Bilateral adrenal haemorrhage in antiphospholipid syndrome and a short review of the literature

Discussion

Described above is a unique example of a woman presenting with initially believed to be trauma-induced left adrenal haemorrhage but then found to have delayed right adrenal haemorrhage. Work-up revealed triple positivity for APS, and the patient was initiated on anticoagulation. Bilateral adrenal haemorrhage in and of itself is a relatively uncommon diagnosis, found in only 22 of 2000, or 1.1%, of patients at autopsy.1 In fact, it is far from being the most common presentation of APS, which more typically presents with deep vein thrombosis (DVT), livedo reticularis or pulmonary embolism (PE).2 Less frequently, thrombosis of the hepatic vein can result in Budd-Chiari syndrome, cerebral thrombosis resulting in intracranial pathology and arterial thrombosis resulting in infarction of downstream organs.2

Bilateral adrenal haemorrhage is not an unheard-of complication of APS, as described in the case report scenarios below, although it is extremely rare. Patients who already have a known diagnosis of APS have subsequently developed adrenal haemorrhage, potentially due to subtherapeutic levels of anticoagulation or medication non-compliance.6 7 Another patient was diagnosed with bilateral adrenal haemorrhage only days after having had a DVT and PE diagnosed, developing signs of shock secondary to AI.8 In fact, it seems a fair amount of patients subsequently found to have bilateral adrenal haemorrhage initially present with signs and symptoms of shock related to AI prior to imaging being obtained, as was one patient presenting with postural hypotension, decreased appetite and fatigue.9 Patients with previous thrombotic events in the setting of rheumatological or endocrinological diseases, such as systemic lupus erythematosus (SLE), may be subsequently diagnosed when anticoagulation is discontinued and results in further thrombotic morbidity, including adrenal haemorrhage.10 In contrast, our patient presented initially with bilateral adrenal haemorrhage rather than another form of a thrombotic event, AI or having been diagnosed previously with a hypercoagulable state, which prompted a further investigation into APS being a possible culprit.

One study involving a cohort of 1000 patients diagnosed with APS discovered only 0.4% (four patients) developed AI as a result of their thrombotic disease, although adrenal haemorrhage was not investigated.11 In one literature review performed of 86 patients diagnosed with primary AI and APS, the primary image finding in 59% of patients was adrenal haemorrhage, although laterality was not discussed.12 A retrospective study of 16 patients diagnosed with bilateral adrenal haemorrhage and AI secondary to APS at a Parisian hospital noted that only 5 patients (31%) had this as the initial manifestation of APS, compared with the remaining 11 patients (69%) who had been previously diagnosed with APS.13 In this study, the median interval between diagnosis of APS and onset of adrenal disease was approximately 5 years, with 10 of these patients having an inciting factor involving pregnancy, infection/inflammation or surgery.13

APS typically presents in association with another underlying medical condition, most commonly rheumatological conditions such as SLE or rheumatoid arthritis, and is defined as secondary APS in these cases. Primary APS, as in our patient, requires an initiating event, usually in the form of infection, overwhelming oxidative stress, surgery or blunt trauma that results in the exposure of endothelial phospholipids, causing antigen formation and subsequently the creation of antibodies.2 In women of childbearing age with associated antibodies, their risk of recurrence of adverse gestational events is about 80%.3 Notably, compared with genetic thrombophilic disorders, APS can present with a combination of arterial and venous thrombosis such that random, unexpected occurrences of either type of clotting warrant evaluation for APS.14

Diagnosis, based on the former ‘Sapporo’ (1999) and then the more recently updated ‘Sydney’ (2006) criteria, requires one laboratory criterion—a positive LA, b2GPI or aCL antibody being present. Additionally, one clinical criterion within a 5 years interval also needs to be present which includes a thrombotic event proven on imaging or histopathology or gestational morbidity.3 14 Pregnancy morbidity is typically defined as one or more unexplained deaths of a normal foetus beyond 10 weeks gestation, premature birth of a morphologically normal neonate prior to 34 weeks gestation due to placental insufficiency or pre-eclampsia/eclampsia, or three or more unexplained spontaneous abortions prior to 10 weeks gestation with other causes excluded.15 Catastrophic antiphospholipid antibody syndrome (CAPS) is defined as small vessel thrombosis in three or greater organs occurring within less than 1 week in the presence of anti-phospholipid antibodies, with histopathological evidence of small vessel thrombosis in the absence of inflammation.14 Occurring typically in the setting of overwhelming infection, mortality approaches 50% due to the multiorgan involvement, namely cardiac and cerebral infarction.14 The patient described in this case, fortunately, did not meet CAPS criteria, as histopathological evidence was not obtained and less than three organ systems were involved.

In regards to the laboratory criteria, two positive antibody laboratory test results should be obtained 12 weeks apart from one another, as transient conditions, such as infections/sepsis, can result in positive antiphospholipid (aPL) titers that are not associated with thrombosis or clinically significant.3–5 16 While LA is the most specific antibody when considering testing for APS, it can result in a false positive if obtained while on most anticoagulants. Importantly, aCL is the most sensitive, as it is not affected by concurrent anticoagulant therapy.3 Triple positivity, meaning the patient has consistently positive LA, b2GPI and aCL antibodies (collectively known as aPL antibodies) denotes a higher risk of recurrent thrombotic/obstetric events.4

There are significant cut-offs in regards to the titers, with moderate-to-high titers (typically at the 99th percentile) indicating a positive test, with lower titers otherwise not indicative of significant antibody presence.16 Historically, unfractionated heparin, often used in IV formulation for anticoagulation while the patient is bridged to other therapy, also alters LA results transiently, leading to false positive results.17 In patients with primarily elevated LA, if deemed necessary and safe, discontinuation of Vitamin K antagonist (VKA) therapy prior to retesting of LA can reduce interference that a therapeutic INR can have on this lab test.17 Traditionally, patients are bridged from heparin or low-molecular weight heparin (LMWH) therapy to warfarin, a VKA, with a goal INR of 2–3.16

It is important to recognise subsets of APS depending on the primary morbidity event, such a venous versus arterial thrombosis or pregnancy morbidity.16 In pregnant patients with diagnosed APS, the HepASA Trial is one of multiple emerging trials which revealed that aspirin (ASA) alone was non-inferior to ASA/LMWH combotherapy in this particular patient population, with no difference in live birth rates between the two groups.18 In patients with arterial thrombosis, consensus discussions and recommendations derived by the 13th Congress on Antiphospholipid Syndrome have promoted either antiplatelet therapy, such as clopidogrel or ASA, or VKA therapy being used.19

In recent years, attempts have been made to trial patients diagnosed with APS on a direct oral anticoagulant (DOAC) rather than VKA therapy, due to convenience mainly stemming from lack of laboratory monitoring.20 The Rivaroxaban in Antiphospholipid Syndrome is a randomised control trial (RCT) completed within the last decade that attempted to assess the mechanism of action of VKA and DOAC therapy rather than clinical safety or efficacy. Recurrent thrombosis, however, was similar between the VKA therapy group and that of rivaroxaban, and quality of life subjectively measured by the data collectors was significantly better in the DOAC group.20 The Trial on Rivaroxaban in Antiphospholipid Syndrome (TRAPS) RCT was conducted in patients who were triple-positive with the goal of evaluating whether or not rivaroxaban was non-inferior to warfarin in this higher-risk population.21 22 This particular trial was terminated early as patients on rivaroxaban therapy experienced a higher rate of arterial thromboembolic events such as ischaemic stroke or myocardial infarction.21 22 Similar to the TRAPS trial, the Rivaroxaban versus Vitamin K Antagonist in Antiphospholipid Syndrome trial, performed in Spain, failed to demonstrate rivaroxaban non-inferiority when compared with VKA therapy in triple-positive APS patients, with more thrombotic events occurring in the patients randomised to the rivaroxaban group.23 These two trials continue to illustrate that VKAs remain the standard of care in triple-positive APS patients.