EP17: Thrombosis in Myeloproliferative Neoplasms: From Mutation to Management

In the 17th article of our series, we focus on Philadelphia-negative myeloproliferative neoplasms, a group of rare hematologic malignancies marked by the excessive production of mature blood cells and a strong association with thrombosis. Let’s continue spreading awareness and driving meaningful change together!

At Werfen, our commitment to Powering Patient Care drives us to continually advance scientific understanding and support clinicians in optimizing outcomes for patients with complex conditions. This episode focuses on myeloproliferative neoplasms (MPNs), a group of rare hematologic malignancies characterized by the overproduction of mature blood cells and a strong association with thrombosis, often the primary cause of morbidity and mortality in affected individuals.

Introduction

The classic Philadelphia-negative MPNs, which include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are myeloproliferative disorders all characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell. This leads to excessive production of mature myeloid elements, such as an overabundance of red blood cells in PV or a marked increase in platelets in ET. Although biologically distinct, these disorders share a common predisposition to thrombosis.

The Thrombotic Burden

Thrombotic events, especially arterial complications in PV and ET, introduce significant risks and may contribute to accelerating progression toward myelofibrosis, increased mortality, and even the development of secondary solid tumors. Importantly, these events frequently appear at diagnosis or even before clear disease onset. For this reason, evaluating (especially young) patients with unexplained or atypically located venous thrombosis for an underlying myeloproliferative disorder is now widely encouraged in thrombophilia workups.

Pathophysiology of Thrombosis

The development of thrombosis in MPNs results from multiple factors. In PV, a substantial elevation of erythrocyte mass increases hematocrit levels and blood viscosity, slowing microcirculation and triggering endothelial activation. In ET, elevated platelet count alone does not fully explain the risk. Qualitative abnormalities, including heightened platelet activation, altered adhesion, and enhanced interactions with neutrophils, play a critical role. These processes promote the formation of neutrophil extracellular traps, structures known to enhance thrombogenesis.

Risk Factors

Several clinical factors (e.g. age over 60, prior thrombosis, and cardiovascular comorbidities) together with elevated blood cell counts contribute differently to thrombotic risk in MPNs. Additionally, the discovery of the JAK2V617F mutation, present in 90–95% of PV cases and approximately 60–70% of ET and PMF cases, marked a turning point in understanding MPN‑related thrombogenesis. This mutation not only drives abnormal cell proliferation but also amplifies systemic inflammation and endothelial dysfunction, reinforcing the pro‑thrombotic state.

Management

Therapeutic strategies aim to correct hematologic abnormalities while preventing thrombotic events. Low‑dose aspirin is recommended for most patients without contraindications, while cytoreductive therapy is used in higher‑risk groups. For venous thromboembolism, emerging evidence suggests that DOACs alone perform comparably to DOACs combined with aspirin in ET and PV, guiding evolving clinical practice. Additionally, JAK inhibitors such as ruxolitinib show promising potential in lowering thromboembolic risk while improving symptom control.

Conclusion and Outlook

Philadelphia‑negative MPNs represent a heterogeneous group of chronic hematologic disorders in which clonal proliferation and systemic inflammation converge to create a substantial thrombotic burden. As knowledge of the biology of these malignancies deepens, ongoing research will further clarify the drivers of thrombosis and support more targeted, effective, and safer therapeutic approaches.