Clinical characteristic of the patients examined in the IVF cycle.
\r\n\tThe applications are those related to intelligent monitoring activities such as the quality assessment of the environmental matrices through the use of innovative approaches, case studies, best practices with bottom-up approaches, machine learning techniques, systems development (for example algorithms, sensors, etc.) to predict alterations of environmental matrices. The goal is also to be able to protect natural resources by making their use increasingly sustainable.
\r\n\r\n\tContributions related to the development of prototypes and software with an open-source component are very welcome.
\r\n\r\n\tThis book is intended to provide the reader with a comprehensive overview of the current state of the art in the field of Ambient Intelligence. A format rich in figures, tables, diagrams, and graphical abstracts is strongly encouraged.
",isbn:"978-1-83969-069-3",printIsbn:"978-1-83969-068-6",pdfIsbn:"978-1-83969-070-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"3fbf8f0bcc5cdff72aaf0949d7cbc12e",bookSignature:"Dr. Carmine Massarelli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10391.jpg",keywords:"Embedded Systems, Technologies, Sensors, Remote Sensing, Smart Homes, Smart Cities, Integrated Monitoring Techniques, Agroecosystem, Smart Public Spaces, Computer Vision, Image Processing, Open-Source",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 12th 2020",dateEndSecondStepPublish:"November 9th 2020",dateEndThirdStepPublish:"January 8th 2021",dateEndFourthStepPublish:"March 29th 2021",dateEndFifthStepPublish:"May 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Environmental technologist expert in the development of Smart Technologies for water management and environmental monitoring, characterization, and monitoring of contaminated and degraded sites, integration of spatial data such as standard methodologies, interoperability, spectral data infrastructures.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"315689",title:"Dr.",name:"Carmine",middleName:null,surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli",profilePictureURL:"https://mts.intechopen.com/storage/users/315689/images/system/315689.jpg",biography:"Main activities:\n-development of Smart Technologies for water management and environmental monitoring;\n-characterization and monitoring of contaminated and degraded sites;\n-implementation of early warning systems and impact assessment systems also from multitemporal monitoring;\n-integration of spatial data: methodologies, standards, interoperability, spatial data infrastructures;\n-use of open source IT systems for the processing, analysis, and integration of remote sensing data with airborne and satellite sensors for thematic purposes such as characterization, control, and analysis of the territory in support of environmental policies relating to contaminated sites;\n-evaluation of the contamination of environmental matrices with specific tests and chemical analyses;\n-installation of airborne sensors and definition of flight parameters for Earth observation, CASI-1500 hyperspectral and TABI-320 thermal sensors;\n-acquisition of spectral signatures of objects through Fieldspec portable spectroradiometer and creation of databases in SQL language;\n-use of tools such as Ground Penetrating Radar for the advanced investigation of the subsoil with law enforcement agencies.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.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. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41088",title:"The Means of Progress in Improving the Results of in vitro Fertilization Based on the Identification and Correction of the Pathology of Hemostasis",doi:"10.5772/52898",slug:"the-means-of-progress-in-improving-the-results-of-in-vitro-fertilization-based-on-the-identification",body:'In most developed countries the problem of infertility has acquired not only medical and sociodemographic, but also economic significance. One of the key and vigorously developing trends in modern obstetrics is aimed at overcoming this problem and requires a multidisciplinary approach. The 2010 Nobel Prize was awarded to Robert Edwards,85-year-old British researcher and recognized the methods of assisted reproductive technologies (ARTs) which introduced a new era in human demography. ARTs are used to solve the problem of infertility; they use all treatment methods and procedures which support in vitro processing of human oocytes, sperm or embryos to become pregnant. These technologies involve in vitro fertilization (IVF) and transcervical embryo transfer, gamete intrafallopian transfer, zygote intrafallopian transfer, embryo intrafallopian transfer, gamete and embryo cryopreservation, oocyte and embryo donation, and surrogacy (Current Practices and Controversies in Assisted Reproduction. Report of.., 2001).
25 July 1978 was marked by a significant event in the history of ARTs. On that day, the first "test tube baby" was born in an obstetrics and gynecology clinic located in Oldham, North WestEngland. This was also the birth date of modern assisted reproduction. In Russia, the first baby born by this method was delivered in 1986 in the ResearchCenter for Obstetrics, Gynecology and Perinatology, the division of the RussianAcademy of Medical Sciences. Other leading centers in Russia are “Fertimed “Center for Reproduction and Genetics (Moscow), “ART-ECO” Clinic for Reproductive Health (Moscow), “ECO” Center for the Treatment of Infertility, LLC (Moscow), InternationalCenter for Reproductive Medicine (Saint-Petersburg), the Baltic Institute of Human Reproductology (Saint-Petersburg), etc.
In vitro fertilization of preovulatory oocytes and transfer of cleaving embryos into the patient\'s uterine cavity has become the prevalent method to overcome the problem of infertility (Pioneers in in vivo Fertilisation.., 1995). The IVF method was initially devised for those women whose Fallopian tubes were removed for one reason or another. However, at present, IVF is the most effective treatment for virtually all types of infertility, including endometriosis, polycystic ovary syndrome, oocyte donation (in infertile patients with oogenesis depletion), fertilization of an egg with a single sperm in cases of virtually absolute forms of male infertility (intracytoplasmic sperm injection - ICSI), carriage of an embryo by a voluntary egg recipient when a woman cannot carry the pregnancy due to some somatic or other diseases (Maheshwari et al., 2008). Despite all achievements, the IVF pregnancy rate is comparatively low. It ranges from 25% to 30% and has not changed considerably in recent years (Nyboe Andersen et al., 2009). This rate relates to a number of diverse factors that affect the reproductive process. Implantation failure following embryo transfer is the major problem in IVF (Bischof et al., 2006; Christiansen et al., 2006). IVF failures may be caused by a variety of factors: diminished ovarian reserve, maternal and paternal age, excessive body weight, endocrine disorders in the hypothalamus-pituitary-ovary system, as well as in the suprarenal and thyroid systems, diminished endometrial receptivity, quantity and quality of transferred embryos, number of transfers, and thrombophilic disorders.
Ovarian reserve. Ovarian reserve is one of the factors that determine the efficacy of IVF (Gregory, 1998; Navot et al., 1987; Scheffer et al., 2003). Assessing the ovarian reserve, specialists draw conclusions based on the prospects of ovarian stimulation in a particular patient. Conclusions may be used to define a specific procedure and further treatment prospects, as well as to make the right choice of the ovarian stimulation scheme and the quantity of drugs of human menopausal gonadotropin or follicle-stimulating hormone (FSH), which are necessary for an adequate response. The routine method for assessing the ovarian reserve measures basal FSH level on the 3rd or 4th day of the menstrual cycle and estimates the quantity of antral follicles with ultrasonography. However, at present, the prognostic significance of ultrasonography is considered less informative, even though it reflects the quantity and quality of oocytes (Damti et al., 2008). The role of new factors capable of reflecting the functional status of the ovary in a more precise manner is under discussion. (Gregory, 1998).
Maternal and paternal age.\n\t\t\t\tLintsen et al. (2007) concluded that the most important prognostic indicator to define the probability of pregnancy after IVF and ICSI is maternal age ( more frequently observed positive results -in 30-year-old women, less frequently - in women under 35, and least frequently - in women over 35). Physiological process of the gradual decline of ovarian function is one of the key obstacles for the efficacy of IVF, which depends on maternal age, current condition of the ovarian reserve and to a lesser extent on chosen schemes of ovulation induction. The cases of women under 41 are treated as relatively promising, to reason the use of donated oocytes in older women (Maheshwari et al., 2008). Paternal age also affects the conception rate: it shrinks with men after 35 due to the quality of sperm to have been deteriorated by this age (Saleh et al., 2002).
Excessive body weight. Menstrual dysfunction, polycystic ovary syndrome, hyperplastic processes in endometrium, infertility, miscarriage, gestoses, fetal hypotrophies, high rate of operative deliveries make up an incomplete list of reproductive disorders typical of obese women. 40% of women seeking for treatment of infertility in medical centers have excessive body weight; over 15% of such women are obese. The IVF program is preferable to start after the patient\'s body weight has become normalized; therefore, patients often fail to meet the required standards (Ku et al., 2006; Lintsen et al., 2005; Mc Clamrock, 2008; Megan et al., 2008). Status of the hypothalamus-pituitary-ovary system, suprarenal and thyroid systems. Interaction of the two key pituitary hormones - FSH and luteinizing hormone (LH) - is essential for the adequate growth of follicles, as well as for the formation of viable oocytes. Studies of ovulation induction in hypogonadotropic patients showed that exogenous FSH stimulates the growth of follicles up to the preovulatory stage and its synthesis primarily depends on LH, i.e. adequate maturation of follicles takes place due to this gonadotropin. Insufficient concentration of LH disturbs paracrine mechanisms regulating granulosa cells, as well as endometrial proliferation, and results in inadequate luteal phase (Alviggi et al., 2009; Balasch et al., 1995; Hull et al., 1994). Excessive concentration of LH also negatively affects the growth of follicles to be the result of suppressed aromatase activity, accompanied by fertilization disorders, decreased pregnancy rate decrease and increased miscarriage rate (Hillier, 1994). Thus, the threshold concentration (1-10 IU/l) is optimal for adequate folliculogenesis (Howles et al., 2006). It has been noted that low estradiol level in the blood serum (<200 pmole/l) on the 3rd day of the patient\'s menstrual cycle is a positive prognostic indicator of successful implantation in the IVF cycle. At the same time, some reports state that basal estradiol level was not a significant indicator of ovarian response to stimulation and did not correlate with the IVF result (Friedler et al., 2005). In recent years, researchers and clinicists have given a lot of consideration to the problem of thyroid gland dysfunction in infertile women (Bellver et al., 2008). Female reproductive system consists of interrelated structural elements: hypothalamus, pituitary gland, ovaries, other endocrine glands and target organs facilitating reproductive function. Thyroid gland is a chief part of the neuroendocrinal system; it significantly affects reproductive function. The hypothalamus-pituitary-gonadal and hypothalamus-pituitary-thyroid systems are closely related due to the presence of common central regulating mechanisms. For example, the spread of thyroid gland dysfunction diagnosed at the examination in women, who seek clinical diagnosis and treatment of infertility, ranges from 2.5 to 38.3% (Lazarus & Premawardhana, 2005). In addition to gonadotropic hormones, ovarian function is determined by adrenal hormones produced under impact of ACTH. When a patient has developed any genetic defects in the enzyme systems, cortisol synthesis in adrenal glands decreases with the increase of level of ACTH followed by the increased production of androgens under normal synthesis. This condition may be typical of congenital adrenal hyperplasia. As a result of adrenal hyperandrogenism, the suppression of ovarian function takes place, which leads to the development of a number of disorders in the menstrual cycle accompanied by anovulation.
Diminished endometrial receptivity. After high-quality embryos have been transferred into the uterine cavity and all evident causes for the failure of the IVF program have been eliminated, the unsuccessful IVF cycle is regarded as a result of disorders that occurred during the embryo implantation stage. A few years ago a new term - "repeated implantation failure" - was introduced (Margalioth et al., 2006; Tan et al., 2005). Recent years have shown that, despite the selection of obviously normal embryos for the transfer, only 20% of human embryos transferred in IVF cycles have been implanted in the uterus (International Committee for Monitoring Assisted Reproductive Technology (ICMART), 2002; Nyboe Andersen et al., 2009). This condition is considered to be based on the endometrial dysfunction occurring on the mollecular-cellular level. Lately, as a result of the tendency to transfer one or two embryos inside of an uterus, the method to determine repeated implantation failure has been modified. Margalioth et al. (2006) concluded that detailed examination should be done after 3 unsuccessful IVF cycles. Thus, the main causes are the factors which diminish endometrial receptivity: anatomical defects in the uterus, chronic endometritis, non-correspondence between the endometrial thickness and the day of embryo transfer, combined gynecologic pathology (adenomyosis, uterine fibroid), somatic diseases (including autoimmune diseases), and thrombophilias (Margalioth et al., 2006; Tan et al., 2005).
Quantity of transferred embryos. Due to the absence of conventional clinical guidelines for the treatment of infertility with the IVF method, there are on-going discussions regarding the elective transfer of one embryo to patients under 40. In2009, a mathematical model was drawn to prove that the transfer of only one embryo shall decrease the pregnancy rate by 20% (Gelbaya et al., 2009).
Embryo transfer on the stages of cleavage or blastocyst. The data obtained during the systematic review and meta-analysis (Papanikolaou et al., 2008) of 1654 patients (blastocyst transferred to 815 patients, cleaving embryo transferred to 839 patients) showed that live birth rate was higher with embryos transferred on the blastocyst stage as compared to the rate at the cleavage stage. Multiple gestation rates were the same for both study groups.
As we have already noted, unsuccessful IVF cycles are caused by many factors, including thrombogenicity of the medical technology itself due to the high estrogen-gestagen rate and frequent presence of thrombogenic risk factors and predisposition to intravascular coagulation (thrombophilia) in women that need IVF. According to up-to-date conceptions, the term "thrombophilia" means predisposition to arterial or venous thrombosis as a result of several hereditary or acquired disorders in the systems of blood coagulation, anticoagulation, or fibrinolysis (Bates et al., 2008; Heit, 2007). We use this term in a different sense, which makes most of the described thrombophilias no more than thrombogenic risk factors that may or may not become evident during the lifespan of a human being. According to our conceptions, thrombophilia should be detected in case of everpresent thrombosis risk factors (thromboses) or miscarriage syndrome in the individual medical history. In order to prove it, we note the fact that, according to the guidelines of the International Society on Thrombosis and Haemostasis (ISTH), diagnosis of antiphospholipid syndrome (APS) shall be considered invalid unless at least one or more clinical implications of this pathology match the results of special laboratory assays (lupus anticoagulant effects, antiphospholipid antibodies in the diagnostic titer) (Harris & Pierangeli, 2008).
Some publications indicate data on typical changes in the system of hemostasis that occurs during the IVF cycle. In particular, demonstration has shown that hormonal stimulation of the ovaries is accompanied by the increased von Willebrand factor, factors V and VIII, fibrinogen, enhanced APC resistance, and the decreased activity of principal physiological anticoagulants - antithrombin, proteins C and S (Andersson, 1997; Biron et al., 1997; Chan & Dixon, 2008; Curvers et al., 2001b; Nelson, 2009). Relationship between the predisposition to intravascular coagulation (thrombophilia) and unsuccessful ART results is actively discussed in current publications; however, mechanisms to produce the impact that increases thrombotic readiness on IVF are not absolutely clear. It is reported that women with thrombophilia may have increased risks for spontaneous abortion, preclinical pregnancy loss and recurrent implantation failure (Christiansen et al., 2006; Coulam et al., 2006b; Curnow et al., 2006; Many et al., 2001; Seghatchian et al., 1996; Stern & Chamley, 2006; Urman et al., 2005; Wichers et al., 2009; Younis et al., 2000). Presently, most studied and prevalent thrombophilias include APS and such risk factors as hereditary antithrombin III deficiency, factor V Leiden mutation, prothrombin mutation, polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, platelet glycoproteins ITGA2, ITGB3, and some others. Beer and Kwak (2000) treated unsuccessful IVF programs as the evident indication for assays capable of detecting hereditary and acquired thrombophilias. In 2004, Azem et al. (2004) demonstrated higher occurrence of hereditary thrombophilia in women with multiple IVF failures as compared to the group of fertile women who became pregnant after the first IVF cycle. In the research conducted by Qublan et al. (2006), 69% of women with recurrent IVF failures had at least one hereditary or acquired thrombogenic risk factor as compared to 25% of women in the group where this reproductive technology was successful. In the publication presented by Grandone et al. (2001), factor V Leiden mutation prevailed (14.4%) in women with recurrent IVF failures as compared to the controls (1%). Recently, Coulam and Jeyendran (2009b) have shown that frequency of genetic polymorphisms has been 1.6 times higher in infertile women with IVF failures as compared to the fertile group; thus, polymorphism of the MTHFR gene has prevailed. It has been also noted that the connection of thrombogenic risk factors with recurrent miscarriages and repeated implantation failures after IVF is mainly evident in the simultaneous carriage of several thrombogenic mutations and polymorphisms (Coulam et al., 2006b).
Mechanisms of hemostasis and implantation pathologies typical of some thrombophilias (carriage of thrombogenic risk factors):
factorVLeiden mutation (1691G>A). As long as activated protein C (APC) blocks activated factor V in regular conditions, resistance of the latter to APC can cause the increase of thrombinemia (Bertina et al., 1994; Dahlbäck et al., 1993). It is considered that patients who experience this mutation have higher risks for thrombosis and subsequent pregnancy loss. (Ridker et al., 1998; Urman et al., 2005; Younis et al., 2000);
prothrombin mutation (20210G>A). This mutation is accompanied by the increased synthesis of prothrombin in the liver and increased risk for venous thrombosis (Girolami & Vianello, 2000; Poort et al., 1996);
MTHFR gene polymorphism (C677>T) potentially causes increase in the level of homocysteine in blood (> 15 μmole/l), which affects human reproductive function (Nelen et al., 1998). In their publication Berker et al. (2009), interconnection between high level of homocysteine in the follicular fluid and decreased quality of oocytes and embryos in IVF programs has been discovered. High level of homocysteine in blood plasma relates to the decreased diameter of blood vessels located in the chorionic villi and miscarriage (Jerzak et al., 2003; Nelenet al., 2000). Thrombogenic action of homocysteine is based on the damage of endothelial cells, inhibition of prostacyclin synthesis, and increased platelet aggregation;
PAI-1 gene polymorphism (5G>4G; 4G/4G) is related to the increased expression of PAI-1 in the blood plasma and endometrium, which disturbs the reaction of plasminogen activation into plasmin (Anteby et al., 2004; Buchholz et al., 2003; Ebish IM, et al., 2008; Kim et al., 1997);
antiphospholipid syndrome. Damaging effect of antiphospholipid antibodies (APLAs) on oocytes and embryos on the early development stages has been indicated (Matsubayashi et al., 2006). Women with APS demonstrate high level of NK cells in the peripheral blood and endometrium. It is possible that disturbed synthesis of mediator molecules which participate in embryo adhesion and invasion by NK cells is one of the causes of disturbed signaling interaction between the blastocyst and endometrium on the earliest implantation stages (Quenby et al., 2009; Sher et al., 2000). APLAs stimulate PAI-1 synthesis that may cause disturbed degradation of intercellular matrix and decreased depth of blastocyst invasion.
Thus, making a brief summary, different forms of thrombophilia refer to different pathogenesis of implantation failures. Fixed and common conception for all thrombophilias is that pathology mechanisms are revealed in the earliest stages of pregnancy and are caused due to microcirculation and hemostasis disorders, as well as vessel wall pathology. Some researchers deny the impact of mutations of certain genes within the hemostasis system or isolated asymptomatic increase in the level of phospholipid antibodies on implantation. However, combination of several factors is believed to considerably increase individual risk of possible implantation failures and miscarriage. While estimating the occurrence of APS and mutations of genes participating in the hemostasis system in infertile women and women with IVF failures, specialists actively investigate qualitative changes on the level of endometrial structures and vascular endothelium accompanied by thrompophilia (Anteby et al., 2004; Coulam & Roussev, 2009a). Local mechanisms in the basis for implantation failures which occur along with thrombophilias are under investigated. Excessive activation of coagulation, imbalance in the coagulation system, endotheliopathy, local haemorrhages and microthrombi in the area of blastocyst invasion are common elements in the mechanism of implantation failures caused by thrombophilias. Thus, different forms of thrombophilia result in disorders on different stages of the coagulation cascade and fibrinolysis.
Analysis of publications demonstrates diverse expert opinions on the role of some mutations, polymorphisms of genes which are part of the hemostasis system and APS role in the development of infertility and ART failures. The American Society of Reproductive Medcine does not find it necessary to examine women who participate in IVF programs in order to detect risk factors for thrombophilia (American Society of Reproductive Medcine.., 2008). On the contrary, approach of the American Society for Reproductive Immunology to treat the same problem is completely opposite (American Society for Reproductive Immunology Antiphospholipid Antibody Committee.., 2000; Gleicher et al., 2002). Inconsistency of the opinions mentioned above may be explained by the absence of vast multicentral studies, use of diverse methodological approaches to diagnosing hemostasis pathologies and interpretation of examination results.
We believe that the most perspective approach in this area may be found in simultaneous consideration of thrombogenic risk factors and monitoring of the results collected with "global" methods which are capable of detecting disorders in the natural balance of pro- and anticoadulants in blood plasma under controlled ovarian hyperstimulation. This approach offers specialists the potential for the thrombin generation assay (TGA). This assay is known to define the dynamics and intensity of thrombin development; thrombin is the key hemostatic enzyme and relates to the group of integral indexes of the coagulation system (Hemker et al., 2000; Hemker et al., 2003; Hemker et al., 2006; Regnault et al., 2003; Wielders et al., 1997). This methodological approach has been successfully tested as a part of the complex estimation of the hemostasis system during pregnancy (Dargaud et al., 2010), preeclampsia (Macey et al., 2010) and oral contraceptive intake (Tchaikovski et al., 2007). Recent publication presented interesting data on the specifics of thrombin generation in blood plasma within IVF cycle (Westerlund et al., 2012). Shifts detected in 31 women were interpreted as the result of estrogen load and ovarian hyperstimulation syndrome and estimated to be vital for thrombosis prediction and IVF monitoring.
Besides, a number of researchers raise a great interest in the decrease of fibrinolytic blood activity, which is often detected in recurrent miscarriages, APS, deep vein thrombosis of lower extremities, oral contraceptive intake, myocardial infarction, and malignant neoplasms (Bertina, 1997; Birkenfeld et al., 1994; Curnow et al., 2006; Dmowski et al., 1995; Egbase et al., 1999; Lisman et al., 2005; Meltzer et al., 2009; Meltzer et al., 2010; Triplett, 1989; Wichers et al., 2009). The system of fibrinolysis, as well as the system of coagulation, is a complex system which gives characteristics to fibrinolytic responses and its central element that plays role in the activation of plasminogen into plasmin. Lately, its pathologies have been treated as new approach that explains the mechanisms of thrombosis pathogenesis (Zorio et al., 2008). The analysis of the fibrinolysis system during the IVF procedure shows the decrease in fibrinolytic responses due to several reasons (Andersson et al., 1997; Aune et al., 1991; Kim et al., 1981; Many et al., 2001; Martinez-Zamora et al., 2011; Meltzer et al., 2010; Nelson, 2009; Rice et al., 1993; Sarto et al., 2000). One of them is a decreased activity of tissue plasminogen activator (t-PA), increased level of its inhibitor - plasminogen activator inhibitor-1 (PAI-1), and increased level of thrombin-activatable fibrinolysis inhibitor (TAFI) dependent on the response of vascular endothelium (Bouma & Meijers, 2003; Martınez-Zamora et al., 2010; Martinez-Zamora et al., 2011; Meltzer et al., 2010).
Analysis of publications shows that correction of imbalanced homeostatic and fibrinolytic responses may be used in case of hormonal load within the IVF program accompanied by thrombophiia or present thrombogenic risk factors in a patient (Martinez-Zamora et al., 2011; Nelson & Greer, 2008; Rova et al., 2012; Urman et al., 2005). This is reasonable to determine thrombotic readiness, which becomes evident through the increase of general coagulation activity and thrombinemia and/or fibrinolysis suppression identified, for example, with the help of the thrombin generation assay upon detecting markers of thrombinemia and estimating fibrin clot lysis time for the fibrin obtained from euglobulins (Lisman et al., 2005; Wichers et al., 2009).
The use of heparins may become one of the methodologies aimed at the decrease of thrombogenicity and increase of IVF efficacy (Nelson & Greer, 2008; Urman et al., 2009). Still, there are no clear indications for the selection of women that need heparin prophylaxis within the IVF cycle.
Correction of hypofibrinolysis within IVF cycle also offers some difficulties for there are no published evidence of any successful drug therapy. Moreover, the hypothetic possibility to use pharmaceutical drugs - fibrinolysis activators (streptokinase, urokinase, and tissue plasminogen activator) - cannot be considered due to the absence of acute thrombosis. In the study conducted by Bjornsson et al. (1989), regular intake of aspirin in high doses (650 mg every 12 hours) caused the acceleration of fibrinolysis. But the mechanism of this effect is not absolutely clear, whereas the use of acetylsalicylic acid in high doses is unsafe due to the potential ulcerogenic effect. Nevertheless, it has been known for about 50 years that some stimuli (venous occlusion, physical load, desmopressin) lead to the acceleration of fibrinolytic responses facilitated by the fast increase of t-PA in blood due to its enhanced secretion by vascular endothelium. The effects of intermittent pneumatic compression (IPC) used to decrease the occurrence of postoperative venous thrombosis became our interests(Browse et al., 1977; Jacobs et al., 1996; Januszko et al., 1967; Holemans, 1963; Keber et al., 1979; Tarnay et al., 1980; Turpie et al., 1977; Weitz et al., 1986). Macdonald et al. (2003) published the results of their randomized pilot study demonstrating the efficacy of heparin prophylaxis combined with IPC in the course of neurosurgical invasions. The study conducted by Tarney et al. (1980) showed that intermittent compression of the calf, along with the increase in linear blood velocity and the decrease in venous stasis, increases local and systemic fibrinolytic potential (according to the shortened fibrin clot lysis time) in patients with acute myocardial infarction and prolonged movement disorders. Thus, the larger the volume of the compressed tissue gets, the more apparent became the response. The increase in blood and t-PA fibrinolytic activity after mechanical exposure on blood vessels is supported by the results presented by many authors (Bjornsson et al., 1989; Christen et al., 1997; Jacobs et al., 1996; Pandolfi et al.,1968; Salzman et al., 1987; Tarnay et al., 1980). However, we were not able to find any published data on the dynamics of PAI-1 activity. In the meantime, the correlation of the activities presented by these participants of the fibrinolysis system determines its overall efficacy. Some publications relate the mechanism of the IPC antithrombotic effect to the inhibition of coagulation cascade due to the expression of the tissue factor pathway inhibitor (TFPI) into blood flow and the decrease in the level of factor VIIa (Chouhan et al., 1999; Christen et al., 1997). Currently IPC is used worldwide for thromboprophylaxis in patients with strokes, after arthroplasty and a number of other operative invasions, in medical emergency,and applicable, firstly, in cases when administration of anticoagulants is dangerous due to the development of haemorrhage (Geerts & Selby, 2003; Gordon et al., 2012). As a rule, IPC is performed on the lower extremities, though some publications present positive results for the upper extremities compression (Knight & Dawson, 1976). Despite the fact that legs weigh more than arms, it was proved that forearm veins have considerably more t-PA than leg veins (Pandolfi et al., 1968). In our study this form of IPC was used to activate fibrinolytic responses within the IVF program and in the presence of relevant indications.
This publication is based on the clinical study carried out to define the role of pathologies in the coagulation and fibrinolysis systems facilitating IVF failures, as well as to estimate the results of their correction.
In the framework of prospective analysis we collected data on 327 women who have been visiting the Center for Saving and Recovering the Reproductive Function, a subdivision of the ClinicalRegionalHospital (Barnaul), from 2010 to 2012, to participate in the IVF program due to infertility. This study was approved by the Regional Ethics Committee of the AltaiMedicalUniversity, and all the participants under study expressed their informed consent.
At the first visit women were interviewed about their obstetric, gynecological, and thrombotic history, possible diabetes, pathologies in the thyroid gland, heart and blood vessels. We have conducted ultrasonography of the genitals in order to detect organic pathologies of the pelvic organs and estimate the ovarian reserve (according to the quantity of antral follicles), aspiration biopsy and histologic examination of the endometrium, as well as to detect infections, including sexually transmitted diseases. We have also conducted general and special laboratory assays, including hormone panel assessment, blood chemistry panel, thrombogenic mutation and polymorphism carriage, coagulation profiles, and homocysteine presence. Then, based on the obtained results, women received professional consultation by obstetrician-gynecologists, physicians, and hematologists.
The study was chronologically conducted in two stages. At the first (observational) stage, we examined a random sampling of 163 women in their IVF cycle. At the second stage, we examined a random sampling of 164 women, 98 of which underwent the correction of the hemostasis and fibrinolysis systems in the presence of relevant indications - increased thrombin generation and/or decreased fibrinolytic activity of blood plasma (controlled group or group with the therapeutic effect on hemostasis and fibrinolysis) (Fig. 1).
Division of women participating in the study into groups and subgroups
The selection criterion for the patients was any form of infertility non-responsive to traditional treatment. The exclusion criteria were somatic diseases serving as contraindications for carrying a pregnancy and delivery, congenital malformations or acquired deformations of the uterine cavity that make embryo implantation or carrying of a pregnancy impossible, ovarian tumors, benign uterine tumors that require operative invasion, malignant neoplasms.
All patients are representatives of the Caucasian race, their age ranged from 21 to 42 years (Table 1)
There was a difference in clinical profiles of women representing the two groups. The second group of patients suffers from chronic endometritis and has lower ovarian reserve. Besides, male infertility factor was more frequent in this group.
We used standard protocols to induce superovulation. In 72.4% (237 patients) of the whole population we used the "prolonged" protocol with diphereline (Ipsen) 0.1 mg or decapeptyl (Ferring) 0.1 mg and gonadotropic preparations - puregon (MSD) 150-250 IU, menopur (Ferring) 225 IU, or gonal (Merck Serono) 225 IU. In 27.6% (90 patients) of the whole population we stimulated superovulation using the same gonadotropic preparations and an antagonist - cetrotide (Merck Serono) 0.25 mg. Transvaginal follicle puncture was conducted with ultrosonic guidance using Medison Sonoace X8 machine. After we counted obtained oocytes and estimated their quality with the conventional scale (normal oocytes of good quality - 4-5 points, modified oocytes - less than 4 points), oocytes and embryos were cultivated in 6-well plates in the IVF medium (Vitrolife, Sweden), at 37 degrees Centigrade, in humid atmosphere containing 5% of CO2. Sperm processing was conducted with the Sil-Select Plus medium (FertiPro, Belgium). The ICSI procedure consisted of fertilization with the injection of a single sperm into the oocyte (177 married couples) in case of decreased sperm mobility or irregular sperm morphology. Embryo transfer was conducted with ultrasonic guidance on the 3rd day of cultivation. Embryos with the highest quality rating (A, AB) were selected for the transfer. Pregnancy was diagnosed two weeks after the embryo transfer by means of detecting b-human chorionic gonadotropin (b-hCG). After three weeks we defined quantity and location of the implanted embryos with ultrasonography (in 124 patients).
Indication | Total (n=327) | Group 1 (n=163) | Group 2 (n=164) | P-value* |
Age, years (mean ± SD) | 33.7 ± 4.1 | 33.2 ±3.6 | 34.4 ± 3.9 | "/> 0.5 |
BMI "/> 25 kg/m2, n (%) | 61 (18.7) | 34 (20.9) | 27 (16.5) | 0.323 |
Genital pathology: | ||||
- Chronic endometritis, n (%) | 108 (33.0) | 42 (25.8) | 66 (40.2) | 0.006 |
- Endometriosis, n (%) | 55 (16.8) | 28 (17.2) | 27 (16.5) | 0.883 |
- Myoma, n (%) | 45 (13.8) | 25 (15.3) | 20 (12.2) | 0.426 |
IVF failure registered in the history, n (%) | 36 (11.0) | 19 (11.7) | 17 (10.4) | 0.727 |
Low ovarian reserve, n (%) | 55 (16.8) | 19 (11.7) | 36 (21.9) | 0.017 |
Extragenital pathology: | ||||
- Hypothyroidism, n (%) | 49 (15.0) | 21 (12.9) | 28 (17.1) | 0.352 |
- Arterial hypertension, n (%) | 6 (1.8) | 2 (1.2) | 4 (2.4) | 0.684 |
Infertility causes: | ||||
- Tubal factor, n (%) | 119 (36.4) | 61 (37.4) | 58 (35.4) | 0.730 |
- Male factor, n (%) | 138 (42.2) | 59 (36.2) | 79 (48.2) | 0.033 |
- Endocrinal factor, n (%) | 29 (8.9) | 14 (8.6) | 16 (9.8) | 0.848 |
Combination of female and male factors, n (%) | 41 (12.5) | 23 (14.1) | 17 (10.7) | 0.316 |
Clinical characteristic of the patients examined in the IVF cycle.
Technique of laboratory assays for hemostatic and fibrinolytic profiles.
Examination was conducted three times: 1-2 days before the start of controlled ovarian hyperstimulation and an IVF program (1st observation point), 2-3 days before the puncture of ovarian follicles (2nd observation point), and on the 12th-14th day after the embryo transfer (3rd observation point), when the outcome in terms of pregnancy was defined by estimating the level of b-hCG.
Sampling of venous blood was in the cubital vein in VACUETTE test tubes with the buffer solution of sodium citrate with the proportion of 9:1 (9NC Coagulation sodium citrate 3.2%). Blood was centrifuged at 1400 g and room temperature for 15 minutes. Plasma samples were generally studied within the two hours after being obtained. Prior to conducting immune-enzyme assays and estimating the endogenous thrombin potential, plasma was stored at -40 degrees Centigrade for the period of time ranging from 24 hours to 1 month.
Measuring of the endogenous thrombin potential was made as a part of the thrombin generation assay (TGA). We believe that this method may be regarded as a historical modification of the two-stage self-coagulogram suggested by Berkarda et al. (1965) and developed to pursue similar goals. It was demonstrated that TGA allows experts to measure the dynamics of thrombin generation and inactivation with high precision (Hemker et al., 2003; Hemker et al., 2006). To perform calibrated automated thrombography, the Fluoroskan Ascent microplate fluorometer was applied (Thermo Fisher Scientific, Finland) equiped with a dispenser with Thrombinoscope 3.0.0.26 software. Coagulation of plasma under study was conducted in the presence of tissue factor (5 μM) and phospholipids (4 μM); thrombin generation was continually registered by measuring the signal of fluorogenic substrate (Z-Gly-Gly-Arg-АМС). The following parameters were considered: endogenous thrombin potential (ETP, nM×min), calculating the area under the thrombin generation curve and taking into account specifics of the enzyme inactivation, and peak thrombin concentration - Peak thrombin (nM/l), maximal thrombin concentration per time unit.
Activity of t-PA and PAI-1 was defined by means of the immune-enzyme analysis with sets of reagents t-PA Combi Actibind ELISA Kit and Actibind PAI-1 ELISA (Technoclone, Austria), while the collected data was estimated by mutual comparison. Due to the fact that these important participants of fibrinolytic responses are antagonistic to each other and have a common origin (vascular endothelium), we calculated the index of endothelial ability to activate fibrinolysis (EAAF index). To do that we applied the following formula:
Defining clot lysis time (CLT). Many authors refer this method to the group of global assays for fibrinolysis assessment. It can be conducted in a variety of ways (Lisman et al., 2005; Martinez-Zamora et al., 2011; Wichers et al., 2009).
Method to define spontaneous lysis time of a fibrin clot obtained from plasma euglobulins was described by Kowarzyk and Buluk (1954). It is based on the precipitation of euglobulin fraction stabilized with sodium citrate in the acid medium with the simultaneous removal of fibrinolysis inhibitors. Then, following this methodology, specialists promote clot formation by recalcifying the reconstituted euglobulin solution and register period for its complete dissolution at fixed temperature (+37 degrees Centigrade). Martinez-Zamora et al. (2011) have recently published original CLT results obtained in women participating in IVF cycles using another method described by Lisman et al. (2002). In particular, this method implies the study of CLT for clots obtained from blood plasma by means of activitaing fibrinolysis with exogenous t-PA. For our study we use a modified method suggested by Kowarzyk and Buluk (1954) and used kaolin that activates the contact phase of coagulation and starts activation cascade. Factor XIIa → kallikrein → plasmin. Description of this method was given earlier by Barkagan and Momot [Barkagan Z.S., Momot A.P. Diagnosis and controlled therapy of hemostasis pathologies. / M., Publisher: Nyudiamed-AO, 2001. -296P.]. Range of normal CLT variations in this modification is 8-12 minutes.
Definition of the D-dimer concentration in blood plasma was conducted with the help of reagent set D-dimer Red-700 (Helena Bioscience, UK) and blood coagulation analyzer Sysmex CA-1500 (Sysmex, Japan). This parameter was considered in accordance with conventional conceptions as a global marker for the completion of fibrin generation and fibrinolysis of stabilized fibrin.
Definition of gene mutations and polymorphisms, predisposing to thrombosis, was conducted with the method of polymerase chain reaction. Thus, we detected the carriers of factor V Leiden (1691G>A) and factor II (20210G>A) mutations, MTHFR (C677>T) and PAI-1 gene polymorphisms related to potential activation of coagulation or decreased plasmin generation, as well as to IVF failures and miscarriages (Coulam et al., 2006a).
Statistical processing of the obtained data was made with the following software: Microsoft Office Excel 2003, Statistica 6.1, and Medcalc 12.2.1. Validity of the differences in mean values was defined with the Student\'s t-test (t). Group distribution normalcy was estimated with the Shapiro-Wilk test. In cases when the distribution deviated from the norm, we used the non-parametric Mann-Whitney U test for two independent groups and the Spearman\'s rank correlation coefficient (R). For experimental data presented in percentages or rates the Fisher\'s exact test was used. Odds ratio (OR) and log-linear rate analysis were calculated as a measure of predictor impact. To estimate the accuracy of obtained values, we defined a 95% confidence interval. Differences P<0.05 were considered statistically significant. We assessed the efficacy of the chosen treatment methods with conventional criteria applied in evidence-based medicine, including Absolute Risk Reduction (ARR), Relative Risk (RR), Relative Risk Reduction (RRR), Number Needed to Treat (NNT), and Confidence Interval (CI).
At the beginning of the study, it was important to investigate shifts in the hemostatic and fibrinolytic systems that may affect IVF outcomes (in terms of the pregnancy rate) and to define their quantitative level that may help in selecting those women who need the correction of disturbed hemostatic and fibrinolytic responses. As a result, we defined that thrombin generation in the observational group had considerably increased after the start of controlled ovarian hyperstimulation in response to a sharp increase in the level of estrogens in blood, which is consistent with recently published data (Westerlund et al., 2012). We have also found that the degree of the increase in thrombin generation is different at successful and unsuccessful IVF outcomes (Table 2). In particular, the values of such thrombin generation factors as ETP and peak thrombin concentration at the 2nd observation point were higher in case of IVF failures (P<0.001) as compared with the similar data in patients with pregnancies.
Indication | At IVF failure (n=107) | At pregnancy (n=56) | ||||
1st observation point | 2nd observation point | 3rd observation point | 1st observation point | 2nd observation point | 3rd observation point | |
ETP, nМ/min | 1655±39.2** | 2060.5±52.7** | 1853.9±55.6** | 1574.8±36.9 | 1723±54.2 | 1632.7±56.4 |
Peak thrombin concentration, nM/l | 328.6±24.8** | 394.1±25.6** | 378.4±25.5** | 313.2±24.6 | 338.3±25.5 | 310.1±26.0 |
t-PA, activity, un/ml | 0.36±0.16 | 0.37±0.18 | 0.38±0.18 | 0.37±0.14 | 0.36±0.16 | 0.35±0.17 |
PAI-1, activity, un/ml | 4.22±2.98 | 4.08±2.76 | 4.10±2.16 | 3.67±2.68 | 3.41±2.87 | 3.25±2.31 |
EAAF index, % | 8.5±3.4 | 9.1±4.1 | 9.3±4.2 | 10.0±4.1 | 10.5±4.9 | 10.7±4.6 |
Clot lysis time, min | 13.5±3.7* | 14.3±3.9* | 14.9±3.8* | 11.2±3.5 | 11.9±2.9 | 12.5±3.3 |
D-dimers, ng/ml | 223.7±31.7** | 266.4±27.8* | 321.0±31.4** | 198.5±25.4 | 251.6±26.1 | 298.4±28.4 |
Quantitative level and change dynamics of hemostatic and fibrinolytic indications (mean ± SD) in women of the 1st (observational) group (n=163)
The most significant adverse indication for this reproductive technology was ETP value, which range limits at different IVF outcomes in the middle of the cycle did not intersect even with the M±3SD limit (Fig. 2). Peack thrombin concentration also changed, but its values in the compared groups did not intersect within the M±SD limit.
With regard to the conducted studies, the threshold value for the positive decision on administering heparin prophylaxis was set according to the following criteria: ETP exceeds 1900 nM/min and/or increased Peack thrombin concentration of over 360 nM/l.
Definition of the threshold values for TGA indications (ETP and peak thrombin concentration) at different IVF outcomes in the 1st (observational) group (at the 2nd observation point).
The level of D-dimers, a known marker for fibrin generation and fibrinolysis, showed less distinctive differences in subgroups 1.1 and 1.2, even though it was slightly decreased, according to the mean data, in case of IVF failures (Table 2). Mean values of this indication in virtually healthy women of fertile age registered in our Center were equal to 205.3 ng/ml, with М±2SD 148.5-262.1 ng/ml. Respectively, registered results of the D-dimer level at the 2nd observation point were within the allowed value limits or slightly exceeded them.
It was more difficult to define the threshold values that reflect the decrease in the activity of fibrinolytic responses and allow specialists to select patients in need of hypofibrinolysis correction. Recent important publications devoted to this field demonstrate that hypofibrinolysis may be typical of some women who participate in the IVF procedure, but this pathology is original and not triggered in the course of controlled hormonal stimulation as a part of the IVF program (Martinez-Zamora et al., 2011; Westerlund et al. 2012). We received similar data proving that the suppression of fibrinolytic responses was actually typical of a number of women before the beginning of the IVF cycle. Suppression was steady throughout the cycle. Dynamics analysis of the changes in t-PA and PAI-1 activities, their EAAF index, and clot lysis time revealed more dramatic shifts at IVF failures, though the difference between the mean values of the parameters under study turned out to be invalid (P<0.05) (Table 2). Nevertheless, we have recorded two facts. First, mean values of the EAAF index defined in the group of 10 virtually healthy female volunteers (20-23 years) were equal (М±SD) to 11.0±3.3%. Second, in case of IVF failures we registered decreased EAAF indexes (less than 11%) in 93.5% (43 out of 46) of women in the 1st (observational) group before the start of the IVF program (1st observational point) as compared to 4,1% (2 out of 49) of women after successful impregnation (P<0.000001) (Table 3).
We used the values of the applied CLT assay to be the method of general fibrinolysis monitoring and refused to consider it as a potential criterion for the selection of women in need of therapeutic invasion in relation to its laboratory standardization. Thus, to select females to undergo IPC procedure we chose EAAF index calculation rate, which records the correlation between t-PA and PAI-1 activities, with the value of less than 11%.
Back to the data presented above and obtained during the study of the hemostasis and fibrinolysis systems in the patients of the 1st or observational group (n=163), one can see significant correlation between the detected pathologies and certain IVF outcomes (Table 3). Adverse shifts in these systems had records in 114 out of 163 women (70%) in the 1st group. In general, the IVF cycle efficacy at this stage of the study was equal to 34.4%, however, certain hemostatic and fibrinolytic pathologies facilitated the decrease in the number of successful impregnations from 95.9% (47 out of 49 women in subgroup 1.1) to 7.9% (9 out of 114 women in subgroup 1.2), i.e. in 12.1 times (P<0,000001).
Correction of the hemostatic system at the excessive thrombin generation initially arranged the administration of heparin prophylaxis by means of subcutaneous introduction of nadroparin calcium (Sanofi-Aventis): 0.3 ml twice a day for 12-14 days. Decision to begin the therapy was based on marking a suprathreshold increase in the major indications of thrombin generation - ETP (over 1900 nM/min) and/or Peack thrombin concentration (over 360 nM/l) at the 2nd observation point.
Patient subgroups | Аbs. (n=163) | % of the whole study population | Impregnation | |
Аbs. (n=56) | % of pregnant women | |||
1.1. Without target indicators of hemostatic and fibrinolytic pathologies | 49 | 30.1 | 47 | 83.9 |
1.2. With hemostatic and fibrinolytic pathologies | 114 | 69.9 | 9 | 16.1 |
1.2.1. With ETP exceeding 1900 nM/min and/or increased Peack thrombin concentration of over 360 nM/l (at the 2nd observational point) | 46 | 28.2 | 3 | 5.4 |
1.2.2. With decreased EAAF index of less than 11% and prolonged clot lysis time of over 12 min. (at the 1st observational point) | 35 | 21.5 | 4 | 7.1 |
1.2.3. With ETP exceeding 1900 nM/min and/or increased Peack thrombin concentration of over 360 nM/l(at the 2nd observational point) and decreased EAAF index of less than 11% (at the 1st observational point) | 33 | 20.2 | 2 | 3.6 |
IVF results in women of the 1st (observational) group depending on the presence or absence of hemostatic and fibrinolytic pathologies
Impact on the vessel wall to increase fibrinolytic activity was made by means of IPC. In the publication byKakkos et al. (2005) a comparative description of the two widely used compression machines - SCD Express™ Compression System (Tyco Healthcare Group LP, Mansfield, MA, USA) was introduced with a rapid inflation device that delivers uniform compression and VenaFlow® (Aircast Inc, Summit, NJ, USA). However neither of them is normally equipped with proper braces to provide mechanical invasion for arm vessels. Still, we found it important to compress this vessel area to exclude even the hypothetic possibilty
Subgroups examined | Аbs. (n=164) | % of total number of women | Impregnation | |
Аbs. (n=68) | % of number of pregnant | |||
2.1. Without the required signs of pathology of hemostasis and fibrinolysis | 26 | 15,8 | 21 | 30,9 |
2.2. Without the required signs of pathology of hemostasis and fibrinolysis | 138 | 84,2 | 47 | 69,1 |
- including an increase in ETP over 1900 nM/min and/or with Peack thrombin more than 360 nM/l (2nd point of observation) | 50 | 30,5 | 19 | 27,9 |
- including those with reduced EAAF index less than 11% (on the 1st point of observation) | 40 | 24,4 | 14 | 20,6 |
- including an increase in ETP over 1900 nM/min and/or increased Peack thrombin more than 360 nM/l (2nd point of observation) and a decrease of the index EAAF less than 11% (on the 1st point of observation) | 48 | 29,3 | 14 | 20,6 |
Received treatment against diseases of hemostasis, including: | 98 | 59,8 | 42 | 61,8 |
2.2.1. After heparin prophylaxis | 38 | 23,2 | 15 | 22,1 |
2.2.2. After IPC course | 23 | 14,0 | 10 | 14,7 |
2.2.3. When combined IPC course with heparin prophylaxis | 37 | 22,6 | 17 | 25 |
2.2.4. Those in need of treatment, but did not receive it | 40 | 24,4 | 5 | 7,3 |
Results of IVF in women of the 2nd (controlled) group in relation to the presence or absence of disorders in hemostasis and fibrinolysis
of the pulmonary artery thromboembolia (e.g. in the presence of clinically non-evident iliofemoral thrombosis) and due to the obtained data on the increased content of t-Pa in endotelial vessels of the upper extremities (Pandolfi et al., 1968). That is why we chose pneumatic massaging device PM-01 (Russia) to apply a 7-chamber compression brace in the upper arm area using the mode of wave compression with the following parameters:
chambers from 30 to 150 mm. Hg. Art., 45 cycles of compression wave with memory for 30 minutes to maintain the pressure in the cuff chambers from 5 to 90., the pressure of compressed air supplied to the compression performed in a course of 8 sessions (twice a week) with 30-minute cuff device to the left or right hand. The starting point of this therapy was to reduce EAAF index below 11% measured in a number of patients just prior to IVF program (1st point of observation).
Studies have found that the total number of favorable outcomes of IVF in the 2nd (controlled) group was 41.5%, an increase of only 7.1%, compared with those in group 1 (34.4%; P <0,21) (Table 3 and Table 4).
However, please note that 40 patients (subgroup 2.2.4) failed our proposed therapy, although prescribed by the above criteria. If to sum up the outcome of IVF in all samples in the study of women who had indications for treatment but did not receive it for a number of reasons (sub 1.2 and 2.2.4; 154 cases) we indicate positive results in 9.1%, whereas in the treated patients (subgroup 2.2.1, 2.2.2 and 2.2.3, 98 cases) - in 42.9%, or 4.71 times more likely (P<0,000001).
Effect of treatment produced on the dynamics of hemostasis and fibrinolysis during IVF is shown in Table 5. You can see the previous trends in Table 2, but the women in group 2, compared to the 1 st group demonstrated lower intensity of thrombin generation and improvement of fibrinolysis regardless of the outcome of IVF.
D-dimer levels in blood plasma has indicated growing trend - the concentration of this indicator has been consistently higher regardless of the period of the survey in patients with unsuccessful IVF outcome (Tables 2 and 5). However, the value of D-dimer levels was within the range of normal variation or slightly exceeded them, hardly matching the identified changes parameters under study (Table 6).
In this regard, we have not put the emphasis on the results of this test upon the following analysis.
Other risk factors of unsuccessful IVF which did not depend on the characteristics of hemostatic and fibrinolytic had its effect on IVF success (see Section 2, Table 13, 14), as well as the fact of receiving or not receiving therapeutic intervention aimed at reducing the thrombogenic potential and increasing fibrinolytic activity of blood. Calculations and observations in tables 7-12 demonstrate a better pattern in this regard. In particular, it appeared that an approved prescription of low-molecular heparin at high thrombin generation at the 2nd stage of the study contributed to the increase in the incidence of pregnancy in 6.4 times (P<0,0001), isolated IPC course application -in 3.0 times (P<0,007), and the combination of IPC course with heparin prophylaxis - in 6.5-times (P<0,0001) (Table 7).
Indication | At failure in IVF cycle (n=96) | At pregnancy (n=68) | ||||
First point of observation | Second point of observation | Third point of observation | First point of observation | Second point of observation | Third point of observation | |
ETP, nM/min | 1825,3±96,8* | 1922,1±64,7* | 1785,4±±89,5 | 1645,6±54,9 | 1762,1±79,8 | 1711,2±84,3 |
Peack thrombin, nM/l | 342,1±26,3** | 381,5±25,7** | 364,4±24,3** | 310,7±27,4 | 329,1±29,3 | 326,4±25,7 |
t-PA, activity un/ml | 0,35±0,14 | 0,51±0,15 | 0,48±0,13 | 0,35±0,15 | 0,47±0,16 | 0,44±0,14 |
PAI-1, activity un/ml | 3,55±1,75 | 2,64±1,91 | 2,32±1,58 | 3,48±2,11 | 1,95±0,75 | 1,86±0,57 |
EAAF index, % | 9,9±4,28 | 19,3±3,88* | 20,6±4,53* | 10,0±3,97 | 24,1±4,39 | 23,6±4,77 |
Clot lysis time, min | 15,5±3,65 | 12,3±3,86 | 11,4±4,04 | 13,4±3,85 | 11,8±3,85 | 10,1±3,11 |
D-dimers, ng/ml | 236,4±26,2* | 258,6±25,1* | 305,6±28,5* | 194,7±32,4 | 233,4±24,5 | 211,7±28,6 |
The dynamics of hemostasis and fibrinolysis (M ± SD) in women of second (controlled) group (n = 164), t - test
Indication | Rank correlation | P value |
ETP, nM/min | 0,09 | 0,017 |
Peack thrombin, nM/l | 0,125 | 0,002 |
t-PA, activity, un/ml | 0,118 | 0,0003 |
PAI-1, activity, un/ml | 0,124 | 0,0004 |
EAAF index, % | 0,107 | 0,0006 |
Clot lysis time, min | 0,111 | 0,0005 |
Pair correlation between the level of D-dimers (by Spearman) and the study of hemostasis and fibrinolysis in different periods of the IVF cycle, regardless of its outcome
Modality | In need of treatment, but did not receive it (sub-1.2 and 2.2.4; n = 154) | In need of treatment, and treated (sub 2.2.1, 2.2.2 and 2.2.3; n = 98) | ||||
Abs. | Became pregnant | % | Abs. | Became pregnant | % | |
1.Heparin Prophylaxis | 64 | 4 | 6,2 | 38 | 15 | 39,5 |
2. IPC course | 48 | 7 | 14,6 | 23 | 10 | 43,5 |
3. Combined effect | 42 | 3 | 7,1 | 37 | 17 | 45,9 |
The influence of the methods of correction of hemostatic and fibrinolytic responses to the effectiveness of IVF (with data 1 and 2 stage of the research)
Criteria such as Absolute Risk Reduction (ARR), Relative Risk (RR), Relative Risk Reduction (RRR), Number Needed to Treat (NNT), Confidence Interval (CI) were determined for further evaluation of the effectiveness of the treatment (Table 8).
Modality | Indication | |||||
ARR | NNT | OR | CI 95% (RRR) | CI 95% (OR) | RRR% | |
Heparin Prophylaxis | 0,27 | 3,7 | 0,22 | 0,52-0,92 | 0,07-0,69 | 31 |
IPC Course | 0,31 | 3,2 | 0,19 | 0,44-0,94 | 0,05-0,65 | 35 |
Heparin prophylaxis combined with IPC course | 0,55 | 1,8 | 0,24 | 0,23-0,60 | 0,02-0,22 | 63 |
The effectiveness of different methods of therapy in women in a cycle of IVF
Indication | In need of treatment, but did not receive it (subgroup 1.2 и 2.2.4; n=154) | In need of treatment, and treated (subgroup 2.2.1, 2.2.2 и 2.2.3; n=98) | ||||
First point of observation | Second point of observation | Third point of observation | First point of observation | Second point of observation | Third point of observation | |
ETP, nM/min | 1459,4±85,1 | 1912,5±108,6** | 1872,8±85,1** | 1490,6±84,1 | 1729,8±89,5 | 1566,4±72,7 |
Peack thrombin, nM/l | 307,1±31,8 | 391,2±25,3** | 385,4±22,5** | 313,1±19,7 | 362,8±23,1 | 341,3±25,6 |
t-PA, activity, un/ml | 0,32±0,15 | 0,34±0,16 | 0,33±0,15 | 0,34±0,12 | 0,48±0,15 | 0,49±0,14 |
PAI-1, activity, un/ml | 3,18±2,32 | 3,22±1,66 | 3,26±1,75 | 3,22±1,71 | 2,76±1,51 | 2,68±1,67 |
EAAF index, % | 10,0±3,2 | 10,5±4,3** | 10,1±4,1** | 10,5±3,5 | 17,3±4,4 | 18,2±4,2 |
Clot lysis time, min | 13,1±3,6 | 14,2±3,9 | 15,4±3,8** | 12,2±4,4 | 10,1±4,5 | 9,2±3,4 |
The dynamics of hemostasis and fibrinolysis (M ± SD) in women in a cycle of IVF when indicated for the correction of hemostasis (n = 138), t - test
The choice was made towards absence of pregnancy after conducted treatment as the negative outcome of IVF. The control group included 154 women who had revealed violations of blood coagulation and fibrinolysis and did not receive treatment (subgroups 1.2 and 2.2.4). The intervention group had patients who received one of three therapies aimed at correcting identified violations in the hemostatic system and hypofibrinolysis (subgroup 2.2.1, 2.2.2, 2.2.3). It was discovered that all of the treatment reduced the risk of a negative outcome of IVF. In particular, in order to prevent one adverse outcome, you need to treat 2 women by the combined treatment option (1.8), using the IPC - 3 women (3.2), and heparin prophylaxis - 4 women (3.7). The relative risk reduction (RRR) in all cases was greater than 25%, which corresponded to clinical effect, and upon combined RRR therapy more than 50%, indicated a pronounced clinical effect.
Evolution of indicators reflecting defects of hemostatic and fibrinolytic reactions in patients in need of therapeutic intervention are shown in Table 9. Obviously, undertaken treatment has a beneficial effect on the rate of thrombin generation and fibrinolysis, and the index EAAF which reflects fibrinolysis-activation ability of the vascular wall indicated the increase in 2 times.
We also made separate calculations of laboratory parameters in women with high thrombin generation in need of heparin prophylaxis (Table 10). As a result, it was found that low molecular weight heparin with a mid-cycle IVF significantly reduces the generation of thrombin. In particular, the background rate nadroparin ETP between the 2nd and 3rd observation points decreased by 18.1%, compared to 3.6% in women who did not receive anticoagulant. The similar dynamics had Peack thrombin, which decreased, respectively, by 13.2% and 1.8%.
Indication | In need of treatment, but did not receive it (subgroup 1.2.1. и 2.2.4.1; n=64) | At heparin prophylaxis (subgroup 2.2.1; n=38) | ||||
First point of observation | Second point of observation | Third point of observation | First point of observation | Second point of observation | Third point of observation | |
ETP, nM/min | 1461,2±81,6 | 1849,3±89,2 | 1782,4±93,5** | 1489,5±85,5 | 1861,2±94,4 | 1524,6±88,9 |
Peack thrombin, nM/l | 310,1±23,1 | 382,4±19,5 | 375,6±25,2** | 321,2±22,3 | 386,3±23,5 | 335,2±20,2 |
t-PA, activity, un/ml | 0,30±0,16 | 0,33±0,15 | 0,31±0,15 | 0,33±0,12 | 0,41±0,16 | 0,42±0,17 |
PAI-1, activity, un/ml | 2,40±1,13 | 2,50±1,22 | 2,44±1,98 | 2,84±1,45 | 3,61±1,75 | 3,50±1,71 |
EAAF index, % | 12,5±3,1 | 13,2±4,2 | 12,7±3,6 | 11,62±3,2 | 11,35±4,2 | 12,0±3,9 |
Clot lysis time, min | 9,4±3,0 | 8,7±3,3 | 10,1±3,5 | 8,4±3,7 | 8,7±2,8 | 9,7±3,2 |
The dynamics of hemostasis and fibrinolysis (M ± SD) in the second group of women in the presence of indications for heparin prophylaxis (n = 102), t – test
It should be noted that the indicators of fibrinolytic activity has not changed and remained stable without regard to heparin and duration of the study.
Indication | In need of treatment, but did not receive it (subgroup 1.2.2. и 2.2.4.2; n=48) | IPC Course recipients (subgroup 2.2.2.2; n=23) | ||||
First point of observation | Second point of observation | Third point of observation | First point of observation | Second point of observation | Third point of observation | |
ETP, nM/min | 1534,4±87,2** | 1575,7±85,6 | 1589,6±96,4 | 1415,1±87,7 | 1562,3±86,1 | 1632,3±93,8 |
Peack thrombin, nM/l | 314,2±30,3* | 322,4±28,2 | 327,7±25,7** | 294,5±24,4 | 322,1±31,1 | 353,3±25,9 |
t-PA, activity, un/ml | 0,36±0,14 | 0,39±0,15 | 0,37±0,14* | 0,35±0,16 | 0,51±0,15 | 0,48±0,15 |
PAI-1, activity, un/ml | 3,98±1,67 | 4,11±2,32 | 4,05±2,54* | 3,55±1,88 | 2,64±1,06 | 2,32±1,32 |
EAAF index, % | 9,0±3,2 | 9,5±3,6** | 9,1±4,0** | 9,9±3,2 | 19,3±3,4 | 20,6±4,5 |
Clot lysis time, min | 13,8±4,3 | 14,4±4,6* | 14,8±3,2** | 14,3±4,1 | 11,4±3,7 | 9,0±3,3 |
The dynamics of hemostasis and fibrinolysis (M ± SD) in the second group of women in the event of Table readings for IPC course (n = 71), t – test
Indication | In need of treatment, but did not receive it (subgroup 1.2.3 и 2.2.4.3; n=42) | At heparin prophylaxis and IPC course recipients (subgroup 2.2.3; n=37) | ||||
First point of observation | Second point of observation | Third point of observation | First point of observation | Second point of observation | Third point of observation | |
ETP, nM/min | 1538,6±78,3 | 1770,4±85,6 | 1756,6±95,7** | 1566,7±86,3 | 1764,4±95,7 | 1542,1±81,3 |
Peack thrombin, nM/l | 322,3±32,4 | 379,3±29,1 | 374,5±31,6** | 324,7±27,6 | 371,2±33,8 | 335,6±30,7 |
t-PA, activity, un/ml | 0,37±0,17 | 0,39±0,15 | 0,36±0,16 | 0,31±0,16 | 0,49±0,15 | 0,46±0,14 |
PAI-1, activity, un/ml | 3,64±2,05 | 4,12±1,77 | 3,45±1,98 | 3,02±1,69 | 2,29±1,14 | 2,09±0,91 |
EAAF index, % | 10,2±2,9 | 9,5±3,1** | 10,4±3,3** | 10,2±2,6 | 21,4±4,5 | 22,0±4,3 |
Clot lysis time, min | 15,4±3,9 | 13,2±4,2** | 15,7±3,4** | 13,8±2,3 | 10,0±3,8 | 9,1±3,9 |
The dynamics of hemostasis and fibrinolysis (M ± SD) in the second group of women when indicated for combination therapy (n = 79), t – test
Similar calculations were performed in women with hypofibrinolysis as well aswith the combination of low fibrinolytic activity with excessive generation of thrombin (Tables 11 and 12). It was found that the isolated effects of IPC in women with original, prior to the IVFcycle hypofibrinolysis indicated a sharp increase in EAAF index combined with the decrease in CLT. Interestingly, vases compression led to the significant increase of t-PA activity as well as to the reduction of PAI-1activityat the end of the IVF cycle. It was also discovered that the application of IPC led to increased thrombin generation which Peack thrombin factor clearly demonstrated.
The evolution of laboratory parameters of hemostasis and fibrinolysis in women who require concomitant therapy, but do not receive it (A) during such therapy (B)
Combined application of IPC and low molecular weight heparin producedcomplex beneficial effect on hemostasis and fibrinolysis to be in correspondence with the maximum increase in the number of IVF successfuloutcomes (Tables 4, 7, 8 and 12).
In Fig. 3 the dynamics of the main parameters studied in the course of the treatment for the correction of hemostasis and fibrinolysis is highlighted.
This section has recorded and compared the effect of risk factors in the failure of IVF in 1st (observation) group and women of (2nd) group. We studied a wide range of adverse prognostic factors which are well-known in Reproduction and discussed in this publication: markers of thrombogenic risk and blood fibrinolytic activity reduction as well as hyperhomocysteinemia, thrombogenic mutations and polymorphisms carriers, presence of an inflammatory response (Bates et al., 2008; Coulam & Jeyendran, 2009b; Heit, 2007; Qublan & Eid, 2006), "0" blood type negative factor [Canonico et al., 2008; Ohira et al., 2007.)
Assessing the reasons for the failure of pregnancy in IVF cycles in 163 patients of the 1st (observation) group based on the analysis of the odds ratio (OR), 9 out of 27 (33.3% ) factors became the most important adverse factors or symptoms to be rated as fairly significant (Table 13). Importantly, indicators reflecting increased thrombin generation and inhibition of fibrinolytic reactions, respectively, 2nd and 3d entered the adverse factors as well. Hypo fibrinolysis factors with high reliabilityproved to be at the 5th and 6th adverse factors ranking. Consequently, in addition to well-known factors listed in Section 2, increased ability to thrombosis, in response to the stress estrogen and inhibition of fibrinolytic reactions are among the leading causes of failure of IVF. It is interesting to note that such a well-known and widely used in clinical practice marker of thrombinemia as high D-dimer plasma levels did not vary in frequency of occurrence in impregnate women at all stages of observation (OR 0,99; 0,95% CI 0,42-2,31 – 21 rank).
Carriage of thrombogenic mutations and polymorphisms were identified in the majority of our patients (71.2%). By the rare mutations - Factor V Leiden and prothrombin in only 4 cases (2.4%), we cannot judge the significance of their influence. However, the combination of polymorphisms MTGFR and PAI-1 was found in a slightly larger percentage of cases with unsuccessful IVF (24.3% vs. 16.0%) to be, however, insignificant. Interestingly,blood type “not 0”did not prove to be protrombogen/unfavorable by nature in our observation aswell as a number of variants of virus infection carriers and the manifestations of inflammation (fibrinosis, leukocytosis).
The number of factors contributing to the failure of pregnancy in IVF changed dramatically after exposure to therapeutic correction of hemostasis and fibrinolysis, used in the present publication. In accordance with the data in Table 14,traditional reasons for Reproduction are among the leaders: early hyperstimulation, male factor, and others. Hyperhomocysteinemia(OR 3,45; 0,95% CI 1,16-10,2) became one of thehemostatic reasons at the 4th rankto be the result of obvious lack of attention to the problem of metabolic methionine in preparation for IVF protocol. The significance level of manifestation of high thrombin generation shifted from the 2nd and 3rd rank to 8th and 9th rank whereas EAAF index - from 6th to 15th rank to be the further proof of the effectiveness of our methods of applied therapeutic intervention. Please, note that the calculations in this table exclude 40 patients with disorders of hemostasis and fibrinolysis who did not receive treatment for a number of reasons (subgroup 2.2.4).
Criterion | Failure of IVF (n=107) | Success of IVF (n=56) | Odds ratio (0,95% CI) | P-value | ||
Abs. | % | Abs. | % | |||
1. Hyperstimulation (early stage) | 22 | 20,5 | 0 | 0 | 29,7 (1,76-500) | < 0,00001 |
2. ETP more than 1900 nM/min (2nd point of observation) | 73 | 68,2 | 4 | 7,1 | 27,9 (9,33-83,4) | < 0,00001 |
3. Peack thrombin more than 360 nM/L (2nd point of observation) | 74 | 69,1 | 5 | 8,9 | 22,8 (8,36-62,5) | < 0,00001 |
4. Oligozoospermia (moderate and severe) | 45 | 42,0 | 2 | 3,5 | 19,5 (4,53-84,6) | < 0,00001 |
5. Clot lysis time of over 12 minutes (1st point of observation) | 69 | 64,5 | 5 | 8,9 | 18,5 (6,81-50,3) | < 0,000001 |
6. EAAF index less than 11% (1st point of observation) | 62 | 57,9 | 6 | 10,7 | 11,5 (4,53-29,1) | 0,00005 |
7. Defective embryo | 23 | 21,4 | 3 | 5,3 | 4,83 (1,38-16,9) | 0,011 |
8. Insufficient number of embryos transferred in IVF cycles(1-2) | 38 | 35,5 | 6 | 10,7 | 4,58 (1,80-11,6) | 0,0007 |
9. Mutation FV (G/A, A/A) | 3 | 2,8 | 0 | 0 | 3,78 (0,19-74,5) | 0,319 |
10. Difficult embryo transfer | 32 | 29,9 | 6 | 10,7 | 3,55 (1,38-9,12) | 0,006 |
11. Hypoplasia of the endometrium | 11 | 10,3 | 3 | 5,3 | 2,02 (0,54-7,57) | 0,383 |
12. Unsuccessful IVF attempt in history | 20 | 18,7 | 6 | 10,7 | 1,91 (0,72-5,08) | 0,260 |
13. Homocysteine in blood of more than 15 mM/l(1st point of observation) | 22 | 20,5 | 7 | 12,5 | 1,81 (0,72-4,54) | 0,280 |
14. Age (36-40 years) | 19 | 17,7 | 6 | 10,7 | 1,79 (0,67-4,80) | 0,262 |
15. High dose-protocol | 35 | 32,7 | 12 | 21,4 | 1,78 (0,83-3,79) | 0,148 |
16. The combination of polymorphisms MTHFR (C/T, T/T) and PAI-I (5 G/4 G, 4 G/4 G) | 26 | 24,3 | 9 | 16,0 | 1,67 (0,72-3,87) | 0,315 |
17. Low ovarian reserve | 19 | 17,7 | 7 | 12,5 | 1,51 (0,59-3,84) | 0,500 |
18. Polymorphism of PAI-I (5 G/4 G, 4 G/4 G) | 42 | 39,2 | 20 | 35,7 | 1,16 (0,59-2,27) | 0,735 |
19. Cytomegalovirus infection | 11 | 10,3 | 5 | 8,9 | 1,16 (0,38-3,54) | "/> 1,00 |
20. Fibrinosis greater than 5.0 g/l (for 2nd point of observation) | 14 | 13,0 | 7 | 12,5 | 1,05 (0,39-2,78) | "/> 1,00 |
21. D-dimer levels over 500 ng/mL (2nd point of observation) | 19 | 17,7 | 10 | 17,8 | 0,99 (0,42-2,31) | "/> 1,00 |
22. Herpes type 1 and 2 | 35 | 32,7 | 21 | 37,5 | 0,81 (0,41-1,59) | "/> 1,00 |
23. Hypothyroidism | 6 | 5,6 | 4 | 7,1 | 0,77 (0,20-2,85) | 0,737 |
24. Leukocytosis over 11,0×109/l (1st point of observation) | 23 | 21,5 | 15 | 26,8 | 0,74 (0,35-1,58) | "/> 1,00 |
25. Blood group - is not "0" | 85 | 79,4 | 47 | 83,9 | 0,74 (0,31-1,73) | 0,535 |
26. Polymorphism of MTHFR (C/T, T/T) | 30 | 28,0 | 23 | 41,0 | 0,55 (0,28-1,10) | 0,113 |
27. Mutation of FV Leiden (G/A) | 1 | 0,9 | 1 | 1,7 | 0,51 (0,03-8,45) | "/> 1,00 |
Factors contributing to the failure of pregnancy in IVF cycles in the 1 st. observation group (n = 163)
Criterion | Failure of IVF(n=61) | Success of IVF(n=63) | Odds ratio (0,95% CI) | P-value | ||
Abs | % | Abs | % | |||
1. Hyperstimulation (early stage) | 12 | 19,6 | 0 | 0 | 32,0 (1,85-555) | < 0,0001 |
2. Oligozoospermia (moderate and severe) | 26 | 42,6 | 4 | 6,3 | 10,9 (3,53-34,0) | 0,0002 |
3. Insufficient number of embryos transferred in IVF cycles (1-2) | 23 | 37,7 | 8 | 12,7 | 4,16 (1,68-10,28) | 0,003 |
4. Homocysteine in blood of more than 15 nM/l (on the 1st point of observation) | 14 | 22,9 | 5 | 7,9 | 3,45 (1,16-10,2) | 0,043 |
5. Difficult embryo transfer | 18 | 29,5 | 7 | 11,1 | 3,34 (1,28-8,74) | 0,013 |
6. Mutation FII (G/A, A/A) | 1 | 1,6 | 0 | 0 | 3,14 (0,12-78,8) | 0,491 |
7. Defective embryo | 17 | 27,8 | 8 | 12,7 | 2,65 (1,04-6,72) | 0,044 |
8. Peak thrombin more than 360 mM/l (for 2nd point of observation) | 43 | 70,4 | 32 | 50,8 | 2,31 (1,10-4,84) | 0,028 |
9. ETP more than 1900 nM/min (2nd point of observation) | 41 | 67,2 | 31 | 49,2 | 2,11 (1,02-4,38) | 0,047 |
10. Unsuccessful IVF attempt in anamnesis | 11 | 18,0 | 6 | 9,5 | 2,09 (0,72-6,06) | 0,198 |
11. D-dimer levels over 500 ng/mL (2-nd point of observation) | 13 | 21,3 | 8 | 12,7 | 1,86 (0,71-4,87) | 0,476 |
12. Age (36-40 years) | 8 | 13,1 | 5 | 7,9 | 1,75 (0,53-5,68) | 0,392 |
13. Polymorphism of PAI-I (5 G/4 G, 4 G/4 G) | 26 | 42,6 | 20 | 31,7 | 1,59 (0,76-3,32) | 0,265 |
14. Cytomegalovirus infection | 3 | 4,9 | 2 | 3,1 | 1,57 (0,25-9,78) | 1,677 |
15. EAAF index less than 11% (1st point of observation) | 33 | 54,0 | 27 | 42,8 | 1,57 (0,77-3,19) | 0,280 |
16. The combination of polymorphisms MTHFR (C/T, T/T) and PAI-I (5 G/4 G, 4 G/4 G) | 17 | 27,8 | 13 | 20,6 | 1,48 (0,64-3,40) | 0,706 |
17. Fibrinosis greater than 5.0 g/l (for the 2nd point of observation) | 8 | 13,1 | 6 | 9,8 | 1,43 (0,46-4,40) | 0,580 |
18. High-dose protocol | 6 | 9,8 | 5 | 7,9 | 1,26 (0,36-4,38) | 0,760 |
19. Blood group - is not "0" | 48 | 78,6 | 47 | 74,6 | 1,24 (0,54-2,89) | 0,673 |
20. Low ovarian reserve | 11 | 18,0 | 10 | 15,8 | 1,16 (0,45-2,98) | 0,813 |
21. Clot lysis time of over 12 minutes (1st point of observation) | 35 | 57,4 | 34 | 53,9 | 1,14 (0,56-2,33) | 0,720 |
22. Leukocytosis over 11,0×109/l (1st point of observation) | 13 | 21,3 | 12 | 19,0 | 1,15 (0,47-2,77) | 0,824 |
23. Hypoplasia of the endometrium | 4 | 6,5 | 4 | 6,3 | 1,03 (0,24-4,33) | "/> 1,00 |
24. Hypothyroidism | 4 | 6,5 | 4 | 6,3 | 1,03 (0,24-4,33) | "/> 1,00 |
25. Herpes type 1 and 2 | 7 | 11,4 | 9 | 14,3 | 0,77 (0,27-2,23) | 0,790 |
26. Polymorphism of MTHFR (C/T, T/T) | 12 | 19,6 | 25 | 39,6 | 0,37 (0,16-0,83) | 0,018 |
Factors contributing to the failure of pregnancy in IVF cycles in the 2nd group (n = 124)
In our publication we studied a number of women with the known risk factors of IVF failures to beless significant regardless of the ongoing correction of hemostasis and hypo fibrinolysis. We also record such risk factors as manifestations of inflammatory reaction (leukocytosis, fibrinosis) of virus (herpes, cytomegalovirus), the pathology of the thyroid gland and a number of others.
We are particularly interested in the reasons for the failure of IVF which remained relevant after therapeutic correction aimed at hemostasis and fibrinolysis. The list is given in Table. 15.
As noted earlier (Table 14), in addition to gynecological risk factors, hyperhomocysteinemia, and manifestations of excessive thrombin generation became the causes of the failure of IVF. Consequently, despite treatment some femalepatients maintained the trend to intravascular coagulation. Earlier, Table 11demonstrated that isolated course of IPCto treat hypo fibrinolysis and other effects led to increased thrombin generation whereas the combination of IPC with dalteparin did not lead to such a shift (Table 12). Considering that we used three variants of therapeutic intervention our attempt was to determine the frequencyof each of them under different outcomes of IVF in women with a high ETP in thrombin generation test.
Criterion | Failure of IVF (n=56) | Success of IVF (n=42) | P-value | ||
Abs. | % | Abs. | % | ||
1. Hyperstimulation (early stage) | 10 | 17,8 | 0 | 0 | 0,004 |
2. Oligozoospermia (moderate and severe) | 22 | 39,3 | 4 | 9,5 | < 0,001 |
3. Insufficient number of embryos transferred in IVF cycles (1-2) | 18 | 32,1 | 5 | 11,1 | 0,029 |
4. Homocysteine in blood of more than 15 nM/l (on the 1st point of observation) | 17 | 30,3 | 4 | 9,5 | 0,039 |
5. Difficult embryo transfer | 19 | 33,9 | 6 | 14,2 | 0,035 |
6. Defective embryo | 18 | 32,1 | 5 | 11,1 | 0,029 |
7. ETP more than 1900 nM/min (2nd point of observation) | 39 | 69,6 | 17 | 40,5 | 0,006 |
8. Peak thrombin more than 360 mM/l (for 2nd point of observation) | 42 | 75,0 | 19 | 45,2 | 0,003 |
Causes for the failure of IVF under conducted therapeutic correction of hemostasis and fibrinolysis (n = 98)
Analysis of the effectiveness of different therapies with excessive thrombin generation (ETP to 1900 nM/min in the 2nd point of observation)
The data in Figure 4 show that the high generation of thrombin and IVF failure is more common in the course of isolating IPC and less - in combination therapy.
To sum up the results we note that excessive thrombin generation and a fibrinolytic inhibition fatal reaction (without correction) reduces the effectiveness of IVF and has a comparable value compared to the traditional risk factors of reproduction. Thus, our study provesa number of recent statements devoted to thisproblem (Martinez-Zamora et al., 2011; Meltzer et al., 2010; Nelson & Greer, 2008; Rova et al., 2012; Westerlund et al., 2012). However, we have made further progress due to suprathreshold values of laboratory parameters whichallow to monitor the increased propensity to blood clotting and / or hypo fibrinolysis and therefore to identify patients with high risk of IVF failure in order to conduct therapeutic correction of disorders. In particular, by the calibrated test of thrombography administration of dalteparin was authorized by its indicators (ETP, Peack thrombin) to lead to the effective reduction of thrombin generation as well as the significant increase in positive outcomes of IVF (6.4 times).
We first proposed and tested method and mode of correction hypo fibrinolysis IPC for women in a cycle of IVF. It was shown that vases compression in these cases leads to the increased activity of t-PA and reduced PAI-1 activity, which is clearly manifested by the sharp increase in the calculated EAAF index, accelerated clotlysis time and the increase in the number of positive outcomes for assisted reproductive technology in 3 times. However, there were no obvious reasons to reduce the dynamic activity of PAI-1 during the course of IPC, even though it appeared to be a favorable result of the non-drug therapy. A negative consequence of the IPC was the phenomenon increasing the generation of thrombin which did not have the prior record. The calculations showed that the IPC in all cases should be combined with heparin prophylaxis to obtain the best clinical results. In this publication, combining vases compression with prophylactic doses of LMWH (low molecular weight heparin) really helped to increase the number of pregnancies in 6.5 times.In our opinion, this non-pharmacological approach to correcting hypo fibrinolysis demonstrates great potential for use in a number of clinical situations, including pregnancy period. In this chapter, we do not include the results of vases compression in women with low fibrinolytic activity after IVF in the first 12 weeks of pregnancy. However, the results are encouraging and will be published later.
The leading role of increased thrombin generation and hypo fibrinolysis in negative consequences of this reproductive technology has been proved in comparative evaluation of the significance of the risk factors of IVF failure. Its valueappeared to be comparable with such risk factors as ovarian hyperstimulation syndrome, male factor, poor embryo or small quantities, or hard to bear embryos. In the meantime, the range of risk factors and their significance has changed dramaticallyafter the treatment and correction of disorders of hemostasis and fibrinolysis. In particular, the list of relevant factors was reduced significantly tohypo fibrinolysis (rated by EAAF index) whereas indicators of excessive thrombin generation remained, thoughin less prominent positions. In addition,risk factors such as male factor, insufficient and difficult embryo transfer, as well as their low quality became more significant. The publicationindicates the important role of hyperhomocysteinemia in the failure of IVF. As you know, it refers to the controllable risk factors which can and must be eliminated by recognized medical methods (by taking vitamins B6, B12, folic acid) at pre-gravid preparation.
In our research, we tested only 7 women with rare mutations FV Leiden (1691G>A) and FII (20210G>A), associated with thrombosis, pregnancy failure and reproductive technologies. Therefore, we were unable to prove their relevance to IVF outcomes. A common gene polymorphisms MTHFR (C677> T) and gene PAI 1 (5G>4G) compared with the results of Coulam and Jeyendran (2009b) did not prove the significance.
The research marks the opportunities to progress and improve outcomes of IVF based on the identification and correction of the pathology of hemostasis and fibrinolysis. The research data may serve as the basis for the development of guidelines and standards which allow improving the efficiency of modern reproductive technologies. The marked problem requires interdisciplinary approach, joint efforts by obstetricians and hematologists and reward bybetter efficiency of IVF despite the increased cost of diagnosis and treatment of disorders of hemostasis and fibrinolysis.
The bile duct carcinoma or known as cholangiocarcinoma (CCA) by the definition is a malignancy that originate from cholangiocytes lining the biliary tree. It is included in liver malignancy and become the second most common primary liver malignancy after hepatocellular carcinoma. [1, 2] Incidence of this malignancy is 10–20% cases of all hepatic cancer. [2, 3] Although cholangiocarcinoma is a rare cancer, it has an aggressive feature with very poor prognosis. The data showed that the incidence of cholangiocarcinoma among gastrointestinal cancer approximately reaches 3% but has nearly 20% of death from all hepatobiliary cancer. [3, 4] In addition, cholangiocarcinoma is a clinically silent disease at early stage. Therefore, the diseases are usually diagnosed at advanced stage with poor prognosis.
CCA may occur anywhere in the biliary tract, however, based on where the tumor arises in the biliary tree, it is classified into intrahepatic (iCCA) and extrahepatic bile duct cholangiocarcinoma (eCCA). Extrahepatic bile duct cholangiocarcinoma is divided into two types, perihilar (pCCA) and distal (dCCA) cholangiocarcinoma. iCCAs arises above the second - order of the bile ducts. In contrary, the point anatomical which is distinction pCCA and dCCA is the insertion of the cystic duct. The majority of cholangiocarcinoma are in the perihilar (50–60% cases) and distal region (20–30% cases), and only 10% of CCA are located in intrahepatic. [5]
The tumor is considered rare in most countries with incidence rate from 2001 to 2015 was 1.26 cases per 100,000 persons and has a mortality rate 1–6 per 100,000. [1, 6] Nevertheless, this malignancy is still an endemic disease with high prevalence and incidence in some countries or regions such as Thailand and South Korea. The epidemiological profile of cholangiocarcinoma varies widely across the world, which is reflecting the exposure of different risk factor, such as chronic inflammatory disease of the biliary tract, specific infectious disease, and congenital malformation. In western countries, primary sclerosing cholangitis (PSC) causing biliary obliterative fibrosis, is the major etiology of CCA. [7] Specific in endemic area, Northeast Thailand, with incidence rate 118.5 per 100.000, which is 100 times higher than the global rate. [8] Number of mortality cases from liver and bile duct cancer is the leading cause of death in Thai males and places the third place in female with total number 28.000 deaths per year. [9] Northeast region of Thailand showed the highest number of liver mortality, comprising 70% of cases. [9] In this area, incidence of CCA is strongly related to liver fluke infestation that is endemic in Mekong River. Liver fluke infection is caused by water-borne parasites known as Opisthorchis viverrini, Clonorchis sinensis, and Opisthorchis feluneus. These parasites are transmitted to human by the consumption of raw, pickled, or undercooked infected fish associated with local tradition and poor income. [10, 11, 12]
The life cycle of this parasite is quite complex, involving two intermediate host (snail to fish) and including several changes of morphological feature. Fish contaminated with metacercaria is ingested by the human. [2] Infected human excretes the egg produced by the mature adult worms in their feces. [2, 13] Feces then contaminated the fresh water and then ingested by snail and the larva develop and hatch in the digestive tract of the snail. [2, 13] After that, thousands of cercariae were excreted into the water and penetrate the skin fish, encyst, and forming metacercaria. In the body of human, this parasite excyst in the duodenum and ascend to the bile duct via the ampulla of Vater then migrate further into the smaller and proximal bile duct, then become mature worm and able to sexually produce. [2, 13] Adult worm could survive up to 25 years in the biliary tree and causing mild symptoms such as malaise, abdominal discomfort, and diarrhea. Long term complication of this infection associated with hepatomegaly, chronic infection, cholecystitis, gallstone, and periportal fibrosis. [2, 13] Long term of chronic inflammation found to be a major etiological precursor of hepatobiliary malignancy, predominantly of CCA. Once a person is infected and suffered from chronic infection and inflammation, the risk for having CCA is increasing and could present within 30–40 years after infection. [11] Until now, the prognosis of CCA is remain poor and death tend to occur within 3–6 months after diagnosis. [11] There are several hypothesizes on the mechanism or pathway how the chronic infection could develop become malignancy: 1) mechanical damage caused by the fluke sucker, 2) fluke toxic secretary product, and 3) immunopathological host response. [11] These pathways then caused proliferative response and formation of precursor lesion such as epithelial and adenomatous hyperplasia, and goblet cell metaplasia. [11]
Beside parasite infection, primary sclerosing cholangitis (PSC) is another common etiology of cholangiocarcinoma, especially in the western population. PSC is a progressive cholestatic biliary characterized by the chronic inflammation that leads to destruction of the intra and extrahepatic bile duct. [14] The incidence rate of PSC ranges from 0 to 1.3 per 100.000 people. [15] At early stage, PSC is asymptomatic and is usually already diagnosed at advanced stage whereas jaundice and pruritus are the major complaint due to cholestasis. It has been also strongly associated with inflammatory bowel disease (IBD). On the other hand, PSC is often found with portal hypertension, cirrhosis, and in hepatobiliary and colorectal malignancies. [16, 17]
The other risk factor for developing CCA is biliary stones which is formed in the biliary tree, substantially in intrahepatic bile duct or known as hepatolithiasis. Biliary stones are typically concomitant with biliary stasis, cholangitis, strictures, and bacterial infection, leading to long term inflammation and biliary injury, and at the end, increasing the risk of malignant cholangiocytes growth. [18] Abnormal morphological also increase the risk for malignant transformation. Choledochal cysts is a rare congenital malformation characterized by dilatation of the biliary tree, can be single or multiple, and can be developed in the intra or extra hepatic bile ducts. [17, 19] Moreover, the coincidence of abnormal pancreatobiliary duct junctions increases the possibility of cholangiocarcinogenesis. This due to pancreatic enzyme reflux, cholestasis, and elevated bile acid concentrations. [19]
Exposure to chemical carcinogens such as Thorotrast, halogenated hydrocarbon solvent, and 1,2-dichloropropane were found to be associated with CCA incidence. [20, 21] Carcinogens-induced liver insult has been showed to promote hepatocyte remodeling, genomic instability, DNA methylation, and disrupt the liver architecture. Moreover, some studies reported few genetic mutations related to hepatobiliary malignancy. [22] Hepatic disease associated with CCA include alcoholic liver disease, cirrhosis, and cholangitis are included become risk factor. [17]
Diagnosis of CCA is quite challenging. CCA is generally asymptomatic in the early stage. Therefore, management of this malignancy is often delayed due to late diagnosed, where it already metastasis or compress the bile duct. The clinical features of CCA are heterogenous, with general malaise, cachexia, abdominal pain, night sweats, fatigue, weight loss, asthenia, and/or jaundice which is more frequent symptom in pCCA and dCCA due to biliary tract obstruction. [23, 24] Diagnosis of CCA is usually confirmed by combining nonspecific biomarkers in serum, biopsy specimens, and imaging technique. To date, there is no specific serum marker available for diagnosing CCA. Liver function parameters such as serum bilirubin, alkaline phosphatase, and aminotransferase enzyme usually elevate when biliary obstruction is presence. [24, 25] However, it is not specific signs for biliary malignancy. Serum tumor marker such as carbohydrate antigen (CA) 19–9, CA-125, and carcinoembryonic antigen (CEA) are the most widely used markers for suspected CCA. [25] But this diagnostic tool should not be used alone due to their poor diagnostic performance and inherent limitations.
Imaging techniques which are required to help diagnosis CCA are trans-abdominal ultrasonography (US), contrast-enhanced ultrasonography (CEUS), CT scan, and MRI. Becoming diagnostic tools, imaging techniques play a key role in the management of CCA in term of diagnosis, staging, follow-up, and assessment of favorable treatment response. The accuracy of diagnosis is depending on the anatomical location and growth pattern of CCA. Magnetic resonance cholangiopancreatography (MRCP) has the higher diagnostic accuracy for sizing strictures and localizing. [24, 25]
But unfortunately, there are no specific CCA radiology pattern exists. Therefore, histopathology or cytological analysis is also necessary for confirming the diagnosis. Definitive diagnosis is usually made by undergoing endoscopic retrograde cholangiopancreatography (ERCP) procedure for fluid cytology, brush cytology, fluorescence in situ hybridization (FISH), and cholangioscope or chromoendoscopy-guided biopsy. [26, 27, 28] Those multiple diagnostic modalities are required to 1) establish strictures anatomical location; 2) distinguish between benign and malignant strictures; 3) differentiate CCA from gallbladder cancer; 4) stage and grade the tumor; and 5) plan treatment approach. Based on WHO classification of biliary tract cancer it is showing an adenocarcinoma or mucinous carcinoma, with tubular and/or papillary structures and a variable fibrous stroma. [24, 25]
Determine staging of CCA is important for choosing the treatment, its resectability, and the outcome of the treatment. TNM classification system of American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) has been used at present to determine the staging of CCA. TNM staging system is based on imaging tests which is evaluating the number of primary nodules, vascular invasion, direct extension in neighboring tissue, and bile duct involvement. [29] pCCA can be further divided according to the Bismuth-Corlette classification, depending on the size of the tumor, disease extension in the main bile duct, hepatic artery and/or portal involvement, lymph node involvement, distant metastasis, and remnant liver volume after resection. [30] iCCA could be classified based on 3 growth pattern which has different prognosis of each pattern: mass-forming (MF-iCCA), periductal infiltration (PI-iCCA), and intraductal growth (IG-iCCA). [31]
Treatment for managing cholangiocarcinoma is quite difficult too and should be managed in the tertiary hospital with a multidisciplinary team experienced in endoscopic, percutaneous, and surgical approaches. Management of this malignancy also depends on the staging of the tumor. Surgical treatment with complete resection could give benefit only for patient with early stage of the disease [32].
Resection could be performed in approximately 30% of patient with CCA. This is the only option that provides a real possibility for long-term survival in patient diagnosed with CCA. The indication and extension of surgery are determined based on clinical features of the patient, functional liver reserve, and the location and extension of the tumor, which include the association with vascular structure and negative metastatic disease. [33, 34]
Criteria for patients who are considered as absolute unresectability are the presence of nonresectable extrahepatic, hepatic metastases, bilateral extension of the tumor with involvement of the secondary biliary tract, complete occlusion of the main portal vein, thrombosis in portal vein contralateral to the tumor. [23] The most common postoperative complications are hemorrhage, infection, liver failure, cardiorespiratory failure, and adrenal failure. Mortality and morbidity for postoperative patient are still remaining high, 8,2% and 50%, respectively. [35] In several condition, drainage should be applied. But in the recent years, increasing number of patients with unresectable intrahepatic and extrahepatic CCA are being included to be candidate for liver transplant. Other treatment modalities as adjuvant therapy are also developed to improve the survival of the patient, such as chemotherapy, radiotherapy, molecular targeted therapy, targeting angiogenesis and EGFR, and immunotherapy.
Cancer immunotherapy is significantly progressing and rapidly advancing. In the recent years, immunotherapy is considered to be the fifth pillar of cancer therapy and management modality besides surgery, cytotoxic chemotherapy, radiation, and targeted therapy. The mechanism of immunotherapy in cancer management is to determine a manipulation of the immune system by using immune agents such as vaccine, cytokine, cell therapies and humoral, transfection agent. Cancer immunotherapy has to stimulate the host anti-tumor response by increasing the effector cell number and production of soluble mediators, decrease the host’s suppressor mechanism by inducing tumor killing environment, and could modulate immune checkpoint. [36, 37]
In 1891, William Coley, who is known today as the Father of Immunotherapy, injected heat inactivated bacteria or known as Coley toxins to the sarcoma patient who was inoperable. [38] This first experiment resulted in long term regression of the sarcoma after an erysipelas infection after injecting the toxin. [38] By late 1970s, immunotherapy for managing cancer was discovered. The first experiment was done in bladder cancer case which is managed by using BCG (Bacillus Calmette-Guerin). Then, it is continued with IFN therapy in malignant melanoma. [39] Brief background review of immune system is classically considered to be comprised of the innate and adaptive arms. Immune system which are included in innate immune system are dendritic cells, natural killer cells (NK), macrophages, neutrophils, eosinophils, basophils, and mast cells. As we known, this group of immune system does not need prior stimulation by antigen, and it plays role as first line of defense against foreign antigens. In the contrary, adaptive immune system consists of B lymphocytes, CD4 helper T lymphocytes, and CD 8 cytotoxic T lymphocytes (CTLs). This group of immune system requires formal presentation by antigen presenting cells (APCs) for its activation. [40, 41]
Several kinds of malignant cells are able to evade the tumor immunosurveillance system by manipulating their own characteristic as well as the cells in their microenvironment to become successful tumors. The concept that the immune system is capable for detecting and killing nascent non-self-malignant cells was developed. Elimination, equilibrium, and escape are three main phases of immunoediting process. [42] The elimination phase is the initial damage process and destruction of the tumor cell by innate immune system, then tumor antigens are presented to the dendritic cells, followed by presentation to the T cell and then create tumor-specific CD4 and CD8 T-cells. Second phase occurs when tumor cells survive after the initial destruction but are not able to progress and being maintained in an equilibrium state. The last phase is escape phase. [42] In this phase, tumor cells are growing rapidly, followed by metastasize of tumor cell due to loss control of the immune system and the tumor cells do not presented antigens on its surface or even losing their MHC class1 expression. Tumor cell could protect their self from T cell by expressing immune checkpoint (IC) molecules on their surface. [42]
The ability of this malignant cells to evade immune destruction by modulating its own cellular characteristic and creating its own “tumor microenvironment” by recruiting apparently normal immune cells to help shield it from attack of immune system. In addition, tumor cell can influence the systemic environment by altering hematopoiesis and tissue parenchyma of organs at distant sites. Cancer immunotherapies play role in manipulating these tumor microenvironments. But the loss of MHC class 1 expression manipulating is remaining challenge. [43, 44, 45]
First, older, and non-specific immunotherapies are the kind of immune stimulator cytokines such as interleukin-2 IL-2) and interferon (IFN). [46] Beside that, synthetic analogue of bacterial cell wall called L-MTP could activate monocytes and macrophages is one of the immunostimulatory cytokines. Vaccine trials using multiple neoantigens specific to and individual patient’s tumor have shown promising results in two small early trials with the aim to expose patients to those tumor antigens which can provoke an antitumor immune response via the generation of tumor specific antibodies and T cells. [46] BCG was the first vaccine used as cancer immunotherapy for treating bladder carcinoma. [47]
Oncolytic viruses are the combination of biologic therapy and immunotherapy. Viruses which are used for this method has genetically modified to lack virulence against normal cell but has a selective feature to invade and lyse cancer cells. Viral-induced tumor cell destruction undergoing further attack by an immune system. [48]
Adoptive cell therapy (ACT) is one type of immunotherapy which involves in the isolation and in-vitro expansion of tumor-specific T-cells, which is given through infusion in the cancer patient. ACT using NK cells could be used to treat solid tumor metastasis and hematological cancers. [49] Several forms of ACT using different techniques are culturing tumor infiltrating lymphocytes directly from the tumor, isolating and expanding one particular T-cell or the clone, using T cell which have been engineered in vitro so that it could recognize and attack the tumor cells or known as chimeric antigen receptor T-cell (CAR T-cell) therapy. ACT has produced remarkable result in clinical trials with melanoma and hematologic malignancies. But some studies reported death have occurred in the trial phase due to cytokine release syndrome or cytokine storm. [50]
Another immunotherapy, Immune checkpoint, work by targeting molecules that serve as checks in the regulation of immune responses and block inhibitory molecules or activate stimulatory molecules and enhance pre-existing anti-cancer immune response. [51]
Cancer immunotherapy works to stimulate the host’s anti-tumor response. The mechanism included are increasing the effector cell number and production of soluble mediators, decreasing the host’s suppressor mechanism by inducing tumor killing environment, and modulating immune checkpoints. The usefulness of cancer immunotherapy was introduced in the beginning to manage bladder cancer. The overall 5-year survival after transmitting immunotherapy is 77%. [39] Patients with moderate and high-grade bladder cancer who received intravesical immunotherapy with BCG have shown good result. Immune checkpoint inhibitors showed a promising clinical research in managing anti-cancer immune responses. Several studies using Nivolumab, Ipilimumab, and Pertuzumab are still on progress in metastatic bladder cancer. Some cytokines which are messenger molecules, play a role to control the growth and activity of immune system cells. [52] Treatment using cytokines as immunotherapy can enhance the activity of the immune system against tumors. The link of IL-2 to the antibody, ALT-801, and cytokines can target IL-2 to cancer cells. [53] Oncolytic virus therapy could also be used to treat bladder cancer using adenovirus which expresses the immune stimulating cytokine GM-CSF. [54]
Immunotherapy is developed to manage some immunogenic cancer cases besides bladder cancer. The using of immunotherapy for managing breast cancer have been improved and approved in the recent years. Although the best treatment of breast cancer is surgery, but combination therapy followed by chemotherapy, radiation therapy, or immunotherapy could increase clinical outcome for patient. A promising immunotherapy using immune checkpoint inhibitors that work by targeting molecules that serve as checks in the regulation of immune response and block inhibitory molecules or activate stimulatory molecules. [39] The other form of immunotherapy which can be used for breast cancer is monoclonal antibodies and adoptive T cell transfer. By definition, adoptive T cell transfer is a process of removing T cell from the patient, then it would be modified genetically or treated with chemical to enhance its activity and re-introduced into the patient. Specifically, in breast cancer, T cell genetically is modified to target the carcinoembryonic antigen (CEA). [55]
Another immunogenic cancer is cervical cancer caused by infection of human papillomavirus (HPV). Cervical cancer is the third most frequent cancer among women in the world. [56] The prevalence of this cancer is decreasing due to development widespread of screening tools Pap test and vaccine to prevent HPV infection. In the recent years, monoclonal antibodies, checkpoint inhibitor, and adoptive T cell transfer have become additional therapy for managing progressivity of cancer cell. [39]
Immunotherapies are also developed as a new modality treatment to treat brain cancer, colorectal cancer, esophageal cancer, and biliary tract cancer. Probably, in time, immunotherapy could lead to personalized medicine that will increase overall survival and progression free survival for many treatments. [39]
Biliary tract malignancy is an invasive carcinoma which can be originated from gallbladder or bile duct. It has been known that the immune system in human body has a significant role in the surveillance and eradication of cancer cells. Tumor that lack the mismatch repair system harbor more mutation than tumor without this deficiency. Thus, the neoantigen generated and be recognize as immunogenic antigen. The characteristic of mismatch repair deficient tumors is microsatellite instability (MSI). There are approximately 3% of CCA are mismatch repair-deficient/MSI-high. [56] This feature makes the tumor cells are susceptible to programmed cell death protein 1 (PD-1) inhibitors. Zhu et al. studied about efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and the correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome in a phase 2 study showed that combination of chemotherapy and immunotherapy have anti-tumor effect with tolerable safety and promising efficacy for managing advanced biliary tract malignancy. This combination treatment was generally well tolerated with less adverse event and manageable toxicity. [57]
Another clinical data about immune-directed therapy in CCA is still scanty. Vaccine for preventing CCA has been developed and tested but no data has showed successful result. [58] CAR T cell immunotherapy in recent years has been developed. Guo et al. in their study about expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor-engineered autologous T (CART) cell immunotherapy. The aim of this study is to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancer. Total sample of this study is 19 patients and showed that CART-EGFR cell infusion was tolerated, 1 achieved complete response and 10 achieved stable disease. We can conclude that CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced biliary tract cancer. [59] Wei et al. showed that in some patients, immune checkpoint blockade using monoclonal antibodies has shown remarkable and durable response rate in a many kind of malignancy cell. [60] Le et al. in their study concluded that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab and achieving objective responses in up to 40% of patients. [61] Study by Ott et al. in KEYNOTE-028 basket trial of pembrolizumab included patients with advanced biliary tract cancer resulted the objective response rate was 17% with median progression-free survival of 1.8 months. [62] However, further studies are required either combination immunotherapeutic approaches targeting both the innate and adaptive immune system or combined strategies involving chemotherapy or radiation.
Bile duct cancer is still one of the challenging malignancies in the gastroenterology field due to the difficulty in early detection and most of patients come in the late stage of the disease. Chemotherapy is still the main option of management despite surgery and biliary drainage. Immunotherapy is a promising treatment option in the future; however, further studies would be needed to give strong evidence before it can be used in common clinical practice.
Supporting women in scientific research and encouraging more women to pursue careers in STEM fields has been an issue on the global agenda for many years. But there is still much to be done. And IntechOpen wants to help.
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