Thrombosis: Grand Challenges Ahead!

Abstract

Thrombosis is the formation of a blood clot that partially or completely hinders blood flow in one or more blood vessels, either in the venous or arterial circulation. Thrombosis is the immediate trigger of a number of acute cardiovascular diseases (CVD), including myocardial infarction, ischemic stroke, and venous thromboembolism (VTE), which are all leading causes of mortality and long-termmorbidity, affecting men and women of all ethnicities all over the world. In 2016, an estimated 17.9million people died fromCVD, representing 31% of all global deaths; of these deaths, 85% were due to myocardial infarction and stroke, half of which due to thromboembolic brain injury1. The number of VTE events is less accurately monitored, but estimates included 684,000 deep vein thrombosis (DVT) events, 435,000 pulmonary embolism (PE) events, and a total of about 543,000 VTE-related deaths among the population of the European Union, of ∼450 million total subjects in 2004 (1). In all these acute conditions, thrombosis is a localized problem, causing ischemia in the downstream vascular bed in case of arterial thrombosis, and impaired return of blood flow to the heart, with a risk of thromboembolic organ injury in the case of VTE, respectively. Thrombosis can also be a more systemic or combined local-systemic phenomenon and the current Covid-19 pandemic introduces a dramatic example of systemic hypercoagulability and localized thrombosis, associated with SARS-CoV-2 virus pneumonia (Covid-19). The latter type of systemic coagulopathy, with bothmicrovascular thrombo-inflammation and large vessel thrombosis (and/or VTE), was initially regarded as disseminated intravascular coagulation (DIC), later thrombotic microangiopathy, both attempts to describe and define the specific type of thrombotic tendency (2, 3). Thrombotic thrombocytopenic purpura (4) and heparin induced thrombocytopenia (5) are yet other systemic thrombotic phenomena. Essentially, thrombosis is an excess response-to-injury, meant to arrest bleeding from a damaged vascular bed, in case of trauma; or, to respond to an infectious attack, involving perturbation of the vascular endothelium by inflammatory cells and platelets (6), secreted inflammatory mediators and generation of extracellular vesicles, challenging the normal anticoagulant endothelial function to turn into amore prothrombotic phenotype (7–10). The latter type of immunemediated thrombosis is also referred to as immunothrombosis (11), but DIC and other systemic coagulopathies also qualify as immune mediated manifestations of thrombo-inflammatory reactions. Whereas, “thrombosis” as a result of an exaggerated response-to-injury is still targeted against exogenous elements (traumatic, pathogens, particulate matter) in case of recognizing “self ” as “foreign” thrombosis can also be part of autoimmune pathologies like antiphospholipid syndrome (APS) (12). Whatever the cause, thrombosis is either directly harmful, due to vascular occlusion, or indicative of an increased likelihood of dying, in conjunction with severe underlying diseases like cancer (13), or sepsis (DIC also referred to as “death is coming”) (14).