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.