Altered Endothelial Cells Properties and Platelets Activity in Treatment NaïVe Patients with Multiple Myeloma (MM ) and Non-Hodgkin Lymphoma (nHL): Association with Thromboembolic Complications
Authors: Usnarska-Zubkiewicz Lidia , Podolak-Dawidziak Maria , Zaleska-Dorobisz Urszula , Olszewska-Szopa Magdalena , Prajs Iwona , Debski Jakub , Kuliczkowski Kazimierz , Robak Tadeusz 
Published: October 2019

Abstract
Multiple myeloma and non-Hodgkin lymphoma and its treatment are frequently associated with increased tromboembolic risk, particularly venous trromboembolism (VTE), cerebrovascular ischemic events and myocardial infarction. The incidence of thrombotic complications dramatically raise after highly prothrombotic therapeutic regimens e.g. thalidomide and lenalidomide in MM.
The current study was designed to examine whether procoagulant microparticles (MPs) derived from endothelial cells (EMPs) and platelets (PMPs) constitute an enhanced risk for venous thrombosis in MM and nHL patients (pts).
We studied 39 pts without history of VTE, 17/22 F/M, aged 24-84 years (mean=60,23±13,45). There were 25 MM pts (15 cases of IgG, 3 of IgA, 1 IgM, 2 non secretory MM, 3 LCD) and 14 nHL (6 cases of DLBCL, 2 anaplastic T cell lymphoma, 2 FL, 4 MCL). All patients underwent routine coagulation tests. Flow-cytometry was used for quantification of endothelial cell (CD133+) microparticles (EMPs) and platelet (CD61+) microparticles (PMPs). In all pts ultrasound examination of venous system of lower extremities was performed. Deep and superficial veins of both limbs were evaluated. Conventional and Doppler imagination, as well as elastography and options to detect microcalcifications (micropure) were used.
The ultrasound examination revealed the presence of vein thrombosis in 18 pts (group I, n =18). 11 out of 18 pts with bilateral lesions in VSM (vena saphena magna, great saphenous vein) and lower leg veins or bilateral in VSM only comprised subgroup Ia. 7 pts with unilateral blood clots in VSM formed group Ib. Thrombosis was observed in 11 pts with MM and 7 with nHL, and bilateral thrombotic lesions were demonstrated in 6 MM and 5 nHL pts. The remaining 21 pts showed no thrombosis (group II). The most frequently thrombosis was observed in IgA-MM (3/3 pts), followed by IgG-MM. In nHL patients thrombosis was found the most frequently in DLBCL. Patients were divided into two groups according to the age: > 60 yrs and <60 yrs. Both in MM and nHL, thrombosis was more frequent in older patients.
The mean percentage of EMPs (CD133+) was 1,44±1,22 (median 0,95, IQR 0,47-2,31), and it did not differ (p=0,83) between thrombotic (group I) (1,48±1,16) and non-thrombotic pts (group II) (1,46±1,31), however the greatest value was assessed in the subgroup Ia (1,74±1,26, p=0,3467). Also, there was a trend marked that EMP percentage was lower in MM patients (1,25±1,31) in comparison to nHL patients (1,76±1,04), p=0,0671 (UM-W test). EMP percentage did not differ according to sex and age.
The percentage of PMPs (CD61+) was 12,06 ± 6,31 (median 10,88, IQR 8,35-15,90), and higher in group I (12,65±3,25) vs. group II (10,93±7,68), p=0,0459 (UM-W test), including subgroup Ia (13,05±3,66), p=0,0885 (UM-W test). The mean PMPs percentage was similar in MM (12,27±7,18) vs. nHL (11,70±4,71), and as EMPs percentage, did not differ according to sex and age.
Mean plasma fibrinogen (FBG) concentration was 3,95±1,82 g/L and did not significantly differ in MM and nHL patients with and without thrombosis (3,84±1,68 vs. 4,10±2,06 g/L), also it has similar level in subgroup Ia (4,06±1,97 g/L). Mean D-dimer level was 2,29±4,15 mg/L (median 1,30, IQR 0,54-2,35), and there was not significantly different in patients with and without thrombosis (2,95±5,29 vs. 1,34±1,25 mg/L), moreover it was not elevated in subgroup Ia (1,96±1,02 mg/L). Type of the disease, sex as well as age did not influenced FBG and D-dimer levels.
Venous thrombosis was confirmed in nearly half of patients with newly diagnosed patients with MM and n-HL. In patients with many thrombotic lesions elevated activity of platelets (PMPs) was observed, as well as a trend towards elevated activity of endothelial cells (EMPs).

Disclosures
Robak: MorphoSys AG: Research Funding.