CD39 activity correlates with stage and inhibits platelet reactivity in chronic lymphocytic leukemia

Abstract

Background: Chronic lymphocytic leukemia (CLL) is characterized by accumulation of mature appearing lymphocytes and is rarely complicated by thrombosis. One possible explanation for the paucity of thrombotic events in these patients may be the presence of the ecto-nucleotidase CD39/ NTDPase-1 on the surface of the malignant cells in CLL. CD39 is the major promoter of platelet inhibition in vivo via its metabolism of ADP to AMP. We hypothesize that if CD39 is observed on CLL cells, then patients with CLL may be relatively protected against platelet aggregation and recruitment and that CD39 may have other effects on CLL, including modulation of the disease, via its metabolism of ATP.

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

“…29 The addition of CLL lymphocytes to platelet rich plasma in vitro has been shown to decrease platelet aggregation responses to ADP. 20 Based on these prior findings we believe that diminished platelet aggregation with both collagen and ADP in CLL patients before treatment with ibrutinib is due to the expression of the CD39/NTDPase-1 protein on the surface of CLL cells. CD39/NTDPase-1 has been shown to be present on the surface of ~95% of B cells (normal or malignant).…”

“…CD39/NTDPase-1 has been shown to be present on the surface of ~95% of B cells (normal or malignant). 20 NTDPase-1 inhibits platelet aggregation in part by converting ADP, an important platelet agonist and critical constituent of dense granules that serves to recruit other platelets, upon activation, to AMP. CD39 is expressed on healthy endothelial cells where its chief function is to down-modulate platelet activation at the interface between blood and the blood vessel wall by degrading ADP to AMP.…”

“…Other studies reported inhibition of collagenmediated platelet aggregation by ibrutinib in platelet rich plasma and concluded that this effect may increase bleeding risk on ibrutinib. [17][18][19] Since CLL cells themselves have been reported to modulate platelet activation 20 we studied collagen-induced platelet aggregation using whole blood aggregometry in patients on ibrutinib, untreated CLL patients, healthy controls, and patients with XLA. Representative tracings from collagen-mediated aggregometry are shown in Online Supplementary Figure S1.…”

Expanding the use of thrombopoietin mimetic drugs: what about chronic lymphocytic leukemia?

“…Side effects associated with the use of TPO agents relate to the possible development of bone marrow fibrosis or the tendency to venous thrombosis [3]. However, to date, no association between CLL and myelofibrosis has been reported, while it is interesting to note that thrombotic complications have been reported to be less frequent in patients with CLL when compared to other malignancies [12]. Nevertheless, these aspects require further evaluation in a larger cohort of patients with a longer follow-up.…”

How to use ibrutinib

“…сам по себе [43]. Дополнительный лимфоцитоз, вызы-ваемый ибрутинибом, подавляет его еще сильнее и, в комбинации с его ингибированием сигнализации от коллагена, может вести к кровотечениям.…”