Shedding New Light on the Magnitude of Thrombosis Risk in Patients With Myeloproliferative Neoplasms

Myeloproliferative diseases were first described by William Dameshek in 1951. In 2008, the World Health Organization established a new classification system and introduced the term myeloproliferative neoplasms (MPNs). Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are the most prevalent MPNs and are characterized by overproduction of leukocytes, erythrocytes, or platelets; development of bone marrow fibrosis; leukemic transformation; and arterial and venous thrombosis. When Dameshek proposed the term myeloproliferative diseases, he also proposed the presence of a then-undiscovered stimulus that drove proliferation. We now understand that mutation of the JAK2 gene, JAK2 V617F, is the most common stimulus, occurring in 95% of patients with PV and 60% of those with ET or PMF. Myeloproliferative neoplasms are relatively rare; are acquired in middle to older age; and are, despite their classification as neoplasms, indolent diseases, with survival measured in decades (1). Yet, MPNs exhibit marked variability in disease presentation and outcomes, especially with regard to thrombotic events. In this issue, Hultcrantz and colleagues report a study that examined thrombosis patterns in 9429 Swedish patients with MPNs diagnosed between 1987 and 2009 compared with 35820 matched control participants (2). As in prior studies, both arterial and venous thrombotic events were increased in patients with MPNs, with the highest risk around the time of MPN diagnosis, although risk persisted throughout patients' lifetimes. Older age and male sex increased cumulative risk for both arterial and venous events in patients with MPNs compared with the general population, but thrombotic risk was higher in the MPN group regardless of age or sex. Of note, the highest hazard ratio that Hultcrantz and colleagues observed was for venous events in the youngest age group. The most notable contribution of this large cohort study is quantification of the magnitude of thrombotic risk that MPNs confer. To put these findings into clinical context, the hazard ratios for arterial events were similar to those for cigarette smoking, and the hazard ratios for venous events were similar to those for factor V Leiden heterozygosity. Approximately 10% of patients with MPNs had a thrombotic event within 30 days before or after diagnosis. Patients and clinicians should be keenly aware of this particularly risky period, during which risk for thrombosis is similar to that in the month after a transient ischemic attack. Unfortunately, the study did not include genomics data, but other studies enable us to speculate on the potential mechanisms responsible for the excess of arterial and venous thrombosis. Discovered in 2005, JAK2 V617F is an acquired mutation of a hematopoietic stem cell that provides a proliferative advantage and drives MPN phenotypes. Not long after its discovery in the MPN population, 2 large general population studies from Denmark (the Copenhagen City Heart Study [n= 10507] and the Copenhagen General Population study [n= 49488]) had similar findings: JAK2 V617F mutations are detected (at low clonal burden levels) in 0.1% to 0.2% of the general population (3). A more recent analysis of the 23andMe customer base (n= 252637) found similar age-dependent rates of JAK2 V617F in asymptomatic populations (4). Of note, despite the absence of overt MPN, JAK2 V617F carriers had higher rates of thrombotic events than control participants. A thrombosis signal associated with somatic mutations in blood cells was also shown in a previous study (5), in which many genes mutated in clonal hematopoietic malignancies were examined simultaneously in a large general population. Mutations were rare in persons younger than 50 years but were identified in almost 6% of those older than 65 years. JAK2 V617F was among the most common mutated genes, which also included DNMT3A, ASXL1, TET2, and PPMD1. It is important to note that in addition to an increased risk for blood disease or cancer, persons with mutations had higher rates of cardiovascular events (5). Collectively, these studies suggest that, rather than elevated blood counts driving thrombosis in MPN, confounding factors may drive risk for developing both mutations and thromboses. Arterial and venous thromboses share risk factors, including smoking, elevated body mass index, older age, and chronic inflammatory states. JAK2 V617F is uniquely connected to inflammatory pathways, both proximally and distallyinflammatory states may predispose persons to acquisition of JAK2 V617F, and JAK2 V617F signaling also drives inflammatory pathways. Persons with JAK2 V617Fpositive MPN have elevated inflammatory cytokines, which are a substantial component of disease burden. Inflammation also seems to play a role in clonal expansion of JAK2 V617F cells, further driving disease expansion (6). Inflammation is a recognized risk factor for thrombosis in the general population and is well-known to play a significant role in atherogenesis, which could enable identification of new therapeutic targets. For example, rosuvastatin reduced cardiovascular events in asymptomatic persons with normal cholesterol levels but elevated high-sensitivity C-reactive protein (hs-CRP) levels (7). More recently, targeting interleukin-1 with a monoclonal antibody reduced cardiovascular events among patients with previous myocardial infarction and elevated hs-CRP levels (8). Traditional therapeutic approaches have focused on antiplatelet agents for arterial events and anticoagulants for venous events. However, the combination of aspirin and low-dose rivaroxaban was recently shown to reduce cardiovascular events in patients with stable cardiovascular disease (9). These studies from the general population should inform future research on strategies to reduce thrombotic risk in patients with MPNs, which will also need to take into account genomics, given that treatment effects may differ by mutation. Hultcrantz and colleagues have opened our eyes to the magnitude of thrombotic risk that MPNs bring to affected patients. Their study shows us that the traditional approach to assessing thrombotic risk in patients with MPNs (age 60 years, prior thrombotic event, and presence of traditional cardiovascular risk factors) lacks precision and personalization. In particular, such an approach does not adequately recognize the risks that younger patients bear (10). The study of JAK2 V617F and its association with inflammation, clonal hematopoiesis, and thrombosis has shed light not only on mechanisms of thrombosis in MPNs but also on mechanisms and risks that are generalizable to the population at large. A personalized, precision medicine approach to primary and secondary thrombosis prevention for patients with MPNs should incorporate genomics, cardiovascular risk assessment, inflammatory biomarkers, and this new appreciation of the magnitude and cumulative nature of excess risk. Care of patients with MPNs should include aggressive treatment of traditional risk factors to reduce risk for arterial and venous thrombosis, regardless of age; adoption of dietary and lifestyle habits that reduce inflammation; and consideration of combined anticoagulant, antiplatelet, and anti-inflammatory treatment strategies.