PB0852 - Bone marrow neoplasms and bleeding, what's the link?

Background: Vascular/Haemostatic changes often accompany the progression of bone marrow (BM) neoplasms. Reduced circulating platelets and defective responses to collagen in lymphoproliferative disorder patients prior to therapy have been sporadically reported. Hyperviscosity, caused by immunoglobulin (Ig)M hypersecretion characterises Waldenstrom Macroglobulinaemia (WM) lymphoma patients and likely exacerbates haemostatic and vascular changes, however this has not yet been addressed.

Aims: To quantify and explore molecular reasons underpinning haemostatic dysfunction in lymphoproliferative disorder patients.

Methods: Whole blood (WB) samples were collected from 36 lymphoproliferative disorder patients and 34 healthy donors (HDs). Platelet receptor levels were measured by flow cytometry, plasma thrombin generation ± platelets by FRET assay, WB clotting potential by rotational thromboelastometry (ROTEM), and plasma soluble GPVI (sGPVI) and serum thrombopoietin (TPO) by ELISA. Donor platelet spreading, aggregation and ability to accelerate thrombin generation in the presence of WM-derived IgM were assessed.

Results: Platelets from lymphoproliferative disorder patients had reduced GPIbα (****p < 0.0001), GPVI (****p < 0.0001) and CD9 (**p < 0.01) levels, while αIIb integrin and sGPVI levels remained within healthy ranges. Patient platelets demonstrated reduced contribution to maximal clot firmness (****p < 0.0001) and reticulation (***p < 0.001) and increased sialylation (*p < 0.05). Patient plasma displayed slower thrombin generation (**p < 0.01) and elevated TPO (**p < 0.01). HD plasma or platelets incubated with patient-derived IgM paraprotein displayed reduced spreading (***p < 0.001), aggregation (****p < 0.0001) and thrombin generation (**p < 0.01). IgM bound to platelets was disrupted by dextran sulfate.

Conclusion(s): Platelet and haemostatic defects unrelated to platelet count were quantified in lymphoproliferative disorder patients. Deficiencies in key adhesio-signalling platelet receptors and altered platelet function, surface sialylation, reticulation and TPO were consistent with changes in platelet production and may indicate disease progression. Vascular thrombin generation and platelet spreading behaviour in the presence of paraprotein were impaired. Monitoring changes to haemostatic parameters might predict poor outcomes or complications in patients with BM neoplasms.