1 Thrombosis and Hemostasis Program and Feist-Weiller Cancer, Louisiana State University Health Sciences Center, Shreveport, LA; 2 Department of Biostatistics, University of Tennessee, Memphis, TN; 3 Department of Epidemiology, East Carolina University, NC; 4 Radiation Oncology, Southwestern University, Dallas, TX, USA
* Correspondence to: Prof. S. Sallah, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103, USA. Tel: +1-318-675-4451; Fax: +1-318-675-4338; Email: reccos42000{at}yahoo.com
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Abstract |
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Patients and methods: We prospectively investigated patients with MGUS for the occurrence of VTD. The diagnosis of MGUS was based on well known criteria for the disorder. The variables examined were sex, age, race, presence of underlying conditions, level and type of immunoglobulin [serum monoclonal (M)-protein] platelet counts and level of fibrinogen.
Results: Of a total of 310 patients with MGUS, 19 (6.1%) developed VTD after a median follow-up of 44 months (range 1267 months). In a univariate analysis, age 65 years (P=0.01), M-protein
16 g/l (P=0.001) and progression to plasma cell or lymphoproliferative disorders (28 of 310 patients; P=0.001) were significant risk factors for VTD. In multivariate analysis, M-spike
16 g/l [risk ratio (RR)=6.3; 95% confidence interval (CI) 2.2517.6; P=0.001] and future development of plasma cell or lymphoproliferative disorder (RR = 4.2; 95% CI 1.6410.7; P=0.003) were variables strongly associated with the occurrence of VTD. A total of 46 patients (14.8%) died during the follow-up period of the study.
Conclusion: This study demonstrates that patients with MGUS are at increased risk for VTD. Although a clear reason for the pre-thrombotic state in these patients is not currently evident, few risk factors were identified in the group of patients examined.
Key words: hypercoagulable state, monoclonal gammopathy of undetermined significance, multiple myeloma, venous thrombosis
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Introduction |
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Monoclonal gammopathy of undetermined significance (MGUS) is a well known condition that predisposes patients for the development of multiple myeloma, with risk approaching 25% at 20 years of follow-up [4]. Since patients with MGUS do not receive any specific treatment directed at the M-spike and because the condition is considered pre-malignant, we hypothesized that these patients may inherently be at high risk for venous thrombosis. The current study was aimed at defining the incidence of VTD in patients with MGUS.
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Patients and methods |
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Blood samples
The presence of serum M-protein was detected using agarose gel electropheresis. Immunofixation was used to determine the type of M-protein [6]. Both electropheresis and immunofixation were performed upon diagnosis on a 24-h collection of urine specimens. Complete blood count, chemistry and fibrinogen were obtained at the time of inclusion. All measurements were repeated every 3 months.
Statistical consideration
The variables examined in this study included sex, age, race, presence of underlying conditions, level and type of M-protein, platelet counts and level of fibrinogen. The cut-off values for these variables were chosen arbitrarily.
Chi-square test or Fisher's exact test was used to compare variables such as race and size of immunoglobulin between patients with and without VTD. Factors found to be associated with the occurrence of VTD in univariate analysis were included in multivariate Cox regression analysis. The KaplanMeier method was used to calculate time to VTD.
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Results |
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Univariate and multivariate analyses
Table 2 shows the results of a comparison between the patients with and without VTD. Predominantly, the patients that were diagnosed with VTD were >65 years of age (P=0.01). Although more African-Americans than Caucasians were identified with MGUS, race was not a significant risk factor for the development of VTD in this study. There were 24 patients with autoimmune disorders, including systemic lupus erythematosous (five patients), rheumatoid arthritis (five patients), fibromyalgia (five patients), vasculitis (two patients), scleroderma (two patients), thyroiditis (one patient) and polyarteritis (one patient). The etiology of liver disease in 19 patients was cirrhosis in 10, hepatitis C in five, chronic active hepatitis in two and unknown in two. Other conditions included sarcoidosis (seven patients), Helicobacter pylori (seven patients), chronic cytomegalovirus infection (five patients), dermatologic disease (four patients) and chronic granulomatous disease (four patients). The presence of an underlying disorder was not a significant risk factor for the occurrence of VTD. At multivariate analysis, serum level 16 g/l [risk ratio (RR) 6.3; 95% confidence interval (CI) 2.2517.6; P=0.001] and future progression to lymphoproliferative disorders including myeloma and amyloidosis (RR 4.2; 95% CI 1.6410.7; P=0.003) were associated with increased risk for VTD.
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Discussion |
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The hallmark of patients with MGUS is the presence of a clone of plasma cells that produce one specific type of protein. By definition, at the time of diagnosis of MGUS, no clinical, biochemical or histological evidence of a malignant process can be identified. Because MGUS is potentially a pre-malignant condition, we hypothesized that an increased risk for thrombosis may exist regardless of whether a transformation to myeloma occurs or not. In the current investigation, an incidence of 6.1% of VTD was observed in 310 patients with MGUS followed for a median of 44 months. The size of immunoglobulin >16 g/l and future progression to multiple myeloma or other lymphoproliferative disorders emerged as risk factors for VTD in the multivariate analysis. The relative merits of these findings can be best addressed in the context of the natural history of patients with MGUS. For example, it has been shown by Kyle et al. that the size of the M-protein is the most important factor in predicting the transformation to a plasma cell disorder [4]. Therefore, a high concentration of M-protein is clearly linked to both an increased risk for VTD and further progression of the disease.
We recognize that in the absence of a controlled arm in the current study, it is not possible to draw a definitive conclusion on the magnitude of risk of VTD in MGUS or, specifically, the relative risk of thrombosis compared with the general population. On the other hand, comparative observations may help to illustrate this risk. For example, the risk of VTD in the general population in our institution is similar to the risk reported for the general population in the United States and approximates 1/1000/year [13]. The observed incidence of VTD in individuals
65 years of age referred or diagnosed in our institution is 0.9% per year. This is not dissimilar to the rate of VTD reported in persons between 65 and 75 years old of 0.40.8% per year [13
]. Finally, the rate of VTD in the current study is slightly lower than the 7.8% (1.8% per year) incidence of VTD in cancer patients that we have recently reported [9
].
It is well known that angiogenesis, an active process in myeloma patients, is present, albeit to a lesser degree, in MGUS [11, 12
]. The increased secretion of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tissue necrosis factor (TNF) has also been demonstrated in patients with MGUS [11
]. While IL-6 is a major growth factor for myeloma cells, both IL-6 and TNF can activate the coagulation and fibrinolytic pathways. Also, chromosome 11 abnormalities and translocation (11;14) in particular can be found in up to 20% of patients with MGUS [14
, 15
]. These abnormalities have been strongly associated with an increased risk for VTD in multiple myeloma [2
]. Finally, it has long been recognized that monoclonal proteins may interfere with fibrin structure leading to the formation of thin gel fibers and an alteration in clot retraction [16
, 17
]. These changes may cause the clots that are formed in patients with MGUS to be resistant to lysis.
While these observations do not necessarily provide an explanation for the increase in thrombotic complications in patients with MGUS, one may speculate that a host of factors are responsible in this case. It is quite conceivable that abnormalities in the stromal cell environment coupled with the effect of the monoclonal protein on fibrin formation may potentiate a thrombogenic state in MGUS. The role of known hereditary and acquired defects predisposing to hypercoagulability is still being examined in this population of patients. None of the other variables examined in the univariate analysis, such as type of underlying illness, platelet count or fibrinogen level, were associated with an increase risk for VTD in this study. These findings do not favor a role for chronic inflammation as a precipitating event for clotting in this group of patients.
Collectively, our results indicate that, not unlike patients with multiple myeloma, patients with MGUS are at increased risk for VTD. Also not unlike myeloma, the thrombotic episodes observed in patients with MGUS are very well managed with anticoagulant therapy. A key concept to keep in mind when examining the findings of our study is the view of MGUS and multiple myeloma as a continuum rather than as separate entities. This is true in at least 25% of patients with MGUS who progress to a plasma cell disorder. The implication here is two-fold. First, some patients with MGUS, e.g. those with a high concentration of M-protein, are at increased risk both for VTD and progression to myeloma. Secondly, and most importantly, it is possible that a diagnosis of VTD in a patient with MGUS may in fact portend a higher risk for transformation to myeloma in the future.
In summary, this is the first study that provides evidence for the presence of a hypercoagulable state in MGUS. Future long-term studies are important to confirm our findings. In particular, research efforts should be directed toward resolving the mechanism for the predisposition to thrombosis in both MGUS and multiple myeloma.
Received for publication March 10, 2004. Revision received May 11, 2004. Accepted for publication May 13, 2004.
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