Association Between Systemic Amyloidosis and Intracranial Hemorrhage

Isolated amyloid deposition in the brain in the form of amyloid Aβ, as seen in cerebral amyloid angiopathy, is associated with intracranial hemorrhage.¹ Systemic amyloidosis is caused by the deposition of insoluble amyloid fibrils, mainly amyloid light-chain, or hepatic-derived transthyretin, in the extracellular space of tissues, which leads to progressive organ failure and death.² Animal studies suggest that peripheral administration of misfolded amyloid aggregates contribute to the transmission of cerebral amyloid pathology.³ It is, however, unknown if systemic amyloidosis increases the risk for intracranial hemorrhage.

Data supporting this study will be available upon approval by the Center for Medicare Services. This study was approved by the Weill Cornell Medicine institutional review board which provided an exemption for informed consent of this deidentified data set.

We used a 5% sample of Medicare claims data from 2008 to 2015. Our exposure variable was a diagnosis of systemic amyloidosis. Our primary outcome was nontraumatic intracranial hemorrhage, a composite of intracerebral hemorrhage, subarachnoid hemorrhage, and subdural hemorrhage. The exposure and outcomes were identified using International Classification of Diseases, Ninth Revision diagnosis codes (Supplemental Material). Secondary outcomes were the intracranial hemorrhage subtypes, assessed separately. We used hip fracture, a common incident condition among the elderly, as a negative control. Cox proportional hazards models were adjusted for demographics, vascular risk factors, and Charlson comorbidities.

Among 1.8 million Medicare beneficiaries, 924 were diagnosed with systemic amyloidosis (Table S1). During a median follow-up of 5.3 years (interquartile range, 2.8–6.7), the cumulative incidence of intracranial hemorrhage with systemic amyloidosis was 19 per 1000 patient-years versus 2 per 1000 without systemic amyloidosis. In the adjusted Cox model, systemic amyloidosis was associated with an increased risk of intracranial hemorrhage (hazard ratio [HR], 3.0 [95% CI, 2.0–4.5]; Figure). In adjusted secondary analyses, systemic amyloidosis was associated with an increased risk of ICH (HR, 3.5 [95% CI, 2.2–5.4]), subarachnoid hemorrhage (HR, 6.7 [95% CI, 4.0–11.4]), and subdural hemorrhage (HR, 2.7 [95% CI, 1.5–4.8]). There was no association between systemic amyloidosis and hip fracture (HR, 0.9 [95% CI, 0.6–1.4]). Additional analyses are shown in the Supplemental Material.

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In a large, heterogeneous cohort of Medicare beneficiaries, we observed an estimated 3-fold increased risk of intracranial hemorrhage after a diagnosis of systemic amyloidosis. Importantly, this elevated risk was present in all intracranial hemorrhage subtypes. Possible mechanisms include increased peripheral deposition of amyloid leading to decreased central nervous system clearance and subsequent accumulation within the brain⁴; and direct hematogenous spread of systemic amyloid to the brain⁴; suggesting a close link between systemic amyloidosis and central amyloid deposition. While further research is warranted, clinicians should be aware of this heightened intracranial bleeding risk, especially in the context of prescribing antithrombotic drugs.

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Supplemental Material

Supplemental Methods

Table S1

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