Japanese Journal of Clinical Oncology Advance Access originally published online on August 11, 2007
Japanese Journal of Clinical Oncology 2007 37(8):609-614; doi:10.1093/jjco/hym074
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© 2007 Foundation for Promotion of Cancer Research
The Prolonged Activated Partial Thromboplastin Time at Diagnosis Indicates Less Favorable Prognosis in IgA Myeloma
1 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang Ming University School of Medicine, Taipei, Taiwan
2 Zhongxiao Branch, Taipei City Hospital, Taipei, Taiwan
For reprints and all correspondence: Jyh-Pyng Gau, No. 201, Section 2, Shih-Pai Road, Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan. E-mail: jpgau{at}vghtpe.gov.tw
Received March 5, 2007; accepted April 17, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: The impact of coagulopathy on survival of patients with myeloma has not been studied in detail. We aimed to assess the correlation between activated partial thromboplastin time/prothrombin time at diagnosis and overall survival in myeloma patients.
Methods: Data including activated partial thromboplastin time and prothrombin time obtained before treatment and at the time of diagnosis of multiple myeloma (excluding monoclonal gammopathy of undetermined significance, POEMS syndrome, IgM myeloma and myeloma with amyloidosis) collected from 222 patients were analyzed.
Results: Twenty-one patients (9.5%) had prolonged activated partial thromboplastin time (nine with prolonged a activated partial thromboplastin time alone, 12 with both prolonged activated partial thromboplastin time and prothrombin time) and 10 (4.5%) had prolonged prothrombin time alone. Coagulopathy occurred only in patients with IgA and IgG myeloma but not light-chain disease. Prolonged activated partial thromboplastin time was an independent prognostic factor in IgA and IgG myeloma (median survival = 12.7 months, P = 0.004), while prolonged prothrombin time alone had no impact on survival. Subgroup analysis revealed that prolonged activated partial thromboplastin time indicated less favorable survival in IgA myeloma (P = 0.001), but not the IgG myeloma (P = 0.341). This observation still holds true in IgA myeloma with Durie–Salmon stage II or III (P = 0.002).
Conclusions: The presence of prolonged activated partial thromboplastin time at diagnosis is a prognostic factor indicating poor outcome in the IgA myeloma.
Key Words: activated partial thromboplastin time • coagulation • myeloma • prothrombin time
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Multiple myeloma is a neoplastic disease of plasma cells. Patients have a median overall survival of 3–4 years (1,2). Bleeding diathesis is commonly seen in this disease and it has been estimated that as many as one-third of the patients with plasma cell myeloma may have this complication (3–6). The common abnormalities contributing to bleeding diathesis include thrombocytopenia, platelet dysfunction related to uremia, hyperviscosity with bleeding tendency, disorders of coagulation factors, etc. The pathophysiology of the coagulopathy in multiple myeloma is multifactorial, including abnormal immunoglobulins (Ig) interfering with the function and metabolism of coagulation factors, a paraprotein with heparin-like anticoagulant activity, and others (5,7). Although it is seemingly important, the incidence of coagulopathy in multiple myeloma and its impact on patient survival have rarely been reported in the literature. This motivated us to analyze the correlation between the presence of coagulopathy at diagnosis and survival in multiple myeloma. In this retrospective study, the prolonged activated partial thromboplastin time (aPTT) with or without prolonged prothrombin time (PT) at diagnosis was found to be a poor prognostic factor in IgA myeloma.
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PATIENTS AND METHODS |
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Patients and Clinical Laboratory Data
Patients with a diagnosis of multiple myeloma were collected between September 1998 and September 2006 at Taipei Veterans General Hospital. Patients with the diagnosis of monoclonal gammopathy of undetermined significance, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome, IgM myeloma and myeloma with amyloidosis were excluded. The diagnosis of these plasma cell dyscrasias is based on commonly accepted criteria (8–10). Patients were considered to have coagulopathy when prolonged aPTT or PT was noted. Prolonged aPTT was defined as clotting time more than the upper limit of normal range (28–39 s in our laboratory). Prolonged PT was defined as international normalized ratio (INR) more than 1.25 (the upper limit of normal range in our laboratory). The coagulopathy could not be ascribed to any known congenital defects or acquired disorders, e.g. disseminated intravascular coagulation, lupus anticoagulant and coagulation abnormalities related to medications or liver disease. The overall survival was defined as the interval between the initial diagnosis and the death of the patient. The clinical stages were determined according to the Durie–Salmon (DS) staging system (11).
Statistical Analyses
Statistical package for the social sciences (version 13; SPSS, Inc., Chicago, IL, USA) was used for analysis. Survival analysis with the Kaplan–Meier estimate was used with the log-rank test for comparison of overall survival rates between groups. The Cox regression analysis was performed to determine whether abnormal aPTT or PT was an independent predictor of survival after controlling for age, sex and stage. Clinical and laboratory parameters were analyzed using logistic regression with coagulopathy as a dependent variable. Parameters shown to be significant in univariate analysis were included in multivariate analysis. The chi-square test was used in the analysis of correlation between coagulopathy and different classes of Ig. The level of statistical significance was set at 0.05 for all tests.
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RESULTS |
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In total, 222 patients (161 males, 61 females; mean age, 69 years) with the diagnosis of multiple myeloma (median age at diagnosis, 72 years) were collected for analysis. Patients' characteristics are listed in Table 1. The median overall survival after the diagnosis was 27.9 months. The median survival according to DS staging was 20.4 months (deaths/total = 92/168) for patients with stage III; 40.7 months (estimated median survival, deaths/total = 21/44) for patients with stage II; and data not available for patients with stage I (deaths/total = 2/10; Fig. 1, P = 0.006).
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In total, 31 patients (14%) had coagulopathy. Prolonged aPTT was found in 21 patients (nine with prolonged aPTT alone and 12 with both prolonged aPTT and PT). Ten patients (4.5%) had prolonged PT alone (Table 1).
Table 2 lists the incidence of coagulopathy occurring in myelomas of different Ig class and DS stage. Coagulopathy was found in both IgG and IgA myelomas and the difference in the incidence of coagulopathy between IgG and IgA myeloma was not statistically significant (P = 0.139, chi-square test). Interestingly, no coagulopathy was found in myeloma patients with light chain disease (P = 0.004, Fisher's exact test). In IgA myeloma, the incidence of prolonged aPTT was not different between patients with DS stage III and stage II (P = 0.264, chi-square test). This finding also held true in IgG myeloma (P = 0.681, Fisher's exact test).
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Because coagulopathy occurred only in IgG and IgA myeloma and not light-chain myeloma patients, survival analysis was performed only for patients with IgG and IgA myeloma (Fig. 2). Median survival of patients with IgG and IgA myeloma was shorter in those with prolonged aPTT than in those without coagulopathy (median survival 12.7 versus estimated 31.2 months, P = 0.004). Prolonged PT alone did not lead to poor prognosis (median survival 27.9 versus estimated 31.2 months, P = 0.635).
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To investigate whether prolonged aPTT is an independent prognostic factor for survival in IgG and IgA myeloma, log-rank survival analysis was performed for various prognostic factors. The significant factors were further analyzed by Cox regression analysis, which confirmed that prolonged aPTT was an independent prognostic factor (P = 0.002, hazards ratio = 2.603). This finding remained statistically significant even after controlling for other prognostic factors like age, sex and DS staging (on the basis of bone lesions, calcium level, Ig and hemoglobin levels) (Table 3).
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Since prolonged aPTT was found to be an independent prognostic factor, further analysis was carried out to identify factor(s) that might lead to the development of prolonged aPTT in patients with IgG and IgA myeloma. Univariate and multivariate logistic regression analyses were performed to find the possible factor(s) (Table 4). Serum Ig class was a more important factor associated with prolonged aPTT than serum Ig level (IgA versus IgG, P = 0.002, odds ratio = 4.776; high versus low level of serum Ig, P = 0.004, odds ratio = 4.257).
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Since there were more IgA than IgG myeloma patients with prolonged aPTT, subgroup analysis for overall survival was performed (Fig. 3). The subgroup analysis revealed that prolonged aPTT was an indicator for poor survival in IgA (Fig. 3a, P = 0.001), but not IgG myeloma (Fig. 3b, P = 0.341). In Fig. 4, the prolonged aPTT still predicted the poor prognosis in IgA myeloma with Durie–Salmon stage II or III (P = 0.002).
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To investigate whether prolonged aPTT is an independent prognostic factor for survival in IgA myeloma, log-rank survival analysis was performed for various prognostic factors. The significant factors were further analyzed by Cox regression analysis, which confirmed that prolonged aPTT was an independent prognostic factor (P = 0.015, hazards ratio = 2.895). This finding remained statistically significant even after controlling for other prognostic factors like age and DS staging (on the basis of bone lesions, calcium level, Ig and hemoglobin levels; Table 5).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Although the association of coagulopathy with paraproteinemia in multiple myeloma is well known, there have been few reports of large series exploring the association between the prognosis and coagulopathy in detail. Our study thus focused on the correlation between coagulopathy (aPTT and PT) at diagnosis and overall survival in myeloma patients.
Coagulopathy was not a rare complication of myeloma in our study. Fourteen percent of our patients were found to have coagulopathy at diagnosis. However, coagulopathy was observed only in patients with IgG or IgA paraproteinemia and not in patients with light-chain disease (Table 2). This implies that intact plasma paraproteins contribute to the development of coagulopathy. Our finding was consistent with the finding by Perkins et al. that abnormalities of coagulation tests were less common in patients with light-chain disease (12). In addition, this difference was also related to the selection of patients. Our study excluded myeloma patients with amyloidosis, while it has been reported that myeloma with amyloidosis is associated with the development of coagulopathy (7,13,14). These evidences indicate that the development of coagulopathy depends on the presence of intact immunoglobulin in the plasma.
The possible mechanisms by which coagulopathy could develop in patients with dysproteinemias include: (1) paraprotein interference with the normal function of coagulation factor(s) (i.e. by complexing with specific clotting factors); (2) enhancement of the clearance of coagulation factor(s) by the reticuloendothelial system; (3) anticoagulant activity of paraproteins; (4) impaired normal platelet function; (5) excessive fibrinolysis; and (6) hyperviscosity per se. In all of these situations, the development of coagulopathy necessitates the presence of paraproteins in the plasma (3–5,7,15–17).
All of the coagulopathy (100%) occurred in patients with DS stage II or III disease (Table 2). This finding is consistent with another finding that the prolonged aPTT was more often seen in patients with high serum Ig levels (Table 4). Thus, in IgA and IgG myeloma, patients with prolonged aPTT had advanced DS stage (II or III) and shorter survival than patients without coagulopathy (median survival 12.7 versus estimated 31.2 months, P = 0.004). However, this reason could not explain completely that the prolonged aPTT was an independent poor prognostic factor after controlling for DS stage (Table 3).
Moreover, in subgroup analysis, prolonged aPTT contributed to significantly poor prognosis in IgA myeloma, but not in IgG myeloma (Fig. 3). Even in the IgA myeloma with DS stage II or III, the prolonged aPTT was still the poor prognostic factor (Fig. 4, P = 0.002). In addition, the prolonged aPTT still remained the independent poor prognostic factor after controlling for other prognostic factors like age and DS staging (Table 5). These results implied that the poor prognosis in IgA myeloma with prolonged aPTT was not only related to advanced stage but also related to other events.
Previous reports showed that IgA myeloma, resembling macroglobulinemia, was associated with more severe and frequent bleeding diathesis than IgG myeloma (12,18–20). The finding was partially consistent with the result of our study that the prolonged aPTT was more often seen in patients with IgA myeloma than with IgG myeloma (type of Ig was a more important factor leading prolonged aPTT than serum level of Ig; Table 4). In the past literature, the IgA-type paraprotein had greater ability to interfere with coagulation factors than IgG-type paraprotein (also including the platelet function and connective tissue) (5,19,21,22). Thus, our speculation was that the poor survival noted in IgA myeloma with the prolonged aPTT was also related to more frequent bleeding events.
In our retrospective study, in total 33 patients with IgA myeloma died and hemorrhage contributed to the cause of death in some cases. These included bleeding diathesis after bone fracture surgery (n = 1), the development of hemothorax after thoracentesis (n = 1), hemoptysis (n = 1) and subdural hemorrhage (n = 1). Coagulopathy with bleeding could directly result in poor survival in some cases.
Otherwise, our study showed that prolonged aPTT with or without prolonged PT is associated with less favorable prognosis in myeloma patients, but the prolonged PT alone did not influence the prognosis. This can be explained by the fact that aPTT test encompasses nearly every coagulation factor except FVII and FXIII. Prolonged PT alone would indicate that FVII is the only abnormality. This should be a rare condition. Besides, the plasma level of FVII needed for a normal PT test is around 50%, while normal hemostasis can be maintained with an FVII level above 10%. There exists a large gap between the in vivo and in vitro conditions. The similar gap in the aPTT test is comparatively smaller than PT (23). Thus, prolonged aPTT could be a better indicator for poor prognosis than prolonged PT alone.
In conclusion, coagulopathy was found in patients with IgG and IgA myeloma, but not in patients with light chain disease. The prolonged aPTT with or without prolonged PT at diagnosis was a prognostic factor indicating poor prognosis in the IgA subgroup only.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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