**4.2 Adrenal hemorrhage**

AH is a potentially devastating complication of aPL due to the resulting adrenal insufficiency. AH represents an infrequent cause of adrenal insufficiency, and besides aPL, it can be caused by other disorders, namely adrenal tumors and anatomical malformations, infections, and bleeding disorders (thrombocytopenia, heparin exposure) [59]. AH is a rare complication of aPL with its prevalence not precisely established. However, a significant proportion - one third - of affected patients have CAPS. The incidence in this subgroup is thus relatively high, between 10 to 16% [56]. A provoking moment usually initiates aPL-induced AH. Trauma, invasive procedures, infections, and warfarin withdrawal have been identified as such moments [60].

The main pathomechanism in aPL-induced AH, supported by the autopsy evidence, is multiple thromboses in the adrenal plexus leading to the secondary hemorrhage and destruction of the adrenal cortex. Due to its unique vascular anatomy (complex arterial system with three supplying arteries, rich vascular plexus in the zona reticularis, single drainage vein), the adrenal gland is prone to develop intraparenchymal hemorrhage in a case of venous obstruction. Vasculitis has not been found in aPL-induced AH [61].

AH usually manifests with back pain. Symptoms related to acute adrenal insufficiency (hypotension, malaise, fever, altered mental status, gastrointestinal symptoms including nausea, vomiting, and diarrhea) complement the clinical picture. Apart from the chronic adrenal insufficiency, skin hyperpigmentation is not present in the aPL-induced AH [59].

Laboratory tests and radiological imagining studies are critical for the confirmation of AH. Decreased cortisol levels and the lack of increase in cortisol levels after an adrenocorticotropic hormone stimulation test represent a typical laboratory finding. Abdominal contrast CT is the standard imagining method. However, CT has its limits, and if performed in the early phases of the bleeding, it may be falsely negative. A repeated CT scan is a must in the case of high clinical suspicion despite an initial negative result. Abdominal magnetic resonance is an alternative imagining method with the best imaging of the adrenal glands [62]. If the laboratory and imaging studies are inconclusive, adrenal biopsy remains the definitive diagnostic procedure. However, it is a high-risk procedure in terms of bleeding, and the risk–benefit ratio has to be evaluated individually. As a general rule, adrenal biopsy should be avoided in aPL-positive patients.

Clinical management has two goals: 1) to provide substitution of adrenal hormones, especially glucocorticoids; 2) to prevent further complications of aPL, namely thromboembolism. Since CAPS is a frequent finding in aPL-positive patients with AH, antithrombotics should be administered as long as possible despite hemorrhage. If their withdrawal is necessary, usually due to the extensive bleeding, the restart should be as soon as possible. The clinical experience stresses the critical importance of antithrombotic therapy. The study with aPL-positive patients and AH observed concurrent thrombotic events during the acute phase in 7 (43%) out of 16 participants. Five of 7 patients with confirmed thrombosis were diagnosed with CAPS [60]. Apart from the glucocorticoid substitution due to adrenal insufficiency, immunosuppressives are not a standard part of treatment since the available evidence does not confirm an effect on the clinical outcome [61]. However, their addition, alone or in combination with IVIg and plasma exchange, can be beneficial in the presence of CAPS.

The long-term prognosis of AH is relatively favorable after the acute phase, especially if antithrombotics are uninterrupted. In a review of 62 patients with AH followed for a mean of 25 (2–60) months, 90% (32 out of 35) of anticoagulated patients survived. Interestingly, overall mortality in the study reached 36% (25 out of 69 participants) [61]. Adrenal dysfunction is irreversible in most cases, although occasional recovery remains possible.
