Revealing the enigma of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment

Endometriosis is a chronic inflammatory disease of women of reproductive age that is defined by the presence of ectopic endometrium. The pathophysiology of the disease is poorly understood, however platelet activation play a crucial role in initiation of inflammation and fibrinogenesis, which in term further activate the coagulation cascade. The relationship between inflammation and coagulation motivated researchers to study whether patients are in a hypercoagulable state and if endometriosis represent an independent risk factor for venous thromboembolism or cardiovascular risk. This review article focuses on the role of coagulation, the risk of thrombosis and a possible beneficial effect of antithrombotic-treatment. Key words: Endometriosis, inflammation, platelets, thrombosis, antithrombotic treatment

Endometriosis is a chronic disease defined as the presence of endometrial tissue outside the uterus. It is an estrogen-dependent disease, affecting roughly 6–10% of women of reproductive age. It is a major contributing cause for dysmenorrhoea, pelvic pain and infertility impacting negatively on the quality of life Three clinically different phenotypes have been described: Endometriotic implants on the surface of the pelvic peritoneum (PE), ovarian endometrioma (OE) and deep infiltrating endometriosis (DIE), the latter being the most severe form of the disease 1. The pathophysiology of endometriosis is poorly understood and endometriotic lesions can be viewed as wounds that undergo repeated tissue injury and repair, ultimately leading to fibrosis2.It has recently been proposed that women with endometriosis may be in an inflammatory and hypercoagulable state and even though inflammation and coagulation are separate entities is increasingly evident that interact each other3,4.Due to the major role of coagulation in disease development, in this review article we study the actual thrombotic risk in women with endome- 66 Kanellopoulou volume 19, issue 2, april - june 2020 triosis and discuss a feasible role of antithrombotic treatment in disease remission. Pathophysiology: the role of coagulation The activation of coagulation in women with en- dometriosis is actually consistent with the notion that endometriotic lesions undergo cyclic bleeding resulting in repeated tissue injury and repair, which in turn causes platelet activation and aggregation4. The activated platelets promote the release of other procoagulant factors like von Willebrand factor, thromboxan A2 (TXA2) causing further platelet aggregation and activation of coagulation cascade. Once the platelets are activated and aggregated, they promote angiogenesis and cellular proliferation, causing smooth muscle metaplasia and ultimately fibrosis5. The activated platelets could also induce the release microparticles (MPs). Studies in other diseases have shown that platelet-MPs play major role in coagulation, as they are highly thrombogenic and elevated MPs have been found in almost all thrombotic diseases and conditions associated with inflammation, cellular activation and angiogenesis. Munros et al. provided data showing higher levels of total MPs in patients with DIE compared with OE or without endometriosis. The higher MPs levels in patients with DIE may represent the more intense grade of inflammation and angiogenesis in this more aggressive type6. After tissue injury, platelets release angiogenic proteins to promote wound healing. In later stage of healing, pro-angiogenic proteins are compensated by the release of angiogenic suppressors from stromal cells and platelets in order to prevent uninhibited growth. Endometriotic stromal cells have elevated expression of tissue factor (TF), and the peritoneal fluid from women with endometriosis has higher concentration of TF as well as thrombin, which is a potent inducer of platelet activation 4. Following vascular disruption, perivascular TF binds to circu- lating factor VIIa to mediate the activation of both factor IX and X and ultimately to generate throm - bin7. An altered expression of several components of the fibrinolytic system in the endometrium and peritoneal fluid of women with the disease has been suggested as a key factor in the establishment of the endometriotic lesions. There is evidence of increased fibrinolytic activity in the eutopic endometrium of these women, resulting in endometrial fragments with a high potential to enable implantation. Proteo- lytic status is determined by the imbalance between plasminogen activators and plasminogen activator inhibitors, which are expressed differently depend- ing on the type of lesion considered and the stage of the disease 8. The risk of thrombosis Coagulation Factors Review of the literature disclosed many clinical studies investigating a possible impact of activation of the coagulation during disease development on laboratory clotting tests. Wu et al. reported that women with OE had a significantly shortened both activated partial thromboplastin time (APTT) and thrombin time (TT) and elevated fibrinogen (FIB) levels as compared with controls, although most of the results were within the normal range. Moreover, the co-occurrence of DIE or PE and more severe stage appeared to further decrease APTT , nevertheless the difference was not statistical significant3. In line with the previous study, Vigano et al. also documented a statistically significant shortening of the APTT in women with OE9 and Lin et al. found that the levels of PT and TT in patients with OE were significantly shorter and levels of FIB and D-dimer significantly higher than those with benign ovarian cysts10. Ding et al. showed that women with OE had a significantly higher platelet activation rate and platelet aggrega- tion rate, elevated plasma D-dimer, FIB, fibrinogen 67 revealing the enigna of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment volume 19, issue 2, april - june 2020 degradation products (FDPs), as well as shortened TT . However, no difference was observed in PT , APTT11. All previous studies published positive results in patients with OE. It should be considered that an en- dometrioma contains free iron, proteolytic enzymes, and inflammatory molecules in concentrations nota- bly higher than those present in peripheral blood or in other types of benign cysts. Sanchez et al. showed that concentrations of some coagulation parameters such as plasminogen activator inhibitor-1 (PAI-1), PAI-2, and urokinase plasminogen activator were found to be in the same range or even much higher in the endometrioma fluid compared to malignant tumors, and it is reasonable to think that this content may leak from the cyst and be absorbed through the peritoneum12. The large amounts of coagulation- related products present in ovarian endometrioma is remarkably described in a case of endometriotic cyst rupture that caused a rapid but transient eleva- tion in plasma D-dimer levels13. Genes of thrombotic risk Due to genetic predisposition, there was a con- cern whether patients share similar genes of high thromboembolic risk. However, no association be- tween inherited thrombophilia and endometriosis has been reported so far, in order to support costly and time-consuming thrombophilia-screening tests in this group of patients. In a small study, screening for thrombophilia showed that the prevalence of prothrombin G20210A mutation and hyperhomocysteinemia in patients with endometriosis was not different from that of the general population and prevalence of factor V-Leiden mutation, was found with a lower prevalence 14. In another study in which emphasis was given in fibrinolysis and plasminogen activator inhibitor-1 (PAI-1) gene, endometriosis was more likely in pa- tients with 4G/5G or 4G/4G which are associated with hypofibrinolysis compared with 5G/5G PAI-1 genotype15.Nevertheless, the existence of 4G allele alone does not represent an independent high risk factor of thromboembolic disease. Thromboembolic Risk Factor It is a great concern if the activation of coagulation not only result to progression of the disease but also increases the thromboembolic risk. However, there are no published data to support a possible associa- tion and there are only anecdotal reports of patients who experienced deep vein thrombosis (DVT) in the presence of other risk factors like immobilization or hormonal therapy16. Special attention should be kept at the rare local- ization of endometriosis that could involve the femo- ral and iliac veins either with extrinsic compression or infiltration. This situation could cause cyclical leg swelling, coincidental with menstruation17-20 and a possible complication due to this localization could be thrombosis21-25. Hormonal Therapy The therapeutic suppression of ovulation and menstruation with hormonal treatment is an effec- tive conservative management of controlling the disease and its associated symptoms. Combined hormonal contraceptives (COC) constitute the most common long-term treatment to control the disease with the best profile in terms of long-term safety, adherence and cost. However, the main concern is a slight increase of the relative risk of venous thromboembolism and arterial thrombosis. Both thrombotic events are associated with estrogen dose, while progestin-only preparations confer no increased risk. Progressively, during the 1970s, the estrogenic content of COC has been was gradually lowered from 150 to 20 μg, with a parallel reduction of venous thrombosis risk from more than 10-fold to only a 4-fold increase among users of formulations containing less than 50 mg of estrogen 26. 68 Kanellopoulou volume 19, issue 2, april - june 2020 Second line treatment include gonadotropin- releasing hormone analog (GnRHa). This drug acts by inhibiting the ovarian production of estrogen. However, there is no clear evidence of increase in either venous thrombosis incidence or cardiovascular risk. Yamaguti et. al showed that in patients treated with GnRHa, there was a 6% increase in antithrombin III, 29% reduction in D-dimers, and 19% increase in tissue plasminogen activator (tPA). Consequently, taking into consideration the coagulation param- eters studied there, there was no association with a procoagulant profile27. Third-line and less tolerated treatment consists of danazol. Ford et al. investigated the effects of treatment with danazol on hemostatic function and showed that plasma FIB levels fell significantly, the PT shortened but remained within normal limits, and there were no significant changes in factors VII, VIIa, or fibrinopeptide A. No significant changes were found in platelet function even if there was an increase in their count. Functional levels of protein C, protein S, and antithrombin III, all rose significantly, above the normal range. Authors concluded that the observed changes might be considered beneficial in the context of venous thromboembolism. The only concern was an increase in whole blood viscosity during treatment that remained significantly elevated during follow-up. The rheological effects, however, indicate a degree of caution in the use of the drug in individuals considered being at risk from arterial cardiovascular disease28,29. Atherosclerosis and Cardiovascular Disease In the last few years, a possible development of accelerated atherosclerosis in patients with endo - metriosis has been hypothesized due to systemic chronic inflammation and increased oxidative stress. Moreover, several studies have documented the pres- ence of a pro-atherogenic lipid profile in women with endometriosis. Moreover, another aspect to take into account when considering the cardiovascular risk of women affected by endometriosis is the frequent use of a variety of medications, including no-steroidal anti-inflammatory drugs (NSAIDs) and/or COC or therapeutic menopause30,31. The risk of cardiovascular events in patients un- der treatment with COC increases with estrogen dosage whereas treatment with progestins alone or GnRH analogues (GnRHa) does not increase the risk26. Ferreira et al. compared the cardiovascular risk factors of patients that were treated either with levonorgestrel intrauterine system (LNG-IUS) or GnRHa. In the LNG-IUS group, after six months of treatment there was a significant reduction in lipid leverls whereas in the GnRHa group, the lipid profile did not show any statistical difference. The impact on the lipid profile with LNG-IUS could lead to a favorable effect on long-term treatment 32. In addition, treatment of endometriosis with hysterectomy and/or oophorectomy may confer one more risk factor inducing menopause at a younger age. In a large prospective study including 116430 patients with a 20-year follow-up, laparoscopically confirmed endometriosis was associated with a significantly increased risk of coronary heart dis - ease and the increased risk was greatest among younger women. It is possible that the observed risk was associated with surgical menopause from hysterectomy and/or oophorectomy among women with endometriosis33. However, in previous smaller case-control studies that included patients of young age with small follow-up, endometriosis was not associated with atherosclerosis34,35. Perioperative Risk – Postoperative period Concerning the perioperative risk, there is no evidence that patients with endometriosis are at increased risk in comparison with patients that un- dergo same operation for benign no endometriotic lesions. Ageno et al. studied the incidence of venous 69 revealing the enigna of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment volume 19, issue 2, april - june 2020 thromboembolism after gynecologic laparoscopy for benign lesions and found no episodes in a group of 266 patients in which 21% had endometriosis36. However, particular attention should be given not only for DVT but also for other rare thrombosis in the postoperative period in order to be early identi- fied. Single cases of ovarian vein thrombosis have also been reported37,38. Wu et al. reported that one month after the surgical removal of endometriotic lesions, the extent of plate- let activation in the peripheral blood is significantly reduced, probably resulting from the reduction or removal of endometriotic foci that are inducers of platelet activation 3 Ding et al. reported that nearly all coagulation parameters return back to the nor - mal levels three months after surgical removal of endometriotic lesions11. Thus, surgical management of endometriosis could result in reducing the hyper- coagulable state of affected women by diminishing the inflammatory burden of the disease. Pregnancy A critical and well-known characteristic of endo- metriosis is the marked relief of pain that affected women experience during pregnancy possibly due to lack of hormonal fluctuations that typically character- ize a menstrual cycle. Accordingly, chronic inflam- mation process should be suppressed. Instead, it is well known that pregnancy and post-partum period is associated with increased risk of VTE due to acti- vated coagulation. Therefore, it is a great concern if endometriosis might trigger VTE especially in this group of patients who suffer from subfertility and may follow in vitro fertilization (IVF) treatment. There are only single cases of patients with en- dometriosis that experienced a thrombotic event during pregnancy39. However, in a recent study in Japan, there is evidence that endometriosis could represent a novel independent VTE risk factor and this is the first study that ever showed positive re- sults. This study included 103,070 pregnancies and the frequency of VTE was 7.5 per 10,000 pregnancies. Even if the incidence of VTE was similar to that in Caucasian population, the results support a positive association because VTE has been speculated to be less frequent in the Japanese population due to the fact that no factor V Leiden and prothrombin muta- tions are found40. Another important issue is the thrombotic risk in women after ovarian stimulation for IVF. Most of reported cases concerning thrombosis have been described in this group of patients with endome- triosis related to pregnancy. Thrombosis is not only in common sites like DVT but could also include un- common sites41,42. Except for vein thrombosis there are also single cases concerning arterial thrombosis like thrombotic stroke 43. Nevertheless, it is well known that high levels of endogenous estradiol due to ovarian hyperstimulation may result in a hyper- coagulable state causing thrombosis. Consequently, since there are no cross-sectional studies about the risk of thrombosis during IVF, endometriosis could not be implicated as a risk factor. The role of antithrombotic treatment Antiplatelet treatment & Platelet depletion The hypercoagulability apparently resulting from endometriosis suggests that anticoagulation or an- tiplatelet therapy could be promising treatment options. Therefore, several preclinical studies in animal models focus on new treatment approaches targeting the hypercoagulative state responsible for fibrinogenesis and development of the disease. Most experiments are designed targeting on the role of platelets and the beneficial effect either of platelet depletion or antiplatelet treatment in dis - ease remission. Acetylsalicylic acid (Aspirin) is the most common used antiplatelet agent, widely available, inexpensive and is generally regarded as safe. The experimental 70 Kanellopoulou volume 19, issue 2, april - june 2020

of Saad-Hossne et al. showed that intralesional aspirin injection resulted in elimination of gross and histological areas of endometriotic tissue, leaving only fibrosis, necrosis, and apoptosis in their place with a good safety profile. As the scar tissue can negatively impact on local tissue function and culmi- nate in clinical manifestations, further investigations should examine the real scar tissue formation rate and its clinical implications, such as fertility, after intralesional aspirin injection44. Siquiera et al. issued also encouraging results with intralesional injection with aspirin in endometriotic lesions in rabbits45. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit platelet cyclooxygenase in a reversible way in contrast to aspirin. Therefore, their use may not be limited for pain management but could also be beneficial in fibrosis inhibition. Efstathiou et al. studied in murine models the effects of celecoxib. Although significant reductions in disease burden were observed when celecoxib was begun immedi- ately after the induction of endometriosis, this effect was not seen when treatment was delayed. These findings show that treatment, while effective on lesion establishment and growth, had no effect on the size of fully established lesions. This suggests that celecoxib inhibits disease development in this model but does not regress established lesions 46. Another study evaluated the efficacy of Ozagrel treatment, which is an antiplatelet agent inhibiting ΤΧA2 synthesis. Low and high dose Ozagrel treat- ment resulted in significant reduction in lesion area along with improved hyperalgesia in mice with sur- gically induced endometriosis. As expected, Ozagrel treatment nearly suppressed platelet aggregation, and significantly reduced expression of other in- flammatory markers. Targeting platelet depletion, pre-emptive depletion of platelets prior to the en- dometriosis induction reduced the lesion growth, suggesting that platelets also play a critical role in the initiation of endometriosis. The observation that later platelet depletion is as effective as the early depletion in reducing lesion weight strongly suggests that platelets play important roles not only in the initiating stage of the development of endometriosis but also in later stages as well 47. In agreement to previous study, research in adenomyosis with either Ozagrel treatment or platelet depletion suppressed myometrial infiltration and slowed down the process of fibrogenesis with a dose-dependently manner48. Like Ozagrel, treatment with a recombinant P-selectin can effectively reduce lesion area in murine models of endometriosis4,47. Research has also been performed with herbals with known antiplatelet action. Tanshinone-IIA (TAN) is a plant used in traditional Chinese medicine and has been demonstrated that inhibits platelet aggregation and fibrogenesis. Zhang et al. induced endometriotic lesions in mice and TAN injection provided in vivo evidence of inhibition of disease progression, resulting in reduced lesion size and extent of fibrosis49. Scutellarin is an herbal flavonoid with multiple pharmacological activities including antithrombotic, antioxidant and anti-inflammatory effects. Scutellarin also reduced the peripheral- activated platelets rate and resulted in significantly reduced platelet aggregation, cellular proliferation, angiogenesis, and the extent of fibrosis50. Heparin Targeting coagulation in a different manner, there is one preclinical study revealed that endometriotic stromal cell (ECSC)-mediated gel contraction was significantly diminished in the presence of heparin in a dose-dependent manner suppressing the ECSC at- tachment to collagen fibers. Therefore, heparin could represent a promising agent for the treatment of en- dometriosis-associated fibrosis51. The use of heparin could represent a challenging tool for better healing and decreasing the severity of adhesions. Preliminary data also present heparin to 71 revealing the enigna of coagulation in endometriosis: the risk of thrombosis and the role of antithrombotic treatment volume 19, issue 2, april - june 2020 diminish adhesion prevention in combination with humidification and dexamethasone during peritoneal full conditioning52. Antiplatelet Treatment and Fertility Another important aspect is the role of antithrom- botic treatment in improving fertility. The role of aspirin in improving fertility or live births is con- troversial, however taking into consideration the encouraging results about beneficial effect in women with other inflammatory diseases, maybe could represent another treatment that could improve pregnancy rates in women with endometriosis 53. Martinez-Zamora et al. studied women attempting conception with elevated CRP and prior pregnancy loss and found that low dose aspirin may increase clinical pregnancy and live birth rates compared with women without inflammation and reduce CRP elevation during pregnancy 54. However, in most studies that investigated the effect of preconcep- tion initiated low dose aspirin, patients with known endometriosis were excluded. Experiments in rats showed that endometriosis treated with intraperitoneal indomethacin resulted in better reproductive performance than in animals treated with other methods. Microsurgery and da- nazol therapy both were effective in preventing residual endometriosis, but the animals tended to be less fertile after treatment. In rats treated with indomethacin, persistent endometriotic cysts were invariably smaller near the site of intraperitoneal injection suggesting a local antiprostaglandin effect55 and clinical and experimental evidence showed an increased concentration of prostaglandins in peri - toneal fluid in cases of endometriosis 56.

Endometriosis is a chronic pelvic inflammatory condition which activates platelets and the coagula- tion cascade. Consequently, women with endome - triosis appear to be in a hypercoagulable state. The activation of platelets and of coagulation cascade faces severe concerns, about a possible increase in thromboembolic risk in patients with endometriosis. There are not available data to support a possible association and most reported cases in the literature correspond to patients with other known thrombo- philia risk factors or topical infiltration of femoral and iliac veins. It is crucial to be clarified if women with endo - metriosis have an additional thromboembolic risk factor in order to consider different approach dur- ing increased risk situations like the postoperative period, pregnancy/postpartum or under hormonal treatment. However, there are insufficient data to support a possible association. Remarkably, some studies have shown that platelet and coagulation activation is improved after surgery or hormonal treatment due to elimination of disease burden3,11,32. Up to now, patients were not supposed to be in higher risk of thrombosis during pregnancy or postpartum than women without endometriosis. Nevertheless, a recent study showed that endometriosis could rep- resent an independent risk factor of VTE in Japanese population40. However, more studies are needed during pregnancy in order to generalize the previous finding because the overall thrombotic risk differs in Japanese population from other populations like Caucasians. A systematic laboratory testing for thrombophilia factors does not seem justified in patients with en- dometriosis before initiation of hormonal treatment or during pregnancy. These tests should be targeted to selected patients with first-degree relatives with a diagnosis of venous thromboembolism or cardio- vascular event in young age. Concerning the use of COC preparations with the lowest possible estrogen dose should constitute the first-line choice, consid- ering that the estrogen content affects the risk of both venous and arterial thrombosis. Progestins are 72 Kanellopoulou volume 19, issue 2, april - june 2020 increasingly used even as monotherapy, and since they do not increase the thrombotic risk, their use can be safely suggested in many women with con- traindications to estrogens as well as in those with other known thrombophilia factors including past history of thromboembolic event, positive family history, smoking, obesity, presence of gross varicose veins, hypertension, diabetes and age >35 years. The demonstration that platelets are involved in the pathogenesis of the disease provides a motivation for the use of anti-coagulants to treat endometriosis, and opens prospects for developing novel biomark- ers for diagnostic or prognostic purposes. Platelet depletion or suppression of platelet aggregation is an interesting approach and preclinical studies are running. Primary results with intralesional aspirin injection 44,45 or other antiplatelets are encouraging by effectively reducing lesion growth and the extent of fibrosis46,50.

Endometriosis is a benign disease and certainly not life-threatening. Therefore, it places higher pre- mium on best treatment approach as compared with other life-threatening diseases. More research is needed to determine the actual thrombotic risk and if antithrombotic treatment could represent an effective treatment in inhibition of disease progres- sion balancing on the hemorrhagic risk and the risk of damage to normal endometrial mucosa, with potential consequences to fertility. Conflicts of interest and funding None to declare

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Dargenio R, Corbucci MG, Lamanna MA, et al. In- domethacin and fertility in experimental endome- triosis. Acta Eur Fertil. 1992;23:85-8. Received 16-12-19 Revised 05-04-20 Accepted 11-04-20