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11 Carbohydrate-Based Antithrombotics
)
(d)
(a)
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356
OH (SO
O
NHAc (SO
CH2OSO
O
NHSO
–
)
3
O
–
3
–
3
–
3
(c)
O
–
CO
2
OH
OSO
IdoA2SO
CH
OSO
2
O
OH
NHAc
O
–
CO
2
OH
O
–
(H)
3
GlcNSO3,6SO
–
3
–
3
O
CH
–
SO
3
O
OH (SO
3
–
(H)
CH
2SO3
O
–
NHSO
3
O
–
3
OH
CO
2
O
OH
O
OH
AT-binding pentasaccharide
–
O
–
)
OH (SO
2
O
NHAc
)
3
O
CO
2
OH
(b)
–
OSO
CH
2
3
O
–
OSO
3
O
–
NHSO
3
IdoA-GalNAc,4SO
–
O
OH
GlcA-GlcNAc
O
–
CO
2
OH
OSO
3
CH
2
O
OH
OH
O
–
3
Figure11.1 Structures of the prevailing (a) and minor (b) heparin disaccharide units, of
the peculiar AT-binding pentasaccharide (c), and of dermatan sulfate repeating disaccharide
unit (d). The forms in parenthesis occur less frequently.
from clams are surprisingly rich in ATBPS and exhibit very potent anticoagulant
properties [23]. Pharmaceutical-grade UFH of porcine origin consists of chains
ranging from under 5000 Da to over 60 000 Da, with a mean molecular weight (M
from 15 to 20
kDa, which also depends on the method of preparation[24, 25].
A further level of complexity of heparin structure, besides its disaccharide composition, sequence of disaccharide components and clustering of similar disaccharides to constitute different domains, is provided by the IdoA conformation, which
1
exists in equilibrium mostly between the chair
C4 and the skew 2S0 conformation.
The relative population of these forms in solution depends on the presence of the
2-O-sulfate group and on the nature and structure of the neighboring units[26].
Whereas the overall geometry of the heparin chains remains similar for the two
IdoA conformers, the spatial arrangement of the sulfate groups is significantly dif-
1
ferent for the two local conformations. While in the
2
groups are more dispersed, in the
S0 form, sulfate groups are arranged in symmetri-
C4 conformation, the sulfate
cally oriented clusters (Figure11.2)[27]. The “plasticity” of IdoA residues, modulated through particular sequences, can generate local distortions in the secondary
structure of the polysaccharide chains, facilitating the most effective docking of the
anionic groups of the GAG to the basic amino acids of proteins. In this regard, it is
noteworthy that iduronate residues of the pentasaccharide sequence adopt a purely
)
w
(a)
(b)
357
–
OOC
1
C
4
0.40 nm
O
OH
1
O
354
2
O
O
–
SO
3
–
OOC
2
S
0
0.24 nm
O
O
O
HO
OSO
–
3
Figure11.2 Structural differences associated with different conformations of iduronate
residues. Structure of heparin sequences of the NS region along and across the chain for
the[1]C
2
(a) and the[2]S0 conformation (b). Source: Adapted from Mulloy etal.[27].
4
S0 conformation when bound to AT, independent of its sulfation, or the structure of
the neighboring units[28–30]. Some of the challenges of studying conformational
aspects of this class of molecules and the application of density functional theory as
a solution have been highlighted in a recent study of heparin tetrasaccharides[31].
11.4 Mechanism ofInteraction
withCoagulation Factors
11.4.1 Antithrombin-Mediated Activity
Heparin exerts its antithrombotic/anticoagulant action in several ways, the most
important of which is through the enhancement of the protein cofactor AT, a plasma
serine protease inhibitor. Heparin catalyzes the inhibitory activity of AT principally
against two key coagulation enzymes, fXa and thrombin, by irreversibly blocking
their procoagulant activity through a proposed combined template-based/allosteric
mechanism. Despite heparin acting at many levels of the coagulation cascade by
accelerating the inhibition of several factors, such as VIIa, IXa, XIa, XIIa, and kallikrein by AT, all of these activities combined are far less significant than the inhibition of fXa and thrombin[32, 33]. (Figure11.3).
Heparin promotes the interaction between AT and thrombin or fXa by binding
with the ATBPS AGA*IA and inducing in the protein a conformational change,
which is mainly driven by specific electrostatic interactions between sulfate groups
11 Carbohydrate-Based Antithrombotics
Contact activation
Cross-linked brin clot
Tissue factor
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358
(intrinsic) pathway
VIII
Figure11.3 A simplified diagrammatic representation of the classical blood coagulation
cascade, with the conventional division into three pathways; the intrinsic, extrinsic, and
common pathways. The intrinsic pathway is activated by internal damage to endothelial
cells of the vessel walls, whereas the extrinsic pathway can be activated in several ways,
including tissue damage outside of the blood vessel, hypoxia, sepsis, malignancy, and
inflammation. The two pathways converge in a final common pathway that ultimately
converts fibrinogen into a fibrin clot. The function of blood coagulation is to maintain
hemostasis, an intricate process, which is achieved by a series of clotting factors (indicated
by Roman numerals) that are transformed in sequence from an inactive to an activated
form (a), each one catalyzing the following reaction in a cascade. Most of these factors are
serine proteases (except for glycoproteins fV, fVIII, and for fXIII, a transglutaminase), which
act by hydrolyzing downstream proteins. Blue arrows represent the conversion of proenzymes into their active forms; red lines indicate the inhibition of coagulation factors fXa
and fIIa, by AT and HCII, accelerated by complexation with heparin or structurally related
molecules. The AT:heparin complex also inhibits factors fVIIa, fIXa, fXIa, and fXIIa.
(extrinsic) pathway
Damaged surface Tissue injury
Thromboplastin
(Tissue factor)
XII XIIa
VIIa VII
X
Xa
Thrombin (lla)
Fibrinogen (l) Fibrin monomer (la)
IX IXa
VIIIa
Prothrombin (II)
V
XIa
X
Va
H
EPARIN
LMWHs
AT :
FONDAPARINUX
AT : H
EPARIN
HEPARIN
HCll :
DS
Common pathway
Xlll
Xllla
and positively charged amino acids. The molecular basis of the high affinity AT:
pentasaccharide interaction has been studied extensively[34–36]. Interestingly, a
two-step mechanism was proposed, consisting of an activating step induced by
AGA* trisaccharide followed by a stabilizing step promoted by IA disaccharide,
which should be facilitated by the conformational flexibility of iduronate residues[37]. Subsequently, Lima etal.[38] suggested that the 3-O-sulfate group in the
central glucosamine could play a stabilizing role of AT rather than an activating
one. More recently, a three-state model for heparin allosteric activation of AT was
proposed,which explains both the need for a core conformational change and the
role of the peculiar reactive-center-loop hinge insertion[39]. Moreover, structural
(a)
(b)
variants of the ATBPS have been also isolated from porcine and bovine heparins,
which appear to contain N-sulfated instead of N-acetylated glucosamine at the nonreducing end and/or a 6-O-desulfated central 3-O-sulfated glucosamine[29, 40].
Extensive details of the mechanism of thrombin and fXa interactions with the
AT-heparin complex have been reported[41, 42]. Importantly, there are substantial
differences between the way thrombin and fXa interact with heparin-activated
AT. Whereas fXa establishes a direct protein–protein interaction, which is favored
by, but not strictly dependent on, direct binding with heparin[36], thrombin must
bind to the same heparin chain that is bound to AT. This additional interaction
requires that the heparin chain is sufficiently long to reach both proteins
(Figure11.4). In particular, a chain extension of at least 13monosaccharide units
toward the nonreducing end of the ATBPS is required. Such an octa-decasaccharide
minimum motif for thrombin inhibition through AT called the C-domain[44], has
been isolated[45] and has a molecular weight of 5400 Da.
For fXa inactivation, the dependence on the molecular weight of heparin is much
less stringent. Interaction with both heparin and AT, while occurring, is not an
essential requirement for fXa inhibition. Accordingly, heparin chains below 5400 Da
containing the ATBPS, can still inhibit fXa [46]. This finding constitutes the biochemical rationale for the development of low molecular-weight heparins. For UFH
the ratio between anti-Xa and anti-IIa activity is 1 but, for low molecular-weight
heparins, is higher [47]. Importantly, by inactivating thrombin, heparin also
359
Figure11.4 Heparin-antithrombin-thrombin (a) and pentasaccharide-antithrombin-FXa
(b) ternary complexes. Antithrombin, thrombin, and fXa are shown in green, cyan, and
orange, respectively. The pentasaccharide sequence is colored in red. Source: Adapted from
Johnson and coworkers[36, 43].
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360
inhibits fibrin formation and additionally prevents thrombin-induced activation of
factor V and factor VIII[48, 49]. The anticoagulant activity of heparin is heterogenous because only approximately one-third of UFH chains contain the ATBPS and
hence are capable of binding with high affinity to AT (high-affinity heparin).
Heparin chains lacking this specific sequence (termed low-affinity heparin) have
minimal anticoagulant activity at therapeutic concentrations. They can activate AT
invitro, but only at very much higher concentrations[50].
11.4.2 Heparin Cofactor II Mediated Activity
The anticoagulant activity of heparin is also mediated by a second plasma cofactor,
HCII, another glycoprotein belonging to the serine protease inhibitor family, with
structural similarities to AT. HCII selectively inhibits thrombin by forming a stoichiometric 1:1 covalent bimolecular complex, which is favored by the presence of
heparin[51, 52], however, the potentiation of thrombin inhibition by HCII is an
order of magnitude smaller than the action of the heparin-AT complex on thrombin[53]. Moreover, HCII binds heparin in a nonspecific manner, the apparent binding affinity being affected by ionic strength and chain length. The minimum heparin
chain length interacting with the HCII binding site comprises 13monosaccharide
units. Interestingly, HCII and AT have the same affinity for low-affinity heparin
(Kd∼25
μM)[54]. HCII can also be activated by other GAGs and, in the vascular
system, it appears to have specificity for DS, indicating that it may represent a potential alternative to heparin for the prevention and treatment of thrombosis[55] (see
Section11.6.1).
11.4.3 Additional Factors
As mentioned previously, heparin antithrombotic activity is not limited to its anticoagulant effect. It is also capable of enhancing the electronegative potential and
hence the antithrombogenic property of vessel walls[56]. Heparin can also act by
enhancing the activity of other two serin protease inhibitors, such as protein C
inhibitor (PCI) and tissue factor pathway inhibitor (TFPI), the former promoting
thrombin generation, the latter inhibiting factors Xa and VIIa. Both PCI and TFPI
together participate in the balancing mechanism between procoagulant and anticoagulant forces that maintain hemostasis[42].
11.4.4 Adverse Effects ofHeparin
The limitations of heparin use are caused by AT-independent mechanisms attributable to its charge-dependent binding properties with numerous proteins, including
plasma proteins released from platelets and endothelial cells[57, 58]. The most
important side effect of heparin, as with many other antithrombotic agents, is bleeding[59]. Owing to the relatively short plasma half-life of heparin, this effect is relatively transient and can be reversed by protamine, a highly basic protein composed
predominantly of arginine residues. Protamine and heparin polyanionic chains
interact in a straightforward manner, forming stable complexes, which are totally
devoid of anticoagulant activity and are removed rapidly from the circulation.
11.4.4.1 Heparin-Induced Thrombocytopenia
A further well-described and potentially life-threatening side effect is the immunemediated heparin-induced thrombocytopenia (HIT), which occurs typically after
10–14 days of heparin therapy in about 5% of treated patients[60]. HIT is a prothrombotic disorder caused by the formation of antigenic complexes of heparin and
platelet factor 4 (PF4), a positively charged protein released by platelets following
their activation. It is usually associated with a fall in platelet count of more than 50%
and with the onset of serious vascular endothelial injury, such as thrombi formation
and disseminated intravascular coagulation [61]. Thus, HIT appears paradoxical
because, despite thrombocytopenia inducing an anticoagulant effect, the major
clinical consequence is a worsening of the venous or arterial thrombotic risk.
11.4.4.2 Osteoporosis
The other common serious side effect of long-term heparin use is osteoporosis, with
an incidence of 2.2–5%. Despite the mechanism by which heparin affects bone
metabolism is unclear, it has been hypothesized that osteoporosis may be caused by
the interaction of heparin with osteoblasts, resulting in the release of factors that
activate osteoclasts [62]. All of these effects are dependent upon heparin chain
length and are significantly reduced by the administration of LMWH.
361
11.5 Low Molecular Weight Heparins
First introduced into clinical practice some 30 years ago, LMWHs have gradually
replaced heparin for the prophylaxis and treatment of DVT. They constitute a class
of depolymerized heparin derivatives endowed with distinct biochemical and pharmacological profiles, which are determined by their composition[63, 64]. Developed
with the intention of minimizing the adverse side effects of heparin, LMWHs should
in principle differ from their parent heparins only in terms of their chain length,
which is approximately one-third of that of the original UFH. They differ not only
in molecular weight but also in monosaccharide composition and disaccharide
sequences, depending on the method used for their manufacture. Different chemical, enzymatic, and physical strategies have been employed to prepare LMWHs,
each one exhibiting its own cleavage selectivity of the heparin chains, and each one
introducing distinct chemical groups, thereby providing process-related fingerprints. An overview of the methods for preparing LMWHs has been reported[65].
The four most used LMWHs in US and Europe are enoxaparin, dalteparin, tinzaparin, and nadroparin each of which is characterized by unique structural modifications at the reducing and/or nonreducing ends of the cleaved heparin chains [66,
67]. Enoxaparin derives from chemical β-eliminative cleavage by alkaline treatment
of heparin benzyl esters that introduces Δ4,5 unsaturation into uronic acid residues
at the nonreducing end. An additional characteristic is the presence of 1,6-anhydro
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362
amino sugars at the reducing end [68]. Tinzaparin, produced by enzymatic
β-eliminative cleavage of UFH by heparinase-I, is also characterized by the presence
of an unsaturated uronate residue at the nonreducing chain end. Dalteparin and
nadroparin are both obtained by deaminative cleavage with nitrous acid followed by
reduction, which results in the formation of an anhydromannitol ring at the reducing end. They differ in the ionic form, dalteparin being a sodium salt, such as enoxaparin and tinzaparin, nadroparin a calcium salt. All of these new, non-native,
residues increase the structural complexity of LMWHs compared to UFH. Moreover,
owing to the domain structure, the fragmentation of heparin chains based on the
distinct preferential cleavage points of the various methods generates oligosaccharides, which differ significantly in their disaccharide sequences. Furthermore, the
important ATPBS, when preserved by the depolymerization method, can be located
differently within the oligosaccharide chain, with consequently different binding
abilities toward AT. Both the reducing and nonreducing extensions of the AGA*IA
sequence, together with possible structural modifications inside the pentasaccharide itself, influence the AT-binding properties of heparin oligosaccharides in a
manner dependent on the structures of those additional residues[14].
Despite the undeniable importance of all these structural alterations, the most
relevant structural differences among LMWHs, directly affecting their pharmacological activity are, nevertheless, still significantly dependent on the average molecular weight and oligosaccharide distribution [69, 70]. In vitro functional assays
assessing plasma protein binding and AT-mediated antiprotease activity identify
wide variations among the commercially available LMWHs[71] (Table11.1). Most
of the anticoagulant and pharmacokinetic differences between LMWHs and UFH,
such as reduced bleeding and lowered risk of thrombocytopenia, sustained
antithrombotic activity, better bioavailability, and longer half-life, can be explained
Table11.1 Average molecular weight (Mw) and polydispersity degree (D), anti-Xa, anti-Xa/anti-IIa ratio
(Xa/IIa) activities, elimination half-life (t½), and percentage content of GA* disaccharide (the structural
marker of ATBPS determined by NMR) of LMWHs in comparison with fondaparinux and a typical UFH.
Anti-Xa
LMWH Mw (Da) D
UFH 17 500[25] 1.14[25] 193[72] 193[72] 1[72] 0.5–2.5[73]
Enoxaparin 5400[70] 1.34[70] 104[71] 32[71] 3.3[71] 4.5[73] 3.2[69]
Dalteparin 6900[70] 1.22[70] 122[71]
Tinzaparin 8300[70] 1.40[70] 90[71] 50[71] 1.8[71] 3.4[73] 2.1[71]
Nadroparin 4500[71] na 94[71] 31[71] 3.0[71] 3.5[73] nd
Bemiparin 3600[75] na 80–120[75] 5–20[75] 8.0[75] 5.2–5.4[75] nd
Fondaparinux 1728
na: not available; nd: not determined; °molecular mass of sodium salt.
◦
1.0 930[75] 0 — 17[73] —
(IU mg−1)
Anti-IIa
(IU mg−1) Xa/IIa t½ (h) GA*
2.6[74]
dose-dependent
60[71] 2.0[71] 2.0–2.3[73] 4.1[71]
11.6 Drugs Based on Natural GAG Mixtures
by their lower affinity for several plasma and tissue proteins resulting from their
reduced chain length [76–78]. Importantly, owing to their lower Mw, they have
reduced ability to inhibit thrombin compared to UFH. The specific activity of
1
LMWHs in anticoagulant assays ranges from 30 to 60 U mg
1
130 U mg
for anti-Xa[71]. The numerous advantages of LMWHs over UFH have
for anti-IIa, and 80 to
limited the current use of the latter mainly to the prevention of clotting during procedures involving the extracorporeal circulation of blood (e.g. cardiopulmonary
bypass and dialysis), owing to its ability to be neutralized by protamine[79].
11.5.1 Ultralow Molecular Weight Heparins
Ultralow molecular weight heparins (ULMWHs) represent the recent evolution of
depolymerized heparin derivatives, a new “second generation” LMWH, designed
with the aim of minimizing the risk of bleeding and HIT[73]. With an average
molecular weight of 36 kDa, an anti-fXa/anti-fIIa activity ratio of 8:1 and a half-life
of about five hours (Table11.1), bemiparin was the first ULMWH that was approved
in Spain in 1998, obtained by chemical β-elimination and fractionation of porcine
mucosal UFH [75]. Currently marketed in 58 countries except for the USA, it is
approved for once-daily subcutaneous use in the treatment and prophylaxis of VTE,
and for the prevention of clotting in the extracorporeal circuit during hemodialysis.
The development of two other ULMWH compounds, semuloparin and RO-14,
the latter being a bemiparin derivative[73, 80, 81], were suspended by their respective manufacturers, despite promising initial clinical results, because they were considered to be commercially unattractive following the introduction of fondaparinux
into clinical use (see paragraph 8).
363
11.6 Drugs Based on Natural GAG Mixtures
Sulodexide, danaparoid, and mesoglycan are the active components of the most
clinically studied drugs based on natural GAG mixtures. These are obtained from
porcine intestinal mucosa following heparin extraction, comprising heparin/HS
and DS in different proportions and, in the case of danaparoid and mesoglycan, also
by a minor amount of chondroitin sulfate (CS). Owing to their overall lower sulfation degree with respect to heparin, they have higher bioavailability, a longer halflife and a reduced effect on systemic clotting and bleeding. Moreover, these
heparinoids are often used as alternatives to heparin therapy in patients who have
developed HIT [82–86]. Their efficacy derives from the dual action of catalysing
thrombin inhibition through the simultaneous activation of AT and HCII, exerted
by both heparin/HS and DS components[87, 88].
The role of DS in these compounds deserves particular attention. Despite it not
being the exclusive constituent of any drug currently available, the contribution of
DS to the regulation of the coagulation cascade has been extensively described,
together with its potential therapeutic role[89–91].
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11.6.1 The Role ofDermatan Sulfate
Dermatan sulfate, a constituent of the extracellular matrix of several tissues also present on the cell surface of vasculature endothelium, is an IdoA containing GAG, like
heparin. It differs significantly, however, from heparin in its lower sulfation degree,
as the IdoA residues are mostly unsulfated, as well as in the position and configuration of glycosidic bonds. DS is largely composed of monosulfated disaccharide
repeating unit [-4)-β-L-IdoA-1→3-α-D-GalNAc,4S-(1-], where α-D-GalNAc,4S is an
N-acetylated galactosamine residue, O-sulfated at position 4. Dermatan sulfate is also
intrinsically heterogenous; some of its uronic acids being β-D-GlcA, and some of its
disaccharide units bearing additional sulfation, either at position 2 of the IdoA residue or, at position 6 of the GalNAc4S residue (Figure 11.1). These over-sulfated
sequences are deemed responsible for the antithrombotic properties of this GAG[92].
Commercial DS preparations are polydisperse mixtures of molecules with M
up to 60
kDa[25].
24–47
kDa. On average, the M
of purified DS extracts varies from approximately
w
Actually, despite HCII not requiring specific structural sequences in heparin, it
does need specific IdoA2SO
-GalNAc, 4SO3 disulfated sequences in DS [93]. The
3
minimum structural motif for binding HCII should be composed of at least three
disulfated disaccharides, but the enhancement of HCII-mediated thrombin inhibition requires at least three to four additional disaccharide units[94]. More precisely,
the longer the disulfated disaccharide sequence, the higher the HCII-mediated
inhibitory activity[95]. Dermatan sulfate polymers from marine invertebrate, mainly
composed of IdoA2SO
polymers mainly composed of IdoA2SO
-GalNAc4SO3 activate HCII at low concentrations, whereas
3
-GalNAc6SO3 exhibit 1000-times lower
3
activity[96, 97].
Dermatan sulfate has been employed for prophylaxis of VTE in patients undergoing surgery for cancer, despite its reduced antithrombotic activity compared to heparin, DS is a safer drug for intramuscular administration, because of reduced
bleeding complications[98]. Dermatan sulfate has also been employed successfully
as anticoagulant therapy in patients who developed renal failure following major
cardiovascular surgery[99]. More recently it has been proposed as an anticoagulant
in regular dialysis treatment instead of the standard use of heparin, providing an
alternative approach in case of thrombocytopenia or other adverse effects of
UFH[100]. As the high molecular weight of DS chains prevents its absorption following subcutaneous administration, low molecular weight DS derivatives, such as
Desmin 370, have also been proposed[101]. Despite a reduced invitro potency, they
exhibit better pharmacokinetic properties, including improved bioavailability and
longer duration of action[102, 103].
values
w
11.6.2 Sulodexide
Sulodexide, present on the European and US markets mainly with the trade names
of Vessel and Sulonex, respectively, is a highly purified GAG composed by 80% of
fast-moving heparin (Fm-Hep) fraction, defined on the basis of its electrophoretic
11.6 Drugs Based on Natural GAG Mixtures
mobility under specific conditions, and 20% DS[104, 105]. According to a recent
detailed structural characterization of sulodexide, the Fm-Hep component has a
molecular weight of about 10–11 kDa and an overall sulfation degree (number of
sulfate groups per disaccharide) of 2.13, both lower than typical current UFH,
15–20 kDa, and 2.45, respectively. The DS component also has a significantly lower
molecular weight than typical DS samples, about 20–21 kDa vs. 30–50 kDa[25, 105].
Sulodexide pharmacological properties, being mediated by both AT and HCII, are
comparable to UFH, as is the release of TFPI, which further contributes to its
antithrombotic effect. Owing to the structural features of its GAG components,
however, it differs from heparin in its extensive absorption by the vascular endothelium both following parenteral and oral routes and in its longer half-life[106, 107].
Several clinical studies demonstrated that prolonged sulodexide administration
decreases the incidence of recurrences of thromboembolic events without detectable risk of bleeding[108]. Currently, sulodexide is widely accepted in many countries as an effective and safe endothelial-protecting agent[106].
11.6.3 Danaparoid
Danaparoid is a low molecular weight heparinoid composed of a mixture of HS, DS,
and CS, and constitutes the active principle of Orgaran. From a recent in-depth
structural study of danaparoid, the quantitative relationship among the three components determined by 2D-NMR is in the following ranges: 77.6–88.4% for HS,
9.0–16.8% for DS, and 2.3–8.0% for CS[109]. Regarding the molecular weight evaluation, the weight average (M
) of the whole mixture ranges between 4.2 and 4.6 kDa,
w
whereas the two fractions comprising DS/CS and HS vary in the range 6.2–7.0 kDa
and 3.3–3.5 kDa, respectively. The prevalence of HS (77.6–88.4%) compared to relatively low levels of DS in the sample explains the relatively low average molecular
weight of the sample. Together with an overall sulfation degree of 1.19–1.32, the
same study describes the presence of oxidized gluco/galactosamine at the reducing
end as process signatures[109]. Owing to its peculiar structural features, danaparoid
has high bioavailability and inactivates fXa more than thrombin by a ratio greater
than 20:1[110]. Moreover, the elimination half-life is in the range 19.2–24.5 hours
during anti-Xa activity and in the range 1.8–4.3 hours during anti-IIa activity[111].
Renal excretion is the main route of elimination, accounting for approximately
40–50% of the total clearance of anti-fXa activity following intravenous administration[111]. Danaparoid does not differ from UFH in terms of efficacy in the treatment of existing DVT and it has been proven effective in the prophylaxis of DVT
following ischaemic stroke, in the treatment of patients with renal failure or dependent on renal replacement therapy, and in patients who developed HIT[83, 112].
365
11.6.4 Mesoglycan
Mesoglycan is marketed in many countries with the trade name Prisma. Despite its
structural characterization never having been reported, mesoglycan is commonly
described as being composed by 47.5–52% of HS, 8–8.5% of slow-moving heparin
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