Abstract

Proteasomes inhibitors have been recently identified as potential agents, which can influence processes leading to thrombosis. We have previously reported a reduced incidence of deep vein thrombosis (DVT) in 69 patients enrolled in Total Therapy III and treated with (B), dexamethasone, thalidomide, cisplatin and doxorubicin with prophylactic anticoagulation. Patients with relapse MM, not previously exposed to B with normal baseline coagulation parameters (PT, PTT fibrinogen and platelet count) were eligible for the study. Except for the two PCR-based genotyping assays Factor V Leiden and Prothrombin Gene, which were assessed only at enrollment, in table one are listed coagulation factors serially assessed at baseline and within 1 hour after the first dose of B on day 1 and 4 of the first treatment cycle. Platelet Aggregation, with epinephrine, collagen, arachidonic acid, ADP and P- selectin by flow cytometry, were obtained at same time points.

Results: Median values of coagulation factors pre and post B infusion are shown in table 1. Platelet count on platelet rich plasma (PRP) decreased after each B treatment (204.1±69.2 × 103 platelets/μL versus 160.8±50.3 × 103 platelets/μL). Platelet aggregation in PRP induced by 10 μM ADP was reduced by 20% and 29% in post-B on day one and four with p-values of 0.033 and 0.009 rispectively. Ristocetin induced platelet agglutination and epinephrine-induced aggregation were both negatively affected by B administration, p=0.0077 and p=0.034. Platelet aggregations elicited by collagen and arachidonic were not affected by B P-selectin expression on platelet surface was overall decrease with each agonist after B administration however no statistical differences were observed. In conclusion this pilot study has shown that even a short in vivo B exposure can significantly impaired platelet number and function and could explain clinical observations.

Table 1
TestDay 1 Pre-dose MedianDay 1 Post-dose MedianDay 4 Pre-dose MedianDay 4 Post-dose Median
PT (sec) 13.4 13.85 13.55 14.4 
PTT (sec) 17.35 26.2 26.95 25.5 
Fibrinogen (mg/dL) 385 360 386 341.5 
Protein C (70%–160%) 114 102 120 115 
Protein S (65–140%) 89 85 92 92.5 
Antithrombin II (190–127%) 98 97.5 100.5 102 
APC Ration 2.345 2.33 2.3 2.22 
T.T. (<20s) 18.2 17.9 17.7 19.45 
D-Dimer (ug/mL) 0.56 0.5 0.5 0.59 
Homocysteine (umol/L) 8.77 8.99 8.69 8.13 
TestDay 1 Pre-dose MedianDay 1 Post-dose MedianDay 4 Pre-dose MedianDay 4 Post-dose Median
PT (sec) 13.4 13.85 13.55 14.4 
PTT (sec) 17.35 26.2 26.95 25.5 
Fibrinogen (mg/dL) 385 360 386 341.5 
Protein C (70%–160%) 114 102 120 115 
Protein S (65–140%) 89 85 92 92.5 
Antithrombin II (190–127%) 98 97.5 100.5 102 
APC Ration 2.345 2.33 2.3 2.22 
T.T. (<20s) 18.2 17.9 17.7 19.45 
D-Dimer (ug/mL) 0.56 0.5 0.5 0.59 
Homocysteine (umol/L) 8.77 8.99 8.69 8.13 

Author notes

Disclosure:Consultancy: Millennium, Celgene, OrthoBioTech. Research Funding: Millennium. Honoraria Information: Millennium, Ortho Biotech, Celgene. Membership Information: Mellennium, Ortho-Biotech, Celgene.