Thrombosis Research 129 (2012) 388391

Contents lists available at SciVerse ScienceDirect

Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Review Article

Old and new heparins

Benilde Cosmi , Gualtiero Palareti
Dept. Angiology and Blood Coagulation Marino Golinelli; University Hospital S. Orsola-Malpighi, Bologna - Italy

a r t i c l e

i n f o

a b s t r a c t

Article history:
Received 15 September 2011
Received in revised form 1 November 2011
Accepted 4 November 2011
Available online 2 December 2011

Heparin is an effective, relatively safe, inexpensive parenteral antithrombotic agent widely used in the prevention and treatment of thromboembolic disorders, but it has several limitations such as the marked
intra- and inter-patient variability in its anticoagulant response, its poor bioavailability at low doses and its
relatively narrow risk to benet ratio. Low molecular weight heparins ( LMWHs), ultra LMWHs and synthetic
pentasaccharides have been developed from heparin to overcome its limitations. The characteristics of these
compounds are reviewed along with the description of their approved clinical uses.
2011 Elsevier Ltd. All rights reserved.

Contents
Introduction . . . . . . . . . . . . . .
Prophylaxis of venous thromboembolism
Major general surgical procedures .
Major orthopedic surgery . . . . .
Medical patients
. . . . . . . . .
Therapy of venous thromboembolism . .
Acute phase . . . . . . . . . . . .
Long-term treatment . . . . . . .
Treatment of arterial diseases . . .
References
. . . . . . . . . . . . . .

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Introduction
Heparin was serendipitously discovered in 1916 by Jay McLean, a
medical student at Johns Hopkins University who extracted it from
dog liver (hepar in Greek) [1]. Charles Best, David Scott, and Arthur
Charles of the University of Toronto worked with heparin extracted
from beef liver in the 20-30's and puried and standardized the drug.
Clinical trials followed and heparin was introduced for human use in
the 40-50's. Heparin belongs to glycosaminoglycans (GAGs) which are
naturally occurring polysaccharides whose common characteristic is
the presence of alternating and variously sulphated residues of a uronic
acid and an amino-sugar or hexosamine [2]. Heparin is synthesized by
mast cells in the connective tissue of several mammalian species and
it can be extracted from a variety of tissues such as lung, intestine and

Corresponding author at: Dept. Angiology and Blood Coagulation Marino Golinelli,
University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy. Tel.: +39
051 6362482; fax: +39 051 341642.
E-mail address: benilde.cosmi@unibo.it (B. Cosmi).
0049-3848/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2011.11.008

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liver, but nowadays the usual source for commercial heparin is porcine
intestinal mucosa.
Heparin is composed of disaccharide repeating units consisting of
14 linked residues of uronic acid and D-glucosamine [2]. Commercial heparin is a heterogeneous mixture of highly sulfated polysaccharide chains of varying length and structure whose molecular weight
ranges from 5,000 to 30,000 D with a range of 15 to 100 monosaccharide residues per chain.
The anticoagulant and antithrombotic activity of heparin is due to
its ability to enhance the activity of the natural occuring serine protease inhibitor antithrombin (AT) and thereby catalyzing the inhibition
of all the serine proteases of the intrinsic coagulation pathway such as
factor IXa, factor XIa, factor XIIa and also of the common pathway
such as thrombin and factor Xa [3]. The binding of heparin to AT requires a specic pentasaccharide sequence present in only about a
third of the chains of mucosal heparins [4]. Heparin is not absorbed
orally and must be given parenterally by either continuous IV infusion
which allows an immediate anticoagulant effect or subcutaneous injection, which is associated with a reduced bioavailability. Heparin
binds to a number of plasma proteins other than AT, to endothelial

B. Cosmi, G. Palareti / Thrombosis Research 129 (2012) 388391

cells and macrophages due to its high negative charge. Heparin non
specic binding reduces its anticoagulant activity and explains the
variability of the anticoagulant response among patients, which requires strict laboratory monitoring [5]. Endothelial cell and macrophages rapidly bind and depolymerize heparin through a saturable
mechanism of clearance, while the kidney clears heparin via a much
slower nonsaturable mechanism. As a result, the anticoagulant response to heparin is nonlinear and dose dependent at therapeutic
doses, with both the intensity and duration of effect rising with increasing doses [5].
Although it is an effective, relatively safe, inexpensive parenteral
antithrombotic agent widely used in the prevention and treatment
of thromboembolic disorders, heparin has several limitations. These
arise from: 1) the marked intra-and inter-patient variability in its anticoagulant response; 2) its poor bioavailability at low doses; 3) a relatively narrow risk to benet ratio which is contributed to by the
interference of heparin with platelet aggregation and with vessel
wall permeability which increase the risk of bleeding; 4) the risk of
the development of heparin-induced thrombocytopenia; 5) the risk
of osteoporosis during long term treatment; 6) the inability of heparin to inhibit clot-bound thrombin.
Low molecular weight heparins (LMWHs) have been developed to
overcome some of heparin limitations. When heparin is either chemically or enzymatically depolymerized or subjected to size fractionation it yields compounds which possess a shorter polysaccharide
chain and a lower molecular weight (4,000-6,500 D) and which are
designated LMWHs [5]. The proportion of high afnity chains is
lower in LMWHs than in heparin (between 10% and 20%). Another
consequence of the degradation process is that only 25% to 50% of
the molecules of commercial LMWHs contain at least 18 saccharide
units. This is the minimum length required to promote thrombin inhibition by providing a template to which both AT and thrombin bind
[5]. Ternary complex formation results in the acceleration of the
rate of the reaction by about 1,000 fold. Chains of shorter length
are unable to catalyze thrombin inhibition, but they retain the ability
to bind AT, thus producing a conformational change in the inhibitor
which accelerates the inhibition of factor Xa [5], therefore the ratio
between their anti-factor Xa activity and anti-factor IIa activity is
4:1 and 2:1 depending on their molecular distribution [5]. LMWHs
have different biochemical and pharmacologic properties than heparin. In particular, LMWHs produce a more predictable dose response
than heparin, which allows them to be administered in weight adjusted xed doses without laboratory monitoring. They also have a better

389

bioavailability at low doses when administered subcutaneously, a reduced haemorrhagic to antithrombotic ratio and a lower risk of developing thrombocytopenia. The half-life of LMWHs, which is 3 to 6 h
after subcutaneous injection, is dose independent, as they are cleared
only by the kidneys, so that their biological half-life is prolonged in
patients with renal failure.
The rst generation LMWHs contain 2550% of fragments with 18
or more saccharides (molecular weight >6000) while newer agents
(second generation or ultra-LMWHs) contain a much higher percentage of short chains (molecular weight b3000 D) with a high percentage of chains containing the high afnity specic pentasaccharide [6].
As a result their anti-Xa to anti-IIa activity ratio is very high (80160
anti-Xa UI /mg : 820 anti-IIa UI/mg). The characteristics of heparin,
LMWHs and ultra-LMWHs are shown in Table 1.
Fondaparinux is a synthetic analogue of the pentasaccharide
found in heparin and LMWH and its structure was modied to increase its afnity for AT [5]. Fondaparinux has a molecular weight of
1,728, with a higher specic anti-Xa activity than that of LMWH
(about 700 U/mg and 100 U/mg, respectively), and a longer half-life
after subcutaneous injection than that of LMWHs (17 h and 4 h, respectively). After subcutaneous injection, fondaparinux is rapidly
and completely absorbed, it has minimal non specic binding and it
can be given in xed doses without laboratory monitoring. It is
cleared only through the renal route and it is contraindicated in
renal failure. One advantage of fondaparinux is that being synthetic
it carries a very low risk of contamination when compared both to
heparin which is still extracted from animal tissues and to LMWHs
which derive from heparin. However, no antidote is available for fondaparinux in case of bleeding, while protamine can neutralize heparin
completely and LMWHs partially. Idraparinux is a hypermethylated
derivative of fondaparinux that binds antithrombin with very high afnity with a resulting plasma half-life of 80 h which allows once a
week injection without monitoring. Idraparinux has no antidote and
in phase III clinical trials has been associated with excessive bleeding.
To overcome the lack of an antidote which is crucial for the clinical
use of this long-lasting anticoagulant, a biotinylated version of idraparinux, idrabiotaparinux, has been synthesyzed. Idrabiotaparinux
has the same pharmacological features of idraparinux, but the addition of the biotin moiety allows a rapid reversal of its anticoagulant
effects after intravenous injection of avidin. Table 1 shows the characteristics of the synthetic pentasaccharides.
Even though their antithrombotic effects are similar, LMWHs are
heterogeneous compounds; they are produced by different processes

Table 1
Characteristics of heparin, LMWHs, ultra-LMWHs and synthetic pentasaccharides.

Heparin
LMWHs
Ardeparin (Normio)
Dalteparin (Fragmin)
Certoparin (Sandoparin, Monoembolex,
Alphaparin, Troparin)
Nadroparin (Fraxiparine)
Tinzaparin (Innohep)
Parnaparin (Fluxum)
Enoxaparin (Clexane, Lovenox)
Reviparin (Clivarine)
Ultra-LMWHs
Bemiparin (Hibor, Ivor, Zivor, Badyket)
Semuloparin
Pentasaccharide
Fondaparinux (Arixtra)
Idraparinux
Idrabiotaparinux (biotinylated idraparinux)

Method of preparation

Mean molecular
weight (Daltons)

Ratio of anti-factor Xa
to anti-factor IIa

Porcine intestinal mucosa extraction

12,000-15,000

Peroxidative depolymerization
Nitrous acid depolymerization
Deaminative cleavage with isoamyl
nitrate degradation
Nitrous acid depolymerization
Heparinase digestion
Hydrogen peroxyde and cupric salt depolymerization
Benzylation and alkaline depolymerization
Nitrous acid depolymerization,
chromatographic purication

6,000
6,000
6,000

1.9
2.7
2.4

4,500
4,500
4,500
4,200
4,000

3.6
1.5
3.0
3.8
3.5

Quaternary ammonium fractionation

Partial and controlled chemioselective
depolymerization

3,600
2,400

8.1
80

Chemical synthesis
Chemical synthesis
Chemical synthesis

1,728
1,728
2,052

~ 850 UI anti-Xa/mg
~ 1600 UI anti-Xa/mg
~ 1600 UI anti-Xa/mg

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B. Cosmi, G. Palareti / Thrombosis Research 129 (2012) 388391

and have distinct biochemical and pharmacological properties and

therefore they may not be completely interchangeable [7]. Few studies have compared LMWHs for clinical equivalence. Some trials have
reported comparable efcacy between LMWHs in the prophylaxis
and treatment of VTE, while others have reported signicant differences in either efcacy or pharmacological properties [7]. Clinical
guidelines on VTE prevention and treatment provide recommendations on the use of LMWHs as a class [810] and recommend that clinicians follow the manufacturer-suggested dosing guidelines for each
of the antithrombotic agents. Clinical guidelines from the ACC/AHA
for the treatment of STEMI and UA/NSTEMI specically recommend
enoxaparin [11].
LMWHs and fondaparinux have been approved for use in the prophylaxis and treatment of venous thromboembolism (VTE-i.e. deep vein
thrombosis-DVT and pulmonary embolism-PE) and for the treatment
of acute coronary syndromes (ACS).
Prophylaxis of venous thromboembolism
Major general surgical procedures
Both low dose heparin (LDH) and LMWHs reduce the risk of asymptomatic DVT and symptomatic VTE by at least 60% in general surgery
compared with no thromboprophylaxis [8]. Most thromboprophylaxis
trials of LDH administered 5,000 U 1 to 2 h before surgery, followed
by 5,000 U bid or tid for approximately 1 week. When LDH and
LMWHs were directly compared, no single study showed a signicant
difference in the rates of symptomatic VTE. The therapeutic equivalence
of LDUH and LMWHs in terms of both efcacy and safety in the general
surgical population is conrmed by at least 10 meta-analyses and systematic reviews [8]. LMWHs have an advantage over LDH as they can
be administerd only once daily and are associated with a signicant
lower risk of heparin induced thrombocytopenia when compared
with LDH.
Fondaparinux has been evaluated in a randomized, blinded clinical trial [8] among almost 3,000 patients undergoing major abdominal surgery. Fondaparinux at 2.5 mg SC once daily started
postoperatively was compared with dalteparin at 5,000 U SC once
daily started before surgery. There were no signicant differences between the two groups in the rates of VTE (4.6% vs 6.1%, respectively),
major bleeding (3.4% vs 2.4%), or death (1.0% vs 1.4%).
Major orthopedic surgery
Although meta-analyses have shown that thromboprophylaxis
with LDH is superior to no thromboprophylaxis, LDH is less effective
than other thromboprophylaxis regimens in this high-risk group. A
meta-analysis comparing vitamin K antagonists (VKAs) with
LMWHs in major orthopedic surgery (including elective total hip
and total knee replacement and hip fracture surgery) found that
VKAs were less effective than LMWHs in preventing total DVT and
proximal DVT [12]. In a meta-analysis of trials in major orthopedic
surgery, fondaparinux at a dose of 2.5 mg once daily was associated
with a lower incidence of symptomatic or asymptomatic VTE, compared with enoxaparin (6.8% vs. 13.7%, respectively;P b 0.001), but it
was also related to a higher incidence of major bleeding (2.7% vs.
1.7%;P = 0.008) [13].
Medical patients
A meta-analysis [14] of nine randomized trials that included almost 20,000 medical patients found that anticoagulant thromboprophylaxis (with either heparin, LMWH or fondaparinux) reduced
fatal PE by 64%, symptomatic PE by 58%, and symptomatic DVT by
53% with no signicant increase in major bleeding compared with

no thromboprophylaxis. However, the absolute benets of thromboprophylaxis were small, and with no effect on all-cause mortality.
Therapy of venous thromboembolism
Acute phase
There is unanimous consensus that treatment of patients with
acute VTE should start with an initial parenteral anticoagulation to
overlap with a long term oral anticoagulation with VKAs [15]. It is
also recommended to administer an immediate anticoagulant treatment while awaiting the results of objective diagnosis, if these are
not immediately available, in subjects with high or intermediate clinical probability and low risk of bleeding. VKA administration is usually started the same day of diagnosis, and 5 to 7 days are needed to
reach an effective anticoagulation. It is therefore recommended that
the initial parenteral anticoagulation should last for non less than
5 days and is to be stopped when INR is >2.0 for two consecutive
days. The initial parenteral anticoagulation has been performed for
many years with IV heparin, then substituted with SC heparin and
more frequently with LMWHs or recently with fondaparinux. The
therapy with IV heparin should start with a bolus of 5000 U (or
7080 U/kg) followed by a continuous infusion (with a pump) of
18 U/kg/h, with dose adjustment according to APTT test, to be performed at least once daily and repeated at around 4 h after any dose
adjustment, in order to achieve and maintain an APTT ratio of twice
that of normal. This type of treatment has several and important disadvantages: it requires hospitalization, a strict laboratory monitoring
and skilful dose adjustment and has a higher burden of bleeding complications. It is currently reserved to particular clinical conditions;
most frequently in patients with severe renal insufciency, where
monitoring the intensity of treatment and subsequent adjustment of
the dose is necessary to avoid an accumulation of the drug and excessive anticoagulation. Other conditions are when surgery, or delivery
or other invasive maneuvers are planned or highly probable in a
short interval time, as is the case for patients with massive PE for
whom thrombolytic therapy is being considered, and in patients
with a very high risk of bleeding complications. In all these conditions
the short half-life of the drug after infusion is stopped and the complete reversal of its anticoagulant effect using protamine sulphate
(1 mg of protamine neutralizes 80100 U of heparin when administered within 15 min of the heparin dose) are clinically important advantages of IV heparin since they allow to plan a short interval time
without therapeutic cover, or to start soon and safely a different antithrombotic treatment, or to neutralize anticoagulation if necessary.
LMWH or fondaparinux are currently used for the initial anticoagulant treatment in most cases of clinical practice. The subcutaneous
administration twice or once daily at xed doses according to the
body weight of the patient, and the absence of any laboratory monitoring are great advantages allowing an immediate or early home
treatment for many patients. A number of meta-analyses [15] have
analyzed the trials addressing the use of LMWHs (the therapeutic
doses are different for the various drugs available in the market) instead of heparin for initial treatment of patients with acute VTE (either DVT or pulmonary embolism). There was no evidence that
heparin was superior to LMWHs. On the contrary, LMWHs were associated with decreased mortality, lower recurrence of VTE and decreased incidence of major bleeding; furthermore, they have a
lower potential for heparin induced thrombocytopenia (10 times
less than heparin). Fondaparinux can also be safely and effectively
used for the initial treatment of DVT or pulmonary embolism. In the
double-blind randomized MATISSE DVT trial [16] patients were treated with a once-daily SC dose of fondaparinux (7.5 mg if 50 to 100 kg;
5.0 mg if b50 kg; 10 mg if >100 kg) or twice-daily SC LMWH (enoxaparin 1 mg/kg) for at least 5 days. There was no difference between
the two treatments in recurrent VTE, major bleeding during

B. Cosmi, G. Palareti / Thrombosis Research 129 (2012) 388391

treatment or death. In the MATISSE PE study, fondaparinux (at the

same xed body weight doses) was compared to IV heparin showing
a similar frequency of recurrent VTE, major bleeding and overall mortality [17].
Both LMWHs and fondaparinux are cleared by the kidney and can
accumulate in patients with renal failure. Due to the difculties in
monitoring treatment with LMWHs (and even more for fondaparinux) both of them are contraindicated in case of severe renal insufciency. The effect of LMWHs on APTT is non-specic and the test
cannot be used for dosage monitoring. The anti-Xa assay is more informative but has many limitations; the test is not performed in
some hospitals and there are problems of standardization. The usual
time to perform the anti-Xa assay is 4 h after an injection, when heparin levels are expected to be at the peak. A target range of 0.6 to
1.0 IU/mL is suggested for twice-daily and 1.0 to 2.0 IU/mL for oncedaily administration. LMWHs can be administered without laboratory
monitoring in the majority of patients. However, in certain clinical
situations, such as renal insufciency, pregnancy, obesity, neonates
and infants dose adjustment may be required using anti-Xa heparin
levels, or in case of unexpected bleeding or before an emergency surgery
in subjects receiving LMWHs.
Long-term treatment
Adjusted-dose SC heparin or LMWHs can be an effective approach
for the long-term treatment of DVT in substitution of VKAs. LMWHs
are preferred to heparin since it can be administered once daily without the need for anticoagulant monitoring and has a lower potential
for osteoporosis. Many studies have compared the clinical results of
treatment with LMWHs or VKAs, each administered for 3 months
after initial heparin therapy, and one meta-analysis has shown a
trend toward less recurrent VTE (OR, 0.66; 95% CI, 0.41 to 1.07) and
less major bleeding (OR, 0.45; 95% CI, 0.18 to 1.11) with LMWHs [18].
The more recent clinical guidelines recommend (Grade 1A) treatment with LMWHs instead of VKAs for the rst 3 to 6 months in patients with VTE and cancer, and subsequent anticoagulant therapy
with VKAs or LMWHs indenitely or until the cancer is resolved [9].
This recommendation is based on the results of studies that compared
VKA therapy or therapeutic dose LMWHs for the rst 3 or 6 months in
patients with cancer-associated VTE and found less recurrent VTE,
less bleeding and lower mortality with LMWHs.
Treatment of arterial diseases
In case of acute limb ischemia, either due to thrombosis or embolism, the initial goal of treatment is to prevent thrombus propagation
and worsening ischemia. An immediate anticoagulation with heparin
is therefore indicated if absolute contraindications are absent. The
standard initial therapy is based on intravenous administration of
therapeutic dose of heparin.
Many studies have shown that treatment with heparin in the acute
phase of unstable angina or non-Q myocardial infarction is associated
with a considerable reduction in the risk of recurrent ischemic events.
However, due to the drawbacks of heparin, LMWHs were expected to
have practical advantages, and have been studied in a number of trials
whose results, though not always consistently, showed signicant benet compared to heparin. Two large studies compared enoxaparin to
heparin (both agents being used at therapeutic dose and in conjunction
with aspirin) and found a reduced incidence of the composite endpoint
(death, MI, or recurrent angina) with LMWHs [19]. Treatment with
enoxaparin proved also effective in reducing the rates of hospital

391

death and re-infarction in patients with acute ST-elevation myocardial

infarction compared to patients receiving heparin.
Fondaparinux (2.5 mg OD) has been compared with enoxaparin
(1 mg/kg sc BID) or intravenous heparin in patients with ACS . In the
study OASIS-5 (patients with nonST elevation MI) fondaparinux was
similar to enoxaparin in reducing the risk of ischemic events but substantially reduced major bleeding by approximately one half, including
fatal bleeding, and improved long term mortality and morbidity [20].

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