Abstract

Treatment of multiple myeloma (MM) with thalidomide or lenalidomide is associated with increased incidence of thrombosis in contrast to treatment with bortezomib. The mechanism of thrombosis is unknown. Monocytes generate potent tissue factor (TF), the main activator of coagulation, in response to various stimuli (endotoxin, cytokins and others) and in diseases with increased incidence of thrombosis. We investigated the capacity of monocytes from patients with MM to generate TF in relation to different modalities of treatments and activation of coagulation. Peripheral blood mononuclear cells (PBMC) were isolated on Ficoll-Hypaque centrifugation and monocytes by adhesion. TF activity was assayed by modified PT using the cells as source of TF and TF antigen by ELISA, in endotoxin stimulated (10 ug/ml) and unstimulated PBMC ( all patients) and purified monocytes (50% of patients), before and after 3-4 courses of treatment. Monocytes were identified by anti CD14 and Plasma Fragment1.2 was assayed by ELISA.

 No TF activity@ (X10-5 U/monocyte) TF antigen@ (X10-5 pg/monocyte) Plasma fragment 1.2@ (nM) 
Endotoxin   
Bortezomib based treat* 12      
 before  2.2 4.8 22 64 0.28 
 after  1.8 4.2 18 57 0.36 
Thalidomide based treat*      
 before  2.4 5.5 26 60 0.24 
 after  1.8 34.8# 20 440# 2.48# 
Lenalidomide based treat^      
 before  2.1 6.2 28 62 0.30 
 after  4.1 58.6# 16 312# 3.42# 
 No TF activity@ (X10-5 U/monocyte) TF antigen@ (X10-5 pg/monocyte) Plasma fragment 1.2@ (nM) 
Endotoxin   
Bortezomib based treat* 12      
 before  2.2 4.8 22 64 0.28 
 after  1.8 4.2 18 57 0.36 
Thalidomide based treat*      
 before  2.4 5.5 26 60 0.24 
 after  1.8 34.8# 20 440# 2.48# 
Lenalidomide based treat^      
 before  2.1 6.2 28 62 0.30 
 after  4.1 58.6# 16 312# 3.42# 

@Mean *First line treatment ^Second line treatment # P<0.05

One patient on thalidomide and 2 on lenalidomide developed thrombosis. The results show that TF was low in unstimulated monocytes from all patients before treatment. It was increased mildely in stimulated monocytes from all patients before treatment and also after treatment with bortezomib (X 2-3). TF in stimulated monocytes and also plasma fragment1.2 were increased significantly after treatment with thalidomide and lenalidomide (x 14-22 and X 10). The phenomenon of enhanced capacity of monocytes to generate potent TF after treatment with thalidomide and lenalidomide but not bortezomib, and the correlation with activation of coagulation suggest a role of monocyte TF in thrombus formation by these drugs. The mechanism of the enhanced capacity is unknown and may be attributed to the immunomodulatory effect of the drugs.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.