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      COVID-19, Low-Molecular-Weight Heparin, and Hemodialysis

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          Are Hemodialysis Patients at a Lower Risk for COVID-19 Infection? Hemodialysis patients are a population displaying impaired lymphocyte and granulocyte function, and, by strict definition, they are, at least theoretically, at an increased risk for infection by COVID-19 given also the characteristics of the average dialysis center, where social distancing is difficult to achieve [1, 2]. However, the scant available data indicate somewhat otherwise; in a report from a university dialysis facility (Zhongnan Hospital) in Wuhan, China, with 201 patients, the prevalence was equal to 5 (2.5%). In addition, cases had no severe symptoms or died [3]. According to another report, related to another university dialysis facility (Renmin Hospital) in Wuhan, China, in the period between January 14, 2020, when the first confirmed case was diagnosed, and February 17, 2020, when the epidemic was declared extinct, among 230 hemodialysis patients 37 (16%) COVID-19 cases were diagnosed. During the epidemic, 7 hemodialysis patients died (18.9%). Symptoms were mild in most surviving patients and there were no cases admitted to the intensive care unit. Laboratory exams showed an impaired cellular immune function (especially lymphocytes of T cells, Th cells, killer T cells, and NK cells) and an incapability of mounting the “cytokine storm” linked to pneumonia, compared to COVID-19 patients not on hemodialysis. The cause of death was related instead to cardiovascular complications [4]. In an Italian experience, among 200 patients 18 were infected and isolated (9%), and in another unit of 170 patients only 4 were infected [5]. In the Piedmont and Aosta regions, among 2,893 patients 98 were infected (3.4%) during the first month of the epidemic [6]. By the way, in none of the mentioned studies was the mode of anticoagulation during hemodialysis mentioned. While they cast doubts on the open-space hospital model now implemented in many hospitals, which is incompatible with the need to counteract epidemics [7], these reports also create uncertainty regarding the concept that these patients are at a particularly increased risk for COVID-19. Hemodialysis and Anticoagulation Heparin actually consists of a heterogeneous mixture of sulfomucopolysaccharides, containing also a minimum peptide component of 2 amino acids (glycine and serine). Heparin exerts a binding capacity to both the endothelial surface and various plasmaproteins (Fig. 1). The molecular weight range of unfractionated heparin (UFH) is 5,000–30,000. Low-molecular-weight heparin (LMWH) fractions effectively inhibit the activated factor X (Factor Xa), while exerting a less inhibitory effect on thrombin, compared to the unfractionated forms. It has been shown that LMWH preparations retain their efficacy toward thromboembolisms and, compared to UFH, show increased bioavailability and the need for less frequent administration. Heparin biological activity crucially depends on the endogenous antithrombin anticoagulant [8, 9]. The serine protease inhibitor activity of antithrombin is exerted toward thrombin and Factor Xa, resulting in the inhibition of both (Fig. 1) [10]. Congenital or acquired antithrombin deficiency is indeed associated with a high risk of thromboembolic complications and an impaired interaction with heparin. Administration of antithrombin is generally indicated for the prophylaxis of thromboembolic accidents in nephrology (e.g., in patients with nephrotic syndrome) [11]. In addition, it has been shown that during sepsis activation of the extrinsic coagulation pathway, together with a relevant decline of both coagulation inhibition and fibrinolytic mechanisms, may result in a procoagulant state, leading to microvascular thrombosis and multiorgan dysfunction [12]. Antithrombin levels decrease in sepsis and, when low, may predict high mortality [13]. In addition, heparin is utilized in this context, also for its immunomodulatory and anti-inflammatory role [14]. During hemodialysis it is necessary to perform anticoagulation of the dialysis circuit to avoid blood clotting in the system due to Factor VII, platelet, and leukocyte activation. Anticoagulation is usually performed utilizing heparin, often in Western Europe in the low-molecular-weight form [15, 16], which has some advantages over UFH. Relative to UFH, in fact, LMWH could induce less undesired bleeding after completion of the dialysis session and perhaps less triglyceride reduction. Evaluating the Risk of Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) is an immune complex-mediated condition defined as a decrease in platelet counts below 150,000 per mm3, with a median nadir of about 55,000 per mm3, associated with a positive test for heparin-dependent antibodies [17, 18]. The typical onset pattern (60% of the cases) results in a platelet decline 5–10 days after exposure. The rapid onset pattern (30% of cases) occurs right after the exposure. The delayed onset pattern (∼10%) occurs 9.2 days after the start of heparin administration therapy, on average, although signs and symptoms may occur up to 3 weeks after the exposure [18]. Careful evaluation and monitoring should be indeed applied toward the risk of HIT [19]. LMWH offers the advantage of a reduced binding to platelet factor 4, thus decreasing the HIT risk [20]. On the other hand, the shorter size of LMWH may hamper the effectiveness of protamine as an antidote [20]. Useful information is provided by reporting a thrombocyte count of less than 50%, which represents an important red flag [19, 20]. Laboratory tests can then be used to confirm the presence of platelet factor 4 (PF4)/heparin antibodies [21]. Attention should be payed when reporting the presence of activating antibodies against PF4-heparin complexes (PF4-H) to the cut-off point for a positive test (e.g., 1 U/mL) [19]. A score has been developed based on 8 clinical features, each scoring between −2 and +3 [22]. Other scoring systems are also available [18]. LMWH and COVID-19 LMWH has some antiviral properties in vitro and it is routinely used in COVID-19 patients to prevent or circumvent the activation of the coagulation cascade induced by inflammation [23]. This is a particularly severe and lethal complication, leading to disseminated intravascular coagulation and venous thromboembolism. In a retrospective study, LMWH therapy reduced interleukin-6 release and activity, which is responsible of the “cytokine storm,” and treated patients had also a higher percentage of lymphocytes [24]. LMWH therapy is also associated with better outcomes in severe COVID-19 patients with sepsis-induced coagulopathy and markedly elevated D-dimer levels [25]. It should be pointed out that uremia offers a unique microenvironment in which the coagulation and anticoagulation balance can be dysregulated in many ways. For example, the presence of anti-protein C and anti-protein S antibodies has been detected [26], which may critically underscore the acute onset of a procoagulant situation in these patients (already characterized by an increased thrombotic risk). These data indeed may prudentially pose the indication of monitoring protein C and free protein S (Fig. 2). It can be hypothesized that, upon SARS-Cov-2 infection, the presence of antibodies with potential inhibitory activity on protein C and protein S may even increase the functional effect of an activated protein C (APC) resistance condition, whereas already present in the patient. Testing for APC resistance is indeed advised in these patients. COVID-19, LMWH, and Hemodialysis: Future Perspectives It is therefore possible that hemodialysis patients could be protected with respect to COVID-19 virus infection by the LMWH used in every hemodialysis session. We propose monitoring, in these patients, of the Anti-Factor Xa activity assay [27], as well as antithrombin, and D-dimer levels, and not just aPTT, in order to possibly even increase the LMWH dosage, in this pandemic period (Table 1). The availability of these exams could therefore lead to optimization of LMWH in this patient population. Disclosure Statement A.F.P. and D.I. received funding from Gnosis, SpA, and EUTox. Funding Sources None. Author Contributions All of the authors contributed equally to the writing of this paper.

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          Most cited references 23

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          Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis.

          Heparin-induced thrombocytopenia (HIT) is an uncommon but potentially devastating complication of anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Our objective was to determine and compare the incidences of HIT in surgical and medical patients receiving thromboprophylaxis with either UFH or LMWH. All relevant studies identified in the MEDLINE database (1984-2004), not limited by language, and from reference lists of key articles were evaluated. Randomized and nonrandomized controlled trials comparing prophylaxis with UFH and LMWH and measuring HIT or thrombocytopenia as outcomes were included. Two reviewers independently extracted data on thromboprophylaxis (type, dose, frequency, and duration), definition of thrombocytopenia, HIT assay, and rates of the following outcomes: HIT, thrombocytopenia, and thromboembolic events. HIT was defined as a decrease in platelets to less than 50% or to less than 100 x 10(9)/L and positive laboratory HIT assay. Fifteen studies (7287 patients) were eligible: 2 randomized controlled trials (RCTs) measuring HIT (1014 patients), 3 prospective studies (1464 patients) with nonrandomized comparison groups in which HIT was appropriately measured in both groups, and 10 RCTs (4809 patients) measuring thrombocytopenia but not HIT. Three analyses were performed using a random effects model and favored the use of LMWH: (1) RCTs measuring HIT showed an odds ratio (OR) of 0.10 (95% confidence interval [CI], 0.01-0.2; P = .03); (2) prospective studies measuring HIT showed an OR of 0.10 (95% CI, 0.03-0.33; P < .001); (3) all 15 studies measured thrombocytopenia. The OR was 0.47 (95% CI, 0.22-1.02; P = .06). The inverse variance-weighted average that determined the absolute risk for HIT with LMWH was 0.2%, and with UFH the risk was 2.6%. Most studies were of patients after orthopedic surgery.
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            An overview of the serpin superfamily

            Serpins (serine protease inhibitors or classified inhibitor family I4) are the largest and most broadly distributed superfamily of protease inhibitors [1,2]. Serpin-like genes have been identified in animals, poxviruses, plants, bacteria and archaea, and over 1,500 members of this family have been identified to date. Analysis of the available genomic data reveals that all multicellular eukaryotes have serpins: humans, Drosophila, Arabidopsis thaliana and Caenorhabditis elegans have 36, 13, 29, and about 9 serpin-like genes, respectively [1,3]. In contrast, serpins in prokaryotes are sporadically distributed and most serpin-containing prokaryotes have only a single serpin gene [4]. The majority of serpins inhibit serine proteases, but serpins that inhibit caspases [5] and papain-like cysteine proteases [6,7] have also been identified. Rarely, serpins perform a non-inhibitory function; for example, several human serpins function as hormone transporters [8] and certain serpins function as molecular chaperones [9] or tumor suppressors [10]. A phylogenetic study of the superfamily divided the eukaryotic serpins into 16 'clades' (termed A-P) [1]. The proteins are named SERPINXy, where X is the clade and y is the number within that clade; many serpins also have alternative names from before this classification was proposed. Serpins are relatively large molecules (about 330-500 amino acids) in comparison with protease inhibitors such as basic pancreatic trypsin inhibitor (BPTI, which is about 60 amino acids) [11]. Over 70 serpin structures have been determined, and these data, along with a large amount of biochemical and biophysical information, reveal that inhibitory serpins are 'suicide' or 'single use' inhibitors that use a unique and extensive conformational change to inhibit proteases [12]. This conformational mobility renders serpins heat-labile and vulnerable to mutations that promote misfolding, spontaneous conformational change, formation of inactive serpin polymers and serpin deficiency [13]. In humans, several conformational diseases or 'serpinopathies' linked to serpin polymerization have been identified, including emphysema (SERPINA1 (antitrypsin) deficiency) [14], thrombosis (SERPINC1 (antithrombin) deficiency) [15] and angio-edema (SERPING1 (C1 esterase inhibitor) deficiency) [16]. Accumulation of serpin polymers in the endoplasmic reticulum of serpin-secreting cells can also result in disease, most notably cirrhosis (SERPINA1 polymerization) [14] and familial dementia (SERPINI1 (neuroserpin) polymerization) [17]. Other serpin-related diseases are caused by null mutations or (rarely) point mutations that alter inhibitory specificity or inhibitory function [18]. Here, we summarize the evolution, structure and mechanism of serpin function and dysfunction. Broad organization of the serpin superfamily Serpins appear to be ubiquitous in multicellular higher eukaryotes and in the poxviridae pathogens of mammals. In humans, the two largest clades of the 36 serpins that have been identified are the extracellular 'clade A' molecules (thirteen members found on chromosomes 1, 14 and X) and the intracellular 'clade B' serpins (thirteen members on chromosomes 18 and 6) [3]. Recent bioinformatic and structural studies have also identified inhibitory serpins in the genomes of certain primitive unicellular eukaryotes (such as Entamoeba histolytica [19]) as well as prokaryotes [4,20]. No fungal serpin has been identified to date, and the majority of prokaryotes do not contain clearly identifiable serpin-like genes. Phylogenetic analyses have found no evidence for horizontal transfer [1,21], and it is instead suggested that serpins are ancient proteins and that most prokaryotes have lost the requirement for serpin-like activity [4]. Functional diversity of serpins Inhibitory serpins have been shown to function in processes as diverse as DNA binding and chromatin condensation in chicken erythrocytes [22,23], dorsal-ventral axis formation and immunoregulation in Drosophila and other insects [24,25], embryo development in nematodes [26], and control of apoptosis [5]. In humans, the majority (27 out of 36) of serpins are inhibitory (Table 1). Clade A serpins include inflammatory response molecules such as SERPINA1 (antitrypsin) and SERPINA3 (antichymotrypsin) as well as the non-inhibitory hormone-transport molecules SERPINA6 (corticosteroid-binding globulin) and SERPINA7 (thyroxine-binding globulin). Clade B includes inhibitory molecules that function to prevent inappropriate activity of cytotoxic apoptotic proteases (SERPINB6, also called PI6, and SERPINB9, also called PI9) and inhibit papain-like enzymes (SERPINB3, squamous cell carcinoma antigen-1) as well as the non-inhibitory molecule SERPINB5 (maspin). SERPINB5 does not undergo the characteristic serpin-like conformational change and functions to prevent metastasis in breast cancer and other cancers through an incompletely characterized mechanism [10,27]. The roles of several other well characterized human serpins are also summarized in Table 1. Numerous important branches of the serpin superfamily remain to be functionally characterized. For example, although plants have a large number of serpin genes, the function of plant serpins remains obscure. Studies in vitro clearly show that plant serpins can function as protease inhibitors [28], but plants lack close relatives of chymotrypsin-like proteases, which would be the obvious targets for these serpins. Thus, it has been suggested that plant serpins may be involved in inhibiting proteases in plant pathogens; for example, they may be targeting digestive proteases in insects [29]. One study convincingly demonstrated a close inverse correlation between the upregulation of Cucurbita maxima (squash) phloem serpin-1 (CmPS) and aphid survival [30]. Feeding experiments in vitro showed, however, that purified CmPS did not affect insect survival [30]. Together, these data suggest that rather than directly interacting with the pathogen, plant serpins, like their insect counterparts, may have a role in the complex pathways involved in upregulating the host immune response. Similarly, the role of serpins in prokaryotes remains to be understood; again, these molecules are capable of inhibitory activity in vitro [20], but their targets in vivo and their function remain to be characterized. Interestingly, several inhibitory prokaryote serpins are found in extremophiles that live at elevated temperatures (for example, Pyrobaculum aerophilum, which lives at 100°C); these serpins use novel strategies to function as inhibitors at elevated temperatures while resisting inappropriate conformational change [4,20,31]. Structural biology of the serpins and the mechanism of protease inhibition Serpins are made up of three β sheets (A, B and C) and 8-9 α helices (termed hA-hI). Figure 1a shows the native structure of the archetypal serpin SERPINA1 [32]. The region responsible for interaction with target proteases, the reactive center loop (RCL), forms an extended, exposed conformation above the body of the serpin scaffold. The remarkable conformational change characteristic of inhibitory serpins is depicted in Figure 1d; the structure of SERPINA1 with its RCL cleaved [33] shows that, following proteolysis, the amino-terminal portion of the RCL inserts into the center of β-sheet A to form an additional (fourth) strand (s4A). This conformational transition is termed the 'stressed (S) to relaxed (R) transition', as the cleavage of native inhibitory serpins results in a dramatic increase in thermal stability. Native serpins are therefore trapped in an intermediate, metastable state, rather than their most stable conformation, and thus represent a rare exception to Anfinsen's conjecture, which predicts that a protein sequence will fold to a single structure that represents the lowest free-energy state [34]. Serpins use the S-to-R transition to inhibit target proteases. Figure 1b shows the structure of an initial docking complex between a serpin and a protease (SERPINA1 and trypsin [35,36]) and Figure 1c shows the final serpin-enzyme complex [12]. These structural studies [12,35,36], combined with extensive biochemical data, revealed that RCL cleavage and subsequent insertion is crucial for effective protease inhibition. In the final serpin-protease complex, the protease remains covalently linked to the serpin, the enzyme being trapped at the acyl-intermediate stage of the catalytic cycle. Structural comparisons show that the protease in the final complex is severely distorted in comparison with the native conformation, and that much of the enzyme is disordered [12]. In addition, a fluorescence study demonstrated that the protease was partially unfolded in the final complex [37]. These conformational changes lead to distortion at the active site, which prevents efficient hydrolysis of the acyl intermediate and the subsequent release of the protease. These data are consistent with the observation that buried or cryptic cleavage sites within trypsin become exposed following complex formation with a serpin [38]. It is possible that cleavage of such cryptic sites within the protease occurs in vivo and thus results in permanent enzyme inactivation. The absolute requirement for RCL cleavage, however, means that serpins are irreversible 'suicide' inhibitors. A major advantage of the serpin fold over small protease inhibitors such as BPTI is that the inhibitory activity of serpins can be exquisitely controlled by specific cofactors. For example, human SERPINC1 (antithrombin) is a relatively poor inhibitor of the proteases thrombin and factor Xa until it is activated by the cofactor heparin [39]. Structural studies of SERPINC1 highlight the molecular basis for heparin function. Figure 2a shows the structure of native SERPINC1. Here, we use the convention of Schechter and Berger, in which residues on the amino-terminal side of the cleavage site (P1/P1') are termed P2, P3, and so on, and those carboxy-terminal are termed P2', P3', and so on; corresponding subsites in the enzyme are termed S1, S2, and so on [40]. The RCL is partially inserted into the top of the 3 sheet; the residue (P1-Arg) responsible for docking into the primary specificity pocket (S1) of the protease is relatively inaccessible to docking with thrombin, as it is pointing towards and forming interactions with the body of the serpin [41,42]. Figure 2b illustrates the ternary complex between SERPINC1, thrombin and heparin [43]. Upon interaction with a specific heparin pentasaccharide sequence present in high-affinity heparin, SERPINC1 undergoes a substantial conformational rearrangement whereby the RCL is expelled from β-sheet A and the P1 residue flips to an exposed protease-accessible conformation [44-46]]. In addition to loop expulsion and P1 exposure, long-chain heparin can bind both enzyme and inhibitor and thus provides an additional acceleration of the inhibitory interaction. Several other serpins, including SERPIND1 (heparin cofactor II), also use cofactor binding and conformational change to achieve exquisite inhibitory control [47]. Structural studies on prokaryote and viral serpins have revealed several interesting variations of the serpin scaffold. Viral proteins are often 'stripped down' to a minimal scaffold in order to minimize the size of the viral genome. Consistent with this requirement, the structure of the viral serpin crmA, one of the smallest members of the serpin superfamily [48,49], shows that it lacks helix hD. More recently, the structure of the prokaryote serpin thermopin from Thermobifida fusca revealed the absence of helix hH [20,31]. These studies also showed that thermopin contains a 4 amino-acid insertion at the carboxyl terminus that forms extensive interactions with conserved residues at the top of β-sheet A (called the 'breach'; see later); biophysical data suggest that this region is important for proper and efficient folding of this unusual serpin. The major conformational change that occurs within both the protease and the serpin as a result of serpin-enzyme complex formation provides an elegant mechanism for cells to specifically detect and clear inactivated serpin-protease complexes. Several studies have shown that the low density lipoprotein-related protein (LRP) specifically binds to and promotes internalization of the final complexes SERPINC1-thrombin, SERPIND1-thrombin and SERPINA1-trypsin. In contrast, native or cleaved serpin alone are not internalized [50]. Additionally, recent studies on SERPINI1 show that both SERPINI1-tissue plasminogen activator complexes and native SERPINI1 are internalized in an LRP-dependent manner. However, while SERPINI1-tissue plasminogen activator complexes can bind directly to LRP, native SERPINI1 requires the presence of an (as yet unidentified) cofactor [51]. The structural basis for interaction of LRP with serpin-enzyme complexes and the subsequent intracellular signaling response remain to be fully understood. It is clear, however, that native serpins and serpin-enzyme complexes can induce powerful responses such as cell migration in an LRP-dependent manner [52]. Inactivation of serpins: latency, polymerization, deficiency and disease The metastability of serpins and their ability to undergo controlled conformational change also renders these molecules susceptible to spontaneous conformational rearrangements. Most notably, the serpin SERPINE1 (plasminogen activator inhibitor-1) uses spontaneous conformational change to control inhibitory activity [53]. Structural and biochemical studies show that, in the absence of the cofactor vitronectin, native SERPINE1 (Figure 3a) rapidly converts to a latent inactive state (Figure 3b). The transition to latency is accompanied by insertion of the RCL into β-sheet A, where it cannot interact with the target protease. Interestingly, the structure of SERPINE1 in complex with the somatomedin B domain of vitronectin [54] shows that the cofactor-binding site on SERPINE1 is located in a similar region to the heparin-binding site of SERPINC1 (on and around helices hD and hE; Figure 3c). Whereas heparin promotes conformational change in SERPINC1, however, vitronectin prevents conformational change in SERPINE1. Several other serpins, including SERPINC1, have been shown to spontaneously undergo the transition to the latent state, and it is suggested that this may be an important control mechanism [55]. Although the transition to latency could be an important control mechanism in at least one serpin, an alternative spontaneous conformational change, serpin polymerization, results in deficiency and disease (or serpinopathy) [14,56]. Serpin polymerization is postulated to occur via a domain-swapping event whereby the RCL of one molecule docks into β-sheet A of another to form an inactive long-chain serpin polymer (Figure 4a, b) [14,57-59]. Several important human serpin variants result in polymerization, the best studied and most common of which is the Z allele (Glu342Lys) of SERPINA1 [14]. Here, failure to properly control the activity of neutrophil elastase (the inhibitory target of SERPINA1) in the lung during the inflammatory response results in the destruction of lung tissue, leading to emphysema. Furthermore, in individuals homozygous for the Z-variant, the accumulation of serpin aggregates or polymers in the endoplasmic reticulum of anti-trypsin-producing cells, the hepatocytes, can eventually result in cell death and liver cirrhosis [14]. Similarly, mutation of SERPINI1 results in the formation of neural inclusion bodies and in the disease 'familial encephalopathy with neuroserpin inclusion bodies' (FENIB) [17,60,61]. In addition to promoting polymerization, several serpin mutations have been identified that promote formation of a disease-linked latent state. Notably, a mutation in SERPINC1, the wibble variant (Thr85Met), results in formation of large amounts of circulating latent SERPINC1 (about 10% of total SERPINC1) [55]. An alternative 'half-way house' conformation of SERPINA3, termed δ, has also been identified (Figure 4c) [62]. The structure of δ-SERPINA3 also highlights the extraordinary flexibility of the serpin scaffold: in this conformation the RCL is partially inserted into β-sheet A and helix hF has partially unwound and inserted into the base of β-sheet A, completing the β-sheet hydrogen bonding (Figure 4c). Finally, the promiscuity of β-sheet A is highlighted by the ability of this region to readily accept short peptides: several structural and biochemical studies have demonstrated that peptides can bind to β-sheet A and induce the S-to-R transition (Figure 4d). Valuable insights into the mechanism of serpin function have been gleaned from the structural location of variants that promote serpin instability [18,63]. The majority of serpinopathy-linked mutations (including antitrypsin Siiyama [64] and Mmalton [65], antithrombin wibble [55] and δ-SERPINA3 [62]) cluster in the center of the serpin molecule, underneath β-sheet A, in a region termed the shutter (marked on Figure 1a). Interestingly, Glu342, the position mutated in the Z allele of SERPINA1, is located at the breach, which is just above the shutter at the top of β-sheet A. This portion of the molecule is the point of initial RCL insertion. It is suggested that destabilization of β-sheet A in either the shutter or the breach is sufficient to favor the transition to a polymeric or latent state over maintenance of the monomeric metastable native state [14]. Interestingly, analysis of conserved residues in the serpin superfamily also reveals a striking distribution of highly conserved residues stretching down the center of β-sheet A from the breach to the base of the molecule [1]. Unsurprisingly, given the important proteolytic processes they control, simple deficiencies such as those caused by null mutations of a large number of human serpins are linked to disease (some of these are summarized in Table 1). Interestingly, however, several (rare) mutations have been identified that do not promote instability but instead interfere with the ability of the serpin to interact correctly with proteases. These include the Enschede variant of SERPINF2 [66], in which insertion of an additional alanine in the RCL results in predominantly substrate-like (rather than inhibitory) behavior upon interaction with a protease. Mutations that alter serpin specificity can also have a devastating effect. For example, the Pittsburgh variant of SERPINA1 (antitrypsin) is an effective thrombin inhibitor as a result of mutation of the P1 methionine to an arginine [67]. The carrier of this variant died of a fatal bleeding disorder in childhood. Our knowledge of the functional biochemistry and cell biology of serpins has been shaped by extensive contributions from structural biology and genomics. The structure of six different serpin conformations, together with analysis of numerous different dysfunctional serpin variants, has allowed the characterization of a unique conformational mechanism of protease inhibition. These data highlight the intrinsic advantages as well as the dangers of structural complexity in protease inhibitors. On the one hand, conformational mobility provides an inherently controllable mechanism of inhibition. On the other, uncontrolled serpin conformational change may result in misfolding and the development of specific serpinopathies. Serpins thus join a growing number of structurally distinct molecules that can misfold and cause important degenerative diseases, such as prions, polyglutamine regions of various proteins and the amyloid proteins that form inclusions in Alzheimer's disease. While the mechanism of serpin function is now structurally well characterized, the precise role and biological target of many serpins remains to be understood.
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              Epidemiology of acute infections among patients with chronic kidney disease.

              The objectives of this review were (1) to review recent literature on the rates, risk factors, and outcomes of infections in patients who had chronic kidney disease (CKD) and did or did not require renal replacement therapy; (2) to review literature on the efficacy and use of selected vaccines for patients with CKD; and (3) to outline a research framework for examining key issues regarding infections in patients with CKD. Infection-related hospitalizations contribute substantially to excess morbidity and mortality in patients with ESRD, and infection is the second leading cause of death in this population. Patients who have CKD and do not require renal replacement therapy seem to be at higher risk for infection compared with patients without CKD; however, data about patients who have CKD and do not require dialysis therapy are very limited. Numerous factors potentially predispose patients with CKD to infection: advanced age, presence of coexisting illnesses, vaccine hyporesponsiveness, immunosuppressive therapy, uremia, dialysis access, and the dialysis procedure. Targeted vaccination seems to have variable efficacy in the setting of CKD and is generally underused in this population. In conclusion, infection is a primary issue when caring for patients who receive maintenance dialysis. Very limited data exist about the rates, risk factors, and outcomes of infection in patients who have CKD and do not require dialysis. Future research is needed to delineate accurately the epidemiology of infections in these populations and to develop effective preventive strategies across the spectrum of CKD severity.

                Author and article information

                Kidney Blood Press Res
                Kidney Blood Press. Res
                Kidney & Blood Pressure Research
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, )
                May 2020
                25 May 2020
                : 45
                : 3
                : 357-362
                aDepartment of Medical Translational Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
                bDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
                Author notes
                *Alessandra F. Perna, First Division of Nephrology, Department of Medical Translational Sciences, University of Campania Luigi Vanvitelli, Via Pansini 5, IT–80131 Naples (Italy), alessandra.perna@
                Copyright © 2020 by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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                Figures: 2, Tables: 1, References: 30, Pages: 6

                covid-19, low-molecular-weight heparin, hemodialysis


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