Long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis.

BACKGROUND: Antithrombotic (anticoagulant or antiplatelet) therapy is withheld from some patients with cerebral cavernous malformations, because of uncertainty around the safety of these drugs in such patients. We aimed to establish whether antithrombotic therapy is associated with an increased risk of intracranial haemorrhage in adults with cerebral cavernous malformations. METHODS: In this population-based, cohort study, we used data from the Scottish Audit of Intracranial Vascular Malformations, which prospectively identified individuals aged 16 years and older living in Scotland who were first diagnosed with a cerebral cavernous malformation during 1999-2003 or 2006-10. We compared the association between use of antithrombotic therapy after first presentation and the occurrence of intracranial haemorrhage or persistent or progressive focal neurological deficit due to the cerebral cavernous malformations during up to 15 years of prospective follow-up with multivariable Cox proportional hazards regression assessed in all individuals identified in the database. We also did a systematic review and meta-analysis, in which we searched Ovid MEDLINE and Embase from database inception to Feb 1, 2019, to identify comparative studies to calculate the intracranial haemorrhage incidence rate ratio according to antithrombotic therapy use. We then generated a pooled estimate using the inverse variance method and a random effects model. FINDINGS: We assessed 300 of 306 individuals with a cerebral cavernous malformation who were eligible for study. 61 used antithrombotic therapy (ten [16%] of 61 used anticoagulation) for a mean duration of 7·4 years (SD 5·4) during follow-up. Antithrombotic therapy use was associated with a lower risk of subsequent intracranial haemorrhage or focal neurological deficit (one [2%] of 61 vs 29 [12%] of 239, adjusted hazard ratio [HR] 0·12, 95% CI 0·02-0·88; p=0·037). In a meta-analysis of six cohort studies including 1342 patients, antithrombotic therapy use was associated with a lower risk of intracranial haemorrhage (eight [3%] of 253 vs 152 [14%] of 1089; incidence rate ratio 0·25, 95% CI 0·13-0·51; p<0·0001; I2=0%). INTERPRETATION: Antithrombotic therapy use is associated with a lower risk of intracranial haemorrhage or focal neurological deficit from cerebral cavernous malformations than avoidance of antithrombotic therapy. These findings provide reassurance about safety for clinical practice and require further investigation in a randomised controlled trial. FUNDING: UK Medical Research Council, Chief Scientist Office of the Scottish Government, The Stroke Association, Cavernoma Alliance UK, and the Remmert Adriaan Laan Foundation.

The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development.

Dendritic spines are small, actin-rich protrusions on the surface of dendrites that receive the majority of excitatory synaptic inputs in the brain. The formation and remodeling of spines, processes that underlie synaptic development and plasticity, are regulated in part by Eph receptor tyrosine kinases. However, the mechanism by which Ephs regulate actin cytoskeletal remodeling necessary for spine development is not fully understood. Here, we report that the Rac1 guanine nucleotide exchange factor Tiam1 interacts with the EphB2 receptor in a kinase-dependent manner. Activation of EphBs by their ephrinB ligands induces the tyrosine phosphorylation and recruitment of Tiam1 to EphB complexes containing NMDA-type glutamate receptors. Either knockdown of Tiam1 protein by RNAi or inhibition of Tiam1 function with a dominant-negative Tiam1 mutant blocks dendritic spine formation induced by ephrinB1 stimulation. Taken together, these findings suggest that EphBs regulate spine development in part by recruiting, phosphorylating, and activating Tiam1. Tiam1 can then promote Rac1-dependent actin cytoskeletal remodeling required for dendritic spine morphogenesis.