3. DISCUSSION
This report presents a case of IDDVT that was potentially associated with adenomyosis. The patient experienced a thrombotic episode on the first day following long-distance travel, which coincided with her menstrual period. We suggest that the combined effects of hypercoagulability related to adenomyosis and blood stasis from long-distance travel may have contributed to the development of IDDVT. The patient was effectively managed with heparin bridging rivaroxaban and subsequently underwent a hysterectomy at another hospital to reduce the risk of recurrence.
The true incidence of adenomyosis-related thrombotic complications remains uncertain. Ischemic stroke has been observed in 0.1~0.8% of patients with adenomyosis according to early single-center studies.25 Limited data are available regarding other types of thrombotic events. To further investigate this association, we conducted a literature search on PubMed using the terms “adenomyosis” AND (thrombo* OR infarction). This search strategy yielded a total of 22 eligible case or series reports (Table 1), including 25 cases of ischemic stroke,3-206 cases of PE,21, 22 and 3 cases (including the present case) of DVT.23, 24 Most patients were between the ages of 30 and 50, and they tended to experience thrombotic events during their menstrual periods. These findings can be attributed to the estrogen-dependent nature of adenomyosis, which is rarely diagnosed in premenarchal or postmenopausal women.
As summarized in Table 1, both arterial and venous thromboembolism have been documented in patients with adenomyosis. Among these cases, multiple cerebral infarctions were the most frequently observed, accounting for 18 out of 34 cases. Notably, 7 of these cases exhibited systemic embolism,3,4,9,13,15,17 resembling Trousseau’s syndrome commonly seen in cancer patients. These observations suggest that hypercoagulability may play a significant role in the pathogenesis of thrombotic complications related to adenomyosis. Consistent with this speculation, previous studies have identified a procoagulant state in patients with adenomyosis, which is further exacerbated during menstruation and accompanied by activation of fibrinolysis.26
The mechanisms underlying hypercoagulability in patients with adenomyosis may be multiple. First, an early study found increased tissue factor (TF) reactivity in ectopic endometrium obtained from women with adenomyosis compared to normal endometrium, and elevated TF activity was associated with the severity of disease.27 Second, the normal endometrium experiences repeated proliferation, decidualization, and shedding across the menstrual cycle, which is a fine balance between tissue injury and repair tuned by the endocrine, immune, vascular, and coagulation systems.28 However, adenomyosis may disrupt this balance, and the ectopic endometrium and its associated vascular malformations can lead to impaired spontaneous decidualization, resulting in persistent inflammation and hemorrhage, which subsequently triggers the thromboinflammation pathway. Last, it is worth noting that the thickened endometrium during menstruation is rich in mucins, which have been associated with thrombophilia in individuals with mucinous cancer. The endometrium serves as the primary source of CA125 in females, which can rise to 8 times the upper reference limit (35 U/mL) during menstruation and return to baseline at the conclusion of the menstrual cycle.29 In the context of adenomyosis, it is plausible to hypothesize that impaired decidualization may lead to sustained elevation of CA125 levels for prolonged durations, thereby increasing the risk of thrombophilia in these patients. The current case, along with previous reports, provides supportive evidence for this hypothesis. Notably, elevated CA125 levels have been observed in certain patients during their nonmenstrual periods,4,7,8 and in our case, the elevated CA125 level persisted for approximately two months until hysterectomy was performed (see Figure 2).
The association between CA125 levels and the severity of adenomyosis remains uncertain. Nevertheless, a pooled analysis of documented cases3-20 revealed a significant increase in CA125 levels among individuals experiencing recurrent or systemic thromboembolism, in contrast to those with nonrecurrent and isolated embolism (see Figure 3). This preliminary investigation emphasizes the need for further research to establish the potential value of CA125 in the treatment and monitoring of thrombotic complications associated with adenomyosis.
The source of emboli has been investigated in several previous case studies. In a subset of 21 cases with cerebral infarcts, nonbacterial thrombotic endocarditis (NBTE) was detected in 7 cases through transesophageal echocardiography, suggesting the potential presence of cardiogenic emboli. Considering that some cases were reported a decade ago, the postulated incidence of NBTE may be higher under current circumstances due to the use of more sensitive ultrasound technology. To date, there have been 6 documented cases of PE, with 5 originating from a single center in Singapore. Of these, two were complicated by lower extremity DVT, indicating the likelihood of peripheral distal emboli. However, the remaining four cases were diagnosed as isolated pulmonary thrombus, suggesting the possible occurrence of in situ pulmonary thrombus formation due to hypercoagulability. This notion could also explain the manifestation of isolated cerebral vein thrombosis in four women with adenomyosis.5,16,18
Isolated DVT associated with adenomyosis is rare, with only three documented cases (including the present case). It is worth noting that two out of these three cases also presented with other thrombotic risk factors in addition to adenomyosis. Specifically, one case had hyperhomocysteinemia, while our case developed DVT after long-distance travel. These findings underscore the necessity for systematic assessment of thrombotic risk and the implementation of thromboprophylaxis education for patients diagnosed with adenomyosis.
The management of thrombotic complications associated with adenomyosis comprises two essential aspects: anticoagulation therapy during the acute phase of thrombophilia and treatment specifically targeting adenomyosis. Consensus regarding the optimal anticoagulation regimens for thrombotic complications related to adenomyosis is lacking. While conventional anticoagulation therapy has demonstrated efficacy in most patients, a significant proportion of individuals experience recurrence within one month. Further evaluation is needed to assess the potential benefits of escalating anticoagulant dosage or prolonging therapy duration. Additionally, the effectiveness of integrating anticoagulation with adenomyosis treatment to control thrombotic exacerbations or recurrences remains uncertain. Although long-term gonadotropin-releasing hormone agonist (GnRHa) therapy has successfully alleviated symptoms in certain cases, there are patients who still encounter thrombosis or experience recurrence despite undergoing GnRHa therapy.9,14,19 In such cases, hysterectomy is often considered a final option.