Risk factors for HIT development during heparin therapy.
\r\n\tThe fundamental research areas of Evolutionary Psychology can be divided into two broad categories: on the one hand, the basic cognitive processes, and the way they evolved within the species, and on the other, the adaptive social behaviors that derive from the theory of evolution itself: survival, mating, parenting, family and kinship, interactions with non-parents and cultural evolution. Indeed, Evolutionary Psychology explains at individual and group level the fundamental behaviors of social life, such as altruism, cooperation, competition, social exclusion, social support, etc. etc. Similar to the mechanisms of natural selection for physical characteristics, not only the mind follows biological laws, but also psychological abilities - such as the theory of mind, the ability to represent the intentions, thoughts, beliefs, and emotions of others - have had to adapt and must make themselves functional to the social life of individuals and groups. In addition, Sociology takes the same aspects into consideration, emphasizing the interaction, symbolic and otherwise, of individuals. The latter investigates the neural mechanisms underlying the same social behaviors that are of interest to evolutionary psychology. To study the neural correlates involved in such behaviors is necessary to understand the biological laws that underlie human behavior and brain functioning.
\r\n\r\n\tThis book aims to open a debate full of theoretical and experimental contributions among the different disciplines in social research, psychology, neuroscience, sociology, useful to give an innovative vision to the present research and future perspective on the topic.
",isbn:"978-1-83968-871-3",printIsbn:"978-1-83968-870-6",pdfIsbn:"978-1-83968-872-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"bd4df54e3fb185306ec3899db7044efb",bookSignature:"Dr. Rosalba Morese, Dr. Vincenzo Auriemma and Dr. Sara Palermo",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10450.jpg",keywords:"Evolutionary Psychology, Human Social Evolution, Human Social Behaviour, Social Cognition, Social Neuroscience, Functional Neuroimaging, Neuropsychology, Altruism, Cooperation, Social Exclusion, Social Support, Social Inclusion",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 18th 2020",dateEndSecondStepPublish:"December 21st 2020",dateEndThirdStepPublish:"February 24th 2021",dateEndFourthStepPublish:"May 15th 2021",dateEndFifthStepPublish:"July 14th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Rosalba Morese is carrying out research in the framework of Neuroscience and Social Psychology. She currently works at the Institute of Public Health of Faculty of Biomedical Sciences and at the Faculty of Communication, Culture, and Society of Università Della Svizzera Italiana, Lugano, Switzerland.",coeditorOneBiosketch:"Dr. Vincenzo Auriemma's focus is on the study of empathy in human interactions. He studied at the University of Essex in England, the University of Pisa, Genoa, Rome in Italy, and the University of Italian Switzerland in Switzerland. He is the principal responsible for the 'PERSEO' research which analyzes the reasons for the 'drop-out' in psychology.",coeditorTwoBiosketch:"Researcher of the EUROPEAN INNOVATION PARTNERSHIP on Active and Healthy Ageing and Assistant Specialty Chief Editor for Frontiers in Psychology - Neuropsychology.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"214435",title:"Dr.",name:"Rosalba",middleName:null,surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese",profilePictureURL:"https://mts.intechopen.com/storage/users/214435/images/system/214435.jpg",biography:"Rosalba Morese obtained a degree in psychology at the University of Parma. She subsequently held various\nteaching positions at the Department of Psychology and the Faculty of Medicine and Surgery of the\nUniversity of Parma.\nHer training continued with the attainment of the title of PhD in Neuroscience at the University of Turin,\nduring which she acquired and developed interdisciplinary skills and point of view through the application\nof bioimaging and psychophysiological methods to investigate the neurophysiological mechanisms involved\nduring communication and social interactions.",institutionString:"Universita della Svizzera Italiana",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Universita della Svizzera Italiana",institutionURL:null,country:{name:"Switzerland"}}}],coeditorOne:{id:"338363",title:"Dr.",name:"Vincenzo",middleName:null,surname:"Auriemma",slug:"vincenzo-auriemma",fullName:"Vincenzo Auriemma",profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:'He is pursuing a PhD in Sociology from the University of Salerno, Italy. He is a researcher of sociology and neurosociology at the University of Salerno, Italy. His focus is on the study of empathy in human interactions and he studied at the University of Essex in England, the University of Pisa, Genoa, Rome 3 in Italy and the University of Italian Switzerland in Switzerland. He has participated in national and international conferences with about 25 reports/communications. He is the principal responsible for the "PERSEO" research which analyzes the reasons for the "drop-out" in psychology, using the methodology of the Gounded Theory and analyzing empathy, fear and panic. He is Co-Editor for Frontiers. He is also a member of the Italian Society of Sociology (AIS).',institutionString:"University of Salerno",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Salerno",institutionURL:null,country:{name:"Italy"}}},coeditorTwo:{id:"233998",title:"Dr.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo",profilePictureURL:"https://mts.intechopen.com/storage/users/233998/images/system/233998.jpeg",biography:"Sara Palermo is a MSc in Clinical Psychology and a PhD in Experimental Neuroscience. Moreover, she obtained the National Scientific Enabling Certificate for Associate Professorship in April 2017 (ASN-2017). She is an expert in experimental neuroscience, clinical neuropsychology and advance neuropsychological testing. Moreover, she performs multidimensional geriatric evaluation and basic neurological symptomatology detection in patients with neurodegenerative disorders. She is also engaged in Activation Likelihood Estimation meta-analysis of neuroimaging studies.\r\nShe worked as a postdoc research fellow at the Department of Neuroscience 'Rita Levi Montalcini” in Turin until July 2017. Since then she works as research fellow at the Department of Psychology in Turin. To date, she owns three research Group memberships at the University of Turin (Italy). She is a member of the 'Center for the Study of Movement Disorders” (research area: Neurology) and the 'Placebo Responses Mapping Group” (research area: Physiology) at the Department of Neuroscience, and a member of the 'Neuropsychology of cognitive impairment and central nervous system degenerative diseases Group” at the Department of Psychology (Research Area: Psychobiology and physiological psychology).\r\nThe main topics of her research are the study of awareness of illness, metacognitive-executive deficits in neuropsychiatric and neurological disorders, physical and cognitive frailty in the elderly, and placebo/nocebo phenomena. Interestingly, all of them may represent appealing perspectives from which to study how neuropsychological abnormalities can be explained in terms of brain activities and with the use of neuropsychiatric and neuropsychological batteries considering a neurocognitive approach. Given her research interests and scientific publications, she has been an ordinary member of the Italian Society of Neuropsychology (SINP), of the Italian Association of Psychogeriatrics (AIP), of the Italian Society of Neurology for Dementia (SiNdem), and – finally – of the international Society for Interdisciplinary Placebo Studies (SIPS). Importantly, she is a member of the European Innovation Partnership on Active and Healthy Aging (EIP on AHA), for which she is involved in the Action Group A3 Functional decline and frailty. \r\n\r\nSara Palermo is Panel Editor for 'EC Psychology and Psychiatry'. She was recently appointed as Specialty Chief Editor for 'Frontiers in Psychology - Neuropsychology'.",institutionString:"University of Turin",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of Turin",institutionURL:null,country:{name:"Italy"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"259492",firstName:"Sara",lastName:"Gojević-Zrnić",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/259492/images/7469_n.png",email:"sara.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"5810",title:"Socialization",subtitle:"A Multidimensional Perspective",isOpenForSubmission:!1,hash:"bfac2e9c0ec2963193e9d15d617c6a01",slug:"socialization-a-multidimensional-perspective",bookSignature:"Rosalba Morese, Sara Palermo and Juri Nervo",coverURL:"https://cdn.intechopen.com/books/images_new/5810.jpg",editedByType:"Edited by",editors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7818",title:"Social Isolation",subtitle:"An Interdisciplinary View",isOpenForSubmission:!1,hash:"db3b513d7d35476f333a0d4a3147935b",slug:"social-isolation-an-interdisciplinary-view",bookSignature:"Rosalba Morese, Sara Palermo and Raffaella Fiorella",coverURL:"https://cdn.intechopen.com/books/images_new/7818.jpg",editedByType:"Edited by",editors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8262",title:"The New Forms of Social Exclusion",subtitle:null,isOpenForSubmission:!1,hash:"29bf235aa7659d3651183fe9ea49dc0d",slug:"the-new-forms-of-social-exclusion",bookSignature:"Rosalba Morese and Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/8262.jpg",editedByType:"Edited by",editors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6494",title:"Behavior Analysis",subtitle:null,isOpenForSubmission:!1,hash:"72a81a7163705b2765f9eb0b21dec70e",slug:"behavior-analysis",bookSignature:"Huei-Tse Hou and Carolyn S. 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MicroRNAs are an emerging class of small non-coding endogenous RNAs that participate on the fine tuning of gene expression at the post-transcriptional level. First discovered at the early 90s in the nematode C. elegans [1], microRNAs have been involved in multiple important biological processes both in animal as in plant cells. These regulatory RNAs are transcribed as primary longer transcripts, which are then processed into 19-23-nt mature miRNAs. One strand of the mature miRNA is then incorporated into the RNA-induced silencing complex (RISC) to regulate gene expression by targeting the 3’-untranslated region (3’UTR) of mRNAs with consequent translational repression and/or target mRNA degradation. This mode of action demonstrates the great regulatory potential of miRNAs, since a unique mRNA can be targeted by diverse miRNAs and conversely each miRNA may have hundreds of different target mRNAs. In recent years miRNAs have been established as important regulators of tumor development, progression and metastasis, and have demonstrated to be useful for tumor diagnosis and classification. Moreover, miRNA regulation might represent a new avenue for cancer treatment in a near future.
Neuroblastoma is the most common extracranial solid tumor in childhood and the most common tumor in infants, which originates from aberrant development of primordial neural crest cells. Several lines of evidence support the idea that microRNA deregulation could contribute to neuroblastoma pathogenesis and progression [2, 3], and the usefulness of miRNA profiles for neuroblastoma diagnostics, classification and prognosis has been recently reported [4]. Neuroblastoma cell lines can be induced to differentiate in vitro by several agents, including Retinoic Acid (RA) [5, 6], the biologically active form of vitamin A. RA treatments lead to proliferative arrest and neuronal differentiation [5, 7] and to a reduction of the biological aggressiveness of neuroblastoma cells, by reducing their migratory and invasive abilities [8-10]. As a consequence of this, RA and its derivatives have been introduced into therapeutic protocols for neuroblastoma patients [11-13].
In this article we want to review the evidences supporting the contribution of miRNA regulation to RA-induced differentiation of neuroblastoma cells. We will show that miRNA contribute to the gene-expression changes associated with neuroblastoma cell differentiation and that specific RA-induced miRNAs target the expression of relevant genes in the context of neural differentiation. In addition RA-regulated miRNAs contribute to the reduction in the biological aggressiveness elicited by RA in vitro. We put forward the idea that miRNA regulation is part of the RA signaling pathway, and that miRNAs are essential mediators of the actions of RA in neuroblastoma cells.
miRNAs use complementary base pairing and the RNA induced silencing complex (RISC) to bind and either block translation and/or promote degradation of their target mRNAs. miRNAs are 19-22 nt-long RNA molecules transcribed mainly from non-coding regions of the genome, although some are embedded within genes, primarily as part of intronic sequences [14]. In addition, clusters of miRNAs were also found in the genome [15]. miRNAs are transcribed as large hairpin-containing molecules, called pri-miRNA, that are cleaved in the nucleus by the microprocessor complex, involving Drosha and Pasha/DGCR8 proteins [16, 17]. The result of this cleavage is a shorter precursor hairpin (approx. 70 nt), called pre-miRNA. Pre-miRNAs are exported through RAN GTPase and exportin-5 to the cytoplasm [18] where undergo further cleavage by Dicer to yield a transient intermediate imperfect duplex of approx 19-22 bp miRNA [19]. Subsequently, the duplex unwinds and miRNA strand is loaded into RISC complex together with proteins of the Argonaute (Ago) family [20]. The miRNA strand in RISC acts as a guide strand to find the complementary site in mRNA, and thereby suppressing the translational activity of the target mRNA. The complementary strand (known as miRNA* or as passenger strand) is degraded when the duplex is unwound, although recent evidences show that in some cases miRNA* accumulated at physiological levels and support the idea of a role for miRNA* on gene regulation [21]. (see Figure 1)
miRNAs interact primarily with the 3’-untranslated (3’UTR) region of their target mRNAs, although recent evidences show that miRNAs can also associate with sites located within the coding region of target genes [22]. In fact, complex arrays of multiple binding sites for either the same or different miRNAs located both in the 3’UTR as well as in the coding region of the target genes have been reported [23]. The base pairing of miRNA and mRNA in vertebrates requires only partial homology, with a preference for contiguous pairing occurring only at the seed region, located at nucleotides 2-7 of the guide strand. The lack of stringency results in a many-to-many relationship between miRNAs and mRNA targets, with the consequence that a high percentage of the genome may be regulated post-transcriptionally by a comparatively small set of miRNAs. A consequence of that is also that bioinformatic prediction of miRNA target mRNAs becomes relatively inaccurate. The guide strand binds to its complementary region in the 3′UTR of its target mRNA through Watson–Crick base pairing of the seed residues. Several alternative seed binding arrangements have been observed that involved different number of residues and therefore could have different binding affinity [24].
miRNA Biogenesis. The scheme depicts the different steps in the biogenesis of miRNAs, the enzymes involved and the intermediate miRNA forms.
The binding of miRNA-RISC complex to its cognate mRNA target leads to mRNA silencing through suppression of mRNA translation and/or mRNA decay. [25, for review] Several mechanisms involving different protein complexes have been proposed. mRNA translation could be blocked at initiation step as well as post-initiation stages. The miRNA-RISC complex inhibits translation initiation by interfering with eIF4F-cap recognition and 40S small ribosomal subunit recruitment or by antagonizing 60S subunit joining and preventing 80S ribosomal complex formation. The interaction of the GW182 protein with the poly(A)-binding protein (PABP) might interfere with the closed-loop formation mediated by the eIF4G-PABP interaction and thus contribute to the repression of translation initiation. The miRNA-RISC might inhibit also translation at post-initiation steps by inhibiting ribosome elongation, inducing ribosome drop-off, or promoting proteolysis of nascent polypeptides. To promote mRNA degradation, the miRNA-RISC complex interacts with the CCR4-NOT1 deadenylase complex to facilitate deadenylation of the mRNA poly(A) tail. Deadenylation requires the direct interaction of the GW182 protein with PABP. Following deadenylation, the 5′-terminal cap (m7G) is removed by the DCP1-DCP2 decapping complex. Although miRNA-mediated deadenylation followed by mRNA degradation appear to be widespread events, not all miRNA-targeted mRNAs are destabilized. miRNA-targeted translationally repressed mRNAs can accumulate in discrete cytoplasmic foci, such as P or GW bodies, or stress granules. A fraction of GW bodies co-localizes with multivesicular bodies (MVBs), membrane structures that play a role in miRNA-mediated repression. Compelling evidences support a role for miRNAs at the nucleus, acting on transcriptional regulation via chromatin remodeling and epigenetic mechanisms [26].
Several studies have addressed the changes in the expression of miRNAs upon RA-dependent induction of differentiation of neuroblastoma cells, with somewhat different results depending on the cell line, treatment duration, analysis platform used, etc. [2, 27-30]. To analyze the contribution of microRNA regulation to RA-induced differentiation of neuroblastoma cells, we have studied the changes in the pattern of expression of 667 different human miRNAs upon RA treatment of SH-SY5Y neuroblastoma cells. We used miRNA profiling with TaqMan RT-PCR Low Density Arrays, and we found that 452 miRNAs were expressed above detection level. From them, 42 specific miRNAs change significatively their expression levels (26 upregulated and 16 downregulated) during RA-induced differentiation (Figure 2). This suggests miRNAs as an additional post-transcriptional regulatory layer under RA control [30].
We have focused our study on the closely related miR-10a and -10b, that showed the most prominent expression changes in SH-SY5Y cell line. Similar results have been reported for other neuroblastoma cell lines, like LA-N-1, LAN5 and SK-N-BE [29, 30].
miRNA expression profiling in differentiating SH-SY5Y cells. Relative expression values detected in TaqMan microRNA Low Density Arrays for microRNAs with FDR<0.05 at least in two of the three treated versus non-treated comparisons, for upregulated (A) and downregulated miRNAs (B). The values for 24 (empty bars), 48 (grey bars) and 96 (black bars) h of RA treatment are represented.
Loss of function experiments with anti-sense anti-miRs antagonists could show that miR-10a and -10b contribute to the regulation of RA-induced differentiation. RA-induced neurite outgrowth was impaired in cells with experimentally reduced levels of miR-10a or -10b, and the expression of several neural differentiation markers like Tyrosine Kinase receptors NTRK2 (trkB) and RET, GAP43, Neuron-specific Enolase (ENO2), medium-size neurofilament protein NEFM and the enzyme Tyrosine Hydroxylase (TH) was abrogated or severely impaired after suppression of miR-10a or -10b (Figure 3).
Knock-down of miR-10a and -10b impaired RA-induced differentiation. Blocking the action of miR-10a and -10b by transfection of their cognate anti-miRs diminished neurite outgrowth (A) and reduced the expression of neuronal differentiation markers NTRK2 (B), RET (C), GAP43 (D) and ENO2 (E), as shown by quantitative RT-PCR. (Statistical signification in the Figures: *: p<0.05; **: p<0.01; ***: p<0,001; ns: non significative)
Conversely, the downregulation of the members of the ID gene family, ID1, ID2 and ID3 was abolished in RA-treated cells transfected with anti-miR-10a and anti-miR-10b. However, miR-10a and -10b did not appear to play a relevant role in RA-induced proliferation arrest, because the strong reduction of the incorporation of 3H-Thymidine (to approximately 30% of the control values) and the decrease in the percentage of cells in S- phase (to 50% of the control) induced by RA treatment, was equivalent in neuroblastoma cells transfected with anti-miR-10a and anti-miR-10b [30]. However, a reduction in the cell growth in SK-N-BE neuroblastoma cells when transfected with pre-miR-10a and -10b has been reported [29]. Overexpression of miR-10 and -10b by transfecting synthetic precursor pre-miRs could not trigger full differentiation itself and although the mRNA levels of RET, NTRK2, GAP43 and ENO2 or the protein levels of NEFM and TH were slightly enhanced by transfection of pre-miR-10a and -10b, the attained expression levels for all the markers analyzed were far below those obtained by RA treatment. Similarly, ectopic expression of miR-10a and -10b led to certain increase in neurite outgrowth, but lower to that obtained for RA treatment [30]. Therefore, miR-10a and-10b appeared to be necessary but not sufficient for full neural differentiation, and consequently additional actions of RA must contribute to differentiation.
It has been reported that RA treatment of neuroblastoma cells results in a reduction in their biological aggressiveness, by decreasing their migratory and invasive abilities [8-10]. We wanted to analyze whether RA-induced expression of miR-10a and -10b could be related to the reduction in migratory and invasive potential of neuroblastoma cells. To test the migratory potential of SH-SY-5Y cells we used a modified, light-opaque Boyden chamber assay (Falcon HTS FluoroBlok, 8 μm pore size). Cells were transfected with anti-miR-10a or -10b or the corresponding Negative Control anti-miR, treated with 1 μM RA or vehicle in culture medium during 96 h, and labeled in the plate with Calcein AM. Labeled cells were counted and added to the upper chamber of the Boyden chamber, and allow to migrate towards de lower chamber, filled with medium containing 10% FBS as chemoattractant. The results show that indeed RA-treatment reduced the migration of neuroblastoma cells. However suppressing miR-10a or -10b expression not only abolished that reduction but increased migration over basal levels, supporting a contribution of RA-induced miR-10a and 10b to the reduction of migratory activity produced by RA [30]. (Figure 4A)
Involvement of miR-10a and -10b on the effects of RA in migratory and invasive potential of neuroblastoma cells. Mock-transfected cells and cells transfected with Negative Control (NC) anti-miR, anti-miR-10a or anti-miR-10b were treated with 1 μM RA or vehicle for 96 h and used in migration (A) or matrigel invasion (B) transwell assays. The graph shows a representative experiment performed in triplicate (mean ± SD). Statistical significance was analyzed by comparing samples transfected with anti-miR-10a and -10b with those transfected with NC-anti-miR.
For invasion assays we used a similar assay, with the difference that the porous membrane separating the upper and lower chambers of the Boyden chamber was covered with BD Matrigel matrix (5 μg/cm2 in serum-free medium). The lower chamber contained 10% FBS as chemoattractant to promote cell invasion. In this case RA treatment results in increased invasive potential, whereas in cells transfected with anti-miR-10a or 10b the same treatment the increase in invasion induced by RA treatment is even larger, supporting the idea that the expression of miR-10a and -10b contributes to a reduction in the invasive potential [30]. (Figure 4B)
To analyze the effects of RA treatment on the metastatic potential of neuroblastoma cells we used the chicken embryo chorioallantoic membrane assays (also known as CAM assay; [31]). This assay is useful to study intravasation and metastasis in vivo, since it recapitulates all the steps of the metastatic process. In the CAM assay the cells to be tested are inoculated on the chorioallantoic membrane of 10-day-old chicken embryos. After a week, the egg is opened, the embryo is obtained and secondary organs like the lungs were dissected. The presence of human cells in the chicken organ is evaluated and quantified after obtaining their genomic DNA, by detecting the presence of human-specific Alu-sequences by Real-Time PCR (Figure 3). As this is a complex technique that requires a higher number of replicate experiments we have simplified the study to analyze only the effects of miR-10a suppression. Neuroblastoma cells could be detected in the chicken lungs after 7 days incubation. Suppression of miR-10a expression with its cognate anti-miR resulted in an increase of the metastatic cells. As expected, RA treatment led to a reduction of the number of neuroblastoma cells reaching the lungs. However this inhibitory effect of RA was abolished in cells having a reduced amount of miR-10a by transfecting the corresponding anti-miR-10a [30].
Chorioallantoic Membrane Metastasis Assay. (A) Schematic representation of the experiment. Cells from the different treatment groups were transferred to the upper chorioallantoic membrane of 10-day-old chicken embryos and the number of metastatized cells into the lungs evaluated 7 days later. (B) Cells transfected with Negative Control (NC) anti-miR or anti-miR-10a were treated with 1 μM RA or vehicle for 96 h as indicated in the figure. The graph represents the values obtained from six parallel assays (mean ± SD). Statistical significance was analyzed by comparing samples transfected with anti-miR-10a with those transfected with NC-anti-miR. In addition samples transfected with NC-anti-miR treated with vehicle were compared to those treated with RA.
In good agreement with our results, it has been reported that miR-10a and -10b reduces the ability of neuroblastoma cells to form colonies in soft agar [29], a phenotype that is characteristic of malignant cells. All these results support the idea that miR-10a and -10b expression contribute to reduction of migratory, invasive and metastatic activities induced by RA. In a recent report it has been shown that a protein involved in cell migration, Tiam1, is targeted by miR-10b in mammary tumor cells. Overexpression of miR-10b suppresses the ability of breast carcinoma cells to migrate and invade [32]. Consistent to that, it has been reported an association between lower miR-10a expression and lower overall survival for a subclass of neuroblastoma tumors (11q- tumor cohort) [29]. However other reports seem to involve the members of the miR-10 family as promoters of migration and metastasis in different tumors [33-40]. This apparent controversy may suggest that the role of the microRNAs from the miR-10 family in tumorigenesis and metastasis would depend on their molecular targets and therefore would depend on the cellular context.
The identification of molecular targets for miRNAs is a crucial step towards the understanding of miRNA function. Because an ever growing number of experimentally validated targets for miRNAs are being reported, a simple way to identify miRNA targets is to search for validated targets in the literature or in databases as TarBase [41]. A validated target for miR-10b in breast cancer cells is the homeobox gene HOXD10 [34, 42]. However, we could not find regulation of HOXD10 in SH-SY5Y neuroblastoma cells, when treated with RA or when the levels of miR-10a and -10b were experimentally altered [30].
A lot of effort has been made to generate computational miRNA target prediction tools [reviewed in 43], mainly based on the search for complementary sequences in the genome. However, that is not an easy task, because short sequences are problematic for the algorithms usually developed for complementarity analysis. As indicated in 2.2, the base pairing of miRNA and mRNA in vertebrates requires only partial homology, with a preference for contiguous pairing occurring only at the “seed” region, located at nucleotides 2-7 of the guide strand, and this makes even more difficult to find the right target sequence in the genome. Several authors have approached this problem from different startpoints, using mainly complementarity analysis of the complete miRNA sequence, complementarity analysis of the seed sequence, or adding thermodynamic stability analysis of duplex sequences or 3’UTR sequence conservation to the complementarity analysis. Nowadays a set of miRNA target prediction resources are available, mainly as web-based tools. However it becomes striking to the new users of these tools how different results can be obtained when using the same sequence with different prediction tools. In addition, prediction tools generate lists of hundreds of genes for each of the miRNAs, and the fact of having sequence diversity at the 3’UTR by alternative polyadenylation sites could also complicate the analysis [for discussion, see 44].
To find relevant targets for miR-10a and-10b in neuroblastoma cells we choose to combine bioinformatic prediction tools together with experimental analysis. We created a list of potential miR-10a and -10b targets by including the common predicted genes using three different prediction resources: miRbase targets [45], TargetScan [46] and PicTar [47]. Only mRNAs that contained evolutionarily conserved miRNA binding sequences on their 3’UTR were considered. This list was crossed with the dataset of an Affymetrix microarray experiment containing the genes downregulated after 48 h RA treatment. In the resulting list, two members of the Arginine/serine-rich splicing factors, SFRS1 (SF2/ASF) and SFRS10 (TRA2B), as well as the nuclear receptor co-repressor NCOR2 (SMRT) were on top [30].
miR-10a/-10b knockdown leads to increased SFRS1 protein and mRNA levels in SH-SY5Y cells. (Left panel) Western blot of SFRS1 protein expression after anti-miR-10a, -10b and negative control NC-anti-miR transfection of SH-SY5Y cells followed by 1μM RA treatment. The blot was reprobed with actin beta antibodies as loading control. (Right panel). RT-qPCR analysis of SFRS1 mRNA levels in same conditions. The graph shows expression levels relative to that of RA untreated, NC-anti-miR transfected cells (mean ± SD of a triplicate experiment). Statistical analysis for right panel was made by comparing the values from cells transfected with anti-miR-10a or -10b to those from cells transfected with NC-anti-miR; ns= non significative.
The regulation of SFRS1 (SF2/ASF) by miR-10a and-10b was experimentally validated at mRNA and protein levels in HeLa and SH-SY5Y cells (Figure 6). In addition regulation by miR-10a and -10b was shown in transfection experiments with reporter plasmids containing SFRS1 3’UTR sequences linked to the Luciferase gene. miR-10a and -10b are new players in the complex regulation of SFRS1 protein through a mechanism involving enhanced mRNA cleavage. In addition, we showed how changes in miR-10a and -10b expression levels may influence some molecular activities in which the product of SFRS1 is involved, such as translation enhancement of certain mRNAs and alternative splicing, that could have importance in the neural differentiation process [30] (Figure 7). We have reported that the activation of signaling pathways by RA treatment results in rapid changes in the phosphorylation pattern of SR proteins, including SFRS1 and subsequently, changes in alternative splicing selection and an increase of the translation of mRNAs containing SFRS1 binding sites take place [48]. In this context, the reduction in SFRS1 levels through miR-10a and -10b regulation could be interpreted as the closing of the feedback regulatory loop of RA on the activities of SFRS1.
Experimental alteration of miR-10a and -10b levels resulted in an impairment of SFRS1 functions in the regulation of alternative splicing. Alternative splicing of tau protein exon 10 is altered by transfection of anti-miR-10a and -10b. RT-PCR was performed on RNA extracted from anti-miR-10a, -10b or negative control (NC) anti-miR transfected SH-SY5Y cells. tau Exon 10 flanking primers were used in RT-PCR reaction according to [49]. Quantification of the percentage of exon 10 inclusion. The graph shows the average from 3 independent experiments. Statistical analysis was made by comparing the values from cells transfected with pre-miR-10a or -10b to those from cells transfected with NC-pre-miR.
The regulation of NCOR2 by miR-10a and-10b was experimentally validated at mRNA and protein levels in SK-N-BE neuroblastoma cells. Moreover, a luciferase reporter construct containing the NCOR2 3’UTR showed a significant decrease in luciferase activity when co-transfected with mature miR-10a, -10b or 10a/10b mimics in SK-N-BE cells. This decrease in luciferase activity was completely abolished when the putative miR-10a and -10b target site was mutated in its seed sequence. Knock-down of NCOR2 expression through transfection of siRNAs to SK-N-BE cells recapitulates most of the changes induced by RA, like neurite outgrowth, proliferative arrest, expression of neural markers, downregulation of MYCN and expression of miR-10a [29]. NCOR2 acts as co-repressor in the regulation of many genes, especially as co-regulator of nuclear receptor-regulated genes. Bound to the unliganded receptor, NCOR2 maintains the promoters of nuclear receptor-regulated genes in a repressed state, and its release from the complex with the receptor upon ligand binding allows transcriptional activation [50]. It has been reported that NCOR2 represses expression of the jumonji-domain containing gene JMJD3, a direct retinoic-acid-receptor target that functions as a histone H3 trimethyl K27 demethylase and which is capable of activating specific components of the neurogenic program [51]. Therefore, downregulation of NCOR2 by miR-10a and -10b would potentiate the actions of RA through RARs and RXRs and could contribute to some of the changes in gene expression associated with neural differentiation.
MicroRNAs are essential players in the process on neural differentiation of neuroblastoma cells, and contribute to the transduction of Retinoic Acid signaling. In addition, miRNAs have been reported to participate in the pathogenesis and progression of human neuroblastoma tumors [2, 3], and miRNA profiles have been recently proven to be useful for classification and prognosis [4]. Finally miRNAs open new avenues for the treatment of neuroblastoma cells, and proof of concept experiments showing a therapeutic action of miRNA-based treatments in animal models of neuroblastoma [52-54] and other tumors [33] have been reported. Therefore, we have to expect in the next years an increased interest in the study of microRNAs among the neuroblastoma researchers community.
The major adverse effect of heparin therapy concerns probably the development of thrombocytopenia and thromboembolic complications, which are directly caused by the drug itself [1, 2, 3, 4, 5, 6]. This heparin paradox is associated with a characteristic platelet fall and thrombosis in some heparin-treated patients, especially when unfractionated heparin (UFH) is used, but it can also occur with low molecular weight heparin (LMWH) therapy. The patient’s clinical context can favor the development of this iatrogenic complication, called heparin-induced thrombocytopenia (HIT) without or with associated thrombosis (HITT). When this complication occurs, it requires an immediate management with the withdrawal of heparin and use of an alternative anticoagulant [7, 8, 9, 10, 11]. If incorrectly managed, it can rapidly cause severe burden and become life-threatening. This complication is reported to occur in about 1–5% of patients treated with UFH and 0.2–0.5% of those treated with LMWH, but the incidence highly depends on the clinical context [1, 3, 5, 6]. Cardiology or orthopedic surgery, trauma, circulatory diseases, and the presence of tumors are increased risk factors for that disease. A recent meta-analysis in the USA reported a different HIT/HITT incidence and clinical association than that usually accepted but shows that it remains a critical clinical issue in hospitals [5]. The first alert signal for HIT is a platelet count drop by more than 30–50% between two successive measures, occurring between 5 and 15 days following the onset of heparin therapy, in the absence of any other thrombocytopenia cause (Table 1). However, platelet fall can develop earlier if patients have been exposed to heparin during the 3 months preceding the treatment. The mechanisms producing HIT involve the generation of a heparin-dependent antibody, usually of the IgG isotype (but IgA and IgM isotypes can also be present). This antibody has been demonstrated to be targeted to complexes of heparin and platelet factor 4 (PF4) in most of the cases [12, 13], but non-PF4 antigens can be present in some atypical patients [14, 15, 16, 17]. Frequently, heparin-dependent antibodies, including IgG isotypes, are asymptomatic [18, 19]. They are symptomatic and harmful only in a few subsets of affected patients. What renders the antibodies pathogenic in those patients is not totally understood, but some evidence becomes available. IgG isotypes present at high concentration, and with high avidity, provoke frequently the development of disease [19, 20]. Clinical diagnosis and laboratory diagnosis are of high importance to rapidly identify the patients with an active disease and treat them [6, 8, 21, 22, 23, 24]. It includes a multiple strategy approach:
early detection of patients with thrombocytopenia
evaluation of their HIT clinical score
testing for the presence of heparin-dependent antibodies with immunoassays
checking the capability of these antibodies to activate platelets in a heparin-dependent mode [25].
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Risk factors for HIT development during heparin therapy.
It is of essence to duly characterize patients with HIT: if this complication is excluded, it is not necessary to deprive them from heparin, as it is the most effective anticoagulant in many acute conditions. Conversely, if HIT/HITT is confirmed, it is mandatory to not reintroduce any heparin treatment and to switch to an alternative anticoagulation. In this book chapter, we will present and discuss the following: (a) the present understandings of conditions which can favor development of heparin-dependent antibodies in heparin-treated patients; (b) why antibodies generate HIT or HITT only in a few subset of patients; (c) the mechanisms of action of these antibodies, as they are presently understood; (d) the available laboratory tools and their indications; (e) the diagnostic strategy for rapidly characterizing patients at risk; (f) the occurrence of atypical presentations of HIT in patients with pre-existing antibodies to PF4 or to interleukin 8 (IL8) or with antibodies to protamine sulfate (PrS); and (g) cross-reactivity of the various polysaccharide anticoagulants in immunoassays and functional methods. This chapter mainly focuses on antibodies generated to heparin-PF4 (HPF4) complexes, which concern most of the patients with HIT/HITT, but other non-PF4 antigens can be involved in few cases and will be rapidly discussed.
Heparin-dependent antibodies develop in many patients treated with UFH or LMWH. Their incidence is higher in patients undergoing extracorporeal circulation (ECC) for cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) [5, 26, 27]. Antibodies’ development is not rare during heparin therapy, but they are often of the IgM isotype with a rapid reversal without any clinical incidence [18, 19]. They can also be of the IgA or IgG isotypes, and the three isotypes are associated in many patients and are frequently asymptomatic. IgGs have been demonstrated to be those which can become pathogenic, especially when present at high concentration, with high affinity for their target heparin-dependent antigen [19, 25]. A subset of the IgG isotype heparin-dependent antibodies can then activate platelets [20], which induce thrombocytopenia, platelet aggregation, and sometimes thrombosis. HIT was first characterized for the white thrombus formed in arteries (platelets and white blood cells), when patients with this complication were first identified, but there is evidence now that arterial (about 30% of cases) or venous (about 70% of cases) thrombosis can occur [28]. Skin necrosis at the injection site or elsewhere, or thrombosis, frequently at limb extremities, is often observed, but thrombosis can occur at many different sites.
In addition to platelet activation, heparin-dependent antibodies can induce activation of endothelial cells (ECs) and of monocytes, and they can release tissue factor (TF) from these cells, which contribute to thrombosis [29, 30, 31]. Platelet-leukocyte aggregates are also formed and contribute to thrombogenicity. When this multiple blood activation process is initiated, it is enhanced at pathological sites where platelet and white blood cells can be chemo-attracted and accumulate with a high density. If blood activation and prothrombotic process are strong enough to overwhelm the antithrombotic body’s defenses, thrombus formation occurs. The first clinical warning for HIT is the occurrence of thrombocytopenia, with a characteristic time kinetics from the onset of therapy, when other causes of decreased platelet counts are excluded [6, 25, 28]. Platelet fall typically occurs between 5 and 15 days following the initiation of treatment, as shown in Figure 1, except if patients already received heparin within the 100 preceding days or in the rare cases with pre-existing anti-PF4 antibodies. Thrombocytopenia can then develop earlier and possibly just at the onset of heparin therapy. In HIT/HITT thrombocytopenia is usually moderate, between 20 and 100 giga platelets per liter (G/L), and it is rarely very severe (<10 G/L). When it develops, the clinical probability for HIT/HITT must be evaluated. It is an important criterion for estimating the risk to develop this complication in heparin-treated patients, and various pretest methods for estimating disease risk are available. The most frequently used is the 4Ts score [28], which considers four major criteria: the presence of thrombocytopenia, the timing of platelet count fall, the occurrence of new thrombosis or sequelae, and the investigation of other causes of thrombocytopenia. For each criterion, a score from 0 to 2 is given, as shown in Table 2. It allows to classify patients from 0 to 8 (risk is low for 0–3, intermediate for 4–5, and high for ≥6, indicating an elevated disease probability). In cardiology patients with ECC, thrombocytopenia is frequently observed, and HIT can be identified when a biphasic platelet count kinetics is present: in the absence of HIT, thrombocytopenia is progressively corrected, but, if present, platelet count starts to increase and falls again when symptomatic antibodies develop [27].
Typical platelet count kinetics in heparin-treated patients who develop heparin-dependent antibodies responsible for heparin-induced thrombocytopenia.
The pretest probability for HIT based on the 4Ts score.
Other HIT clinical evaluation approaches have been proposed (such as the expert score), but the 4Ts score remains the most widely used. When HIT is suspected, heparin treatment must be stopped and replaced by another anticoagulant. The possible drugs which can be used include argatroban, direct oral anticoagulants (DOACs), danaparoid sodium, fondaparinux, and bivalirudin [7, 9, 10, 11, 32, 33]. Nevertheless, if HIT is excluded, heparin can be reintroduced, as it can be of full benefit for the patient, especially in cardiac surgery and circulatory diseases. Establishing rapidly a safe and reliable diagnosis of HIT is then of essence for the right management of patients [6, 25, 28].
HIT/HITT occurs in some of the patients who develop heparin-dependent antibodies, a major risk factor for the disease occurrence. In most of the cases, they are targeted to stoichiometric complexes of heparin and PF4 (HPF4) and are of the IgG isotype but are the only ones present in few patients with atypical HIT/HITT antibodies to IL8 or to PrS [12, 14, 15, 17]. In rare cases, the antibody specificity remains non-identified, although patients present the suggestive clinical complication of heparin therapy. What causes the heparin-dependent antibodies’ generation is not yet fully understood, but drug immunogenicity tends to develop when heparin forms complexes with its high-affinity binding blood protein, PF4, a chemokine from the CXC family [34, 35, 36], and eventually IL8 [37, 38]. In healthy individuals, PF4 is normally present at very low concentrations in blood circulation (<10 ng/ml). It is released from platelets’ α-granules upon activation or aggregation, as a complex of eight PF4 tetramers with a platelet proteoglycan dimer, with a molecular weight (MW) of about 350 kDa. This complex is rapidly cleared from circulation as PF4 is captured by endothelial cells’ glycosaminoglycans (GAGs) and remains in this endothelial storage pool. In patients with inflammation or blood activation, PF4 concentrations can be much higher, either in blood circulation or on the endothelial storage pool. In addition, at pathological sites, platelets and white blood cells can be chemo-attracted and stimulated. Much higher PF4 concentrations can be present at these sites. At the onset of heparin therapy, PF4, which has a higher affinity for this drug than for GAGs or physiological proteoglycans, forms complexes with it, as presented in Figure 2. In some circumstances these complexes can activate the immune system and induce the generation of antibodies. The immune response can be innate, mediated via the toll-like receptors, and adaptive with a T cell-mediated response, followed by the generation of antibodies. The three isotypes (IgG, IgA, or IgM) can be present [13, 19], but IgGs are formed very rapidly, which is unusual in the early stage of the immune response, and IgGs can become rapidly pathogenic [19]. In rare cases, only IgA (especially in patients with cancer) or IgM isotypes are identified [39]. Following heparin treatment cessation, antibodies disappear from blood circulation within about 3 months. The respective concentrations of PF4 and heparin in blood circulation or at pathological sites are key factors for inducing immunogenicity [40, 41]. The clinical context is then a risk factor for heparin-dependent antibodies’ development. Another initial cause which can favor generation of antibodies has been described and concerns a previous exposure of patients to bacterial infections [42]. PF4 can complex with bacterial polysaccharides and then becomes immunogenic. The immune response induces generation of antibodies to this chemokine. When patients with this former stimulation receive heparin, PF4 released from endothelium forms HPF4 complexes which reactivate the immune system (Figure 1), and IgG isotypes are rapidly generated. In addition to PF4, heparin treatment (and more especially LMWH) can also release tissue factor pathway inhibitor (TFPI) bound to ECs into blood circulation. No immune reaction to TFPI has been observed until now, but its increased concentration contributes to elevate the anticoagulant activity of heparin at the beginning of treatment.
At the onset of heparin therapy, TFPI and PF4 “storage pool” are displaced from endothelial cells and released into blood circulation. Heparin complexes with PF4, and this can stimulate the immune system (especially if heparin and PF4 stoichiometric concentrations are met), and antibodies to these complexes are generated.
The major heparin-dependent antigen involved in HIT/HITT is PF4, a CXC chemokine present in platelet α-granules and released upon platelet activation and aggregation. PF4 is a 70 amino acid (AA) protein with a MW of 7800 kDa, released in blood circulation as a tetramer with a MW of about 30 kDa [34, 35, 36, 43]. This chemokine has a structure involving one α-helix and three β-sheets organized in an antiparallel manner; it is highly electropositive, with many lysine and arginine residues, and has two disulfide bridges per monomer. The tetramer is organized in such a way that it exposes an external ring of positive charges, as shown in Figure 3. The formation of HPF4 complexes depends on the respective concentrations of heparin and PF4 [13, 24, 44]. Stoichiometric complexes are formed at a concentration of about 150 μg of heparin (i.e., about 27 IU UFH) per mg of PF4 (Figure 4). High- and low-affinity heparin molecules have the same reactivity with PF4, as well as LMWH, and the sulfation grade is of essence for these interactions. Patients who develop antibodies are those with the highest extracellular concentrations of PF4 in blood circulation, or at pathological sites, and with heparin concentrations permitting the formation of stoichiometric HPF4 complexes.
Reaction of heparin with PF4 tetramers at stoichiometric concentrations. There is an intimate interaction between the ring of positive charges on the PF4 tetramer and the negative charges of the sulfated polysaccharide, heparin. This strong interaction induces an alteration of PF4 structure, rendering it immunogenic. Heparin (UFH or LMWH) molecules with at least 12 monosaccharides are required for this interaction.
PF4 is released from platelets as a complex with a proteoglycan dimer and is displaced by heparin for which it has a higher affinity. Complexes of heparin and PF4 depend on their respective ratios. When heparin and PF4 are at a stoichiometric concentration, large multimolecular complexes are formed and can be exposed on platelets or other blood cells. They can bind heparin-dependent antibodies and focus the deleterious immune reaction onto these cells. This can induce HIT or HITT in some patients.
If heparin treatment is given through continuous infusion, heparin concentration remains constant in blood circulation, and the risk to form stoichiometric HPF4 reactive complexes is reduced. When heparin is given through the subcutaneous route, blood concentrations present high variations, from <0.1 IU/ml at trough to >0.7 IU/ml at peak. For current curative UFH treatments (2–3 injections/day), the PF4 concentrations needed for forming stoichiometric complexes must be of about 4 μg/ml for heparin concentrations ≤0.1 IU/ml (trough) or of ≥28 μg/ml for heparin concentrations ≥0.7 IU/ml (peak). Required PF4 concentrations are high comparatively to expected heparin concentrations in blood circulation, even in disease states, but these high concentrations could be present at pathological sites. In ECC, blood heparin concentrations are high (about 4–5 IU/ml) and constant: formation of stoichiometric complexes can only occur with 25–30 μg/ml of PF4, which is unlikely. For information, the total amount of PF4 releasable from platelets, when they are totally activated and aggregated, is of about 5 μg per ml of blood (depending on platelet count and PF4 content; it is of ±12.5 ng/106 platelets).
But PF4 can accumulate and be at higher concentrations at pathological sites. Immunogenic stimulation occurs when body detects a non-self-component, which can be heparin used as anticoagulant. When bound to PF4, it forms large complexes, which can activate the immune response, which is targeted to these complexes and possibly extended to PF4 itself, through epitope spreading. Generated antibodies can be considered as alloantibodies. In few cases, PF4 antibodies can be pre-existing chronically or generated transitory as a side response to an infectious disease [14, 42, 45]. Anti-PF4 autoantibodies can bind to HPF4 complexes formed during heparin therapy and are then targeted to platelets or other blood cells which expose HPF4 complexes, focusing the deleterious immune response [22, 29, 30, 46]. In few cases, non-PF4 antigens can be involved [14, 15, 17, 46, 47]. HIT/HITT presentation and disease kinetics are then frequently atypical, although a moderate or characteristic thrombocytopenia develops during heparin therapy. IL8 has been reported in some patients as another heparin-dependent antigen in HIT/HITT. Anti-IL8 antibodies are pre-existing in many patients with chronic inflammation and are generated as a regulatory response to control this pathological context. Pathogenicity can occur because IL8 can bind heparin, and these complexes are fixed onto platelets and other blood cells through IL8 receptors (IL8-RA and IL8-RB) or through direct heparin binding [37, 38]. Interestingly, heparin binding to platelets increases with their activation grade. Anti-IL8 antibodies then focus the immune response deleterious effects to blood cells exposing heparin IL8 complexes which are then activated or destroyed. Neutrophil-activating peptide 2 (NAP-2), the β-thromboglobulin precursor, is another platelet CXC chemokine reported as a possible heparin-dependent antigen in rare HIT cases [14]. Lastly, in patients undergoing ECC [16, 26, 27], heparin is used as anticoagulant and is neutralized with a defined concentration of PrS at the end of the process. Anti-PrS or anti-heparin-PrS antibodies have been the only ones identified in few patients treated with heparin and presenting with a HIT-/HITT-like syndrome [17], with a possible fatal outcome. These antibodies can activate platelets in the presence of heparin [15, 46, 47]. Recent investigations have shown that anti-PrS antibodies are rather frequent in patients receiving this drug for heparin neutralization, but only very few of them develop severe clinical complications. Recurrent ECC in the same patient, with various exposures to heparin and PrS over time, can be an increased risk for development of antibodies and associated pathogenicity, with a HIT-/HITT-like syndrome.
Heparin-dependent antibodies, and especially those to HPF4 complexes, induce thrombocytopenia and thrombosis in some clinical circumstances [46]. Particularly IgG isotypes can activate platelets, ECs, or other white blood cells such as monocytes, when they bind to their target antigenic structure, present at the surface of these cells [28, 29, 44, 46, 47]. There is now evidence that heparin and HPF4 complexes bind to platelets’ surface, and this binding increases with their activation grade. HPF4 complexes fix antibodies and target the immune response, provoking platelet activation, aggregation, and interaction with other blood cells. During the process, IgGs react with platelet CD32, which is the FcɣRIIa receptor [44, 46]. This contributes to amplify platelet activation and aggregation. The CD32 surface density is an important factor for the amplitude of platelet activation induced by antibodies. In patients with platelets presenting a CD32 polymorphism (131 Arg-His), activation is enhanced: the 131-Arg-His heterozygous or 131-His-His homozygous CD32 phenotypes are more reactive than the 131-Arg-Arg one. The patient propensity to develop HIT or HITT can depend on platelet activation grade and density or polymorphism of CD32. Antibodies to HPF4 can activate ECs and monocytes, favoring the release of TF, a potent procoagulant starter [29, 30]. In patients with HIT/HITT, neutrophils are activated and form aggregates with platelets, which can be detected in blood circulation. Therefore, the presence of anti-HPF4 IgG antibodies initiates multiple abnormal activities in blood circulation, which induce platelet activation and destruction and a concomitant prothrombotic risk (Figure 5). Blood activation can be out of control from body’s antithrombotic defenses, which are overwhelmed, and thrombosis occurs. Interestingly, thrombosis tends to occur at pre-existing pathological sites, where blood activation and inflammation are already activated, and the risk is greatly amplified by anti-HPF4 antibodies, as summarized in Figure 4. We have the experience that an additional factor is very important for the initiation and amplification of the pathological process. This concerns the antibody avidity for HPF4 complexes [20]. In three patients with HIT or HITT, we succeeded to separate anti-HPF4 IgGs into two groups: the most important (>90%) one had a low affinity for HPF4 and no or only a weak platelet activation capacity, while the minor one (≤10%) activated highly platelets, as evidenced with the C14-serotonin release assay. In few cases, only IgA isotypes specific for HPF4 complexes were identified in patients with HITT and malignant diseases. Although rare, IgAs can be pathogenic in some autoimmune disorders [49, 50], and this is not unexpected to note their effect in HIT. More rarely, IgM can be present at high concentration in patients with HIT, without IgGs. The mechanisms involved are not totally understood, but recently it was demonstrated that anti-HPF4 IgM antibodies can activate complement and induce platelet destruction [39]. Altogether, the different activities described here above help to understand why HPF4 antibodies, including IgG isotypes, can remain asymptomatic in many patients and produce (especially IgG isotypes with high HPF4 affinity) HIT or HITT only in a few of them. The pathogenic process is multifactorial and involves activation and interaction of various blood cells, with the prothrombotic activity of TF. Patients’ pathophysiological history and clinical status provide additional risk factors for the occurrence of disease [5, 6].
Scheme showing how heparin-dependent antibodies, targeted to HPF4 complexes, bind to platelets and endothelial cells but also to monocytes and induce platelet and EC activation, monocyte stimulation, release of TF, and formation of aggregates, all contributing to thrombocytopenia and thrombosis.
Nevertheless, there is still a fortuity context for the occurrence of the HIT/HITT complication, which relies on the formation of the immunoreactive HPF4 complexes, requiring defined concentrations of PF4 and heparin, exposed on blood cells [48]. This is a pre-requisite condition for permitting the binding of antibodies and starting the pathogenic process. This explains why this disease develops so rapidly when the critical conditions are met.
Many different assays are available for the diagnosis of heparin-dependent antibodies and for testing their capability to activate platelets. They are classified into two groups: immunoassays [23, 25, 51, 52], developed following the discovery of PF4 as the major target heparin-dependent antigen, and functional assays, performed with a low and a high heparin concentration, which were already used before [53]. A murine monoclonal antibody (KKO) has been developed and mimics HIT-associated antibodies, with platelet activation capability [54]. Here below we discuss the laboratory methods, and their combination, for the diagnosis of HIT/HITT. Diagnosis combines the clinical probability pretest with laboratory investigations [25]. For laboratory testing, the specimen used is plasma or serum for immunoassays and citrated plasma or heat-inactivated serum for functional assays. These techniques provide a laboratory support to establish, confirm, or exclude the diagnosis of HIT/HITT and must always be used in association with the pretest clinical probability. When HIT is suspected with a characteristic thrombocytopenia, heparin must be discontinued and replaced with another anticoagulant.
With the discovery of the major target antigen for heparin-dependent antibodies, i.e., HPF4 complexes, immunoassays were developed, optimized, and standardized [23, 24, 52]. The first immunoassay introduced was a two-site enzyme-linked immunosorbent assay (ELISA), for measuring antibodies to HPF4 [12]. The antigen, HPF4, is coated on the plate, which is then saturated and stabilized. A well-defined stoichiometric concentration of PF4 tetramer and heparin (about 150 μg heparin per mg PF4) must be used for presenting epitopes reactive with antibodies. Heparin-dependent antibodies can be caught from the diluted tested plasma or serum (usually a 1:100 dilution is used), during the first incubation step. Following a washing step, the immunoconjugate, specific for human immunoglobulins or their isotypes, is introduced, and a second incubation step is performed. The immunoconjugate is often a rabbit or goat antibody, specific for human whole immunoglobulins (IgGAM) or for only an isotype (IgG, IgA, or IgM), and labeled with peroxidase. In current practice, this tag reagent is an antihuman IgG-peroxidase conjugate. Following a new washing step, the substrate is introduced, and a color develops. Tetramethylbenzidine (TMB) with hydrogen peroxide (H2O2) is now the most often used substrate, producing a blue color, which turns yellow when the reaction is stopped with sulfuric acid. Absorbance is measured using a microplate reader at 450 nm. Different variant methods have been introduced. Heparin can be replaced with another sulfated polymer (electronegative) such as polyvinyl sulfonate. However, using heparin matches better with the context of antibody generation and in vivo pathogenicity. Magnetic latex particles can be used in place of the solid phase capture micro-ELISA. Different tag antibody labels can be used instead of peroxidase, such as alkaline phosphatase (with its appropriate substrate). The “enzyme-substrate” detection system with chemiluminescence or fluorescence can also be used (direct measurement). Combining latex magnetic particles and chemiluminescence or fluorescence allows immunoassay automation. Lastly, performing immunoassays in the presence of an excess of heparin allows confirming antibody specificity [25, 55].
Figure 6 shows the general immunoassay principle for detecting heparin-dependent antibodies. For testing the non-PF4 antigen-dependent antibodies, similar immunoassays can be designed by replacing PF4 with the concerned protein (e.g., IL8 or PrS). We developed an original patented approach, where heparin in excess is coated in the presence of PrS and remains biologically available. The tested patient’s sample is then incubated in the presence of a concentrated platelet lysate (containing all the platelet releasable proteins, but not plasma factors). If antibodies are present, a ternary complex is formed between tetrameric PF4 (or eventually another platelet protein), immobilized heparin, and antibodies. Caught antibodies are then detected as previously described [24]. This method offers a kinetic model for testing antibodies and mimics their binding to heparin-protein complexes bound onto platelet or blood cell surfaces. This assay reflects better the mechanisms occurring in pathology and offers improved and optimized sensitivity and specificity.
General principle of immunoassays used for heparin-dependent antibodies, either globally or for specific isotypes. Enzyme tag with substrate is used in ELISA. Chemiluminescent immunoassays, using magnetic latex particles, can be automated on immunological analyzers. Using heparin in excess in sample diluent allows confirming antibody specificity.
Functional assays rely on testing the capability of heparin-dependent antibodies to activate platelets at a low (0.1–1.0 IU/ml) and a high (10–100 IU/ml) heparin concentration. In HIT/HITT, platelets are only activated at the low heparin concentration. Functional assays need to use normal donor platelets, freshly prepared. They must be duly selected for the right reactivity. This is the constraint which limits the use of this technique. Platelets are used as platelet-rich plasma (PRP) or as washed platelets. What induces donor to donor responsiveness in platelet activation assays used for HIT antibodies is not totally understood. The CD32 platelet density or His polymorphism could favor reactivity. In practice, platelets need to be qualified with a known positive sample for their appropriateness. Frequently, platelets from four normal donors are used, and the assay is positive if at least two out of the four donors give a positive platelet activation test. Other factors can regulate platelet activity, and interestingly washed platelets are usually more reactive than PRP. This can be explained by some platelet activation induced by the washing process, and a higher amount of PF4 is present on platelet surface. Functional assays concern PAT, SRA, heparin-induced platelet activation (HIPA), and flow cytometric assays (FCA); but other assays have been reported and elegantly reviewed in 2017 [53]. PAT is a simple aggregation assay performed with PRP and the tested patient citrated plasma. SRA is performed with washed platelets labeled with C14, incubated with tested patient’s plasma, and released C14-serotonin is measured. HIPA is also performed with washed platelets, incubated with the tested sample, and platelet activation/aggregation is visually evaluated. FCA is a technique that requires to mix PRP (washed platelets are possible) with patient’s citrated plasma and to measure platelet activation through the expression of P-selectin [24]. FCA can also be used for the measurement of antibody-induced release of platelet microparticles. SRA is considered as the reference and most sensitive method. PAT has a poor sensitivity. HIPA needs trained laboratory operators and is mainly used in Germany and some neighboring countries. FCA is now a more standardized approach and looks promising but needs to be confirmed through practical experience in clinical laboratories. This method can be available in many centers for testing in emergency, provided a flow cytometer and fresh platelets are available.
The diagnosis of HIT/HITT must be done accurately and reliably for a safe management of concerned patients [25]. The first alert signal is thrombocytopenia occurring 5–15 days following the onset of heparin therapy or earlier if the patient had a previous exposure to that drug within the 3 preceding months. HIT, or HITT if thrombosis is present, is then suspected and must rapidly be confirmed. If this complication is excluded, patients can continue to receive heparin, the most effective anticoagulant in many critical clinical situations. If the disease is confirmed or cannot be excluded, or if HIT is suspected but the diagnosis cannot be conducted, heparin must be replaced by another anticoagulant, according to the clinical context and practitioners’ experience. Figure 7 shows an algorithm for establishing or excluding the diagnosis of HIT. When HIT is suspected, the pretest clinical probability must be evaluated with the 4Ts method or another one in use in the clinical setting [28]. The 4Ts score is simple and relatively well-standardized. When HIT/HITT is suspected, heparin is immediately stopped, and another anticoagulant is used to avoid any risk of severe complication. Nevertheless, the diagnosis must be established and confirmed, as the patient can need heparin later. The first laboratory investigation involves immunological testing for antibodies. If the test is negative, and the clinical probability is low or moderate, HIT can be excluded. But if clinical probability is high, HIT cannot be excluded and remains possible with non-PF4 heparin-dependent antigens involved. If positive, antibodies are present. HIT develops mainly when IgGs are generated and present at high concentration. Many authors consider that HIT occurs when the optical density (OD) in ELISA is >1.00 (the cutoff value for the positive range being at ≥0.5). When the IgG immunoassay is positive, a functional assay must be performed for confirming the diagnosis, as many heparin-dependent antibodies are asymptomatic. This functional assay must be as sensitive and specific as possible. In any case if clinical probability is high, the possibility of HIT complication remains present, whether the laboratory testing is. Testing must be repeated [56], and other antigens than HPF4 can be investigated.
Scheme showing the algorithm for the diagnosis of HIT/HITT: when suspected (thrombocytopenia and/or thrombosis), the disease diagnosis involves the clinical probability estimation and laboratory testing, first with immunoassay, which allows ruling out disease when not present, and then with a confirmatory functional assay.
HIT/HITT is associated with UFH or LMWH therapy, both drugs being sulfated polysaccharides. Other heparin-like anti-FXa anticoagulants, such as fondaparinux or danaparoid sodium, do not generate drug-specific antibodies [7, 10]. However, cross-reactivity of these drugs with antibodies present in patients with characterized HIT/HITT can be observed in laboratory assays [57]. This cross-reactivity has been reported for danaparoid sodium when it is tested in the immunoassay at a high concentration in the presence of PF4 (about 3.00 mg danaparoid sodium per mg of PF4). This can be due to the high-affinity heparan sulfate component present in this drug, which represents about 4% of the total. Cross-reactivity has also been reported in functional assays. However, there is no evidence that danaparoid sodium can generate drug-induced antibodies, and cross-reactivity is opposed by the other non-affinity components (about 80% low-affinity heparan sulfate, 12% dermatan sulfate, and 4% chondroitin sulfate), present in large excess, which disrupt the possible complexes formed, as do other low-sulfated polysaccharides [9, 58]. Therefore, there is no evidence that danaparoid sodium can provoke HIT/HITT, and the reported results and long-term clinical experience in many countries suggest that cross-reactivity is totally inhibited by the major non-affinity fractions. Furthermore, danaparoid sodium at therapeutic concentrations can inhibit the heparin-induced platelet aggregation. Conversely, pentosan polysulfate was found to be as effective as heparin and to form complexes with PF4 at similar ratios than UFH, for binding all heparin-dependent antibodies [8, 14]. Lastly, fondaparinux is not expected to induce drug-dependent antibodies or to cross-react with existing antibodies [32].
In this chapter we have reviewed the present understanding of the generation of heparin-dependent antibodies in UFH- or LMWH-treated patients, which are the primary cause for HIT/HITT and a major adverse effect of heparin therapy. This risk is much higher when UFH is used, and disease develops more frequently in some clinical situations including cardiac or orthopedic surgery, traumatology, or malignancy. The occurrence of HIT/HITT tends to decrease thanks to a better control of therapy with UFH, shorter treatment times, and the use of LMWH when possible. When heparin therapy needs to be stopped, a large panel of alternative anticoagulants is available, although in some applications heparin remains the most effective one.
The mechanisms, which can induce generation of heparin-dependent antibodies, and pathogenicity for some of them have been extensively described and discussed in literature [14, 19, 20, 22, 42, 46]. Immunization develops when defined concentrations of heparin and PF4, forming stoichiometric multimolecular complexes, are present. In vivo, immunogenic complexes with PF4 can also be formed with other polyanions such as polyphosphates [59]. Various isotypes can be generated, IgM, IgA, or IgG, but almost all clinical complications of this iatrogenic disease are reported with IgGs present at high concentration and with high affinity. For HIT/HITT pathological development, various patient-associated and fortuity factors are required. Stoichiometric HPF4 complexes must be present for stimulating the immune system and developing antibodies but also for expressing pathogenicity. Heparin-dependent antibodies are harmful only if they bind to target antigenic structures (mainly HPF4 stoichiometric complexes), present on platelets, ECs, or other blood cells, focusing the immunological response. The immune system is then deviated from its protective role and destroys the patient’s own cells [60].
HIT/HITT diagnosis is of essence for confirming or excluding this disease, and heparin treatment can be continued if the risk is ruled out. The first step when thrombocytopenia and/or thrombosis occur is to suspect this heparin adverse effect and to evaluate the pretest clinical probability. The 4Ts score is frequently used and allows risk classification from 0 to 8, 6–8 being the highest risk. Concomitantly, performing an immunoassay allows to detect and to measure IgG heparin-dependent antibodies targeted to HPF4. If the assay is negative and if clinical probability is low or moderate (score ≤ 5), HIT can be excluded, but patients need to be monitored closely, especially if thrombocytopenia is not corrected. If positive, IgG heparin-dependent antibodies are present, and HIT probability is higher if ELISA OD ≥ 1.00. Finally, the use of functional assays allows differentiating asymptomatic antibodies from those which can activate platelets and provoke disease. The presence of HIT or HITT is confirmed when the functional assay is positive [60]. However, even when negative, if clinical probability is high (6–8), HIT/HITT remains possible, and patients must be managed accordingly. Heparin cannot be continued in any patient with a possible or probable HIT diagnosis, and an alternative anticoagulant must be used.
The authors would like to thank the research groups with whom they had the opportunity and honor to collaborate and especially Profs. D. Meyer (Paris, France), A. Greinacher (Greifswald, Germany), T. Bakchoul (Tübingen, Germany), S. Panzer (Vienna, Austria), M. Poncz and G. Arepally (Philadelphia, USA), J. Fareed and J. Walenga (Chicago, USA), Y. Gruel and C. Pouplard (France), I. Elalamy (France), I. Gouin and P. Guéret (France), and all those who gave us the opportunity to investigate HIT.
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