymerisation is not
clear, but endoglycosidases present in lysosomes
from rat splenic and renal tissue preparations have
been shown to degrade UFH in vitro (Hook et al.
1977; Mastacchi & Barbanti 1987). There is also
evidence to suggest that N-deacylation and Ndesulfation playa role in UFH clearance (Bjornsson et al. 1988).
In comparison, the elimination of LMWH appears to occur only by a nonsaturable mechanism
(Boneu et al. 1987). When anti-factor Xa activity
is used to examine the disposition of LMWH, a
first-order elimination process is seen (Bratt et al.
1986; Lockner et al. 1986). After intravenous injection the elimination curve is biexponential with
the distribution phase lasting from 0 to 5 min
(Briant et al. 1989; Palm & Mattsson 1987a). The
t'l2 ofLMWH is approximately twice as long as that
of UFH and is not dose dependent (Bara & Samama 1988; Boneu et al. 1987; Lockner et al. 1986).
When subcutaneous and intravenous LMWH are
compared, subcutaneous LMWH has a longer t'l2
(Dawes et al. 1986).
Endothelial cell binding and internalisation appear to play a minimal role in the clearance of
LMWH. Since LMWHs have a lower charge density they do not have as high an affinity for endothelial cells. In fact, the reticuloendothelial system
appears to play only a small role in the elimination
of LMWH (Palm & Mattsson 1987a). The primary
route of elimination for LMWH appears to be renal
(Larsen et al. 1986; Palm & Mattsson 1987a,b; van
Rijn et al. 1987).
LMWH is eliminated only by the nonsaturable
route, has a low affinity for endothelial cells, and
is found in high concentrations in the urine. For
these reasons it is likely that endothelial binding
and internalisation is the saturable mechanism of
heparin elimination and the renal route is the nonsaturable mechanism.
4. Pharmacokinetics and Other
Physiological States
4.1 Effects of Age
There is little information regarding the effect
of age on the pharmacokinetics of heparin. Studies
in newborn piglets and adult pigs have demonstrated that there is no significant age-related difference in UFH tljz when measured by either
anti-factor Xa activity or radiolabelled UFH, although both clearance and Vd are increased in the
piglets (Andrew et al. 1988). The same was found
with LMWH when adult pigs are compared with
newborn piglets (Andrew et al. 1989). Premature
neonates appear to have a shorter t'l2> Vd, and
367
Heparin Kinetics and Dynamics
clearance, all of which are inversely related to age
when compared with adult humans (McDonald et
a1. 1981). No controlled pharmacokinetic studies
of heparin in the human geriatric population are
available at this time.
4.2 Pregnancy
UFH has been considered to be the anticoagulant of choice to treat thromboembolic disorders
during pregnancy since it is not transported across
the placenta (Flessa et a1. 1965). Studies using
LMWH in both sheep (Andrew et a1. 1985) and
humans (Fore stier et a1. 1987; Omri et a1. 1989)
also demonstrate a lack of transport across the placenta when heparin concentrations are determined
in the pregnant mother and the fetus.
4.3 Thromboembolic Disease
Patients with pulmonary embolism require
higher dosages of heparin than those with deep
venous thrombosis. This may be due to a higher
UFH clearance in patients with pulmonary embolism (Hirsh et a1. 1976; Simon et a1. 1978), but
this is not a consistent finding (Cipolle et a1. 1981;
Kandrotas et a1. 1990b). The increased requirement for UFH may in fact be due to a difference
in pharmacodynamic rather than pharmacokinetic
response between the 2 types of patients (Kandrotas et a1. 1990b) resulting in higher dose requirements for those with pulmonary embolism.
4.4 Renal Disease
The t1;' of UFH is longer in patients with endstage renal disease than in those with normal renal
function (Perry et a1. 1974; Teien et a1. 1976). This
probably reflects a decrease in the elimination of
the lower molecular weight fractions of the heterogenous heparin preparations. There is a high degree of interpatient variability in t1;', Vd, and clearance in patients receiving haemodialysis (Kandrotas
et a1. 1989); however, there is little intrapatient
variation in these parameters (Kandrotas et a1.
1990a).
The disposition of LMWH as determined by
anti-factor Xa activity follows a biphasic elimination curve and the elimination t1/2 is approximately twice as long in patients with end-stage renal
disease as in patients with normal renal function
(Follea et a1. 1986: Goudable et a1. 1986: Palm &
Mattsson 1987b).
4.5 Hepatic Disease
UFH has a biphasic elimination curve in
patients with hepatic disease which is similar to
that seen in other disease states. The t'l2 is slightly
prolonged, indicating that the liver may play some
role in heparin elimination (Teien 1977).
5. Pharmacodynamics
Heparin produces a variety of pharmacodynamic effects including prolongation of in vitro clotting times such as APTT or ACT, inhibition ofspecific clotting factor activities such as those of
anti-factor Xa or anti-factor IIa, and an in vivo
reduction in the weight of a clot or delay in thrombus formation.
5.1 Anticoagulant Versus Antithrombotic
Activity
The first suggestion that the anticoagulant and
antithrombotic effects were independent came in
1940. Experiments with intravenous UFH in dogs
demonstrated that thrombus formation was delayed beyond the point at which the clotting time
had returned to normal (Solandt & Best 1940).
The anticoagulant effect is measured by tests
such as the APTT. Prolongation of the APTT to
approximately twice the patient's baseline APTT
is currently used as the therapeutic endpoint in the
clinical use of UFH. Two clinical studies offer evidence that patients being treated for thromboembolic disease have a lower incidence of morbidity
and mortality if the APTT ratio of 1.5 to 2.5 times
baseline is achieved within the first 24 to 48h of
the onset of symptoms (Basu et a1. 1972; Hull et
al. 1986). This ratio is therefore considered to be
368
necessary in order to prevent thrombus formation.
However, there are no controlled studies in humans which directly correlate this in vitro anticoagulant activity with the in vivo antithrombotic activity such as reduction in size or weight of the
thrombus. Phlebographic evidence suggests that
there is a weak but significant correlation between
resolution of thrombus and APTT, anti-factor Xa
activity measured by chromogenic substrate assay
or thrombin time (Holm et al. 1984).
The antithrombotic effect was thought to be due
to anti-factor Xa activity; however, evaluation of
LMWH and very low molecular weight heparin
fragments (3000D) revealed that factor Xa inhibition alone is insufficient to produce an antithrombotic effect (Ockelford et al. 1982). It appears
that inhibition of thrombin is also necessary to prevent thrombus formation (Buchanan et al. 1985).
Thus, on the basis of knowledge of the minimum
number of monosaccharide units necessary to bind
both AT-III and thrombin (18 to 22), the minimum effective molecular weight to produce thrombin inhibition is approximately 4500 to 5000D. This
has been confirmed with a thrombosis model in
rabbits (Bergqvist et al. 1985). Since anti-factor Xa
activity continues to increase when the molecular
weight decreases below 5000D, it cannot be the sole
correlate to antithrombotic activity (Holmer et al.
1982, 1986; Mattsson et al. 1989; Ockelford et al.
1982).
Since heparin accelerates the inhibitory effect of
AT -III on factor Xa and thrombin, it might be concluded that only HAH is responsible for producing
the antithrombotic effect. Comparisons of HAH
with LAH have revealed that LAH alone has very
little anti thrombotic effect while HAH is responsible for most of this activity (Holmer et al. 1982;
Mattsson et al. 1989; Thomas et al. 1982). The
presence of LAH in small amounts is necessary
since it seems to enhance the anti thrombotic effect
of HAH (Barrowcliffe et al. 1984; Holmer et al.
1982; Mattsson et al. 1989; Thomas et al. 1982).
The mechanism of this enhancement is unknown.
An additional effect which may play a role in
limiting thrombus size is the induction of a thrombolytic effect. Both tissue plasminogen activator and
Clin. Pharmacokinet. 22 (5) 1992
urokinase have an affinity for heparin (Paques et
al. 1986). This fibrinolytic activity is significantly
higher after heparin than placebo when administered to rats, resulting in a statistically significant
reduction in thrombus weight (Doutremepuich et
al. 1988, 1989).
5.2 Variability of Response
There is a high degree of interpatient variability
in response to heparin. The effect of heparin
administration to healthy volunteers and hospitalised medical and surgical patients is highly variable
between patients but little intrapatient variation is
seen (Whitfield & Levy 1980; Whitfield et al. 1982).
This is also true for patients with end-stage renal
disease who require haemodialysis (Kandrotas, et
al. 1990a). Disease state may contribute to varying
pharmacodynamic response, as is the case when
comparing patients who have pulmonary embolism with those with deep venous thrombosis (Kandrotas et al. 1990b).
Little information is available regarding neonatal response to heparin; however, when cord
blood is used as a model of neonatal response, significant interpatient variability is observed (Holmes
et al. 1991).
6. Clinical Implications
6.1 Clinical Use of Heparin
Heparin is used in a variety of clinical situations, the most common of which are the prophylaxis and treatment of thromboembolic disease and
thrombosis associated with cardiac problems such
as atrial fibrillation, unstable angina, acute myocardial infarction and mural thrombosis, as well as
to prevent clot formation during extracorporeal
circulation as in haemodialysis and cardiopulmonary bypass surgery.
The prophylaxis of deep venous thrombosis requires significantly lower daily doses of UFH than
the treatment of active thromboembolic disease. A
large number of studies have been conducted which
have demonstrated the usefulness of low dose UFH
(5000U subcutaneously every 8 to 12h) and these
369
Heparin Kinetics and Dynamics
are reviewed elsewhere (Kakkar & Adams 1986).
The exact reason why less UFH is required is unknown at this time. LMWH is effective for DVT
prevention (Kakkar et al. 1982). Since the t,;,. of
LMWH (as determined by anti-factor Xa assays)
is greater than UFH, a single daily subcutaneous
injection appears to provide adequate prophylaxis
against DVT (Kakkar et al. 1986).
In treating thromboembolic disease, the usual
method of determining heparin dosages is empirical and can result in over-anticoagulation, exposing the patient to the risk of bleeding. The more
common difficulty, however, is inadequate anticoagulation within the first 24 to 48h of initiating
heparin. Nomograms have been developed to help
circumvent these problems (Cruickshank et al.
1991). While nomograms offer a significant improvement over empirical dosage, they only partially address the issue of interpatient variability
since most start with a standardised loading dose
(usually 5000U) rather than adjusting the dose on
the basis of patient's bodyweight. They are also
based on the APTT in seconds rather than the
APTT ratio on the basis of the patient's baseline
APTT, thus ignoring the individual patient's response to heparin. Also, after each dosage adjustment, a period of 6h must elapse before rechecking
the APTT in order to see the full effect of the change
in dosage. The possibility of delay in attaining the
therapeutic range, therefore, still exists.
Recent investigations have attempted to address this problem in patients with deep venous
thrombosis through the use of non-steady-state
heparin concentrations as determined by protamine titration (Groce et al. 1987) and the anti-factor
Xa chromogenic substrate assay (Kandrotas et al.
1991 b). Using these heparin concentrations, the
clearance ofUFH can be determined in each patient
and the infusion rate adjusted accordingly. A comparison of dosage adjustment using the chromogenic substrate assay with that of adjusting dose
based on APTT alone resulted in a significantly
greater number of subtherapeutic patients in the
APTT group at both 12 and 24h (18 and 33%, respectively). In the group that used anti-factor Xa
heparin concentrations to determine the infusion
rates all of the patients were in the therapeutic range
at 12 and 24h (Kandrotas et al. 1991 b).
6.2 Therapeutic Monitoring
Currently the APTT is used to monitor the
clinical efficacy of heparin treatment. With the exception of the ACT which is used to monitor response during haemodialysis and cardiopulmonary
bypass surgery, most other whole blood clotting
methods are rarely used. There is good evidence
that maintaining the APTT between 1.5 and 2.5
times the patient's baseline is correlated with a reduction in the recurrence rate of thromboembolic
disease (Basu et al. 1972; Hull et al. 1986).
The chromogenic substrate assay method for
determination of anti-factor Xa activity is a convenient and precise laboratory method used to determine response to heparin. Since the results of
this method are highly correlated with actual heparin concentrations (Teien & Lie 1977) the results
are reported as heparin concentration (U jml). The
usual therapeutic range is 0.2 to 0.7 Ujml (van
Putten et al. 1982).
6.3 Adverse Effects
The most common adverse effect of heparin
therapy is bleeding. The incidence of major bleeding has been reported to range from 1 to 33% by
various investigators. Most of the studies suffer
from design problems such as a lack of randomisation, no control group or insufficient patient
numbers. However, several observations can be
made.
Intermittent injection of heparin is associated
with a higher incidence of bleeding than continuous infusion (Fagher & Lundh 1981; Glazier &
Crowell 1976; Mant et al. 1977; Salzman et al. 1975;
Wilson & Lampman 1979; Wilson et al. 1981). It
is difficult to determine whether this higher incidence is a function of the method of administration or the dosage administered. In all but 1 of
these studies (Mant et al. 1977), the total daily dose
of heparin was higher for the patients treated with
intermittent injection. It is possible that the total
370
Clin. Pharmacokinet. 22 (5) 1992
daily dose necessary to maintain adequate anticoagulation is lower with continuous infusion because wide swings between peak and trough concentrations are avoided. Another possible cause is
the high degree of interpatient variability. This,
combined with the difficulty in accurately regulating the heparin dose, may contribute to bleeding
complications.
The other major adverse effect associated with
heparin therapy is thrombocytopenia (Bell et al.
1976). Heparin induces platelet aggregation in vitro
(Nelson et al. 1978). There are 2 types of heparininduced thrombocytopenia seen clinically. A transient, mild form usually occurs within the first week
of therapy with only a slight drop in platelet count
and reverses with continued administration ofheparin. A more severe form occurs between 2 and 20
days after initiating heparin and is thought to be
mediated by an immunological process (Trowbridge et al. 1978). The platelet count may fall below
20000/mm 3 and will not return to normal unless
heparin is discontinued. Thrombosis, bleeding or
disseminated intravascular coagulation may result
(Battey & Salam 1985; Silver et al. 1983; Towne et
al. 1979). The mild form of thrombocytopenia is
not associated with any of these complications. It
has been suggested that LMWH can be used as a
treatment for heparin-induced thrombocytopenia
(Leroy et al. 1985; Vitoux et al. 1986); however,
platelet aggregation has also been demonstrated
with higher doses of LMWH (Brace & Fareed 1986)
so caution should be used with this approach.
Other adverse effects which only occur rarely
include osteoporosis (when heparin is used in high
doses for long periods of time), necrosis, alopecia
and hypo aldosteronism.
7. Conclusions
Our knowledge of the complex nature of heparin, its interaction with the coagulation system and
the nature of the coagulation system itself is still
evolving. Further clarification of the specific roles
of other glycosaminoglycans in conjunction with
the use of heparin is also needed.
The availability of LMWH preparations has
contributed significantly to our knowledge of heparin pharmacokinetics and pharmacodynamics. Use
of these preparations in the prophylaxis and treatment of thromboembolic disease offers significant
advantages over UFH, including better bioavailability, longer t'l2 and potentially fewer complications from bleeding, all of which will make heparin
easier and safer to use.
References
Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims
GEe. Anticoagulant properties of heparin fractionated by af·
finity chromatography on matrix-bound antithrombin III and
by gel filtration. Thrombosis Research 9: 575-583, 1976
Andrew M, Boneu B, Cade J, Cerskus AL, Hirsh J, et al. Placental
transport oflow molecular weight heparin in the pregnant sheep.
British Journal of Haematology 59: 103-108, 1985
Andrew M, Ofosu F, Brooker L, Buchanan MR. The comparison
of the pharmacokinetics of a low molecular weight heparin in
the newborn and adult pig. Thrombosis Research 56: 529-539,
1989
Andrew M, Ofosu F, Schmidt B, Brooker L, Hirsh J, et al. Heparin clearance and ex vivo recovery in newborn piglets and
adult pigs. Thrombosis Research 52: 517-527, 1988
Atha DH, Stephens AW, Rosenberg RD. Evaluation of critical
groups required for the binding of heparin to antithrombin.
Proceedings of the National Academy of Sciences of the United
States of America 81: 1030-1034, 1984
Bara L, Billaud E, Kher A, Samama M. Increased anti-Xa bioavailability for a low molecular weight heparin (PK 10169)
compared with unfractionated heparin. Seminars in Thrombosis and Hemostasis II: 316-317, 1985
Bara L, Samama M. Pharmacokinetics of low molecular weight
heparins. Acta Chirurgica Scandinavica 543: 65-72, 19811
Barrowcliffe TW, Merton RE, Havercroft SJ, Thunberg L, Lindahl U, et al. Low-affinity heparin potentiates the action of
high-affinity heparin oligosaccharides. Thrombosis Research
34: 125-133, 1984
Bartl K, Dorsch E, Lill H, Ziegenhorn J. Determination of the
biological activity of heparin by use of a chromogenic substrate. Thrombosis and Haemostasis 42: 1446-1451, 1979
Barzu T, Molho P, Tobelem G, Petitou M, Caen J. Binding and
endocytosis of heparin by human endothelial cells in culture.
Biochimica et Biophysica Acta 845: 196-203, 1985
Barzu T, van Rijn JLML, Petitou M, Molho P, Tobelem G, et
al. Endothelial binding sites for heparin: specificity and role
in heparin neutralization. Biochemical Journal 238: 847-854,
1986
Barzu T, van Rijn JLML, Petitou M, Tobelem G, Caen JP. Heparin degradation in the endothelial cells. Thrombosis Research
47: 601-609, 1987
Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the
value of monitoring heparin treatment with the activated partial thromboplastin time. New England Journal of Medicine
287: 324-327, 1972
Battey PM, Salam AA. Venous gangrene associated with heparininduced thrombocytopenia. Surgery 97: 618-620, 1985
Bell WR, Tomasulo PA, Alving BM, Duffy TP. Thrombocytopenia occurring during the administration of heparin: a prospective study in 52 patients. Annals of Internal Medicine 85:
155-160, 1976
Bergqvist D, Nilsson B, Hedner U, Pedersen PC, Ostergaard PB.
Heparin Kinetics and Dynamics
The effect of heparin fragments of different molecular weights
on experimental thrombosis and haemostasis. Thrombosis Research 38: 589-60 I, 1985
Bick RL, Ross ES. Clinical use of intrapulmonary heparin. Seminars in Thrombosis and Hemostasis II: 213-217,1985
Bjornsson TD, Levy G. Pharmacokinetics of heparin I: studies
of dose dependence in rats. Journal of Pharmacology and Experimental Therapeutics 210: 237-242, 1979a
Bjornsson TD, Levy G. Pharmacokinetics of heparin II: studies
of time dependence in rats. Journal of Pharmacology and Experimental Therapeutics 210: 243-246, 1979b
Bjornsson TD, Nash PV. Variability in heparin sensitivity of APTT
reagents. American Journal of Clinical Pathology 86: 199-204,
1986
Bjornsson TD, Schneider DE, Hecht AR. Effects of N-deacylation
and N-desulfation of heparin on its anticoagulant activity and
in vivo disposition. Journal of Pharmacology and Experimental
Therapeutics 245: 804-808, 1988
Bjornsson TD, Wolfram KM. Intersubject variability in the anticoagulant response to heparin in vitro. European Journal of
Clinical Pharmacology 21: 491-497, 1982
Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics determined by three assay methods. Clinical Pharmacology and
Therapeutics 31: 104-113, 1982
Boneu B, Buchanan MR, Caranobe C, Gabaig AM, Dupouy D,
et al. The disappearance of a low molecular weight heparin
fraction (CY 216) differs from standard heparin in rabbits.
Thrombosis Research 46: 845-853, 1987
Boneu B, Caranobe C, Gabaig AM, Dupouy D, Sie P, et al. Evidence for a saturable mechanism of disappearance of standard
heparin in rabbits. Thrombosis Research 46: 835-844, 1987
Boneu B, Dol F, Caranobe C, Sie P, Houin G. Pharmacokinetics
of heparin and related polysaccharides. Annals of the New York
Academy of Sciences 556: 282-291, 1989
Brace LD, Fareed J. Heparin-induced platelet aggregation: dose!
response relationships for a low molecular weight heparin derivative (PK 10 169) and its subfractions. Thrombosis Research 42: 769-782, 1986
Brandt JT, Triplett DA. Laboratory monitoring of heparin: effect
of reagents and instruments on the activated partial thromboplastin time. American Journal of Clinical Pathology 76
(Suppl.): 530-537, 1981
Bratt G, Tornebohm E, Widlund L, Lockner D. Low molecular
weight heparin (Kabi 2165, Fragmin): pharmacokinetics after
intravenous and subcutaneous administration in human
volunteers. Thrombosis Research 42: 613-620, 1986
Briant L, Caranobe C, Saivin S, Sie P, Bayrou B, et al. Unfractionated heparin and CY 216: pharmacokinetics and bioavailabilities of the antifactor Xa and IIa effects after intravenous and subcutaneous injection in the rabbit. Thrombosis and
Haemostasis 61: 348-353, 1989
Buchanan MR, Boneu B, Ofosu F, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to the
antithrombotic effects of heparin. Blood 65: 198-201, 1985
Caranobe C, Petitou M, Dupouy D, Gabaig AM, Sie P, et al.
Heparin fractions with high and low affinities to antithrombin
III are cleared at different rates. Thrombosis Research 43: 635641, 1986
Carlstrom AS, Lieden K, Bjork I. Decreased binding of heparin
to antithrombin following the interaction between antithrombin and thrombin. Thrombosis Research II: 785-797, 1977
Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, et al. The
relationship between the hemorrhagic and antithrombotic
properties of low molecular weight heparin in rabbits. Blood
59: 1239-1245, 1982
Carter CJ, Kelton JG, Hirsh J, Gent M. Relationship between the
anti thrombotic and anticoagulant effects of low molecular
weight heparin. Thrombosis Research 21: 169-174, 1981
Chiu HM, Hirsh J, Yung WL, Regoeczi E, Gent M. Relationship
371
between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombis. Blood 49: 171-184, 1977
Choay J, Lormeau JC, Petitou M, Sinay P, Fareed J. Structural
studies on a biologically active hexasaccharide obtained from
heparin. Annals of the New York Academy of Sciences 370:
644-649, 1981
Cipolle RJ, Seifert RD, Neilan BA, Zaske DE, Haus H. Heparin
kinetics: variables related to disposition and dosage. Clinical
Pharmacology and Therapeutics 29: 387-393, 1981.
Cruickshank MK, Levine MN, Hirsh J, Roberts R, Siguenza M.
A standard heparin nomogram for the management of heparin
therapy. Archives of Internal Medicine 151: 333-337, 1991
Damus PS, Hicks M, Rosenberg RD. Anticoagulant action of
heparin. Nature 246: 355-357, 1973
Dawes J, Bara L, Billaud E, Samama M. Relationship between
biological activity and concentration of a low molecular weight
heparin (PK 10 169) and unfractionated heparin after intravenous and subcutaneous administration. Haemostasis 16: 116122, 1986
Dawes J, Pepper DS. Catabolism of low-dose heparin in man.
Thrombosis Research 14: 845-860, 1979
Denson KWE, Bonnar J. The measurement of heparin: a method
based on potentiation of antifactor Xa. Thrombosis et Diathesis Haemorrhagica 30: 471-479, 1973
de Swart CAM, Nijmeyer B, Roelofs JMM, Sixma 11. Kinetics
of intravenously administered heparin in normal humans. Blood
60: 1251-1258, 1982
Doutremepuich C, De Seze 0, Doutremepuich F, Anne C, Castrioto T, et al. tPA-like activity of an experimental thrombus
in the presence of heparin and a heparin fraction. Annals of
the New York Academy of Sciences 556: 435-436, 1989
Doutremepuich C, Toulemonde F, Doutremepuich F, de Seze 0,
Bayrou B, et al. The tPA-like activity induced by heparin and
a heparin fragment binds on experimental thrombus. Thrombosis Research 50: 335-338, 1988
Eggleton CA, Barrowcliffe TW, Merton RE, Thomas DP. In vitro
and in vivo studies of the anti-Xa activity of heparin. Thrombosis Research 24: 319-328, 1981
Emanuele RM, Fareed J. The effect of molecular weight on the
bioavailability of heparin. Thrombosis Research 48: 591-596,
1987
Esquerre JP, Boneu B, Guiraud R. Kinetics of technetium-labelled heparin in thromboembolism: preliminary report. International Journal of Nuclear Medicine and Biology 6: 215-220,
1979
Estes JW. The fate of heparin in the body. Current Therapeutic
Research 18: 45-56, 1975
Estes JW, Pelikan EW, Kruger-Thiemer E. A retrospective study
of the pharmacokinetics of heparin. Clinical Pharmacology and
Therapeutics 10: 329-337, 1969
Estes JW, Poulin PF. Pharmacokinetics of heparin. Distribution
and elimination. Thrombosis et Diathesis Haemorrhagica 33:
26-37, 1974
Fagher B, Lundh B. Heparin treatment of deep vein thrombosis.
Acta Medica Scandinavica 210: 357-361, 1981
Fareed J, Walenga JM, Hoppensteadt, Huan X, Nonn R. Biochemical and pharmacologic inequivalance of low molecular
weight heparins. Annals of the New York Academy of Sciences
556: 333-353, 1989
Fareed J, Walenga JM, Williamson K, Emanuele RM, Kumar A,
et al. Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments. Seminars in Thrombosis and Hemostasis II: 56-74, 1985
Flessa HC, Kapstrom AB, Glueck HI, Will 11. Placental transport
of heparin. American Journal of Obstetrics and Gynecology
93: 570-573, 1965
Follea G, Laville M, Pozet N, Dechavanne M. Pharmacokinetic
studies of standard heparin and low molecular weight heparin
372
in patients with chronic renal failure. Haemostasis 16: 147151, 1986
Forestier F, Daffos, F, Rainaut M, Toulemonde F. Absence de
passage transplacentaire de la fraxiparine (heparine de bas poids
moleculaire) au cours du troisieme trimestre de la grossesse.
Journal de Gynecologie, Obstetrique et Biologie de la Reproduction - Paris 16: 981-986, 1987
Frydman M, Bara L, Le Roux Y, Woler M, Chauliac F, et a!.
The antithrombotic activity and pharmacokinetics of enoxaprine, a low molecular weight heparin, in humans given single
subcutaneous doses of 20-80mg. Journal of Clinical Pharmacology. 28: 609-618, 1988
Glazier RL, Crowell EB. Randomized prospective trial of continuous vs intermittent heparin therapy. Journal of the American
Medical Association 236: 1365-1367, 1976
Glimelius B, Busch C, Hook M. Binding of heparin on the surface
of cultured human endothelial cells. Thrombosis Research 12:
773-782, 1978
Godal He. Heparin assay methods for control of in vivo heparin
effects. Thrombosis et Diathesis Haemorrhagica 33: 77-80, 1974
Goudable C, That HT, Damani A, Durand D, Caranobe C, et a!.
Low molecular weight heparin half life is prolonged in haemodialysis patients. Thrombosis Research 43: 1-5, 1986
Griffith MJ. Kinetics of the heparin-enhanced antithrombin III/
thrombin reaction: evidence for a template model for the
mechanism of action of heparin. Journal of Biological Chemistry 257: 7360-7365, 1982
Groce JB, Gal P, Douglas JB, Steuterman Me. Heparin dosage
adjustment in patients with deep-vein thrombosis using heparin concentrations rather than activated partial thromboplastin time. Clinical Pharmacy 6: 216-222, 1987
Hiebert LM, McDuffie NM. The intracellular uptake and protracted release of exogenous heparins by cultured endothelial
cells. Artery 16: 208-222, 1989
Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, et a!.
Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 53: 691-695, 1976
Holm HA, Abildgaard U, Kalvenes S, Anderssen N, Anker E, et
a!. The antithrombotic effect of heparin in deep venous thrombosis: relation to four heparin assays. Acta Medica Scandinavica 216: 287-293, 1984
Holmer E, Mattsson C, Nilsson S. Anticoagulant and anti thrombotic effects of heparin and low molecular weight heparin fragments in rabbits. Thrombosis Research 25: 475-485, 1982
Holmer E, Soderberg K, Bergqvist D, Lindahl U. Heparin and
its low molecular weight derivatives: anticoagulant and antithrombotic properties. Haemostasis 16 (Supp!. 2): 1-7, 1986
Holmes C, Gal P, Ransom JL, Weaver RL, Wyble LE, et a!. Heparin pharmacodynamics in premature infants. Abstract no. 40.
Pharmacotherapy II: 270, 1991
Hook M, Bjork I, Hopwood J, Lindahl U. Anticoagulant activity
of heparin: separation of high-activity and low-activity heparin
species by affinity chromatography on immobilized antithrombin. Federation of European Biochemical Societies Letters 66:
90-93, 1976
Hook M, Pettersson I, Ogren S. A heparin degrading endoglycosidase from rat spleen. Thrombosis Research 10: 857-861,
1977
Howell WH, Holt E. Two new factors in blood coagulation-heparin and pro-antithrombin. American Journal of Physiology
47: 328-341, 1918
Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, et a!. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein
thrombosis. New England Journal of Medicine 315: 1109-1114,
1986
Kakkar VV, Adams pe. Preventive and therapeutic approach to
venous thromboembolic disease and pulmonary embolism can death from pulmonary embolism be prevented? Journal
Clin. Pharmacokinet. 22 (5) 1992
of the American College of Cardiology 8 (Supp!. B): 146B-158B,
1986
Kakkar VV, Djazaeri B, Fok J, Fletcher M, Scully MF, Westwick
J. Low-molecular-weight heparin and prevention of postoperative deep vein thrombosis. British Medical Journal 284: 375379, 1982
Kakkar VV, Kakkar S, Sanderson RM, Peers CEo Efficacy and
safety of two regimens of low molecular weight heparin fragment (Fragmin) in preventing postoperative venous thromboembolism. Haemostasis 16 (Supp!. 2): 19-24, 1986
Kandrotas RJ, Gal P, Douglas JB. Lack of parallelism between
decline of heparin concentration and effect. Abstract no. 72.
Pharmacotherapy 11: 275, 1991a
Kandrotas RJ, Gal P, Douglas JB, Deterding J. Heparin pharmacokinetics during hemodialysis. Therapeutic Drug Monitoring 11: 674-679, 1989
Kandrotas RJ, Gal P, Douglas JB, Deterding J. Pharmacokinetics
and pharmacodynamics of heparin during hemodialysis: interpatient and intrapatient variability. Pharmacotherapy 10:
349-356, 1990a
Kandrotas RJ, Gal P, Groce JB, Douglas JB. Altered heparin
pharmacodynamics in pulmonary embolism. Abstract no. 66.
Pharmacotherapy 10: 241, 1990b
Kandrotas RJ, Groce JB, Douglas JB, Gal P. Rapid determination of maintenance heparin infusion rates with the use of
non-steady state heparin concentrations. Abstract no. 106.
Pharmacotherapy 11: 280, 1991 b
Lam LH, Silbert JE, Rosenberg RD. The separation of active and
inactive forms of heparin. Biochemical and Biophysical Research Communications 69: 570-577, 1976
Larsen AK, Hetelekidis S, Langer R. Disposition and anticoagulant activity of biologically active heparin fragments in the
rat. Journal of Pharmacology and Experimental Therapeutics.
231: 373-378, 1984
Larsen AK, Lund DP, Langer R, Folkman J. Oral heparin results
in the appearance of heparin fragments in the plasma of rats.
Proceedings of the National Academy of Sciences of the United
States of America 83: 2964-2968, 1986
Larsen AK, Newberne PM, Langer R. Comparative studies of
heparin and heparin fragments: distribution and toxicity in the
rat. Fundamental and Applied Toxicology 7: 86-93, 1986
Laurent TC, Tengblad A, Thunberg L, Hook M, Lindhal U. The
molecular-weight dependence of the anti-coagulant activity of
heparin. Biochemical Journal 175: 691-701, 1978
Leroy J, Leclerc MH, Delahousse B, Guerois C, Foloppe P, et a!.
Treatment of heparin-associated thrombocytopenia and
thrombosis with low molecular weight heparin (CY 216). Seminars in Thrombosis and Hemostasis 11: 326-329, 1985
Lindahl U, Backstrom G, Thunberg L, Leder IG. Evidence for a
3-0-sulfated D-glucosamine residue in the antithrombin-binding sequence of heparin. Proceedings of the National Academy
of Sciences of the USA 77: 6551-6555, 1980
Lockner D, Bratt G, Tornebohm E, Aberg W. Pharmacokinetics
of intravenously and subcutaneously administered fragmin in
healthy volunteers. Haemostasis 16 (Supp!. 2): 8-10, 1986
Mahadoo J, Hiebert L, Jaques LB. Vascular sequestration ofheparin. Thrombosis Research 12: 70-90, 1977
Mant MJ, O'Brien BD, Thong KL, Hammond GW, Birtwhistle
RV, et a!. Hemorrhagic complications of heparin therapy.
Lancet 1: 1133-1135, 1977
Mastacchi R, Barbanti M. Inactivation of the heparin anticoagulant activity by rat kidney lysosomal enzymes. Thrombosis
Research 47: 101-106, 1987
Mattsson CH, Palm M, Soderberg K, Holmer E. Antithrombotic
effects of heparin oligosaccharides. Annals of the New York
Academy of Sciences 556: 323-332, 1989
McDonald MM, Jacobson LJ, Hay WW, Hathaway WE. Heparin
clearance in the newborn. Pediatric Research 15: 10 15-10 18,
1981
Heparin Kinetics and Dynamics
McLane J. The thromboplastic action of cephalin. American
Journal of Physiology 41: 250-257. 1916.
Nader HB. Takahashi HK, Straus AH, Dietrich CPo Selective distribution of the heparin in mammals: conspicuous presence of
heparin in lymphoid tissues. Biochimica et Biophysica Acta
627: 40-48, 1980
Nelson JC, Lerner RG, Goldstein R, Cagin NA. Heparin-induced
thrombocytopenia. Archives ofinternal Medicine 138: 548-552,
1978
Nielsen JI, Ostergaard P. Chemistry of heparin and low molecular
weight heparins. Acta Chirurgica Scandinavica 543: 52-56, 1988
Ockelford PA, Carter CJ, Mitchell L, Hirsh J. Discordance between the anti-Xa activity and the anti thrombotic activity of
an ultra-low molecular weight heparin fraction. Thrombosis
Research 28: 401-409, 1982
Ofosu F, Blajchman MA, Hirsh J. The inhibition by heparin of
the intrinsic pathway activation of factor X in the absence of
antithrombin-III. Thrombosis Research 20: 391-403, 1980
Ofosu FA, Modi G, Cerskus AL, Hirsh J, Blajchman MA. Heparin with low affinity to antithrombin III inhibits the activation of prothrombin in normal plasma. Thrombosis Research
28: 487-497, 1982
Olsson P, Lagergren H, Ek S. The elimination from plasma of
intravenous heparin. An experimental study on dogs and humans. Acta Medica Scandinavica 173: 619-630, 1963
Omri A, Delaloye JF, Andersen H, Bachmann F. Low molecular
weight heparin Novo (LHN-I) does not cross the placenta during the second trimester of pregnancy. Thrombosis and
Haemostasis 61: 55-56, 1989
Owen WG. Evidence for the formation of an ester between
thrombin and heparin cofactor. Biochimica et Biophysica Acta
405: 380-387, 1975
Palm M, Mattsson e. Pharmacokinetics of Fragmin: a comparative study in the rabbit of its high and low affinity forms for
antithrombin. Thrombosis research 48: 51-62, 1987a
Palm M, Mattsson Ch. Pharmacokinetics of heparin and low molecular weight heparin fragment (Fragmin) in rabbits with impaired renal or metabolic clearance. Thrombosis and Haemostasis 58: 932-935, 1987b
Paques EP, Stohr HA, Heimburger N. Study on the mechanism
of action of heparin and related substances on the fibrinolytic
system: relationship between plasminogen activators and heparin. Thrombosis Research 42: 797-807, 1986
Perry MO, Horton J. Kinetics of heparin administration. Archives of Surgery 111: 403-409, 1976
Perry PJ, Herron GR, King Je. Heparin half-life in normal and
impaired renal function. Clinical Pharmacology and Therapeutics 16: 514-519,1974
Pomerantz MW, Owen WG. A catalytic role for heparin: evidence for a ternary complex of heparin cofactor thrombin and
heparin. Biochimica et Biophysica Acta 535: 66-77, 1978
Proctor RR, Rapaport SI. The partial thromboplastin time with
kaolin: a simple screening test for first stage plasma clotting
factor deficiencies. American Journal of Clinical Pathology 36:
212-219,1961
Psuja P. Kinetics of radiolabelled (99mTc) heparin and low molecular weight heparin fractions CY 216, CY 222, in patients
with uncomplicated myocardial infarction. Folia Haematologica Leipzig 115: 661-668, 1988
Rosenberg RD. Actions and interactions of antithrombin and
heparin. New England Journal of Medicine 292: 146-151, 1975
Rosenberg RD, Damus PS. The purification and mechanism of
action of human antithrombin-heparin cofactor. Journal of
Biological Chemistry 248: 6490-6505, 1973
Rosenberg JS, McKenna PW, Rosenberg RD. Inhibition of human factor IXa by human antithrombin. Journal of Biological
Chemistry 250: 8883-8888, 1975
Salzman FW, Deykin D, Shapiro RM, Rosenberg R. Manage-
373
ment of heparin therapy: controlled prospective trial. New
England Journal of Medicine 292: 1046-1050, 1975
Silver D, Kapsch DN, Tsoi EKM. Heparin induced thrombocytopenia, thrombosis, and hemorrhage. Annals of Surgery 198:
301-306, 1983
Simon TL, Hyers TM, Gaston JP, Harker LA. Heparin pharmacokinetics: increased requirements in pulmonary embolism. British Journal of Haematology II: 111-120, 1978
Sinay P, Jacquinet JC, Petitou M, Duchaussoy P, Lederman I, et
al. Total synthesis of a heparin pentasaccharide fragment having high affinity for antithrombin III. Carbohydrate Research
132: C5-C9, 1984.
Solandt DY, Best CH. Time-relations of heparin action on bloodclotting and platelet agglutination. Lancet 233: 1042-1044, 1940
Stead N, Kaplan AP, Rosenberg RD. Inhibition of activated factor XII by antithrombin-heparin cofactor. Journal of Biological Chemistry 251: 6481-6488, 1976a
Stead NW, Kaplan AP, Rosenberg RD. The inhibition of human
activated Hageman factor (HF) by human antithrombin-heparin cofactor (AT). Abstract. Clinical Research 24: 321A, 1976b
Straus AH, Nader HB, Dietrich CPo Absence of heparin or heparin-like compounds in mast-cell-free tissues and animals.
Biochimica et Biophysica Acta 717: 478-485, 1982
Teien AN. Heparin elimination in patients with liver cirrhosis.
Thrombosis and Haemostasis 38: 701-706, 1977
Teien AN, Bjornsson J. Heparin elimination in uraemic patients
on haemo-dialysis. Scandinavian Journal of Haematology 17:
29-35, 1976
Teien AN, Lie M. Evaluation of an amidolydic heparin assay
method: increased sensitivity by adding purified antithrombin
III. Thrombosis Research 10: 399-410, 1977
Teien AN, Lie M, Abildgaard U. Assay of heparin in plasma us. ing a chromogenic substrate for activated factor X. Thrombosis Research 8: 413-416, 1976
Thomas DP, Merton RE, Barrowcliffe TW, Thunberg L, Lindahl
U. Effects of heparin oligosaccharides with high affinity for
antithrombin III in experimental venous thrombosis. Thrombosis and Haemostasis 47: 244-248, 1982
Thunberg L, Backstrom G, Lindahl U. Further characterization
of the antithrombin-binding sequence in heparin. Carbohydrate Research 100: 393-410, 1982
Towne JB, Bernhard VM, Hussey C, Garancis Je. White clot
syndrome. Archives of Surgery 114: 372-377, 1979
Trowbridge AA, Caraveo J, Green JB, Amaral B, Stone MJ. Heparin-related immune thrombocytopenia: studies of antibodyheparin specificity. American Journal of Medicine 65: 277-283,
1978
van Putten J, van de Ruit M, Beunis M, Hemker He. Interindividual variation in relationships between plasma heparin
concentration and the results of five heparin assays. Clinica
Chimica Acta 122: 261-270, 1982
van Rijn JLML, Trillou M, Mardiguian J, Tobelem G, Caen J.
Selective binding of heparins to human endothelial cells: implications for pharmacokinetics. Thrombosis Research 45: 211222, 1987
Vannucchi S, Pasquali F, Porciatti F, Chiarugi V, Magnelli L, et
al. Binding, internalization and degradation of heparin and
heparin fragments by cultured endothelial cells. Thrombosis
Research 49: 373-383, 1988
Vitoux JF, Mathieu JF, Roncato M, Fiessinger IN, Aiach M.
Heparin-associated thrombocytopenia: treatment with low
molecular weight heparin. Thrombosis Haemostasis 55: 37-39,
1986
Whitfield LR, Levy G. Relationship between concentration and
anticoagulant effect of heparin in plasma of normal subjects:
magnitude and predictability of interindividual differences.
Clinical Pharmacology and Therapeutics 28: 509-516, 1980
Whitfield LR, Schentag JJ, Levy G. Relationship between concentration and anticoagulant effect of heparin in plasma of
Clin. Pharmacokinet. 22 (5) 1992
374
hospitalized patients: magnitude and predictability of interindividual differences. Clinical Pharmacology and Therapeutics 32: 503-516, 1982
Wilson JE, Bynum U, Parkey RW. Heparin therpay in venous
thromboembolism. American Journal of Medicine 70: 808-816,
1981
Wilson JR, Lampman J. Heparin therapy: a randomized prospective study. American Heart Journal 971: 155-158, 1979
Yin ET, Wessler S, Butler JV. Plasma heparin: a unique, practical, submicrogram-sensitive assay. Journal of Laboratory and
Clinical Medicine 81: 298-310, 1973
Zucker S, Cathey MH. Control of heparin therapy. Sensitivity of
the activated partial thromboplastin time for monitoring the
antithrombotic effects of heparin. Journal of Laboratory and
Clinical Medicine 73: 320-326, 1969
Correspondence and reprints: Dr Robert J. Kandratas, Department of Pharmacy Practice, College of Pharmacy, University of
Utah, Salt Lake City, UT 84112, USA.
Symposium on
Interethnic Variation in Drug Handling
and Response
Date: 22-24 July 1992
Venue: Bangkok, Thailand
For further information, please contact:
Dr D.M. Burley
The Centre for Pharmaceutical Medicine
Dorna House,
West End, Woking,
Surrey GU24 9PW
ENGLAND