ORIGINAL ARTICLE Acute promyelocytic leukemia cell adhesion to vascular endothelium is reduced by heparins Alfonso Vignoli 1 & Marina Marchetti 1 & Anna Falanga 1 Received: 6 November 2017 /Accepted: 21 April 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Adhesion of acute promyelocytic leukemia (APL) cells to endothelial cells (EC) is among the mechanisms of the APL-associated coagulopathy, responsible for early hemorrhagic deaths in affected patients. We compared the effects of dalteparin and enoxaparin, two low-molecular-weight heparins (LMWH), and unfractionated heparin (UFH), on APL NB4 adhesion to micro- (HMEC-1) and macro-vascular EC (HUVEC), in resting and interleukin-1β (IL-1β)-stimulated conditions. The heparin effect on EC adhesion molecule (ICAM-1, VCAM-1, E-selectin) expression was also assessed. In HMEC-1, dalteparin inhibited IL1β-induced NB4 adhesion by 80%, enoxaparin by 52%, and UFH by 44%. Similar results were obtained in HUVEC. This was associated with a significant decrease of VCAM-1 and ICAM-1 expression. In conclusion, we show that LMWH significantly counteract APL cell adhesion to the vessel wall, by modulating EC adhesion molecule expression. This property of heparins may represent one approach for hampering excess clotting activation and microthrombi deposition in APL. Keywords Acute promyelocytic leukemia . Endothelium . Cell adhesion . Low-molecular-weight heparin . Cancer and thrombosis Introduction Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (M3) genetically characterized by the t(15;17) chromosomal translocation and the PML–RARα fu- sion gene. Blood coagulation abnormalities consistent with the diagnosis of disseminated intravascular coagulation (DIC) and thrombo-hemorrhagic symptoms [1, 2] are typical- ly associated with the onset of this myeloid leukemia. Currently, the use of induction therapy with all-trans retinoic acid (ATRA)-based regimens yields complete remission rates of > 90% and long-term disease-free survival rates exceeding 80%. However, the severe coagulopathy remains a relevant cause of early hemorrhagic death in these patients [3, 4]. Several leukemic cell-dependent pathogenic mechanisms are involved in clotting activation in APL [1] and include the following: (1) the production by APL cells of procoagulant factors, non-specific proteolytic enzymes, fibrinolytic pro- teins, and pro-inflammatory and pro-angiogenic cytokines [i.e., interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α)]; and (2) the direct interaction of leukemic cells with host vascular and blood cells (i.e., endothelial cells, leuko- cytes, and platelets) by means of adhesion molecules. The adhesion of APL cells to endothelial cells (EC) promotes lo- calized clotting activation and thrombus formation. The leu- kemic cells attached to the endothelium can release their cy- tokine content into a protected milieu that favors their pro- thrombotic and pro-angiogenic activities [5–7]. Impairing APL cell-EC adhesion mechanism may be relevant for preventing the associated coagulopathy and organ infiltration by APL blasts. Heparins, a group of glycosaminoglycans with a wide spectrum of biological activities [8], are widely used as anti- coagulant drugs for the prevention and treatment of thrombo- sis in a variety of conditions, including cancer [9]. Heparins are known to have additional biological effects that are unre- lated to their anticoagulant activity [10, 11]. Experimental evidences suggest that heparins have the capability to interfere with mechanisms of tumor cell/EC interaction [12]. Along this line, our group could demonstrate that heparins (both unfractionated heparin (UFH) and low-molecular-weight * Anna Falanga annafalanga@yahoo.com 1 Department of Immunohematology and Transfusion Medicine & Hemostasis and Thrombosis Center, Hospital Papa Giovanni XXIII, Piazza O.M.S., 1, 24127 Bergamo, Italy Annals of Hematology https://doi.org/10.1007/s00277-018-3343-4