{"paper_id":"e6903cf6-f543-434a-a4cc-772f3d2963e4","body_text":"Review\nAn Obstetrics and Gynecology  \nInternational Journal \n65\nvolume 19, issue 2, april - june 2020\nRevealing the enigma of coagulation  \nin endometriosis: the risk of thrombosis  \nand the role of antithrombotic treatment\nTheoni Kanellopoulou\nDepartment of Clinical Hematology, Blood Bank, Hemostasis, Onassis Cardiac Surgery Center, Greece\nCorresponding Author\nTheoni Kanellopoulou, MD, PhD, Onassis Cardiac Surgery Center 356, Andra Syggrou ave.\n176 74 Kallithea-Attiki, Greece, Tel: +30-2109493953, Fax:+30-2109493867, Email: theokanel@gmail.com\nHjoG 2020, 19 (2), 65-76\nAbstract \nEndometriosis is a chronic inflammatory disease of women of reproductive age that is defined by the \npresence of ectopic endometrium. The pathophysiology of the disease is poorly understood, however platelet \nactivation play a crucial role in initiation of inflammation and fibrinogenesis, which in term further activate \nthe coagulation cascade. The relationship between inflammation and coagulation motivated researchers \nto study whether patients are in a hypercoagulable state and if endometriosis represent an independent \nrisk factor for venous thromboembolism or cardiovascular risk. This review article focuses on the role of \ncoagulation, the risk of thrombosis and a possible beneficial effect of antithrombotic-treatment.\nKey words: Endometriosis, inflammation, platelets, thrombosis, antithrombotic treatment\nIntroduction\nEndometriosis is a chronic disease defined as the \npresence of endometrial tissue outside the uterus. It \nis an estrogen-dependent disease, affecting roughly \n6–10% of women of reproductive age. It is a major \ncontributing cause for dysmenorrhoea, pelvic pain \nand infertility impacting negatively on the quality of \nlife Three clinically different phenotypes have been \ndescribed: Endometriotic implants on the surface of \nthe pelvic peritoneum (PE), ovarian endometrioma \n(OE) and deep infiltrating endometriosis (DIE), the \nlatter being the most severe form of the disease\n1.\nThe pathophysiology of endometriosis is poorly \nunderstood and endometriotic lesions can be viewed \nas wounds that undergo repeated tissue injury and \nrepair, ultimately leading to fibrosis2.It has recently \nbeen proposed that women with endometriosis may \nbe in an inflammatory and hypercoagulable state \nand even though inflammation and coagulation are \nseparate entities is increasingly evident that interact \neach other3,4.Due to the major role of coagulation in \ndisease development, in this review article we study \nthe actual thrombotic risk in women with endome-\n\n66\nKanellopoulou\nvolume 19, issue 2, april - june 2020\ntriosis and discuss a feasible role of antithrombotic \ntreatment in disease remission.\nPathophysiology:  \nthe role of coagulation\nThe activation of coagulation in women with en-\ndometriosis is actually consistent with the notion \nthat endometriotic lesions undergo cyclic bleeding \nresulting in repeated tissue injury and repair, which \nin turn causes platelet activation and aggregation4.\nThe activated platelets promote the release of other \nprocoagulant factors like von Willebrand factor, \nthromboxan A2 (TXA2) causing further platelet \naggregation and activation of coagulation cascade. \nOnce the platelets are activated and aggregated, they \npromote angiogenesis and cellular proliferation, \ncausing smooth muscle metaplasia and ultimately \nfibrosis5. The activated platelets could also induce \nthe release microparticles (MPs). Studies in other \ndiseases have shown that platelet-MPs play major \nrole in coagulation, as they are highly thrombogenic \nand elevated MPs have been found in almost all \nthrombotic diseases and conditions associated with \ninflammation, cellular activation and angiogenesis. \nMunros et al. provided data showing higher levels \nof total MPs in patients with DIE compared with OE \nor without endometriosis. The higher MPs levels in \npatients with DIE may represent the more intense \ngrade of inflammation and angiogenesis in this more \naggressive type6.\nAfter tissue injury, platelets release angiogenic \nproteins to promote wound healing. In later stage of \nhealing, pro-angiogenic proteins are compensated by \nthe release of angiogenic suppressors from stromal \ncells and platelets in order to prevent uninhibited \ngrowth.  Endometriotic stromal cells have elevated \nexpression of tissue factor (TF), and the peritoneal \nfluid from women with endometriosis has higher \nconcentration of TF as well as thrombin, which is \na potent inducer of platelet activation 4. Following \nvascular disruption, perivascular TF binds to circu-\nlating factor VIIa to mediate the activation of both \nfactor IX and X and ultimately to generate throm -\nbin7. An altered expression of several components \nof the fibrinolytic system in the endometrium and \nperitoneal fluid of women with the disease has been \nsuggested as a key factor in the establishment of the \nendometriotic lesions. There is evidence of increased \nfibrinolytic activity in the eutopic endometrium of \nthese women, resulting in endometrial fragments \nwith a high potential to enable implantation. Proteo-\nlytic status is determined by the imbalance between \nplasminogen activators and plasminogen activator \ninhibitors, which are expressed differently depend-\ning on the type of lesion considered and the stage \nof the disease\n8. \nThe risk of thrombosis\nCoagulation Factors\nReview of the literature disclosed many clinical \nstudies investigating a possible impact of activation \nof the coagulation during disease development on \nlaboratory clotting tests. Wu et al. reported that \nwomen with OE had a significantly shortened both \nactivated partial thromboplastin time (APTT) and \nthrombin time (TT) and elevated fibrinogen (FIB) \nlevels as compared with controls, although most of \nthe results were within the normal range. Moreover, \nthe co-occurrence of DIE or PE and more severe stage \nappeared to further decrease APTT , nevertheless the \ndifference was not statistical significant3. In line with \nthe previous study, Vigano et al. also documented a \nstatistically significant shortening of the APTT in \nwomen with OE9 and Lin et al. found that the levels \nof PT and TT in patients with OE were significantly \nshorter and levels of FIB and D-dimer significantly \nhigher than those with benign ovarian cysts10. Ding \net al. showed that women with OE had a significantly \nhigher platelet activation rate and platelet aggrega-\ntion rate, elevated plasma D-dimer, FIB, fibrinogen \n\n67\nrevealing the enigna of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment\nvolume 19, issue 2, april - june 2020\ndegradation products (FDPs), as well as shortened TT . \nHowever, no difference was observed in PT , APTT11.\nAll previous studies published positive results in \npatients with OE. It should be considered that an en-\ndometrioma contains free iron, proteolytic enzymes, \nand inflammatory molecules in concentrations nota-\nbly higher than those present in peripheral blood or \nin other types of benign cysts. Sanchez et al. showed \nthat concentrations of some coagulation parameters \nsuch as plasminogen activator inhibitor-1 (PAI-1), \nPAI-2, and urokinase plasminogen activator were \nfound to be in the same range or even much higher \nin the endometrioma fluid compared to malignant \ntumors, and it is reasonable to think that this content \nmay leak from the cyst and be absorbed through the \nperitoneum12. The large amounts of coagulation-\nrelated products present in ovarian endometrioma \nis remarkably described in a case of endometriotic \ncyst rupture that caused a rapid but transient eleva-\ntion in plasma D-dimer levels13.\nGenes of thrombotic risk\nDue to genetic predisposition, there was a con-\ncern whether patients share similar genes of high \nthromboembolic risk. However, no association be-\ntween inherited thrombophilia and endometriosis \nhas been reported so far, in order to support costly \nand time-consuming thrombophilia-screening tests \nin this group of patients. \nIn a small study, screening for thrombophilia \nshowed that the prevalence of prothrombin G20210A \nmutation and hyperhomocysteinemia in patients \nwith endometriosis was not different from that of the \ngeneral population and prevalence of factor V-Leiden \nmutation, was found with a lower prevalence 14.\nIn another study in which emphasis was given in \nfibrinolysis and plasminogen activator inhibitor-1 \n(PAI-1) gene, endometriosis was more likely in pa-\ntients with 4G/5G or 4G/4G which are associated \nwith hypofibrinolysis compared with 5G/5G PAI-1 \ngenotype15.Nevertheless, the existence of 4G allele \nalone does not represent an independent high risk \nfactor of thromboembolic disease. \nThromboembolic Risk Factor\nIt is a great concern if the activation of coagulation \nnot only result to progression of the disease but also \nincreases the thromboembolic risk. However, there \nare no published data to support a possible associa-\ntion and there are only anecdotal reports of patients \nwho experienced deep vein thrombosis (DVT) in the \npresence of other risk factors like immobilization or \nhormonal therapy16. \nSpecial attention should be kept at the rare local-\nization of endometriosis that could involve the femo-\nral and iliac veins either with extrinsic compression \nor infiltration. This situation could cause cyclical leg \nswelling, coincidental with menstruation17-20 and a \npossible complication due to this localization could \nbe thrombosis21-25.\nHormonal Therapy\nThe therapeutic suppression of ovulation and \nmenstruation with hormonal treatment is an effec-\ntive conservative management of controlling the \ndisease and its associated symptoms. Combined \nhormonal contraceptives (COC) constitute the most \ncommon long-term treatment to control the disease \nwith the best profile in terms of long-term safety, \nadherence and cost. However, the main concern \nis a slight increase of the relative risk of venous \nthromboembolism and arterial thrombosis. Both \nthrombotic events are associated with estrogen \ndose, while progestin-only preparations confer no \nincreased risk. Progressively, during the 1970s, the \nestrogenic content of COC has been was gradually \nlowered from 150 to 20 μg, with a parallel reduction \nof venous thrombosis risk from more than 10-fold to \nonly a 4-fold increase among users of formulations \ncontaining less than 50 mg of estrogen\n26.\n\n68\nKanellopoulou\nvolume 19, issue 2, april - june 2020\nSecond line treatment include gonadotropin-\nreleasing hormone analog (GnRHa). This drug acts \nby inhibiting the ovarian production of estrogen. \nHowever, there is no clear evidence of increase in \neither venous thrombosis incidence or cardiovascular \nrisk. Yamaguti et. al showed that in patients treated \nwith GnRHa, there was a 6% increase in antithrombin \nIII, 29% reduction in D-dimers, and 19% increase \nin tissue plasminogen activator (tPA). Consequently, \ntaking into consideration the coagulation param-\neters studied there, there was no association with \na procoagulant profile27. \nThird-line and less tolerated treatment consists \nof danazol. Ford et al. investigated the effects of \ntreatment with danazol on hemostatic function and \nshowed that plasma FIB levels fell significantly, the \nPT shortened but remained within normal limits, \nand there were no significant changes in factors \nVII, VIIa, or fibrinopeptide A. No significant changes \nwere found in platelet function even if there was an \nincrease in their count. Functional levels of protein C, \nprotein S, and antithrombin III, all rose significantly, \nabove the normal range. Authors concluded that the \nobserved changes might be considered beneficial in \nthe context of venous thromboembolism. The only \nconcern was an increase in whole blood  viscosity \nduring treatment that remained significantly elevated \nduring follow-up. The rheological effects, however, \nindicate a degree of caution in the use of the drug \nin individuals considered being at risk from arterial \ncardiovascular disease28,29.\nAtherosclerosis and Cardiovascular Disease \nIn the last few years, a possible development of \naccelerated atherosclerosis in patients with endo -\nmetriosis has been hypothesized due to systemic \nchronic inflammation and increased oxidative stress. \nMoreover, several studies have documented the pres-\nence of a pro-atherogenic lipid profile in women with \nendometriosis. Moreover, another aspect to take into \naccount when considering the cardiovascular risk of \nwomen affected by endometriosis is the frequent use \nof a variety of medications, including no-steroidal \nanti-inflammatory drugs (NSAIDs) and/or COC or \ntherapeutic menopause30,31. \nThe risk of cardiovascular events in patients un-\nder treatment with COC increases with estrogen \ndosage whereas treatment with progestins alone \nor GnRH analogues (GnRHa) does not increase the \nrisk26. Ferreira et al. compared the cardiovascular \nrisk factors of patients that were treated either \nwith levonorgestrel intrauterine system (LNG-IUS) \nor GnRHa. In the LNG-IUS group, after six months \nof treatment there was a significant reduction in \nlipid leverls whereas in the GnRHa group, the lipid \nprofile did not show any statistical difference. The \nimpact on the lipid profile with LNG-IUS could lead \nto a favorable effect on long-term treatment\n32.\nIn addition, treatment of endometriosis with \nhysterectomy and/or oophorectomy may confer one \nmore risk factor inducing menopause at a younger \nage. In a large prospective study including 116430 \npatients with a 20-year follow-up, laparoscopically \nconfirmed endometriosis was associated with a \nsignificantly increased risk of coronary heart dis -\nease and the increased risk was greatest among \nyounger women. It is possible that the observed \nrisk was associated with surgical menopause from \nhysterectomy and/or oophorectomy among women \nwith endometriosis33. However, in previous smaller \ncase-control studies that included patients of young \nage with small follow-up, endometriosis was not \nassociated with atherosclerosis34,35. \nPerioperative Risk – Postoperative period\nConcerning the perioperative risk, there is no \nevidence that patients with endometriosis are at \nincreased risk in comparison with patients that un-\ndergo same operation for benign no endometriotic \nlesions. Ageno et al. studied the incidence of venous \n\n69\nrevealing the enigna of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment\nvolume 19, issue 2, april - june 2020\nthromboembolism after gynecologic laparoscopy \nfor benign lesions and found no episodes in a group \nof 266 patients in which 21% had endometriosis36.\nHowever, particular attention should be given not \nonly for DVT but also for other rare thrombosis in \nthe postoperative period in order to be early identi-\nfied. Single cases of ovarian vein thrombosis have \nalso been reported37,38.\nWu et al. reported that one month after the surgical \nremoval of endometriotic lesions, the extent of plate-\nlet activation in the peripheral blood is significantly \nreduced, probably resulting from the reduction or \nremoval of endometriotic foci that are inducers of \nplatelet activation\n3 Ding et al. reported that nearly \nall coagulation parameters return back to the nor -\nmal levels three months after surgical removal of \nendometriotic lesions11. Thus, surgical management \nof endometriosis could result in reducing the hyper-\ncoagulable state of affected women by diminishing \nthe inflammatory burden of the disease.\nPregnancy \nA critical and well-known characteristic of endo-\nmetriosis is the marked relief of pain that affected \nwomen experience during pregnancy possibly due to \nlack of hormonal fluctuations that typically character-\nize a menstrual cycle. Accordingly, chronic inflam-\nmation process should be suppressed. Instead, it is \nwell known that pregnancy and post-partum period \nis associated with increased risk of VTE due to acti-\nvated coagulation. Therefore, it is a great concern if \nendometriosis might trigger VTE especially in this \ngroup of patients who suffer from subfertility and \nmay follow in vitro fertilization (IVF) treatment. \nThere are only single cases of patients with en-\ndometriosis that experienced a thrombotic event \nduring pregnancy39. However, in a recent study in \nJapan, there is evidence that endometriosis could \nrepresent a novel independent VTE risk factor and \nthis is the first study that ever showed positive re-\nsults. This study included 103,070 pregnancies and \nthe frequency of VTE was 7.5 per 10,000 pregnancies. \nEven if the incidence of VTE was similar to that in \nCaucasian population, the results support a positive \nassociation because VTE has been speculated to be \nless frequent in the Japanese population due to the \nfact that no factor V Leiden and prothrombin muta-\ntions are found40.\nAnother important issue is the thrombotic risk \nin women after ovarian stimulation for IVF. Most of \nreported cases concerning thrombosis have been \ndescribed in this group of patients with endome-\ntriosis related to pregnancy. Thrombosis is not only \nin common sites like DVT but could also include un-\ncommon sites41,42. Except for vein thrombosis there \nare also single cases concerning arterial thrombosis \nlike thrombotic stroke 43. Nevertheless, it is well \nknown that high levels of endogenous estradiol due \nto ovarian hyperstimulation may result in a hyper-\ncoagulable state causing thrombosis. Consequently, \nsince there are no cross-sectional studies about the \nrisk of thrombosis during IVF, endometriosis could \nnot be implicated as a risk factor.\nThe role of antithrombotic treatment\nAntiplatelet treatment & Platelet depletion  \nThe hypercoagulability apparently resulting from \nendometriosis suggests that anticoagulation or an-\ntiplatelet therapy could be promising treatment \noptions. Therefore, several preclinical studies in \nanimal models focus on new treatment approaches \ntargeting the hypercoagulative state responsible \nfor fibrinogenesis and development of the disease. \nMost experiments are designed targeting on the \nrole of platelets and the beneficial effect either of \nplatelet depletion or antiplatelet treatment in dis -\nease remission. \nAcetylsalicylic acid  (Aspirin) is the most common \nused antiplatelet agent, widely available, inexpensive \nand is generally regarded as safe. The experimental \n\n70\nKanellopoulou\nvolume 19, issue 2, april - june 2020\nresults of Saad-Hossne et al. showed that intralesional \naspirin injection resulted in elimination of gross and \nhistological areas of endometriotic tissue, leaving \nonly fibrosis, necrosis, and apoptosis in their place \nwith a good safety profile. As the scar tissue can \nnegatively impact on local tissue function and culmi-\nnate in clinical manifestations, further investigations \nshould examine the real scar tissue formation rate \nand its clinical implications, such as fertility, after \nintralesional aspirin injection44. Siquiera et al. issued \nalso encouraging results with intralesional injection \nwith aspirin in endometriotic lesions in rabbits45.\nNonsteroidal antiinflammatory drugs (NSAIDs) \ninhibit platelet cyclooxygenase in a reversible way \nin contrast to aspirin. Therefore, their use may not \nbe limited for pain management but could also be \nbeneficial in fibrosis inhibition. Efstathiou et al. \nstudied in murine models the effects of celecoxib. \nAlthough significant reductions in disease burden \nwere observed when celecoxib was begun immedi-\nately after the induction of endometriosis, this effect \nwas not seen when treatment was delayed. These \nfindings show that treatment, while effective on \nlesion establishment and growth, had no effect on \nthe size of fully established lesions. This suggests \nthat celecoxib inhibits disease development in this \nmodel but does not regress established lesions\n46.\nAnother study evaluated the efficacy of Ozagrel \ntreatment, which is an antiplatelet agent inhibiting \nΤΧA2 synthesis. Low and high dose Ozagrel treat-\nment resulted in significant reduction in lesion area \nalong with improved hyperalgesia in mice with sur-\ngically induced endometriosis. As expected, Ozagrel \ntreatment nearly suppressed platelet aggregation, \nand significantly reduced expression of other in-\nflammatory markers. Targeting platelet depletion, \npre-emptive depletion of platelets prior to the en-\ndometriosis induction reduced the lesion growth, \nsuggesting that platelets also play a critical role in \nthe initiation of endometriosis. The observation that \nlater platelet depletion is as effective as the early \ndepletion in reducing lesion weight strongly suggests \nthat platelets play important roles not only in the \ninitiating stage of the development of endometriosis \nbut also in later stages as well 47. In agreement to \nprevious study, research in adenomyosis with either \nOzagrel treatment or platelet depletion suppressed \nmyometrial infiltration and slowed down the process \nof fibrogenesis with a dose-dependently manner48. \nLike Ozagrel, treatment with a recombinant P-selectin \ncan effectively reduce lesion area in murine models \nof endometriosis4,47.\nResearch has also been performed with herbals \nwith known antiplatelet action. Tanshinone-IIA \n(TAN) is a plant used in traditional Chinese medicine \nand has been demonstrated that inhibits platelet \naggregation and fibrogenesis. Zhang et al. induced \nendometriotic lesions in mice and TAN injection \nprovided in vivo evidence of inhibition of disease \nprogression, resulting in reduced lesion size and \nextent of fibrosis49. Scutellarin is an herbal flavonoid \nwith multiple pharmacological activities including \nantithrombotic, antioxidant and anti-inflammatory \neffects. Scutellarin also reduced the peripheral-\nactivated platelets rate and resulted in significantly \nreduced platelet aggregation, cellular proliferation, \nangiogenesis, and the extent of fibrosis50.\nHeparin \nTargeting coagulation in a different manner, there \nis one preclinical study revealed that endometriotic \nstromal cell (ECSC)-mediated gel contraction was \nsignificantly diminished in the presence of heparin in \na dose-dependent manner suppressing the ECSC at-\ntachment to collagen fibers. Therefore, heparin could \nrepresent a promising agent for the treatment of en-\ndometriosis-associated fibrosis51.\nThe use of heparin could represent a challenging \ntool for better healing and decreasing the severity of \nadhesions. Preliminary data also present heparin to \n\n71\nrevealing the enigna of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment\nvolume 19, issue 2, april - june 2020\ndiminish adhesion prevention in combination with \nhumidification and dexamethasone during peritoneal \nfull conditioning52.\nAntiplatelet Treatment and Fertility\nAnother important aspect is the role of antithrom-\nbotic treatment in improving fertility. The role of \naspirin in improving fertility or live births is con-\ntroversial, however taking into consideration the \nencouraging results about beneficial effect in women \nwith other inflammatory diseases, maybe could \nrepresent another treatment that could improve \npregnancy rates in women with endometriosis 53. \nMartinez-Zamora et al. studied women attempting \nconception with elevated CRP and prior pregnancy \nloss and found that low dose aspirin may increase \nclinical pregnancy and live birth rates compared \nwith women without inflammation and reduce CRP \nelevation during pregnancy 54. However, in most \nstudies that investigated the effect of preconcep-\ntion initiated low dose aspirin, patients with known \nendometriosis were excluded. \nExperiments in rats showed that endometriosis \ntreated with intraperitoneal indomethacin resulted \nin better reproductive performance than in animals \ntreated with other methods. Microsurgery and da-\nnazol therapy both were effective in preventing \nresidual endometriosis, but the animals tended to \nbe less fertile after treatment. In rats treated with \nindomethacin, persistent endometriotic cysts were \ninvariably smaller near the site of intraperitoneal \ninjection suggesting a local antiprostaglandin effect55 \nand clinical and experimental evidence showed an \nincreased concentration of prostaglandins in peri -\ntoneal fluid in cases of endometriosis\n56.\nDISCUSSION\nEndometriosis is a chronic pelvic inflammatory \ncondition which activates platelets and the coagula-\ntion cascade. Consequently, women with endome -\ntriosis appear to be in a hypercoagulable state. The \nactivation of platelets and of coagulation cascade \nfaces severe concerns, about a possible increase in \nthromboembolic risk in patients with endometriosis. \nThere are not available data to support a possible \nassociation and most reported cases in the literature \ncorrespond to patients with other known thrombo-\nphilia risk factors or topical infiltration of femoral \nand iliac veins. \nIt is crucial to be clarified if women with endo -\nmetriosis have an additional thromboembolic risk \nfactor in order to consider different approach dur-\ning increased risk situations like the postoperative \nperiod, pregnancy/postpartum or under hormonal \ntreatment. However, there are insufficient data to \nsupport a possible association. Remarkably, some \nstudies have shown that platelet and coagulation \nactivation is improved after surgery or hormonal \ntreatment due to elimination of disease burden3,11,32.\nUp to now, patients were not supposed to be in higher \nrisk of thrombosis during pregnancy or postpartum \nthan women without endometriosis. Nevertheless, a \nrecent study showed that endometriosis could rep-\nresent an independent risk factor of VTE in Japanese \npopulation40. However, more studies are needed \nduring pregnancy in order to generalize the previous \nfinding because the overall thrombotic risk differs \nin Japanese population from other populations like \nCaucasians.\nA systematic laboratory testing for thrombophilia \nfactors does not seem justified in patients with en-\ndometriosis before initiation of hormonal treatment \nor during pregnancy. These tests should be targeted \nto selected patients with first-degree relatives with \na diagnosis of venous thromboembolism or cardio-\nvascular event in young age. Concerning the use of \nCOC preparations with the lowest possible estrogen \ndose should constitute the first-line choice, consid-\nering that the estrogen content affects the risk of \nboth venous and arterial thrombosis. Progestins are \n\n72\nKanellopoulou\nvolume 19, issue 2, april - june 2020\nincreasingly used even as monotherapy, and since \nthey do not increase the thrombotic risk, their use \ncan be safely suggested in many women with con-\ntraindications to estrogens as well as in those with \nother known thrombophilia factors including past \nhistory of thromboembolic event, positive family \nhistory, smoking, obesity, presence of gross varicose \nveins, hypertension, diabetes and age >35 years. \nThe demonstration that platelets are involved in \nthe pathogenesis of the disease provides a motivation \nfor the use of anti-coagulants to treat endometriosis, \nand opens prospects for developing novel biomark-\ners for diagnostic or prognostic purposes. Platelet \ndepletion or suppression of platelet aggregation is \nan interesting approach and preclinical studies are \nrunning. Primary results with intralesional aspirin \ninjection\n44,45 or other antiplatelets are encouraging \nby effectively reducing lesion growth and the extent \nof fibrosis46,50.\nConclusion\nEndometriosis is a benign disease and certainly \nnot life-threatening. Therefore, it places higher pre-\nmium on best treatment approach as compared \nwith other life-threatening diseases. More research \nis needed to determine the actual thrombotic risk \nand if antithrombotic treatment could represent an \neffective treatment in inhibition of disease progres-\nsion balancing on the hemorrhagic risk and the risk \nof damage to normal endometrial mucosa, with \npotential consequences to fertility.\nConflicts of interest and funding\nNone to declare\nReferences\n1. Vercellini P , Viganò P , Somigliana E, et al. Endome-\ntriosis: pathogenesis and treatment. Nat Rev En-\ndocrinol. 2014;10:261-75.\n2. Burney RO. The genetics and biochemistry of \nendometriosis. Curr Opin Obstet Gynecol. \n2013;25:280-6.\n3. Wu Q, Ding D, Liu X, et al. Evidence for a Hyperco-\nagulable State in Women With Ovarian Endome-\ntriomas. Reprod Sci. 2015;22:1107-14.\n4. Ding D, Liu X, Duan J, et al. Platelets are an unin-\ndicted culprit in the development of endometrio-\nsis: clinical and experimental evidence. Hum Re-\nprod. 2015;30:812-32.\n5. \nZhang Q, Duan J, Liu X, et al. Platelets drive smooth \nmuscle metaplasia and fibrogenesis in endome-\ntriosis through epithelial mesenchymal transition \nand fibroblast-to-myofibroblast transdifferentia-\ntion. Mol Cell Endocrinol. 2016;428:1-16.\n6. Munrós J, Martínez-Zamora MA, Tàssies D, et al. \nTotal circulating microparticle levels are increased \nin patients with deep infiltrating endometriosis. \nHum Reprod. 2017;32:325-331.\n7. Krikun G, Lockwood CJ, Paidas MJ. Tissue factor \nand the endometrium: from physiology to pathol-\nogy. Thromb Res. 2009;124:393-6.\n8. Gilabert-Estelles J, Ramon LA, España F, et al. 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Ovar-\nian vein thrombosis after total laparoscopic hys-\nterectomy with unilateral adnexectomy: A case re-\nport. Int J Surg Case Rep. 2017;41:1-4.\n39. Panaych KPS, Hazarika A, Hazarika B, et al. Cere-\nbral Venous Thrombosis: A Complicated Anaes-\nthetic Scenario for Caesarean Section. J Anesth \nClin Res 2016;7:661.\n40. Sugiura-Ogasawara M, Ebara T , Matsuki T , et al; \nand the Japan Environment & Children’s Study \n(JECS) Group. Endometriosis and Recurrent Preg-\nnancy Loss as New Risk Factors for Venous Throm-\nboembolism during Pregnancy and Post-Par-\ntum: The JECS Birth Cohort. Thromb Haemost. \n2019;119:606-17.\n41. Belaen B, Geerinckx K, Vergauwe P , et al. Internal \njugular vein thrombosis after ovarian stimulation. \nHum Reprod. 2001;16:510-2.\n42. Hirata M, Yano H, Taji T , Shirakata Y. Mesenteric \nvein thrombosis following impregnation via in vi-\ntro fertilization-embryo transfer. World J Gastro-\nintest Surg. 2017;9:209–13.\n43. Chua N, Wang J, Loh S, et al. Thrombotic stroke in \nassociation with ovarian hyperstimulation and ear-\nly pregnancy rescued by thrombectomy. Case Re-\nports in Perinatal Medicine 2012 ;1: 43-5.\n44. Saad-Hossne R, Barretto AB, Siqueira JM, et al. \nEvaluation of peritoneal endometriosis treatment \nusing intralesional acetylsalicylic acid injection in \nrabbits. Acta Cir Bras. 2016;31:227-34.\n45. Siqueira JM, Barreto AB, Saad-Hossne R. Treat -\nment of endometriosis with local  acetylsalicyl -\nic acid injection: experimental study in rabbits. J \nMinim Invasive Gynecol. 2011;18:800-6.\n46. Efstathiou JA, Sampson DA, Levine Z, et al. Non-\nsteroidal anti-inflammatory drugs differentially \nsuppress endometriosis in a murine model. Fer-\ntil Steril. 2005;83:171-81.\n47. Guo SW, Ding D, Liu X. Anti-platelet therapy is ef-\nficacious in treating endometriosis induced in \nmouse. Reprod Biomed Online. 2016;33:484-499.\n48. Zhu B, Chen Y, Shen X, et al. Anti-platelet thera-\npy holds promises in  treating adenomyosis: ex -\nperimental evidence. Reprod Biol Endocrinol. \n2016;14:66.\n49. Zhang Q, Liu X, Guo SW. Progressive development \nof endometriosis and its hindrance by anti-plate-\nlet treatment in mice with induced endometriosis. \nReprod Biomed Online. 2017;34:124-136.\n50. Ding D, Cai X, Zheng H, et al. Scutellarin Suppresses \nPlatelet Aggregation and Stalls Lesional Progres-\nsion in Mouse With Induced Endometriosis.  Re-\nprod Sci. 2018 [Epub ahead of print].\n51. \nNasu K, Tsuno A, Hirao M, et al. Heparin is a prom-\nising agent for the treatment of endometriosis-\nassociated fibrosis. Fertil Steril. 2010;94:46-51.\n52. Koninckx PR, Corona R, Timmerman D, et al. Peri-\ntoneal full-conditioning reduces postoperative \nadhesions and pain: a randomised controlled tri-\nal in deep endometriosis surgery. J Ovarian Res. \n2013;6:90.\n\n75\nrevealing the enigna of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment\nvolume 19, issue 2, april - june 2020\n53. Sjaarda LA, Radin RG, Silver RM, et al. Precon-\nception Low-Dose Aspirin Restores Diminished \nPregnancy and Live Birth Rates in Women With \nLow-Grade Inflammation: A Secondary Analysis \nof a Randomized Trial. J Clin Endocrinol Metab. \n2017;102:1495-1504.\n54. Martínez-Zamora MA, Tàssies D, Reverter JC, et \nal. Increased circulating cell-derived microparti-\ncle count is associated with recurrent implanta-\ntion failure after IVF and embryo transfer. Reprod \nBiomed Online. 2016;33:168-73.\n55. Golan A, Dargenio R, Winston RM. The effect of \ntreatment on experimentally produced endometri-\nal peritoneal implants. Fertil Steril. 1986;46:954-8.\n56. Dargenio R, Corbucci MG, Lamanna MA, et al. In-\ndomethacin and fertility in experimental endome-\ntriosis. Acta Eur Fertil. 1992;23:85-8.\nReceived 16-12-19\nRevised 05-04-20\nAccepted 11-04-20","source_license":"CC0","license_restricted":false}