Adrenal hemorrhage following direct oral anticoagulant (DOAC) therapy: two case reports and literature review

Adrenal hemorrhage(AH) is considered a rare but potentially lethal condition that can occur in both traumatic and non-traumatic conditions [1]. Formerly, AH was mostly diagnosed during post-mortem examinations, with incidence rates ranging from 0.14% to 1.1% [1‐4]. Due to tremendous advancements in imaging technology, AH is now diagnosed with a higher frequency in hospitalized patients, ranging from 1.5% to 5% [1, 5, 6].

Factors that may lead to AH include focal adrenal lesions, abdominal trauma, anticoagulation therapy, congenital or acquired bleeding disorders, sepsis, and pregnancy [1, 7, 8]. AH can be presented in asymptomatic settings to fatal conditions, mostly resulting from bilateral AH [8, 9]. It has been revealed that bilateral AH through adrenal insufficiency (AI) induction can be detrimental. A key difference between unilateral and bilateral AH is that the former is mostly biochemically silent, while the latter is potentially fatal [10, 11].

Anticoagulation options have rapidly expanded over the last decade, with the United States Food and Drug Administration (FDA) approval of the first direct oral anticoagulant (DOAC) in 2001, rivaroxaban in 2011, apixaban in 2012, and edoxaban in 2015 [12, 13]. Compared to vitamin K anticoagulants (VKA), DOACs have fewer interactions with medications and diet, have a more stable pharmacokinetics profile, and do not require routine laboratory monitoring. These findings led to the replacement of DOACs with VKA [14].

Herein, we reported for the first time a case of unilateral AH attributed to apixaban treatment in a newly diagnosed patient with previously confirmed autoimmune Addison disease (AAD) and the second case of bilateral AH following administration of rivaroxaban in an elderly woman.

In a PubMed search, we searched for articles published between January 2000 and February 2021 containing the keywords "autoimmune Addison disease and adrenal hemorrhage", "DOAC".

treatment and adrenal hemorrhage", "adrenal insufficiency and adrenal hemorrhage", and "AH and long-term AI as well as "AH and autoimmune polyendocrine syndrome type 2". A comprehensive review of all relevant studies was conducted, and all references were manually checked for additional studies that may have been relevant.

Here, we report two cases of AH post-DOAC prophylaxis. It is a novel case of unilateral AH caused by apixaban usage in a patient with newly diagnosed AAD. An APS-2 diagnosis was made that included Hashimoto hypothyroidism as well. In another case of bilateral AH after prophylactic rivaroxaban usage, the patient developed AI, which persisted during 3 months follow-up.

AH is a rare medical emergency, with an incidence rate of 0.14%-1.1% reported in some of the largest (> 25,000 cases) autopsy series [1‐4, 15]. Several underlying stress conditions can cause non-traumatic AH, such as sepsis, pregnancy, post-abdominal surgery, anti-phospholipid syndrome, and, in rare cases, anticoagulation therapy [2, 16‐20]. Bleeding is a potential risk associated with every anticoagulant medication and is the most common side effect of these medications, leading to hospitalizations and deaths [12, 21].

The most similar case to ours in the search for the etiology of AH is an article by Zachary Sanford et al. [22]. It described a case of AH in a patient with APLS who had previously been on warfarin prophylaxis, with reoccurring AH presented with right flank pain followed by retinal hemorrhage precipitated during a transition from warfarin to apixaban. It is noteworthy that this is the only case reported in which a unilateral AH occurred in a patient receiving apixaban anticoagulation [22]. We reported here the second unilateral AH due to apixaban use that was accidentally detected in CT of adrenal glands in a newly diagnosed patient with AAD and probable adrenocortical atrophy.

Clinical suspicion and prompt diagnosis of bilateral AH are clinically vital because 16–50% of patients with bilateral AH eventually develop life-threatening AI [1, 23]. CT scans with and without IV contrast or MRI with Gadolinium are commonly used to diagnose AH [24, 25].MRI is more accurate than other imaging modalities in diagnosing adrenal hematoma, and it may also differentiate between subacute and chronic hemorrhage [25, 26]. In our case with AAD, Hashimoto thyroiditis, and APS-2, the patient had left adrenal thick wall cystic mass with the enhanced peripheral rim on CT scan imaging, which suggests adrenal masses or AH. MRI findings in our case include an oval shape well-encapsulated cystic mass 20 × 14 mm with a thick and low signal intensity rim in the left adrenal gland. This mass was high signal intensity on both T1 and T2 weighted images, the findings suggestive of sub-acute AH [27].

Primary AI is the result of partial or complete bilateral adrenal cortex destruction leading to deficiency of all adrenocortical hormones (also known as AD). Tuberculosis was the most common cause of AD in the first half of the twentieth century, but AAD has recently overtaken it[23]. In patients with APLS, AH is a relatively uncommon cause of AD as a result of bilateral AH [7, 23, 28].

Diagnosis of AH is difficult due to the nonspecific clinical presentation. Therefore, having a high level of clinical suspicion plays a crucial role in facilitating an earlier diagnosis and avoiding undesirable outcomes. These signs and symptoms include pain in the back or flanks, nausea, vomiting, hypotension, and fever [29‐31]. Our patient with AAD and unilateral AH had no symptoms related to unilateral AH excluding loss of appetite, nausea, vomiting, and buccal hyperpigmentation, which were more likely to be caused by deficiency of adrenocortical hormones. To the best of our knowledge, no other case of AAD associated with autoimmune polyendocrine syndrome type 2 (APS-2) before AH diagnosis has been reported. APS-2 is the most common autoimmune polyendocrine syndrome [32]. A hallmark of this condition is its combination of autoimmune AD with thyroid autoimmune disease and/or type 1 diabetes mellitus [32]. Similar to our first case, AD and Hashimoto thyroiditis (Schmidt syndrome) are the most common clinical combinations [32]. The presence of 21-hydroxylase autoantibodies (21OHAb), is used as a confirmation test for the diagnosis of AAD [33]. One of the limitations of our study is the country's limited access to antibody tests, which made it difficult to confirm the diagnosis based on laboratory autoimmune tests.

Due to their stable pharmacokinetic profile and fewer interactions with other medications and diets, DOACs currently do not require routine laboratory monitoring. As a result, DOACs have supplanted VKA as the first-line anticoagulant in international guidelines for managing and preventing thrombotic diseases [12‐14, 34]. Because routine coagulation tests cannot be used to determine the degree of anticoagulation in individuals receiving a DOAC, managing bleeding can be challenging [12].To the best of our knowledge, only five cases of AH have been reported as a result of the use of the latest anticoagulant drugs (Table 3). Four with the use of rivaroxaban [10, 35‐37], and only one through the use of apixaban [22] prophylactic treatment. However, all of the evaluated cases demonstrated AI as a result of bilateral AH. Although bilateral AH is more commonly associated with AI, the contralateral adrenal gland may become "exhausted" in unilateral AH [15]. This may result in hypocortisolemia due to decreased cortical lipids, as demonstrated in a case presented by B.Ly [37], a case of unilateral AH with confirmed AI in the laboratory test. Two of these four were under prophylactic anticoagulation following knee surgery in the patients [10, 37], and the rest were due to APLS [35, 36]. Our second case was similar to the mentioned cases because AH also occurred following rivaroxaban treatment after femur fixation surgery. In addition, she had bilateral AH, which could lead to AI.

DOACs have shown equivalent or greater efficacy and safety compared to vitamin K agonists or enoxaparin in frail or elderly subjects and after orthopedic surgeries [12]. However, because DOAC antidotes (idarucizumab for reversal of dabigatran, and andexanet alfa for reversal of the direct FXa inhibitors apixaban and rivaroxaban), are not available in our country, the elderly woman with a femoral neck fracture, was not a good candidate for DOAC agents; instead, warfarin or low molecular weight heparin (LMWH) agents with available antidotes might be a better prophylactic treatment [13, 21].

In patients with bilateral AH, the long-term follow-up of glucocorticoid and mineralocorticoid function has been assessed in only a few articles [38‐43]. After a follow-up of four patients up to 19 years with acute bilateral AH and glucocorticoid insufficiency, the researchers showed the absence of need for long-term mineralocorticoid replacement. They also demonstrated the improvement in serum cortisol levels in three of the four patients and the ability of one case to function normally without cortisol replacement for 4 years. In our second case with bilateral AH, we found the need for continued adrenocortical replacement therapy after three months of follow-up.

As a limitation, we did not perform an adrenocorticotropic hormone stimulation test in our cases for confirmation of AI, however, according to the guideline released by “Endocrine Society Clinical Practice Guideline “If a corticotropin stimulation test is not feasible, using morning cortisol < 5 μg/dL in combination with high ACTH ( i.e. > twofold upper limit of the reference range) is suggestive of adrenal insufficiency [44]. Moreover, as suggested by many authors [23, 45] morning cortisol concentrations lower than 3 μg/dL are strongly predictive of adrenal insufficiency. In both of our cases with AI, the levels of cortisol were less than 1.5 μg/dL and the value of ACTH levels were more than 3 folds of the upper limits of the normal range.

In the current study, we presented two cases of AH caused by DOAC use. The first unilateral AH occurred after the therapy with apixaban in a newly diagnosed patient with AAD and the second one was a bilateral AH that occurred after the prophylactic therapy with rivaroxaban following femur fixation surgery. Any patient with any medical background might adversely develop side effects like AH when treated with DOACs, even patients that are low risk such as the young 35-year-old patient that was presented in case 1. probable adrenocortical atrophy.