Transthyretin amyloidosis (ATTR) is a group of diseases caused by the deposition of insoluble fibrils derived from misfolded transthyretin, which compromises the structure and function of various organs, including the heart. Thromboembolic events and increased bleeding risk are among the most important complications of ATTR, though the underlying mechanisms are not yet fully understood. Transthyretin plays a complex role in the coagulation cascade, contributing to the activation and regulation of the coagulation and fibrinolytic systems. The prevalence of atrial fibrillation, cardiac mechanical dysfunction, and atrial myopathy in patients with ATTR may contribute to thrombosis, though such events may also occur in patients with a normal sinus rhythm and rarely in properly anticoagulated patients. Haemorrhagic events are modest and mainly linked to perivascular amyloid deposits with consequent capillary fragility and coagulation anomalies, such as labile international-normalised ratio during anticoagulant therapy. Therefore, it is paramount to carefully stratify the thrombotic and haemorrhagic risks, especially when initiating anticoagulant therapy. Our review aims to ascertain the prevalence of thromboembolic and haemorrhagic events in ATTR and identify potential risk factors and predictors and their impact on antithrombotic therapy.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease that has emerged as a significant cause of heart failure. Advances in the understanding of ATTR-CM pathophysiology have revolutionised its therapeutic landscape over the past decade, with the development of targeted therapies that are able to improve survival and quality of life. TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation. Clinical trials have demonstrated their efficacy both in improving survival and quality of life in patients with ATTR-CM. Gene-silencing therapies using small interfering RNAs (siRNAs), such as patisiran and vutrisiran, or antisense oligonucleotide inhibitors (ASOs), such as inotersen and eplontersen, serve as powerful therapeutic options by decreasing TTR production; trials on patients with ATTR-CM have been recently published or are ongoing. Novel, emerging therapies aim to enhance fibril clearance using monoclonal antibodies, such as NI006, that target amyloid deposits in the myocardium, promoting their depletion, plausibly with regression of the structural and functional impairments caused by the disease. Concurrently, advancements in diagnostic modalities have facilitated earlier detection of this disease, allowing the timely initiation of treatment with a more significant impact on patients’ survival and quality of life. Despite these strides, challenges remain, including the high cost of disease-modifying therapy and the need for response criteria to monitor treatment’s efficacy. Future directions will involve improving patients’ screening to achieve earlier diagnoses, optimising patients’ selection for disease-modifying therapy and identifying criteria for the treatment’s response or lack thereof to possibly consider therapy switch or associations. In this review, we will explore the more recent therapeutic advancements in ATTR-CM, starting from traditional heart failure therapies and moving to disease-modifying therapies with a detailed evaluation of the registration trials to explore the strengths and shortcomings of each treatment.

Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and β-catenin signaling. CK1α is a negative regulator of the Wnt/β-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM–MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/β-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments.