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Dermatan Sulfate Synthesis Essay

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Dermatan sulfate

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dermatan sulfate — der·ma·tan sul·fate (dur″mə tan) a glycosaminoglycan found mostly in the skin but also in blood vessels, tendons, heart valves, and pulmonary connective tissues. It consists of repeating disaccharide units in specific linkage, each… … Medical dictionary

sulfate — A salt or ester of sulfuric acid. acid s. SYN: bisulfate. active s. SYN: adenosine 3′ phosphate 5′ phosphosulfate. s. adenylyltransferase an enzyme that catalyzes a step in the pathway for the synthesis of active s.; the enzyme reacts ATP wit … Medical dictionary

Chondroitin sulfate — Chemical structure of one unit in a chondroitin sulfate chain. Chondroitin 4 sulfate: R1 = H; R2 = SO3H; R3 = H. Chondroitin 6 sulfate: R1 = SO3H; R2, R3 = H … Wikipedia

Heparan sulfate — (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (PG) in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. [cite book | title=Proteoglycans:… … Wikipedia

chondroitin sulfate — n any of several sulfated forms of chondroitin found in various tissues (as cartilage, adult bone, and tendons) * * * chon·dro·i·tin sul·fate (kon droґĭ tin) 1. a glycosaminoglycan that predominates in the ground substance of cartilage, bone … Medical dictionary

Chondroitin sulfate proteoglycan — Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans[1] consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage. The following CSPGs have been identified … Wikipedia

Chondroitin-sulfate-ABC endolyase — Identifiers EC number Databases IntEnz IntEnz view … Wikipedia

Chondroitin-sulfate-ABC exolyase — Identifiers EC number Databases IntEnz IntEnz view … Wikipedia

DSE (gene) — Dermatan sulfate epimerase Identifiers Symbols DSE; DSEPI; SART2 External IDs OMIM … Wikipedia

CHST14 — Dermatan 4 sulfotransferase 1, also known as D4ST1, is a human gene.cite web | title = Entrez Gene: D4ST1 dermatan 4 sulfotransferase 1| url = Cmd=ShowDetailView TermToSearch=113189| accessdate = ] … Wikipedia

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Dermatan sulfate - ScienceDirect Topics

Dermatan sulfate Lamina densa structural components Dermatan sulfate

Dermatan sulfate, also known as chondroitin B, is the primary GAGs found in the skin (dermis and ECM ). It is a linear polysaccharide with disaccharides units containing N acetyl galactosamine or glucuronic acid, with additional complexity conferred by variably positioned iduronic acid and sulfation as well as variable total length. Core proteins with which it mostly associates in the skin include decorin, biglycan, versican, and thrombomodulin. The dermatan sulfate proteoglycans (DSPG) are able to interact with a large variety of matrix proteins, growth factors. cytokines. chemokines. and pathogen virulence factors (Trowbridge and Gallo, 2002 ). Known interactions with the dermatan sulfate GAG itself, however, are more limited and include tenascin‐X (Elefteriou et al. 2001 ). As previously discussed, it is hypothesized that this interaction is what mediates the association with collagen fibrils, as decorin‐deficient mice exhibit the same Ehlers Danlos‐like phenotype as tenascin X‐deficient mice (Mao et al. 2002 ). Tenascin‐X deficiency mimics Ehlers‐Danlos syndrome in mice through alteration of collagen deposition (Mao et al. 2002). Given the whole host of other molecules with which these DSPGs interact, it is also not surprising that they may also play a role in tumorigenesis and wound repair. During wound repair, dermatan sulfate is found to be released at high concentrations in quantities sufficient to activate FGF2. a mitogen that mediates mesenchymal cell migration, proliferation, and differentiation. In fact, wound fluid analysis suggests that dermatan sulfate may play more of a role in the FGF2 pathway than heparin sulfate, a more well studied binding partner of FGF2 (Penc et al. 1998 ). Dermatan sulfate release also appears to result in increased ICAM–1 expression and leukocyte adhesion to endothelial cells and increased circulating ICAM1 levels, indicating another role for these molecules in the inflammatory response to injury (Penc et al. 1999 ). Tumor metastasis is similarly supported. For example, melanoma and endothelial cell lines treated with chondroitinase b exhibited less proliferation and invasion (Denholm et al. 2001 ).

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Chapter: Determination of Substrate Specificity of Sulfotransferases and Glycosyltransferases (Proteoglycans)

Hiroko Habuchi, Osami Habuchi, Kenji Uchimura, Koji Kimata, Takashi Muramatsu. in Methods in Enzymology. 2006.

Heparan Sulfate and Heparin

Heparan sulfate has repeating units composed of glucosamine (GlcN) derivatives and uronic acids, which are either glucuronic acid (GlcA) or L‐iduronic acid (IdoA). The polysaccharide chain is formed by a molecular complex of two proteins called EXT1 and EXT2 (Lind et al. 1998; McCormick et al. 1998, 2000 ). Both of them have two domains of glycosyltransferases. One catalyzes the transfer of an N ‐acetylglucosamine (GlcNAc) residue and the other catalyzes the transfer of a GlcA residue. The synthesized chain has a repeating unit of GlcNAcα1‐4 GlcAβ1‐4. The polysaccharide is then modified by sulfotransferases and an epimerase. Heparan sulfate is a heterogeneous molecule with various degrees of modification. When the modification is extensive, the molecule is called heparin. the fundamental repeating unit of which is GlcNS (6S) α1‐4 IdoA(2S) α1‐4, in which S is an SO group attached to N or O atom of monosaccharides.

The key enzyme of the modification is a heparan sulfate/heparin N ‐deacetylase N ‐sulfotransferase (NDST), which catalyzes both de‐N ‐acetylation and N ‐sulfation of a GlcN residue, because other modifying enzymes either require or prefer N ‐sulfated structures in the substrate. Four species of NDSTs are present: NDST‐1 is involved in the synthesis of heparan sulfate, and NDST‐2 in the synthesis of heparin in mast cells (Aikawa et al. 2001; Eriksson et al. 1994; Kusche‐Gullberg et al. 1998 ). Glucuronyl C‐5‐epimerase catalyzes the epimerization of C‐5 of GlcA to IdoA (Li et al. 1997 ). The enzyme requires an adjacent N ‐sulfated GlcN (GlcNS) toward the non‐reducing end‐side. Heparan sulfate 2‐sulfotransferase sulfates C‐2 of uronic acids and prefers IdoA rather than GlcA (Kobayashi et al. 1997 ). There is only one species of 2‐sulfotransferase.

Heparan sulfate 6‐sulfotransferase (HS6ST) sulfates the 6‐position of GlcN, and three molecular species of the enzyme are present (Habuchi et al. 1998, 2000; Jemth et al. 2003; Smeds et al. 2003 ). All three enzymes prefer a GlcNS residue for action but exhibit a low level of activity toward structures with a GlcNAc residue. Each isoform shows different specificity toward the isomeric uronic acid adjacent to the targeted GlcNS; HS6ST‐1 prefers the IdoA‐GlcNS while HS6ST‐2 has a different preference, depending on the substrate concentration, and HS6ST‐3 acts on either substrate, as long as a GlcA‐GlcNS repeating polysaccharide and a IdoA‐GlcNS repeating polysaccharide are used as acceptor substrates. However, when heparan sulfate is a substrate, all of them have a preference for IdoA‐containing targets with or without 2‐sulfation. HS6ST‐1 shows relatively higher activity toward target sequences lacking 2‐sulfation, and HS6ST‐2 and ‐3 show a preference for 2‐sulfated substrates.

Finally, the C‐3 position of a GlcN residue is sulfated by heparan sulfate 3‐sulfotransferase; this sulfated residue is essential for the formation of an antithrombin III (ATIII)–binding site but is present only in the restricted portion of the polysaccharide chain. There are six molecular species of 3‐sulfotransferases with different specificities (Chen et al. 2003; Liu et al. 1999a,b; Mochizuki et al. 2003; Shworak et al. 1997 ).

The general order of modification in heparan sulfate is N ‐deacetylation/N ‐sulfation. followed by C‐5 epimerization and finally 2‐, 3‐, and 6‐sulfation. As can be seen from the in vitro specificities of the enzymes. this sequence of events is not strict, and in ES cells lacking both NDST‐1 and ‐2, a 6‐sulfated structure without N ‐sulfation is found (Holmborn et al. 2004 ).

Chondroitin Sulfates and Dermatan Sulfate

Chondroitin sulfates and dermatan sulfate have building blocks composed of uronic acids and N ‐acetylgalactosamine (GalNAc). The polysaccharide backbone of chondroitin sulfates is chondroitin with repeating units of GalNAcβ1‐4GlcAβ1‐3 and is formed by chondroitin synthase (DeAngelis and Padgett‐McCue, 2000; Kitagawa et al. 2001; Yada et al. 2003a,b ). Chondroitin glucuronyl C5‐epimerase changes GlcA to IdoA in the chain, forming dermatan with repeating units of GalNAcβ1‐4IdoAα1‐3, which is the backbone of dermatan sulfate.

Chondroitin 6‐sulfate is formed as the result of 6‐sulfation of chondroitin by chondroitin 6‐sulfotransferase (Fukuta et al. 1995 ). Chondroitin 4‐sulfate (also called chondroitin sulfate A ) and dermatan sulfate are formed by 4‐sulfation of the GalNAc residue by chondroitin/dermatan 4‐sulfotransferase. Three molecular species of the 4‐sulfotransferase are present, and they have different specificities in terms of uronic acids in the substrates (Hiraoka et al. 2000; Mikami et al. 2003; Yamada et al. 2004; Yamauchi et al. 2000 ). One enzyme preferentially uses chondroitin and yields chondroitin 4‐sulfate, the second one preferentially uses dermatan and yields dermatan sulfate, and the last one uses both substrates with similar efficiency. Chondroitin sulfate E, which has GalNAc(4S, 6S)β1‐4GlcAβ1‐3 unit, is formed by 6‐sulfation of chondroitin 4‐sulfate by GalNAc 4‐sulfate 6‐sulfotransferase (Ohtake et al. 2001 ). Chondroitin sulfate D, which has GalNAc(6S)β1‐4GlcA(2S)β1‐3 units, is suggested to be formed by 2‐sulfation of GlcA in chondroitin 6‐sulfate. Uronosyl 2‐sulfotransferase sulfates C‐2 of IdoA in dermatan sulfate and C‐2 of GlcA in chondroitin sulfate with lesser activity (Kobayashi et al. 1999 ). This enzyme is probably involved in the synthesis of chondroitin sulfate D.

Keratan Sulfate

Keratan sulfate has repeating units of Galβ1‐4GlcNAcβ1‐3, in which GlcNAc is always 6‐sulfated and Gal is occasionally sulfated. The polysaccharide chain is believed to be extended by the alternative actions of a β‐1,4‐galactosyltransferase (β4GalT) and a β‐1,3‐N ‐acetyl glucosaminyltransferase (β3GnT). The sequence of biosynthesis is N ‐acetylglucosaminylation, 6‐sulfation of a GlcNAc residue exposed at the non‐reducing end, and galactosylation. After formation of the polysaccharide chain, a part of Gal residue is sulfated. Using appropriate oligosaccharides as substrates, β4GalT‐IV was shown to effectively act on substrates with exposed 6‐sulfated GlcNAc and is suggested to be the enzyme performing galactosylation (Seko et al. 2003 ). Similarly, β3GnT‐7 is suggested to be the enzyme responsible for N ‐acetylglucosaminylation (Seko and Yamashita, 2004 ).

GlcNAc 6‐sulfation is catalyzed by GlcNAc 6‐sulfotransferases (GlcNAc6STs). GlcNAc6ST‐5 is involved in the biosynthesis of keratan sulfate in the cornea, and its null mutation in humans leads to macular corneal dystrophy (Akama et al. 2000 ). GlcNAc6ST‐1 and ‐3 (Akama et al. 2001; Lee et al. 2000; Uchimura et al. 1998, 2002 ) also participate in the synthesis of keratan sulfate. 6‐Sulfation of Gal is performed by keratan sulfate Gal‐6‐sulfotransferase (Fukuta et al. 1997 ).

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Proteoglycans Proteoglycans Are ECM Molecules

There are four classes of proteoglycan: CSPG, dermatan sulfate proteoglycan, heparan sulfate proteoglycan, and keratan sulfate proteoglycan. Proteoglycans are components of the ECM that are involved in adhesion, growth, receptor binding. migration, barrier formation, and interactions with other ECM molecules. Proteoglycans consist of a protein core to which glycosaminoglycan (GAG) side chains are bound by a tetrasaccharide link ( Figure 3 Figure 3 CSPGs and the action of chondroitinase ABC. CSPGs are often anchored to cell membranes, hyaluronan, and other ECM components (gray bar). (a) CSPGs are composed of a core protein linked to GAG side chains by a tetrasaccharide linker of xylose, glucose, and uronic acid. GAGs are disaccharides of N-acetylglucosamine or N-acetylgalactosamine and uronic acid. These disaccharides repeat to form a long chain. (b) Chondroitinase ABC (ChABC) is a bacterial enzyme that cleaves GAG chains, resulting in a stub of carbohydrates. This abolishes the majority of inhibition from CSPGs. ). These GAG chains are composed of repeating disaccharide units formed from two alternating monosaccharides, usually either N -acetylglucosamine or N -acetylgalactosamine followed by uronic acid. GAG chains can vary dramatically in length, and as many as 100 can be attached to the core protein. The number of GAG chains along with their sulfation pattern and the core protein to which they are bound yield a tremendous amount of variability within and between classes.

CSPGs are inhibitory ECM molecules

CSPGs include aggrecan, brevican, neurocan, NG2, phosphacan (also classified as a keratan sulfate proteoglycan), and veriscan. CSPGs are present throughout development and are crucial for axon guidance in the roof plate. the midline of the rhombencephalon and mesencephalon. the dorsal root entry zone (DRE2), the optic tract and chiasm, and the retina. An elegant study utilized the enzyme chondroitinase ABC (ChABC) from the bacterium Proteus vulgaris to digest the GAG chains of CSPGs in the developing retina. The absence of the CSPG GAG chains resulted in pathfinding errors of RGC neurons whose axons grew aberrantly into regions of the retina from which they are normally excluded. The expression of CSPGs changes after the critical period as the animal matures and the axons have reached their targets.

More on the inhibitory nature of CSPGs

The physical nature of the glial scar barrier takes several weeks to months to fully develop, which cannot explain the inhibition to axonal growth observed acutely following injury. Interestingly, CSPG expression is robustly upregulated by mature astrocytes in the glial scar within 24h of CNS injury in adult mammals and maintained for several months. This evidence, along with their inhibitory role in embryonic pathfinding in specific regions, implicated CSPGs as a barrier to regeneration in the CNS. In the early 1990s, it was shown that CSPGs are potently inhibitory to adult neurite outgrowth both in vitro and in vivo and play a significant role in CNS regeneration failure. CSPGs are not only potent inhibitors of axonal growth when encountered alone, but they can also block the growth-promoting effects of substrates such as laminin, fibronectin, and L1. In vitro adult neurites avoid stripes of laminin mixed with aggrecan when given the choice between this combination of substrates and stripes containing laminin alone. When RGCs are cultured on scar explants that are removed from the adult (but not the neonatal) brain, they can only extend long neurites if the wound tissue is pretreated with ChABC, indicating that CSPGs are potent inhibitors of neurite outgrowth in vivo as well.

Different neuronal populations experience varying degrees of growth retardation when exposed to CSPGs in vitro. RGCs are able to extend further up a stepwise gradient of aggrecan on laminin than either forebrain neurons or embryonic dorsal root ganglion cells (DRGs), although growth was significantly stalled at the transitions between steps. Immature neurons seem to be able to grow on CSPGs by upregulating integrin receptor expression until a threshold concentration of the inhibitory substrate is reached, and they can grow no further. This threshold is different for different populations of neurons. As mentioned earlier, adult DRGs grow up a smooth gradient of CSPG until the potently inhibitory rim is reached, where they stall and form dystrophic endings ( Figure 2 Figure 2 Normal and dystrophic growth cones. (a) Normal growth cone of adult DRG on laminin. The growth cone uses filopodia and lamellopodia to sample the environment for cues. (b) Dystrophic growth cone on a decreasing gradient of laminin plus an increasing gradient of inhibitory proteoglycan (arrow). The growth cone forms a bulbous, dystrophic ending when it encounters inhibitory CSPG, as is characteristic in the CNS lesion environment. Scale bar=10μm. ). In development, some neurons are capable of growing through proteoglycan-rich areas. For example, embryonic hippocampal neurons and thalamocortical fibers growing through the subplate are capable of extending neurites on oversulfated CSPGs. In vitro. when neurons are plated on low concentrations of CSPGs mixed with laminin, neurites fasciculate tightly as they would in the subplate in vivo. In both embryonic and adult systems in vitro and in vivo. the balance of proteoglycans and other ECM molecules is critical to the determination of growth cone behavior as well as bundling and branching patterns of axons.

Chondroitinase ABC ChABC digests inhibitory GAG chains on proteoglycans

The use of ChABC is currently the most effective method of removing the inhibition of CSPGs ( Figure 3 ). A single injection of ChABC into the normal uninjured brain causes a widespread reduction in the concentration of CSPGs within the ECM for at least 4weeks. It is important to note that ChABC digestion only cleaves the GAG side chains of CSPGs and that some carbohydrate residues remain attached to the core protein. These residues can be labeled with specialized antibodies to demonstrate digestion of CSPGs in a ChABC-specific manner. While the core proteins of CSPGs are somewhat inhibitory to neurite outgrowth, the vast majority of the inhibitory nature of CSPGs lies within their GAG side chains, which is evident from the work by various laboratories showing that removal of CSPGs from the glial scar enhances regeneration and can provide some functional recovery. Administration of ChABC following a nigrostriatal pathway lesion promoted regeneration of dopaminergic neurons to the point of re-innervating their target area in the striatum. In animals receiving a bilateral dorsal column injury, intrathecal delivery of ChABC induced growth of ascending sensory and descending motor axons into and possibly slightly past the lesion, which resulted in improved function of both proprioception and locomotion. ChABC treatment has also resulted in increased regeneration of Clarke’s nucleus neurons following a hemisection lesion. Similar CSPG digestion and improved regeneration have also been observed in cats receiving hemisection and rats receiving contusion injuries. This gives hope that continuing efforts to increase the efficacy of this technique could potentially lead to treatments for spinal cord injury in primates and hopefully in humans. Typically, ChABC is administered to the CNS through a pump or by direct injection. ChABC then remains active for 3days in vivo. An alternative strategy might be to genetically engineer CNS cells to express ChABC, allowing for controlled, continuous delivery of the enzyme.

The perineuronal net and the regulation of synaptic plasticity

Proteoglycans in the gray matter of the brain and spinal cord may encapsulate synapses with a lattice-like accumulation of ECM known as the perineuronal net (PNN) and prevent neuritic sprouting and synaptic plasticity. PNNs consist mostly of CSPGs produced as the animal passes through critical periods of CNS maturation. As the animal matures, PNN production increases and the potential for plasticity decreases as the synaptic connections are firmly established. Application of ChABC to the uninjured cerebellum in rats induces sprouting of unmyelinated Purkinje cell axon terminals. This CSPG-mediated inhibition of sprouting prevents changes in functional connectivity, which could lead to formation of aberrant synaptic connections. However, it may be advantageous to restore plasticity following injury. For instance, when the adult visual cortex is treated with ChABC, plasticity can be recovered. This has important applications in restoration of vision in adult strabismic animals that have been monocularly deprived since weaning and are therefore cortically blind in one eye. ChABC-induced plasticity could also be important during rehabilitation after stroke and in treating epilepsy.

Other Inhibitory ECM Molecules

In addition to CSPGs, there are many other molecules known to be upregulated following CNS injury. It is well known that axon repellants such as semaphorins. slits, and Eph/ephrins play critical roles in embryonic development, but their roles as inhibitors of regeneration in the mature CNS are just beginning to be understood.


The expression of semaphorin 3, a chemorepellant to growing axons during development, is upregulated by invading fibroblasts following stabbing types of injuries to the spinal cord. cortex, and lateral olfactory tract. Semaphorin 3’s high-affinity receptor, neuropilin 1, is upregulated in neurons attempting to regenerate into the lesion. Regenerating axons are excluded from areas near the lesion core that contain semaphorin 3, indicating that semaphorins may be another inhibitory cue present in fibroblast-rich lesions of the CNS.


The Eph receptor and its ligand. ephrin. function in cell migration, axon guidance, and tissue patterning during development and are upregulated following CNS injury. Often, the interaction of the Eph receptor and ephrin ligand results in cell repulsion. This finding suggests that Eph/ephrin signaling might be inhibitory to axon regrowth at the lesion site, or may be important in cell migration and tissue repair. Recent work has shown a correlation between segregation of reactive astrocytes and meningeal fibroblasts and ephrinB2 and EphB2 expression, respectively, following spinal cord injury in the adult rat. EphrinB2-positive astrocytes and infiltrating meningeal fibroblasts expressing EphB2 undergo a period of intermingling, which is followed by strict segregation during formation of the glial/mesenchymal scar. EphrinB3 has been characterized as a myelin-based inhibitor of axon outgrowth and is present on myelinating oligodendrocytes. Additionally, adult corticospinal neurons express EphA4, the receptor for ephrinB3, suggesting that these axons may be inhibited by Eph/ephrin signaling in the lesion environment.

Slit proteins also play important roles in cell migration and axon guidance during development and have been implicated in regeneration failure because they are upregulated after injury. The slit proteins are ligands of glycipan-1 and the Robo receptor. Cortical astrocytes express both slit and glycipan-1 mRNA following cortical injury. Robo-1 mRNA is also present on macrophages and fibroblasts following injury, which further implies that slit-mediated repulsion could be playing a role in the inhibitory environment of the lesion. While ChABC treatment removes much of the inhibition in the glial scar due to CSPGs, additional strategies must be developed to overcome inhibition resulting from other molecules present in the lesion environment.

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Alternative Anticoagulation for Hemodialysis Patients with Heparin-Induced Thrombocytopenia Type II Danaparoid

Danaparoid. a heparinoid of 5.5 kd, consists of heparan sulfate (83%), dermatan sulfate, and chondroitin sulfate. It is used as an alternative anticoagulant in HD patients with HIT type II in Canada and the European community. Danaparoid binds to antithrombin and heparin cofactor II. It inhibits factor Xa more selectively than LMWH does. 6 In 6.5% of patients with HIT, cross-reactivity against HIT antibodies may result in thrombocytopenia. For monitoring of danaparoid therapy, anti-Xa activity has to be measured. The half-life of the anti-Xa activity of danaparoid is 25 hours in patients with normal kidney function and is further prolonged in uremia. An antidote is not available. 6

Lepirudin is a recombinant hirudin preparation. It is mainly eliminated by the kidney. Thus, its half-life is markedly prolonged in patients with ESRD. After a single loading dose (0.1 mg/kg), therapeutic anticoagulation may persist for 1 week or even longer. Hirudin does not cross-react with HIT antibodies, but 44% to 74% of patients treated with hirudin for more than 5 days develop antihirudin antibodies. Antilepirudin antibodies are not necessarily associated with a decrease in efficacy. Only in 2% to 3% of patients with antilepirudin antibodies is an inhibitory effect seen, and dose adjustments are required. Target APTT is 1.5 to 2.5 times the normal value. 6,7


Argatroban is a potent arginine-derived synthetic thrombin inhibitor. It is metabolized primarily by the liver. Its half-life is only moderately extended in patients with impaired kidney function. Argatroban does not cross-react with HIT antibodies. A loading dose of 250 µg/kg before HD and a maintenance dose of 1.7 to 3.3 µg/kg per minute are recommended. Target APTT of argatroban-treated HD patients is 1.5 to 3.0 times mean of normal range. 6

In critically ill patients with HIT type II and necessity for continuous renal replacement therapy (CRRT) due to acute renal failure, critical illness scores such as the Acute Physiology and Chronic Health Evaluation (APACHE) II, the Simplified Acute Physiology Score (SAPS) II, and the indocyanine green plasma disappearance rate (ICG-PDR) can help predict the required argatroban maintenance dose for anticoagulation. 8 Argatroban dosing during CRRT in those patients is recommended as follows: the loading argatroban dose is 100 µg/kg followed by a maintenance infusion rate (µg/kg per minute), which is

2.15–0.06 × APACHE II (for APACHE II)

2.06–0.03 × SAPS II (for SAPS II)

−0.35 + 0.08 × ICG-PDR (for ICG-PDR)


Fondaparinux. a fully synthetic pentasaccharide, is a selective factor Xa inhibitor. Its half-life is prolonged in patients with impaired kidney function, but it is safe. Subgroup analysis of the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5) showed that benefits of fondaparinux over enoxaparin (when it is administered for non–ST-segment elevation acute coronary syndrome) are most marked among patients with renal dysfunction (GFR <58 ml/min per 1.73 m 2 ) and are largely explained by lower rates of major bleeding with fondaparinux . 9 In addition, fondaparinux had significant benefit in decreasing the composite outcome of death, myocardial infarction. and refractory ischemia at day 30 in this population of patients. It is, however, not yet recommended for use in patients with HIT type II.

Regional Anticoagulation with Citrate

Citrate infused into the arterial line during HD inhibits the coagulation cascade in the extracorporeal circulation by the chelation of calcium and magnesium. The local deficit in ionized calcium is corrected by calcium substitution into the venous line before the blood is reinfused to the patient. In HD patients, regional citrate anticoagulation reduces bleeding complications and improves biocompatibility of dialysis membranes compared with systemic anticoagulation with UFH or LMWH (see also Chapter 89 ).

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