Aberrant erythrocyte rigidity in JAK2myeloproliferative neoplasms underlies concurrent thrombosis and hemorrhage.
Key claim: JAK2V617F makes erythrocytes intrinsically rigid via membrane and cytoskeletal remodeling, impairing clot contraction and producing larger, more occlusive but unstable thrombi that explain concurrent thrombosis and hemorrhage in MPNs.
Abstract
Thrombotic events are the leading cause of death in myeloproliferative neoplasms (MPNs) driven by the JAK2 Val→Phe (JAK2V617F) mutation. We investigated how JAK2V617F alters hemostasis and thrombosis in humans and in lineage-specific knockin mice to test whether red blood cell (RBC) mechanics contribute directly to clot pathology.knockin mice form structurally aberrant clots characterized by extended clot formation times and unstable hemostatic plug formation. Whole-blood clot contraction in vitro was impaired in humans and mice carrying the JAK2V617F mutation, even whenerythrocytes were resuspended in normal plasma with normal platelets. Thus, in addition to increasing the hematocrit, the JAK2V617F mutation imparted intrinsic changes in erythrocytes critical for mediating abnormal clot formation. Biophysical analysis showed thaterythrocytes had stiffened membranes, making them less compressible during clot contraction. Proteomic and lipidomic analysis oferythrocytes revealed the loss of key membrane and cytoskeleton proteins, a sparse spectrin cytoskeletal network, increased membrane lipid content, and deep plasma membrane invaginations that were consistent with biaxial cytoskeletal stretching and altered lipid packing. These JAK2V617F-driven changes in erythropoiesis generated intrinsically rigid erythrocytes that impaired clot contraction and produced larger and more occlusive, yet mechanically unstable thrombi. This mechanism may explain the contradictory coexistence of thrombosis and hemorrhage in MPNs and why both complications improve when blood counts are lowered, suggesting that targeting erythrocyte mechanics may provide previously unidentified therapeutic opportunities.
Why this matters
The simultaneous occurrence of thrombosis and bleeding is a defining and long-unexplained feature of JAK2V617F-driven MPNs, cutting across PV, JAK2-mutant ET, and PMF. Framing erythrocyte rigidity as a shared mechanical driver of both complications gives the subtype-general vascular-risk narrative a red-cell-intrinsic mechanism distinct from platelet, von Willebrand, and clonal-hematopoiesis axes, and predicts that JAK2V617F allele burden should track with clot-contraction defects across subtypes. If validated, it would reshape how thrombo-hemorrhagic risk is modeled and monitored specifically within JAK2-mutant MPN subtypes.