Thrombosis – Besieged but Poorly Understood

In biology, thrombosis is a mechanism of maintaining the integrity of biological surfaces in higher mammals, limiting fluid loss, and facilitating the recognition, containment, and destruction of pathogens and foreign materials by a scaffold of fibrin and DNA strands. However, thrombosis may also lead to vascular occlusion and subsequent tissue damage. In medicine, thrombosis is a hallmark of life-threatening cardiovascular diseases, such as myocardial infarction, stroke, or venous thromboembolism representing major causes of death in the Western civilization. Every year 17 million individuals die from cardiovascular disease (1, 2), comprising almost half of the global death toll in Europe. For example, in Austria, 34,000 patients suffered a cardiovascular death in 2012, accounting for 42.7% of all deaths, which is 1.7-fold the death toll of malignant diseases (3). Cardiovascular science beyond clinical observation and anatomical dissection emerged in the late 19th and early 20th centuries. A key observation was the epidemiological connection of hypertension and elevated plasma lipids with atherosclerotic vascular disease (4). Based on a more profound understanding of these risk factors, including exercise, body weight, and glucose metabolism, preventive measures were tested, leading to both primary and secondary preventions that have become powerful modulators of disease decreasing events by almost half. Since then, the establishment of coronary care units, cardiac catheterization, angioplasty, and surgery and the advent of modern medications many of which interfere with thrombosis and platelet aggregation, have contributed to fundamental improvements in cardiovascular care. However, much of the advances in cardiovascular science have been in the thrombosis field, stimulated by the discovery that myocardial infarction was due to thrombi in the coronary arteries (5). Traditionally, thrombosis has been viewed as the biochemical result of regulated cascades of protein interactions characterized by the activation of factor X and the activation of thrombin, resulting in the formation of fibrin. Accordingly, treatments for myocardial infarction, stroke, and venous thromboembolism have targeted pathways or more recently, individual protein moieties (Figure 1). Table 1 summarizes landmark trials leading to the approval of individual compounds. Over 50 years, a plethora of treatments has been brought to market (Table 1), with high efficacy and safety profiles that have contributed to the observation that death rates per 100,000 population were decreased from 450 in the 1950s to 150 around 2010 (6). For example, while 20–30% of hospitalized patients with myocardial infarction died within 30 days due to their underlying disease, this number has been substantially decreased to <5% most recently (7). The public domain is thrilled with advances of cardiovascular medicine, and needs for deeper insights are hardly convincing in an environment of harmonized health care providing infarction networks, stent-for-life programs, and generally high standard guidelines in cardiovascular care. However, do we understand thrombosis, do we understand recurrence, or do we prefer, for example, to mandate life-long factor X inhibition (38, 46–48) and statins (49) in patients at risk, without further investigation of underlying mechanisms? More recently, a new view of thrombosis has emerged accounting for thrombosis as a vascular disease involving the dynamic interaction between platelets, circulating inflammatory cells, nucleic acids and proteins, and resident cells of the vascular wall. Milestones along the way of integrating the vessel wall in the thrombotic process were the discovery and action of nitric oxide (50, 51), the delineation of the LDL-cholesterol pathway (52, 53), the role of soluble and membrane bound tissue factor in atherosclerosis (54), and most recently the concept of “immunothrombosis” (55), linking inflammation and thrombosis as regulators of vascular integrity. Consequently, it was understood that the hemostatic system is a modulator of atherosclerosis (56). Thrombosis comprises both acute clotting and the more time-consuming process of thrombus resolution, which represents a vascular remodeling process that is driven by inflammation, angiogenesis, and cells of the innate immune system. A stimulus leading to thrombus formation induces an innate immune response that is supported by neutrophils, lymphocytes, macrophages, by specific thrombosis-related molecules, and neutrophil extracellular traps (NETS), underpinning the importance of the following questions: Is thrombosis the underlying process behind both arterial and venous disease that oftentimes combines in individual patients? (57) Do we understand endothelial dysfunction, and is it the nidus for thrombosis, and eventually vascular occlusion? And why do acute pulmonary emboli transform into chronic vascular obstructions in chronic thromboembolic pulmonary hypertension? Do