Possible association between adenomyosis and disseminated intravascular coagulation and thromboembolism: A systematic review
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- Published online on: June 24, 2022 https://doi.org/10.3892/wasj.2022.162
- Article Number: 27
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Copyright: © Kobayashi . This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Adenomyosis is characterized by the presence of ectopic endometrial glands and stroma located within the hypertrophic and hyperplastic myometrium (1). Clinical manifestations are abnormal uterine bleeding (AUB), dysmenorrhea and infertility; however, approximately one third of these cases are completely asymptomatic (2). Adenomyosis often co-exists with endometriosis that causes dysmenorrhea and infertility (3). Researchers have accumulated clinical, histological and genetic, genomic, and proteomic data supporting the pathogenesis of adenomyosis and endometriosis (4). However, it remains inconclusive as to whether adenomyosis and endometriosis are two different diseases (2,5) or different phenotypes of a single disease (3). The clinical manifestations are similar between endometriosis and adenomyosis, although adenomyosis is characterized by AUB (2,6). Recently, some cases of life-threatening disseminated intravascular coagulation (DIC) or thromboembolic events associated with adenomyosis have been reported (7,8). Empirically, giant adenomyosis is considered to cause massive bleeding. On the other hand, such life-threatening events secondary to endometriosis have not been observed to date, at least to the best of the author's knowledge. Adenomyosis and endometriosis are similar diseases; however, studying and elucidating the pathogenic mechanisms of rare complications may provide insight into the pathophysiology and etiology of adenomyosis. The purpose of the present systematic review was to provide evidence of the clinical features and risk factors of DIC or thromboembolism associated with adenomyosis, and to explore the potential mechanisms of this rare complication. The present systematic review is comprised of sections focusing on ‘reviews of the existing literature on adenomyosis-associated DIC or thromboembolism’ and ‘their underlying mechanisms’. Finally, future directions on diagnostic and treatment strategies based on the conclusions drawn herein are discussed.
Data and methods
Search strategy and selection criteria
A computerized literature search was performed to identify relevant studies reported in the English language. The study was conducted in accordance with the PRISMA guidelines updated in 2020 (http://www.prisma-statement.org/) (9). The PubMed and Google Scholar electronic databases were searched for studies published between January, 2000 and November 2021, combining the following key words: Adenomyosis, AUB, DIC and thromboembolism. As a result of the PubMed search, there have been no reports of patients with adenomyosis with DIC or thromboembolism prior to 2000; thus, the search was performed for articles published after January, 2000. The inclusion criteria were as follows: Publications of original studies and review articles, and reference lists of the included studies. The exclusion criteria were letters to the editor, poster presentations, and literature unrelated to the research topic.
A two-step screening process was performed to obtain eligible results. First, the PubMed search was conducted using keywords with the following search combination: Group 1 (‘adenomyosis’ AND ‘abnormal uterine bleeding’), group 2 (‘adenomyosis’ AND ‘disseminated intravascular coagulation’) and group 3 (‘adenomyosis’ AND ‘thromboembolism’). Second, the Google Scholar search was performed using keywords with the following search combination: (‘adenomyosis’, AND ‘thromboembolism’, OR ‘disseminated intravascular coagulation’). Given the heterogeneity in the research theme, data from the studies were synthesized using a descriptive review design with narrative methods. As illustrated in Fig. 1, the first identification phase included records identified through a database search. Terms in the titles and abstracts were focused on in the first screening stage. However, duplicates were removed during the second screening phase, and titles, abstracts and full-text articles were read to remove inappropriate articles. Citation tracking was conducted to identify additional relevant citations. The final eligibility phase included the full-text articles for analysis after excluding those for which detailed data could not be extracted. The last computerized literature search was conducted on January 25, 2022.
Results
Selection of studies
The search in the PubMed database provided 195 literature citations (n=176 in group 1, n=7 in group 2, and n=12 in group 3). Following the removal of overlaps, 183 records (n=167, n=6 and n=10) were obtained, of which 86 were excluded, and 12 relevant articles (n=5, n=2 and n=5) were cited by the tracking of references, and 78 (n=55, n=8 and n=15) met the inclusion and exclusion criteria (Fig. 1). Following a literature search on PubMed, eight records reporting 8 women with DIC and 13 records reporting 23 women with thromboembolic complications were identified. Second, 64 records met the eligibility criteria by key word searches on Google Scholar. Of the 64 records, 47 records were excluded as their content was not relevant to the study.
Reviews of the literature on adenomyosis-associated massive AUB or DIC
Subsequently, reviews of the literature on patients with adenomyosis with life-threatening massive AUB or DIC were performed. The clinical manifestations, sites of bleeding events, etiology, and risk factors are summarized in Table I. Some case reports on the topic are presented below.
 | Table IReviews of the literature on patients with adenomyosis-related massive abnormal uterine bleeding or DIC. |
Yamanaka et al (10) examined the effects of adenomyosis on the blood coagulation/fibrinolysis system during menstruation. They demonstrated that the blood levels of markers of coagulation and fibrinolysis [thrombin-antithrombin complex (TAT), soluble fibrin (SF), D-dimer and plasmin-alpha 2-plasmin inhibitor complex (PIC)] could increase during menstruation. Patients with extensive adenomyosis may be potentially associated with the risk of activation of coagulation and fibrinolysis during menstruation (10). Yoo et al (11) also presented a case of a patient with diffuse adenomyosis with DIC followed by acute renal failure. Massive blood transfusion and hysterectomy were necessary to achieve successful hemostasis (11). Zhang et al (12) reported a rare case of adenomyosis with acute DIC following dilation and curettage for missed abortion. Uterine tissue injury following dilation and curettage for missed abortion can lead to the development of DIC through tissue damage, bleeding, degeneration, necrosis, thrombus formation, coagulation system activation, coagulation factor depletion and hyperfibrinolysis (12). It could be managed successfully with tranexamic acid, blood transfusions and subtotal hysterectomy (12). Son et al (13) reported a case of acute kidney injury resulting from menstruation-related DIC in a patient with diffuse adenomyosis treated for primary infertility. A 40-year-old woman who had received gonadotropin for ovulation induction therapy developed renal dysfunction and DIC (13). DIC may be triggered by the activation of the coagulation system due to myometrial injury resulting from heavy intra-myometrial menstrual flow by gonadotropins (13). In 2002, Nakamura et al (14) also reported that local hemorrhage, blood vessel injury and subsequent thrombosis in the myometrial lesions of diffuse adenomyosis may play a crucial role in the pathophysiology of a rapid progression of DIC. Ohashi et al (15) presented a case of a 51-year-old woman with adenomyosis with hemolytic anemia, DIC and acute renal failure after 6 months of gonadotrophin-releasing hormone (GnRH) antagonist treatment. Nishino et al (16) presented a case of a 37-year-old woman with nulliparous adenomyosis who developed massive AUB during dienogest therapy. Hemostasis was successfully achieved using balloon tamponade to prevent severe uterine bleeding (16). AUB caused by dienogest may occur from fragile and leaky endometrial vessels (17). Yagi et al (18) also presented a case of a 57-year-old woman with hemorrhagic shock and cardiopulmonary arrest caused by massive AUB from diffuse adenomyosis. She had very large adenomyosis with a diameter of 22x20x16 cm and was treated with dienogest therapy (18). Moreover, Takamura et al (7) presented a case of a 45-year-old woman who necessitated a surgical management (i.e., emergency hysterectomy) due to refractory hemorrhagic shock occurred during dienogest therapy for adenomyosis. The patient was commenced on dienogest following 6 months of GnRH antagonist. At 9 months after commencing dienogest therapy, it caused a life-threatening massive AUB. Surgical intervention successfully controlled massive AUB (7).
Taken together, eight cases of adenomyosis with DIC have been reported since 2002. Patients with extensive adenomyosis are sometimes at a risk of developing a life-threatening massive AUB or DIC. Surgical procedures (e.g., dilatation and curettage) and pharmacological interventions (e.g., gonadotropins and progestin-only pill) can cause vascular injury, local microthrombosis, systemic coagulopathy and hemostastic abnormalities, and ultimately, life-threatening DIC and further massive AUB (15,19). Several studies have reported the risk of developing massive AUB in patients with adenomyosis treated with a dienogest-based regimen (7,16-18,20). Of note, even women with diffuse adenomyosis, but without overt clinical manifestations already bear high levels of blood markers reflecting the activation of coagulation and fibrinolysis (10). Abnormal blood vessels in diffuse adenomyosis create a rich uterine vasculature and enter the eutopic endometrium (17). Adenomyosis creates an abnormal vascular structure and a network characterized by fragile and leaky blood vessels (4,17,21). Therefore, some diffuse adenomyosis, consisting of a large number of immature blood vessels, may have a high risk of developing DIC.
Reviews of the literature on adenomyosis-associated thromboembolism
A search of the association between thromboembolic events and adenomyosis was then performed, and the sites of thromboembolic events, etiology and risk factors are reported. The clinical information is summarized in Table II. Some case reports on the topic are presented below.
Hong et al (22) reported 5 patients with adenomyosis who developed pulmonary thromboembolism and/or deep venous thrombosis. However, there were no significant differences in the clinicopathological characteristics between VTE and non-VTE patients; thus, it was unclear whether there was a causal association between adenomyosis and thromboembolism (22). Some patients with adenomyosis with a history of cerebral infarction or pulmonary thromboembolism have been shown to have elevated levels of plasma TAT, SF, D-dimer and PIC, suggesting an increased predisposition to thromboembolic events (10). Kimura et al (23) also presented a rare case of adenomyosis causing the activation of the coagulation system following a complete loss of the endometrium following microwave endometrial ablation. The authors of that study suggested that the formation of microhemorrhage within adenomyotic lesions ws associated with elevated serum levels of the TAT complex and SF, reflecting a hypercoagulable state (23). Yamashiro et al (24) reported four cases of middle-aged women with adenomyosis with concomitant acute cerebral infarction. In addition to cerebral infarction, imaging analyses revealed multiple thromboembolisms in the fingers, kidneys, brachiocephalic trunk and left subclavian artery (24). Increased tissue factor (TF) expression levels, increased mucinous tumor marker levels (e.g., CA125 and CA19-9), and/or menstruation-related coagulopathy were commonly observed in these patients (24). Cancer-associated thrombotic events are well known as Trousseau's syndrome. However, no malignant tumors other than severe adenomyosis were found. Certain benign adenomyotic cells are associated with a hyperviscosity nature and hypercoagulable state due to upregulation of mucinous tumor markers and TF (24). Yamashiro et al (25) reported a 42-year-old woman with adenomyosis who presented with acute cerebral infarction in the left frontal lobe and right parietal lobe with motor aphasia. A hyperviscosity nature and hypercoagulable state may be associated with diffuse adenomyosis, accompanied by the production of mucinous tumor marker, such as CA125 (1750 U/ml) (25). Hijikata et al (26) presented a case of a 59-year-old woman with adenomyosis with multiple cerebral infarctions. She had long been maintained on combined estrogen-progestin hormone replacement therapy for 10 years for the treatment of menopausal symptoms (26). A laboratory examination revealed an elevated serum CA125 level (334.8 U/ml) (26). Aiura et al (27) reported the case of a 48-year-old woman with middle cerebral artery occlusion and recurrent cerebral infarction caused by adenomyosis progression. She was successfully treated with catheter-directed mechanical thrombectomy and by hysterectomy (27). Kim et al (28) reported a case of multiple infarctions, including the bilateral cerebellum and the right precentral gyrus associated with non-bacterial thrombotic endocarditis (NBTE) in a patient with adenomyosis. NBTE is associated with a hypercoagulable state and an inflammatory response and often accompanies cancer (28). An adenomyosis-related hypercoagulable state can lead to multiple infarctions with NBTE. Yin et al (29) summarized three cases with adenomyosis who developed acute ischemic stroke during menstruation. These patients were also accompanied by NBTE (29). Elevated levels of CA125, CA19-9 and D-dimer have been observed only during menstruation (29). Mechanisms, such as mucin protein-related hyperviscosity and hypercoagulability increase the risk of thrombosis formation (29).
Taken together, 18 cases of adenomyosis with thromboembolisms have been reported since 2012. The number of reported cases is limited (24); however, adenomyosis causes serious thromboembolism, including multiple cerebral infarctions. Diffuse adenomyosis, elevated levels of mucinous tumor markers, CA125 and CA19-9, and coexistence of NBTE may be at increased risk of developing thromboembolism (23-32).
Mechanisms underlying the pathogenesis of DIC and thromboembolism in adenomyosis
Heavy menstrual bleeding is one of the most common clinicopathological characteristics of women with adenomyosis (33). Although adenomyosis and endometriosis are both characterized by ectopic endometrial glands and share a similar clinical presentation, patients with adenomyosis have a unique symptom, such as AUB and hypercoagulability. Common patterns of aberrant gene expression, including KRAS mutations, increased estrogen biosynthesis, progesterone resistance and inflammation, have been reported both in adenomyosis and endometriosis (34), suggesting that gene expression profiles are similar in the early stages of disease onset. However, endometrial cells in adenomyosis markedly alter the gene expression patterns during adapting to ever-changing host environments, such as tissue injury, repair, and remodeling. Xiaoyu et al (5) identified the patterns of differentially expressed proteins between adenomyosis and endometriosis using a proteomic approach coupled using mass spectrometry. The proteomics analysis revealed that the most significantly enriched protein pathway in adenomyosis was coagulation cascades, while endometriosis was tightly associated with chronic inflammation (5). This indicates that the coagulation system is closely involved in the pathophysiology of established adenomyosis. As evidence, patients with adenomyosis during menstruation may have laboratory abnormalities associated with hypercoagulability and excessive hyperfibrinolysis (10,23). Elevated TAT, SF, D-dimer and PIC levels in patients with adenomyosis reflect a hypercoagulable and hyperfibrinolytic condition (10,23). In addition, patients with adenomyosis had prolonged activated partial thromboplastin time and a shortened thrombin time than those with uterine fibroids, indicating that adenomyosis affects the hemostatic system (19). These hemostasis abnormalities suggest a potential anti- or pro-thrombotic state in this pathology and predispose patients to bleeding and thrombotic complications.
In addition, adenomyosis is a progressive disease involving pathological angiogenesis and, unlike normal uterine vessels, increases uterine vascularity due to the abundant blood vessels penetrating within the myometrium (6,35). Recently, Stratopoulou et al (36) reported that the total number of adenomyotic vessels was significantly higher in lesions than in the healthy endometrium, and fewer vessels were surrounded by α-smooth muscle actin. This suggests structural abnormalities of the normal vasculature that is composed of endothelial cells, smooth muscle cells and fibroblasts. Therefore, the vasculature of adenomyosis is morphologically abnormal and characterized by the development of leaky, fragile and easily rupturing new vessels (6). Similarly, the tumor vasculature is also characterized by immature, leaky, tortuous, dilated and fragile vessels, and the loss of hierarchical architecture and is known to cause spontaneous hemorrhages (8). These data indicate that the blood vessel formation of adenomyosis may be regulated through a mechanism similar to the carcinogenesis theory, affecting angiogenesis and vasculogenesis (6). Indeed, increased microvascular density (MVD) and higher vascular endothelial growth factor (VEGF) expression have been shown in the endometrium of patients with adenomyosis as compared with the normal endometrium of women without disease (6) (Fig. 2). Pro-angiogenic markers [e.g., TF, VEGF, von Willebrand factor and nuclear factor-κB (NF-κB)] have also been shown to be higher in the adenomyosis than the control group, and to be positively associated with the amount of bleeding (6,37). The angiogenesis-related genes and their multiple signal pathways, such as VEGF, TF, matrix metalloproteinase (MMP)-2, MMP-9 and cyclooxygenase-2 are downstream targets for NF-κB in adenomyosis (6,38). NF-κB regulates the expression of a number of molecules and pathways responsible for angiogenesis, cell invasion, proliferation, anti-apoptosis and impaired cytokine expression (6). The abnormal dysregulation of NF-kB is considered to be a hallmark of adenomyosis (6). Furthermore, endothelial nitric oxide synthase (eNOS) is highly expressed in the endometrial and myometrial tissues of women with adenomyosis-related heavy menstrual bleeding (39,40). Nitric oxide (NO) synthesized in endothelial cells by eNOS may cause AUB possibly through the vascular relaxation and platelet aggregation inhibition (39,40). Therefore, repeated microbleeding episodes from fragile and more permeable vessels within the adenomyosis lesions may trigger activation of the TF and VEGF-dependent coagulation pathways through tissue damage (10,14,29). Furthermore, the persistent activation of the coagulation cascade can lead to massive AUB and life-threatening DIC.
On the other hand, endometriotic cells that are abundant in diffuse adenomyosis produce excessive CA125 and CA19-9 during menstruation (10,25,29). Indeed, markedly elevated levels of CA125 and CA19-9 hare detected most often in patients with adenomyosis who develop multiple thromboembolisms during menstruation (10,25,29). Members of the mucin family glycoproteins, CA125 and CA19-9, are relatively large molecules that can increase blood viscosity. The entry of CA125 and CA19-9 into the systemic circulation leads to blood hyperviscosity (10,25,29). The hyperviscosity is a risk factor for hypercoagulability and predisposes patients to thrombosis. Therefore, elevated levels of these tumor markers may be associated with an increased risk of the development of thrombosis. Furthermore, the hypercoagulable state and the hyperviscosity nature are likely to be associated with a risk of the development of NBTE (41). The ability of diagnosis and management of adenomyosis-related hemostasis abnormalities is important in reducing life-threatening complications, such as DIC and thromboembolism.
Discussion
The present systematic review summarizes the clinical features, risk factors and potential mechanisms of severe hemorrhagic and thrombotic events associated with adenomyosis. DIC and thromboembolism are rare, yet life-threatening complications in adenomyosis. The clinical characteristics and risk factors for adenomyosis-associated DIC and thromboembolism are summarized in Table III. That is, clinical features, such as adenomyosis phenotypes (e.g., diffuse or type 1) may increase the risk of developing severe hemorrhagic events, while a marked increase in mucinous tumor markers may confer the risk of developing severe thrombotic events. In addition, adenomyosis-specific abnormal blood vessels can cause thrombo-hemorrhagic events, but they are clinically undetectable until surgical procedures are performed. More specifically, the pathophysiology of adenomyosis-associated thrombo-hemorrhagic events could be related to disease-specific endogenous risk factors and exogenous factors such as current therapeutic strategies. Examples of the former include changes in the gene and protein expression patterns related to the coagulation and fibrinolysis systems, abnormal vascular distribution and network formation, a marked elevation in serum mucinous tumor markers, and subtypes of adenomyosis, while examples of the latter include treatment with progestin-only pill or dilation and curettage for abortion. In particular, the extent and subtype of adenomyosis lesions are the most clinically influential factors in predicting the onset. Adenomyosis is composed of multiple heterogeneous subtypes. Types I (intrinsic) and II (extrinsic) consist of adenomyosis that occurs in the uterine inner and outer layer, respectively (42). Immature and fragile blood vessels penetrate the endometrial-myometrial barrier in type I adenomyosis (17). Moreover, Turner et al (43) suggested that ‘impaired venous drainage and endometrial vascular ectasia, secondary to increased intramural pressure’ can cause AUB in diffuse adenomyosis. Therefore, adenomyosis-specific angiogenesis, increased MVD and morphologically abnormal blood vessels with leaky and fragile features are considered to cause vascular damage, leading to the extravasation of blood, damage to surrounding tissue, and subsequently, to thrombo-hemorrhagic events (43). In patients with diffuse or type I adenomyosis, surgical procedures, such as dilatation and curettage for abortion and pharmacological interventions, such as gonadotropins and progestin-only pill, may be a potential risk factor for massive hemorrhage and life-threatening DIC. Additionally, markedly elevated levels of mucinous tumor markers, CA125 and CA19-9 during menstruation may pose as risk factors for thromboembolism. The fragile blood vessels in adenomyosis can lead to massive uterine bleeding during menstruation, while locally produced pro-angiogenic factors, coagulation-related factors and mucins may cause hypercoagulability and hyperviscosity, leading to thrombosis. The clinical manifestations are secondary to different conditions, such as structural vascular abnormality, a hyperviscosity state, or a hypercoagulable state, and range from asymptomatic and sub-clinical illness to severe, life-threatening DIC and thromboembolism.
| Table IIIThe clinical characteristics and risk factors for adenomyosis-associated DIC and thromboembolism. |
Finally, based on the present systematic review, future directions of diagnostic and therapeutic strategies for the field are explored. As a first step towards clinical diagnosis, it is crucial to distinguish focal and diffuse adenomyosis or type I and type II adenomyosis through the assessment of transvaginal ultrasound. In patients with type I adenomyosis, the damaged microvessels are contiguous with endometrial stromal cells at the inner myometrium and endometrium (17). Blood vessels in patients with diffuse adenomyosis demonstrate a morphologically and functionally abnormal phenotype that includes leaky, fragile and easily rupturing vessels (6). Therefore, type I and diffuse adenomyosis may be associated with severe unpredictable bleeding (17). Microvascular damage induced by surgical procedures or hormonal treatment in these patients can contribute to excessive bleeding. Moreover, CA125 and CA19-9 are mucin glycoproteins produced by endometrial cells. Diffuse adenomyosis is particularly rich in endometrial cells and is considered to be more likely to produce these mucins. Elevated levels of mucin protein (CA125 and CA19-9)-related hyperviscosity and hypercoagulability increases the risk of thromboembolism in women affected by extensive adenomyosis (24,29). Additionally, estrogen is generally considered to induce the activation of coagulation (e.g., factors II, VII, IX, X and XII, and protein C) and fibrinolysis (e.g., plasminogen) genes that play roles in coagulation, fibrinolysis and inflammation (44). However, it is currently unknown when and how these genes and proteins are regulated in adenomyosis lesions. Collectively, patients with diffuse or type I adenomyosis may develop AUB/DIC or thromboembolism; thus, specific attention should be paid to surgical and hormonal therapy.
Acknowledgements
The author would like to thank Mrs. Toyomi Kobayashi (Clef Co., Ltd., Nara, Japan) for generating all the figures.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Author's contributions
HK performed all of the following regarding the preparation of this manuscript: Conception and design, acquisition of data, analysis and interpretation of data, and writing the manuscript. HK confirms the authenticity of all the raw data. The author has read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The author declares that he has no competing interests.
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