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References
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11
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Carbohydrate-Based Antithrombotics
Antonella Bisio, Marco Guerrini, and Annamaria Naggi
Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, V. G. Colombo 81, Milan, 20133, Italy
11.1 Introduction
The history of carbohydrate-based antithrombotics began in Toronto about a century ago, with the chance discovery of heparin by Jay McLean and William Henry
Howell[1, 2]. They had actually been looking for a procoagulant substance and
suspected that their fat-soluble anticoagulant tissue extract might be a phospholipid. Despite their initial misinterpretation, the commercial potential of heparin
was recognized immediately, and the first pharmaceutical heparin product appeared
in the US market in 1939, produced by Roche Organon with the trade name
Liquaemin. It was only in the early 1960s though, following the publication of a
landmark clinical trial based on the use of heparin for the treatment of pulmonary
embolism (PE)[3], that heparin was recognized as a powerful therapeutic drug for
the prevention and treatment of venous thrombosis by intravenous administration.
In the early 1970s, with the publication of a seminal paper by the group Kakkar,
introducing the concept of subcutaneous administration of low-dose heparin for the
prevention of postoperative deep vein thrombosis (DVT)[4], heparin entered routine clinical use as an anticoagulant drug.
In parallel with clinical studies, extensive chemical and biochemical investigations have been undertaken, contributing to the elucidation of the molecular basis
of the anticoagulant and antithrombotic activities of heparin and heparin-like glycosaminoglycans (GAGs), such as heparan sulfate (HS) and dermatan sulfate (DS),
in particular regarding their role in the coagulation system. The mechanism of the
interaction of heparin and DS with two key proteins of the coagulation process,
antithrombin (AT) and heparin cofactor II (HCII), and the subsequent enhancement of inactivation of the two key coagulation enzymes, factor Xa (fXa) and thrombin (also named fIIa) has been unraveled at the molecular level.
The wealth of knowledge acquired, especially from the mid-1970s onward, has
led to the development of low molecular weight heparins (LMWHs) derived from
353
Carbohydrate-Based Therapeutics, First Edition. Edited by Roberto Adamo and Luigi Lay.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
11 Carbohydrate-Based Antithrombotics
354
unfractionated heparin (UFH) through distinct chemical or enzymatic depolymerization processes and to a unique pentasaccharide obtained by chemical synthesis,
as distinct drugs.
11.2 Antithrombotic Drugs
Under physiological conditions, blood flows smoothly and efficiently in the arteries
and veins, but if a clot or thrombus breaks free from the vessel wall and obstructs
blood flow, the result–termed thrombosis–can have serious, even lethal, consequences. Thrombosis can occur both in arteries, which carry blood from the heart to
the rest of the body, as well as in veins, which carry blood from the body back to the
heart. Arterial thrombosis can result in a heart attack when it occurs in coronary
arteries, or in stroke when it occurs in blood vessels in the brain. Venous thrombosis
can lead to DVT, often in the legs, groin or arms, and later to PE: DVT and PE are
known collectively as venous thromboembolism (VTE). Both arterial and venous
thromboses are major healthcare concerns, causing an estimated 18 million deaths
worldwide each year[5].
The most important components of a thrombus are platelets and fibrin, the latter
being the final product of the coagulation cascade and is a protein that forms a mesh
encapsulating a high concentration of red blood cells. Both platelets and fibrin stabilize the thrombus and prevent it from breaking down, whereas fibrin predominates in venous thrombi, and platelets are the main component of arterial clots.
Accordingly, two classes of antithrombotic drugs have been developed; antiplatelet
drugs and anticoagulants. Whereas the former prevents platelets from clumping,
anticoagulants slow down clotting by reducing fibrin production and preventing the
formation and growth of clots. All carbohydrate-based antithrombotic agents of a
GAG nature, such as heparin, DS, LMWHs, and fondaparinux, together with drugs
based on GAG mixtures, share this latter mode of action. Defibrotide (DF) and pentosan polysulfate (PPS), the only non-GAG antithrombotic drugs considered here,
have a broader and more complex spectrum of action.
11.3 Heparin
Heparin originates in mammalian mast cell granules as a large (about 80 kDa) polymeric component of the proteoglycan serglycin[6]. Its biosynthesis begins with the
formation of a tetrasaccharide linkage region, which is synthesized from the proteoglycan core protein and continues with the alternating addition of 1→4linked α-Nacetyl--glucosamine (GlcNAc) and β--glucuronic acid (GlcA), which leads to
linear polysaccharide chain elongation. Immediately after polymerization, the
sequential and coordinated action of a series of enzymes gives rise to important
enzymatic modifications to the sequence. First, N-deacetylase–N-sulfotransferase
partially removes the N-acetyl group from GlcNAc by simultaneously adding a sulfate group (GlcNS), and then uronyl C-5 epimerase converts some GlcA into
11.3 Heparin
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α--iduronic acid (IdoA) and various O-sulfotransferases catalyze the addition of
sulfate groups at position 2 of IdoA, 6 of glucosamine or, less frequently, position 3
of glucosamine. The final result is the formation of structural domains with different substitution patterns and sulfation degrees[7]. Such an array of structural features can generate potentially a total of 48 different disaccharide combinations, but
due to the restrictions of the biosynthetic route, only 23 disaccharides have been
identified to date in heparin[8]. Based on the analysis of HS/heparin biosynthetic
enzymes, a biosynthetic scheme structured in two branches has been proposed, the
major one containing commonly occurring IdoA–GlcNS disaccharides, and the
minor one involving less represented structures, such as IdoA–GlcNAc [9]. The
nodal aspect of this scheme arises from the different efficiency with which epimerase converts GlcA–GlcNS into IdoA–GlcNS and GlcA–GlcNAc into IdoA–GlcNAc.
Following mast cell activation and consequent degranulation, heparin is released
in the extracellular matrix of endothelium and partially hydrolyzed by heparanase,
an endo-β-glucuronidase into fragments ranging in mass from 5 to 30
kDa [10],
resulting in a mixture of highly heterogenous polymeric chains arising from both
the different molecular weight as well as the number and position of sulfate groups
of the constituent disaccharides. The main repeating disaccharide structure of the
resulting polymer is the trisulfated unit [-4)-α--IdoA2S (1→4) α--GlcNS,6S-(1-],
which constitutes the regular polymer regions, accounting for more than 70% of
heparin chains and resulting in an overall degree of sulfation of about 2.4 per disaccharide[11, 12]. The remaining 30% of the heparin polymer, constituting the socalled irregular regions, has a more complex composition, including both less
O-sulfated and N-acetylated domains, and an important pentasaccharide sequence,
containing a 3-O-sulfated glucosamine, which interestingly, is usually preceded by
an un-sulfated IdoA residue, IdoA–[GlcNAc,6S–GlcA–GlcNS,3S,6S–IdoA2S–
GlcNS,6S–][13, 14]. Such a pentasaccharide, also called AGA*IA, with the asterisk
indicating the peculiar 3-O sulfation, is endowed with a high affinity for the plasma
protein AT. The structures of the basic disaccharide units, together with the
AT-binding pentasaccharide are shown in Figure11.1. Despite the observation that
irregular regions do not appear to be distributed in an orderly manner, a low- sulfated
domain resides close to the original heparin core protein [15]. Moreover, the
3-O-sulfated pentasaccharide turns out to be enriched toward the nonreducing terminus of the heparin chain[16–19], in agreement with the finding that NMR signals typically associated with the “linkage region” [20] are missing in heparin
fractions with high affinity for AT[21]. In contrast, other studies have suggested a
random distribution[22].
The heterogeneity of heparin can be related to the species and organs of origin
and to the process of production. Heparins from different tissues and/or animal
sources appear to have different IdoA2S and IdoA content. In particular, the trisulfated disaccharide comprises up to 90% of bovine lung heparin extracts, an organ
that was formerly a major source of heparin, whereas it represents about 75% of
porcine mucosa, which has largely replaced bovine lung as the principal source of
clinical heparin. Heparins from various animal origins also exhibit distinct levels of
the antithrombin binding pentasaccharide sequence (ATBPS). Heparins extracted
355
11 Carbohydrate-Based Antithrombotics
)
(d)
(a)
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
w
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
)
(a)
(b)
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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
358
(intrinsic) pathway
Damaged surface Tissue injury
XII XIIa
XIa
IX IXa
X
Prothrombin (II)
V
Va
VIII
XI
VIIIa
(extrinsic) pathway
(Tissue factor)
VIIa VII
X
Xa
Thrombin (lla)
Fibrinogen (l) Fibrin monomer (la)
H
LMWHs
AT :
ONDAPARINUX
F
AT : H
HEPARIN
HCll :
Common pathway
EPARIN
EPARIN
DS
Xlll
Xllla
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.
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)
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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].
11 Carbohydrate-Based Antithrombotics
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
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