Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment

Field: Medicine (Health Sciences)

Summary. Venous thromboembolism (VTE) is a major com-plication in patients with multiple myeloma (MM) duringtreatment with thalidomide combined with chemotherapyand/or dexamethasone. The pathophysiology is not clear. Weperformed a cross-sectional study in 20MM patients who weretreated with thalidomide for refractory/relapsed disease. Sevenpatients (35%) experienced an episode of VTE. Plasma sampleswere analyzed for known risk factors for VTE and comparedwith those from 30MM patients without thalidomide treatment.The patients groups differed in their baseline characteristics inactivity status only. Extremely high levels of factor VIII-coa-gulant activity (FVIII:C, mean 352%) and von Willebrand factorantigen (VWF-Ag, 374%) were found in all patients usingthalidomide. All other prothrombotic risk factors were normal.In patients with VTE, VWF-Ag but not FVIII:C, levels weresigniﬁcantly higher as compared with patients without VTE.Patients without thalidomide treatment had signiﬁcantly lowerlevels of both coagulation factors but the difference was onlydue to difference in activity status. High FVIII:C/VWF-Aglevels are found in patients with active MM and this is probablya reﬂection of increased bone marrow angiogenesis in MM.These prothrombogenic circumstances could contribute to thehigh incidence of VTE during treatment with thalidomide incombination with dexamethasone/chemotherapy.Keywords: factor VIII, myeloma, thalidomide, venous throm-bosis, von Willebrand antigen.Even in spite of intensive treatment, multiple myeloma remainsa disease in which cure is seldom reached and refractory diseaseisa frequentencountered problem.Thalidomideasa single drugregimen has been shown to have substantial antitumor activityin refractory myeloma patients, with a total response rate of32% [1]. Based on these results as single agent in refractorymyeloma, thalidomide in combination with chemotherapy isnow under study. Several groups have reported an unexpectedhigh incidence of 28% of venous thromboembolism (VTE)[2,3]. In comparison, the incidence of VTE during chemother-apy without thalidomide in newly diagnosed multiple myelomais 4–10% and during thalidomide combined with dexametha-sone 7% [2–4].It is unknown why the combination of thalidomide andchemotherapy in myeloma patients increases the incidence ofvenous thrombosis. Recently, acquired activated protein C(APC) resistance and the concomitant use of adriamycin havebeen suggested as risk factors [5].In this report, we postulate that extremely high levels ofclotting factor (F)VIII:C and von Willebrand factor antigen(VWF-Ag), which are frequently found in MM patients withactive disease, contribute to the high incidence of VTE duringtreatment with thalidomide.Patients and methodsA cross-sectional study was performed from 1 June until 1November 2001, for risk factors of venous thrombosis in 20patients with multiple myeloma who were treated with thali-domide at the Department of Haematology, University MedicalCenter, Utrecht, the Netherlands. Disease status was deﬁnedaccording to standard criteria [6–8]. Plateau phase is deﬁned asa period of stability of at least 3months (stable M-componentmeasured at least twice), absence of or presence of minimalmyeloma-related symptoms, low tumor burden (less than 10%myeloma plasma cells in bone marrow with a low plasma celllabeling index) and receiving no speciﬁc treatment. Activedisease is characterized by untreated symptomatic disease,refractory disease, and progressive disease for patients withoutprior response or relapsing disease from partial or complete.Thalidomide was prescribed for refractory or relapsed dis-ease after at least two lines of therapy. Six patients receivedthalidomide combined with adriamycin 9mgm