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Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma


The incidence of venous thromboembolism (VTE) is more than 1‰ annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2–3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.


Deep vein thrombosis (DVT) and its potentially lethal complication, pulmonary embolism (PE), are manifestations of venous thromboembolism (VTE). The age- and sex-adjusted incidence of VTE is more than 1‰ annually, including 0.5‰ for DVT and 0.7‰ for PE.1 In cancer patients, the incidence of VTE is more than 7%.2 Hematological neoplasia patients, in particular those with multiple myeloma (MM), have the highest risk of thrombosis.3 The oral immunomodulatory drugs, thalidomide and lenalidomide, further increase the risk of VTE. Various VTE prophylaxis strategies have been investigated in clinical studies. This review summarizes the results of these trials and recommends a prophylaxis strategy according to a risk-assessment model.

Incidence and risk factors in general population

VTE is a disease of older age, the incidence of which rises markedly from less than 2‰ in individuals younger than 55 years to more than 5‰ in those older than 65 years.1 VTE may be a lethal disease, mostly due to PE: the 1-week survival rate after PE is 71%, and one-fourth of all cases of PE present as sudden death.4 Patients at risk must be identified and must receive the appropriate prophylaxis to reduce the incidence of this serious adverse event. The most important risk factors can be categorized into individual and disease-related risk factors.5, 6, 7, 8, 9 Individual factors include patients' general characteristics (such as age and body mass index), inherited thrombophilic abnormalities, central venous catheter (CVC), previous superficial vein thrombosis, pregnancy/puerperium and drug use. Major inherited prothrombotic conditions are antithrombin III deficiencies, protein C and protein S deficiencies, activated protein C resistance, factor V Leiden mutation, prothrombin gene (G20210A) mutation and high levels of homocysteine.9 The presence of inherited thrombophilia should be evaluated, especially in patients with previous history of VTE. The disease-related factors include recent (generally less than 3 months) clinical conditions such as surgery, trauma or hospital admission, and chronic clinical conditions such as nursing home confinement, malignant neoplasm with or without chemotherapy and neurologic disease with extremity paresis6 (Table 1). As shown in Table 1, the increased relative risk of these conditions is quite heterogeneous, varying from 2 to 40. The simultaneous presence of more than one risk factor exponentially increases the risk of thromboembolic complications.

Table 1 The most important noninherited risk factors for deep vein thrombosis and pulmonary embolism6

Thrombosis and cancer

The overall risk of VTE is increased 7- to 10-fold in patients with malignancy. In hematological cancer, the risk is increased as much as 28-fold.3 The pathophysiology of thrombosis in cancer is a complex process. The interaction between malignant cells and monocyte/macrophage cells stimulates the release of tumor necrosis factor, interleukin-1 and -6, all causing endothelial damage. The interaction between tumor cells and macrophages also activates platelets, factor XII and X. Cysteine protease and tissue factor are highly expressed in cancer cells, have procoagulant activity, and can directly activate factor X and VII.10, 11 The risk of VTE is increased 4.1-fold in malignant neoplasms without chemotherapy, and 6.5-fold with chemotherapy. Patients are most likely to develop VTE in the first few months after diagnosis. In a recent study, the adjusted odds ratio within the first 3 months was found to be as high as 58.2, to decrease from the third month to the first year to 13.4 and to continue to decrease thereafter.6 The conditions that increase the risk of VTE in cancer patients are active therapy, immobilization, surgery, CVC and erythropoiesis-stimulating agents. In two large clinical trials of women with node-negative breast cancer, the 5-year incidence of VTE was 0.2% in those who received placebo, 0.9% in those who received tamoxifen and 4.2% in those who received tamoxifen plus chemotherapy.12, 13 Cancer patients undergoing surgery have at least twice the risk of postoperative DVT and more than three times the risk of fatal PE than noncancer patients who are undergoing similar procedures.14 In the general population, the presence of CVC is an independent risk factor for thrombosis in axillary/subclavian veins.6 In cancer patients with indwelling CVC, the rate of thrombosis varied between 5 and 40%.15, 16, 17, 18 Recently, the Food and Drug Administration discussed concerns about risks of thromboembolic disease, promotion of tumor growth and decreased survival associated with the erythropoiesis-stimulating agents used to treat anemia caused by chemotherapy.19 In two phase 3 clinical trials, an increased risk of sudden death or a cardiovascular or thromboembolic event was reported in patients with chronic renal failure who received erythropoiesis-stimulating agents to drive hemoglobin levels into the normal range (13.5 g dl−1 or higher), but was not shown in those treated to achieve levels in a subnormal range (10.5–11.5 g dl−1).20, 21 In summary, cancer patients are at increased risk for developing hypercoagulable events, and this is confounded further by several factors, including therapy.

Thrombosis and plasma cell dyscrasia

In 310 patients with monoclonal gammopathy of undetermined significance (MGUS), the incidence of VTE was 6.1% after a median follow-up of 44 months.22 By univariate analysis, age 65 years, M protein 16 g l−1 and disease progression were the significant risk factors for VTE. In another series of 174 MGUS patients, the incidence of VTE was 7.5%, and all events occurred within the first 6 months of follow-up. The risk of VTE was increased 8-fold if a personal history of VTE was present and 27-fold in immobilized patients.23 However, it cannot be determined from these studies if there is a true increased risk of VTE with MGUS, since the risk may be solely related to the underlying medical problems that prompted laboratory testing for monoclonal proteins in the first place. The incidence of VTE in MM patients is difficult to estimate and varies from 3%24 to 10%.23 However, based on the available data using standard treatments for MM, the risk of VTE in the first 4 months following diagnosis is approximately 3–4% in patients receiving either dexamethasone alone24 or melphalan/prednisone therapy.25, 26 This risk could be as high as 10% with nonbiologic therapy.23 The exact mechanisms behind VTE in MM are not known. The type of drug therapy used to treat the disease is the dominant factor determining the risk of VTE. Procoagulant antibody formation, paraprotein interference with fibrin structure, activated protein C resistance and endothelial damage may play a significant role.27 Furthermore, increased secretion of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor can activate coagulation pathways.28 Elevated von Willebrand and factor VIII, as well as decreased protein S and activated protein C resistance, have been described.29 Unfortunately, no single prothrombotic abnormality can be used to predict which patients will develop VTE.

Thrombosis and thalidomide

As a single agent, thalidomide does not increase the risk of VTE compared to dexamethasone alone or melphalan/prednisone. The risk of VTE is highly variable, even within the same combination. This difference is likely to be related to both individual and therapy-related risk factors, including the dose of novel agents or, more importantly, the dose of dexamethasone. Thalidomide alone does not increase the risk of VTE: in newly diagnosed MM the incidence of VTE was 3–4%30, 31 and in relapsed/refractory MM it was 2–4%.32, 33, 34 The combination of thalidomide with dexamethasone significantly increased the incidence of VTE to 14–26% in newly diagnosed MM patients24, 35, 36 and to 2–8% in relapsed/refractory patients.37, 38 In a randomized trial comparing thalidomide/dexamethasone with placebo/dexamethasone, the incidence of VTE was 17% in the thalidomide arm versus 3% in the placebo arm. No specific thromboprophylaxis was mandated in this trial.24 When thalidomide was combined with melphalan, the incidence of VTE was 10–20% in newly diagnosed patients25, 26, 39 and 11% in relapsed/refractory patients.40 In two independent phase III trials, the combination of melphalan, prednisone and thalidomide at diagnosis caused VTE in 12–20% of patients who did not received any prophylaxis.25, 26 Thalidomide plus doxorubicin and dexamethasone further increased the risk of VTE to 10–27% at diagnosis41, 42, 43 and to 58% in a single study.44 Table 2 summarizes the incidence of VTE as it relates to different agents and regimens.24, 25, 26, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 No significant increase in incidence of VTE was reported in patients who received thalidomide alone, or in combination with prednisone as a maintenance therapy.54 Overall, the median time to onset of a thrombotic event was around 3 months. The risk of VTE was higher in newly diagnosed patients.

Table 2 Venous thromboembolism incidence in trials of thalidomide or lenalidomide without thromboprophylaxis

To further define the relative risk of VTE as it relates to the different therapeutic agents, Zangari et al.63 analyzed risk factors associated with the development of VTE in 535 patients treated either with thalidomide in combination with multiagent chemotherapy or with dexamethasone only. Overall, the incidence of VTE was 15%. By multivariate analysis, doxorubicin-containing regimens were associated with a 4.3-fold increase in VTE, while newly diagnosed disease was associated with a 2.5-fold increase of VTE in comparison with relapsed/refractory disease. In a retrospective analysis, erythropoietin did not increase the risk of VTE.64

Thrombosis and lenalidomide

Lenalidomide is an immunomodulatory drug that is structurally similar to thalidomide yet functionally distinct. As a single agent, lenalidomide did not significantly increase the risk of VTE at relapse.55, 56 By contrast, when lenalidomide was combined with dexamethasone, the incidence of VTE was 75% in a small group of newly diagnosed patients57 and 8–16% in relapsed/refractory patients59, 60 (Table 2). In two large randomized trials in which relapsed patients received lenalidomide–dexamethasone or dexamethasone alone without mandatory prophylaxis, the incidence of VTE was 8–16 and 4%, respectively.59, 60When lenalidomide was combined with cyclophosphamide in relapsed patients, the incidence of VTE was 14%.61 The combination of lenalidomide–bortezomib did not increase the risk of VTE in relapsed/refractory patients.62 The incidence of VTE according to different agents and regimens is summarized in Table 2. Risk factors associated with an increased risk of VTE were the dexamethasone dose and erythropoietin administration. In a recent report, lenalidomide was delivered at diagnosis with high-dose dexamethasone (480 mg per month) or low-dose dexamethasone (160 mg per month); the incidence of VTE was 23 and 8%, respectively.58 In patients receiving lenalidomide and dexamethasone at relapse, the concomitant administration of erythropoietin significantly increased the risk of VTE (23 versus 5%) in one study,65 and though the risk was also elevated in a second study, the difference failed to reach statistical significance (31 versus 14%).54

VTE prophylaxis in medical and surgical patients

Models to estimate risk on the basis of number and type of risk factors present in an individual patient have been proposed,66, 67 but none have been prospectively validated. Anticoagulant prophylaxis is generally considered reasonable for hospitalized patients who are older than 40 years, are limited in their mobility for more than 3 days, or have at least one risk factor. A meta-analysis,68 including nine randomized studies comparing anticoagulant prophylaxis with no treatment in hospitalized medical patients, showed that anticoagulant prophylaxis is effective in preventing symptomatic VTE. All these trials included only patients considered to be at high risk for VTE because they had been hospitalized for such conditions as congestive heart failure, acute and chronic respiratory failure, acute infectious disease or rheumatologic disease. In the three largest randomized trials, the administration of anticoagulant prophylaxis in hospitalized patients decreased the risk of VTE 3-, 2- and two-fold, respectively. In the first randomized study (MEDENOX), 1102 patients were randomly assigned to receive enoxaparin or placebo.69 Patients randomized to prophylaxis with 40 mg of enoxaparin daily had a significantly lower rate of VTE than the placebo group (5.5 versus 14.9%, P<0.001). In the second study, 3706 patients received deltaparin or placebo;70 deltaparin significantly decreased the rates of VTE (2.8 versus 5.0%, P=0.002). In the third study, 849 hospitalized patients received fondaparinux or placebo.71 Once again, fondaparinux significantly reduced the incidence of VTE (5.6 versus 10.5%, P=0.03).

No study has directly compared different commonly used anticoagulant regimens. A meta-analysis of eight trials comparing unfractionated heparin with low-molecular-weight heparin (LMWH) for prophylaxis in high-risk hospitalized patients72 showed no significant differences between the two treatment groups in the rates of VTE, but patients receiving LMWH had a twofold decrease in the risk of major bleeding (relative risk, 0.48; 95% CI, 0.23–1.00).

Recent recommendations73 are based on the above-summarized results and are consistent with the guidelines of the American College of Chest Physicians.74 They strongly recommend the use of either unfractionated or LMWH in acutely ill hospitalized patients with heart failure, severe respiratory disease, acute stroke, immobility or multiple risk factors.

Like medical patients, surgical patients also derive significant benefit from thromboprophylaxis with LMWH.74 Individual trials of antiplatelet therapy, usually used to prevent arterial thromboembolism, revealed discrepant results, but a meta-analysis indicated a reduction of about one quarter in the risk of VTE in surgical and high-risk medical patients who received antiplatelet therapy.75 In a large randomized study, 17 444 patients undergoing orthopedic surgery were randomized to receive 160 mg per day of aspirin or placebo. VTE occurred in 1.6% of patients assigned aspirin compared with 2.5% of those assigned placebo, with an absolute reduction of the risks of VTE of about one third.76

VTE prophylaxis in cancer patients

Very few randomized studies in cancer patients who received anticoagulant prophylaxis or placebo are available. The previously described three studies on hospitalized patients included only a small number of cancer subjects, and they were not balanced for the additional risk factors that occur in cancer patients.69, 70, 71 With these limitations, a subset analysis of cancer patients in the MEDENOX study reported that enoxaparin reduced by twofold the risk for VTE (relative risk 0.50, 95% CI 0.14–1.72) in the cancer cohort.77

In one randomized trial,78 311 women with stage IV breast cancer were randomized to receive low-dose warfarin or placebo for the duration of their multiagent chemotherapy. Warfarin was given at 1 mg daily for the first 6 weeks and then the dose was adjusted to maintain the international normalized ratio (INR) at 1.3–1.9. VTE was observed in 4% of patients receiving placebo and in 0.6% of those taking low-dose warfarin. The VTE risk was reduced by sixfold in warfarin patients (P=0.03). No difference in any major bleeding was found. Despite these results, the use of low-dose warfarin is not frequently used in cancer patients for a number of reasons. First, low-dose warfarin is poorly tolerated in some patients and the use of low-dose warfarin with INR monitoring is a laborious task often unattractive to both patients and physicians. Second, the relatively low risk of VTE of 4% in the control patients in this study raises the question of whether routine prophylaxis is warranted. Third, the influence of cytochrome P-450 CYP2C9 polymorphisms and warfarin-drug interactions may increase warfarin sensitivity and lead to over anticoagulation with higher risk of hemorrhage.79 Finally, there has been no other study that confirms these findings.

VTE prophylaxis in myeloma patients receiving thalidomide or lenalidomide

Given the high risk of VTE with combination regimens including either thalidomide or lenalidomide, at least all newly diagnosed patients should receive thromboprophylaxis. To address this issue several studies have added anticoagulant prophylaxis to induction therapies (Table 3). In one study, the thalidomide–dexamethasone combination was delivered at diagnosis without any prophylaxis and the incidence of VTE was 26%. The protocol was then amended, low-fixed-dose prophylactic warfarin (1.25 mg daily) was introduced and the incidence of VTE dropped to 13%.35 In another study thalidomide, dexamethasone and low-fixed-dose warfarin were administered; the incidence of VTE, at 25%, did not appear to be impacted.31 In a rather small series of 26 patients who received thalidomide–dexamethasone at diagnosis, either therapeutic LMWH or warfarin (INR 2.0-3.0) was used, and VTE was seen in 8%.80

Table 3 Venous thromboembolism incidence in trials of thalidomide or lenalidomide with thromboprophylaxis in newly diagnosed patients

In a randomized trial, melphalan, prednisone and thalidomide were administered as induction therapy. In the first 65 patients who did not receive anticoagulant prophylaxis, the incidence of VTE was 20%, but dropped to 3% when enoxaparin was introduced at 40 mg per day for the first 4 months of therapy. All thromboembolic events occurred within 2 months after the discontinuation of enoxaparin.25 In a randomized study, 412 newly diagnosed patients received vincristine–doxorubicin–dexamethasone or thalidomide–doxorubicin–dexamethasone. Patients who received thalidomide were treated with nadroparin. The incidence of VTE was 5% in the control group and 9% in the thalidomide group, with all events occurring in the first 6 months of therapy.81 In a smaller study, 50 patients received thalidomide, pegylated liposomal doxorubicin, dexamethasone and low-fixed-dose warfarin (1.25 mg per day), and the incidence of DVT was 14%.82 In another study, 105 patients received a combination of pegylated doxorubicin, vincristine, thalidomide and dexamethasone at diagnosis without any prophylaxis; VTE incidence was 58%. The protocol was then amended and the remaining 58 patients received aspirin (81 mg per day), resulting in a VTE incidence of 18%.44

In one study, 256 newly diagnosed myeloma patients received multiagent chemotherapy (including doxorubicin, dexamethasone, etoposide, cyclophosphamide, cisplatin) with or without thalidomide. Without anticoagulant prophylaxis, VTE was 14% in patients who received chemotherapy only and 34% in those who received chemotherapy plus thalidomide. VTE was 31% in patients who received chemotherapy, thalidomide and low-fixed-dose warfarin (1 mg per day), but 15% in those who received chemotherapy, thalidomide and enoxaparin (40 mg per day).83 In another study, the incidence of VTE among 162 patients randomly assigned to multiagent chemotherapy plus thalidomide versus no thalidomide was 34 versus 18%, respectively. The protocol was subsequently amended and LMWH was introduced, but VTE remained at 24% among the patients enrolled in the multiagent chemotherapy plus thalidomide group, and at 15% in the patients enrolled in the multiagent chemotherapy control group.51 These data clearly show that the combination of multiagent chemotherapy with thalidomide causes the highest risk of VTE, and that LMWH at a prophylactic dose may not effectively prevent this adverse event.

Among 34 patients who received lenalidomide, dexamethasone and aspirin (80–325 mg per day) at diagnosis, VTE was as low as 3%.84 In a larger randomized study, newly diagnosed patients received lenalidomide with high-dose dexamethasone (480 mg per month) or low-dose dexamethasone (160 mg per month); the incidence of VTE was 23 and 8%, respectively, without any prophylaxis, but dropped to 14 and 5%, respectively, after the introduction of aspirin.58 This study clearly suggests both that high-dose dexamethasone by itself represents a major risk factor for VTE, and that aspirin prophylaxis seems appropriate in patients treated with low-dose dexamethasone. In another trial, patients received melphalan, prednisone and lenalidomide plus aspirin (100 mg per day), and VTE was 5%.85 In a combination study of lenalidomide, doxorubicin and dexamethasone, 85% of patients received erythropoietin therapy; the incidence of VTE was 9% with the use of aspirin (81 mg per day).86 Numbers are limited and only a few trials have addressed the question of VTE prophylaxis with lenalidomide-containing regimens. The dose of aspirin is still an open issue: on the one hand, the full dose (325 mg) inhibits both prostaglandins and prostacyclines, and on the other hand, the 81–162 mg dose inhibits only the prostaglandins, leaving the antiplatelet protective prostacycline levels intact.87 With these limitations, aspirin nevertheless seems an effective anticoagulant prophylaxis for lenalidomide treatment.

A black box warning was recently added to the package inserts for thalidomide and lenalidomide, indicating that patients treated with these drugs and dexamethasone may benefit from VTE prophylaxis.88, 89 The American College of Chest Physicians recommends the use of LMWH for VTE prophylaxis in high-risk cancer patients and strongly recommends against the use of aspirin.74 Randomized trials are urgently needed to define the best anticoagulant prophylaxis. On the one hand, full-dose warfarin with a target INR of 2.0–3.0 and LMWH are both highly effective, but are cumbersome and require close monitoring, in the case of warfarin, or subcutaneous injections, in the case of LMWH. Moreover, elderly patients may have difficulty complying with and following these strategies. On the other hand, aspirin as well as low-fixed-dose warfarin are quite simple options, but their efficacy must be validated.

In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. The treatment decision needs to be individualized based on the type of therapy and patients' individual risk factors.

Recommendations in myeloma patients receiving thalidomide or lenalidomide

The choice of thromboprophylaxis needs to be modified depending on the baseline risk of VTE associated with a given regimen. The goal should be to use the safest and least cumbersome form of thromboprophylaxis that reduces the risk of VTE to at least below 10%.


In published articles, thalidomide alone as induction therapy or maintenance after chemotherapy has consistently shown an incidence of VTE below 5%.30, 31, 54 In accordance with these data, anticoagulant prophylaxis is not recommended for patients receiving single-agent thalidomide. In newly diagnosed patients, who received the combination of thalidomide and dexamethasone, the risk of VTE was effectively reduced by full-dose warfarin, while low-fixed-dose warfarin was ineffective31, 35, 80 and no report is available for either LMWH or aspirin. For newly diagnosed patients treated with combinations including melphalan, LMWH was quite effective, but no other anticoagulant prophylaxis has been studied.25 Low-fixed-dose warfarin and full-dose aspirin were ineffective in patients who received thalidomide plus doxorubicin or multiagent chemotherapies.44, 83 LMWH was equally ineffective for the combination of thalidomide and doxorubicin, except when used in a regimen containing bortezomib.90 LMWH with the combination of thalidomide and multiagent chemotherapies was not effective, with a 24% incidence of VTE.51 The heterogeneity of data reported in the literature does not allow a precise recommendation. In the majority of studies, both LMWH and full-dose warfarin were effective, while results with aspirin were negative or not available. In relapsed/refractory patients, very limited data are available on the efficacy of thromboprophylaxis. The risk of VTE (2–15%) at relapse is much lower than at the time of diagnosis (3–34%). For these reasons, anticoagulant prophylaxis in relapsed patients may be suggested only in those with a high risk of VTE.


Lenalidomide alone does not induce a high risk of VTE and thromboprophylaxis is not suggested when lenalidomide is used as a single agent. In the reported studies, aspirin has been appropriate prophylaxis in patients who received lenalidomide in combination with low-dose dexamethasone, melphalan or doxorubicin, reducing the incidence of VTE to less than 10%.59, 84, 85, 86 High-dose dexamethasone is an additional risk factor and may mandate the delivery of more aggressive prophylaxis, such as LMWH or full-dose warfarin.

Choice of thromboprophylaxis

Thromboprophylaxis should be tailored to the presence of risk factors that may increase the risk of VTE, as shown in Table 4. The relative risk of these factors is quite heterogeneous, varying from 2 to 40. Accordingly, the hazard ratio of a specific risk should be taken in account in the choice of the appropriate anticoagulant prophylaxis.

Table 4 Risk assessment model for the management of venous thromboembolism in multiple myeloma patients treated with thalidomide or lenalidomide

Risk factors

  • Individual risk factors, such as, age, obesity, history of VTE, central-venous catheter, comorbidities (diabetes, infections, cardiac diseases), surgical procedures (including vertebroplasty and kyophoplasty) and inherited thrombophilia;

  • myeloma-related risk factors such as diagnosis per se as well as hyperviscosity;

  • therapy-related risks such as high-dose dexamethasone, doxorubicin or multiagent chemotherapies.

  • Both individual and myeloma-related risks of VTE should be taken into account in determining the type of thromboprophylaxis. Therapy-related risk factors should be considered, per se, high-risk factors.


  • Although aspirin is more appealing because of its convenience and ease of administration, the rate of thrombosis, especially in patients treated with thalidomide-based combinations is relatively high when full-dose is used. Until further evidence becomes available, aspirin should only be recommended for low-risk patients, such as those with no risk factor or one individual/myeloma-related risk factor;

  • LMWH or full-dose warfarin should be recommended in the presence of at least two individual/myeloma-related risk factors;

  • LMWH or full-dose warfarin should be considered in all patients who receive high-dose dexamethasone or doxorubicin or multiagent chemotherapy, independent of the presence of additional risk factors.

Given the limitations of the data upon which these recommendations are made, they should not be considered firm guidelines. The specific form of thromboprophylaxis recommended for a given patient ultimately should be based on the treating physician's best clinical judgment.

Without a published direct comparison of different anticoagulants in this setting, the choice may be based on specific clinical factors. For example, the initiation of anticoagulant prophylaxis and, more importantly, of antiplatelet agents, warrants exclusion of acquired von Willebrand disease, a rare but typical complication of lymphoproliferative diseases. Full-dose warfarin might best be avoided in patients in whom severe thrombocytopenia is likely to develop, such as with thalidomide or lenalidomide combined with chemotherapy. Note, though, that since such combinations are associated with a relatively high risk of VTE, LMWH (with its lower risk of secondary bleeding and a short half-life) is a more suitable option than either warfarin or aspirin. The most widely used schema of LMWH prophylaxis employ enoxaparin 40 mg once daily or deltaparin 5000 U once daily. Renal failure may limit the use of LMWH since renal clearance is the primary mode of elimination for this drug. In patients with reduced creatinine clearance (<30 ml min−1), LMWH is not an optimal choice because it may accumulate and increase the risk of bleeding. The best choice in this situation could therefore be full-dose warfarin.91, 92

The duration of prophylaxis may vary according to length of treatment. In cancer patients, the majority of VTE appear within 12 months from diagnosis.6 In myeloma, the vast majority of VTE has been reported in the first 6 months of treatment and all episodes occurred within the first 12 months.25, 52, 83 It may be reasonable to deliver anticoagulant prophylaxis for 4–6 months, while longer periods may be considered in the presence of additional patient- or treatment-specific risk factors.

The major adverse event of thromboprophylaxis is bleeding. Prophylactic doses of LMWH or aspirin confer very little risk of major bleeding. The vitamin K antagonist warfarin may slightly increase the risk of bleeding, especially, in patients who develop thrombocytopenia due to chemotherapy. Mechanical methods of prophylaxis including graduated compression stockings, the use of intermittent pneumatic compression devices and the venous foot pump reduce stasis within the leg veins and reduce the frequency of VTE. Unfortunately, no data from large studies are available. For patients in whom anticoagulant prophylaxis may carry excessive bleeding risk because of coexisting conditions such as active gastrointestinal or intracranial bleeding, the use of mechanical prophylaxis is a reasonable alternative.93, 94

Management of thromboembolism

Diagnosis of venous thromboembolism

DVT typically originates in the distal deep veins of the lower extremities but occasionally originates in the proximal veins, usually in response to trauma or surgery. Approximately 25% of untreated distal thromboses extend into the proximal veins, usually within a week after presentation.95 Proximal-vein thrombosis is complicated by PE, either symptomatic or asymptomatic, in approximately 50% of patients.96 In the case of suspect VTE, the diagnostic test of choice is compression ultrasonography, which has sensitivity and specificity of more than 95%. When PE is suspected, imaging remains the mainstay for diagnosis. Computed tomography pulmonary angiography is now the most widely used diagnostic test. Nuclear medicine techniques are used much less frequently. Magnetic resonance pulmonary angiography may be considered an alternative to computed tomography pulmonary angiography in patients who have contraindications to iodinated contrast media.97

Treatment of venous thromboembolism

All patients should be instructed to promptly inform the physician if clinical symptoms of VTE, such as, redness of the skin, pain in the extremities and/or chest, shortness of breath or rapid heartbeat occur. When deep-vein thrombosis is diagnosed, the goals of treatment are relief of symptoms and prevention of embolization and recurrence. The appropriate initial therapy for outpatients is LMWH. The optimal doses of the most commonly used LMWH are 100 U kg−1 every 12 h or 200 Ukg−1 daily for deltaparin; 1 mgkg−1 every 12 h or 1.5 mgkg−1 daily for enoxaparin; 86 Ukg−1 every 12 h or 171 Ukg−1 daily for nadroparin. If the risk of concomitant thrombocytopenia is low, oral anticoagulation should generally be started on the first day of treatment. Heparin should be given for a minimum of 5 days and not stopped until the patient's INR has been from 2.0 to 3.0 for 2 consecutive days. The optimal duration of therapy remains controversial. However, in cancer patients who have had a VTE, the risk of recurrence in the year after discontinuation of anticoagulant therapy is more than 10%.98 A randomized trial showed that long-term maintenance therapy with LMWH resulted in halving the recurrence risk as compared to maintenance with coumarin derivatives.99 On the basis of these results, extended therapy with LMWH should be considered in cancer patients balancing its advantages with such possible disadvantages as cost, the need for daily injections and the risk of osteoporosis.

In myeloma patients treated with thalidomide or lenalidomide who develop VTE, it is reasonable to briefly discontinue thalidomide or lenalidomide and resume the treatment when full anticoagulation has been established.81 As with other cancer patients, long-term therapy with LMWH, or with warfarin if heparin is not practical, should be continued for the total duration of thalidomide or lenalidomide therapy.


Myeloma patients treated with thalidomide or lenalidomide in combination with steroids or chemotherapy have an increased risk of VTE and hence require routine thromboprophylaxis. LMWH, full-dose warfarin and aspirin (especially lower dose) have all been shown to be effective in reducing the incidence of VTE. Although attractive, low-fixed-dose warfarin needs more extensive investigation. On the basis of available data, we recommend specific thromboprophylaxis strategies according to the type of therapy and the individual risk of patients (Table 4). Aspirin alone is recommended for patients who have either no risk factor or only one individual/myeloma-related risk factor. Patients who have at least two individual/myeloma-related risk factors or therapy-related (high-dose dexamethasone, doxorubicin or multiagent chemotherapy) should receive LMWH (equivalent to enoxaparin 40 mg once daily) or full-dose warfarin (target INR 2–3) as thromboprophylaxis. All patients with therapy-related risks (high-dose dexamethasone, doxorubicin or multiagent chemotherapy) should receive LMWH or full-dose warfarin. The ongoing randomized trials comparing aspirin, warfarin and LMWH will soon determine the optimal prophylaxis strategy. The goal remains to define a strategy that will reduce the risk of VTE below 10% in patients receiving thalidomide or lenalidomide.


  1. 1

    Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ . Trends in the incidence of deep vein thrombosis and pulmonary embolism. A 25-year population-based study. Arch Intern Med 1998; 158: 585–593.

    CAS  Google Scholar 

  2. 2

    Sallah S, Wan JY, Nguyen NP . Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thromb Haemost 2002; 87: 575–579.

    CAS  Google Scholar 

  3. 3

    Blom JW, Doggen CJ, Osanto S, Rosendaal FR . Malignancy, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715–722.

    CAS  Google Scholar 

  4. 4

    Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ . Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 1999; 159: 445–453.

    CAS  Google Scholar 

  5. 5

    Samama MM . An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415–3420.

    CAS  Google Scholar 

  6. 6

    Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ . Risk factors for deep vein thrombosis and pulmonary embolism. Arch Intern Med 2000; 160: 809–815.

    CAS  Google Scholar 

  7. 7

    Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism. Arch Intern Med 2002; 162: 1245–1248.

    Google Scholar 

  8. 8

    Ageno W, Squizzato A, Garcia D, Imberti D . Epidemiology and risk factors of venous thromboembolism. Semin Thromb Hemost 2006; 32: 651–658.

    Google Scholar 

  9. 9

    Bauer KA . The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001; 135: 367–373.

    CAS  Google Scholar 

  10. 10

    Bick RL . Cancer-associated thrombosis. N Engl J Med 2003; 349: 109–111.

    CAS  Google Scholar 

  11. 11

    Prandoni P, Falanga A, Piccioli A . Cancer and venous thromboembolism. Lancet Oncol 2005; 6: 401–410.

    Google Scholar 

  12. 12

    Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with mode-negative breast cancer who have estrogenreceptor-positive tumors. N Engl J Med 1989; 320: 479–484.

    CAS  Google Scholar 

  13. 13

    Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor positive breast cancer. J Natl Cancer Inst 1997; 89: 1673–1682.

    CAS  Google Scholar 

  14. 14

    White RH, Zhou H, Romano PS . Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost 2003; 90: 446–455.

    CAS  Google Scholar 

  15. 15

    Bona RD . Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Haemost 1999; 25: 147–155.

    CAS  Google Scholar 

  16. 16

    Bern MM, Lokich JJ, Wallach SR, Bothe Jr A, Benotti PN, Arkin CF et al. Very low doses of warfarin can prevent thrombosis in central venous catheters: a randomized prospective trial. Ann Intern Med 1990; 112: 423–428.

    CAS  Google Scholar 

  17. 17

    Monreal M, Alastrue A, Rull M, Mira X, Muxart J, Rosell R et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices-prophylaxis with low molecular weight heparin (Fragmin). Thromb Haemost 1996; 75: 251–253.

    CAS  Google Scholar 

  18. 18

    Verso M, Agnelli G . Venous thromboembolism associated with long term use of central venous catheters in cancer patients. J Clin Oncol 2003; 21: 3665–3675.

    Google Scholar 

  19. 19

    FDA Alert. Information For Healthcare Professional: Eyrthropoiesis Stimulating Agents (ESA) [Aranesp (Darbopoietin), Epogen (Epoietin Alfa), and Procrit (Epoietin Alfa)]. Food and Drug Administration: Rockville, MD, March 9, 2007. Accessed May 25, 2007, at

  20. 20

    Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M et al. Correction of anemia with epoietin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085–2098.

    CAS  Google Scholar 

  21. 21

    Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: 2071–2084.

    CAS  Google Scholar 

  22. 22

    Sallah S, Husain A, Wan J, Vos P, Nguyen NP . The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance. Ann Oncol 2004; 15: 1490–1494.

    CAS  Google Scholar 

  23. 23

    Srkalovic G, Cameron MG, Rybicki L, Deitcher SR, Kattke-Marchant K, Hussein MA . Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer 2004; 101: 558–566.

    Google Scholar 

  24. 24

    Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR, Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 431–436.

    CAS  Google Scholar 

  25. 25

    Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367: 825–831.

    CAS  Google Scholar 

  26. 26

    Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet 2007; 370: 1209–1218.

    CAS  Google Scholar 

  27. 27

    Zangari M, Saghafifar F, Mehta P, Barlogie B, Fink L, Tricot G . The blood coagulation mechanism in multiple myeloma. Semin Thromb Hemost 2003; 29: 275–282.

    CAS  Google Scholar 

  28. 28

    Fox EA, Kahn SR . The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 2005; 94: 362–365.

    CAS  Google Scholar 

  29. 29

    Auwerda JJA, Sonneveld P, de Maat MPM, Leebeek FWG . Prothromboic coagulation abnormalities in patients with newly diagnosed multiple myeloma. Haematologica 2007; 92: 279–280.

    Google Scholar 

  30. 30

    Rajkumar SV, Gertz MA, Lacy MQ, Dispenzieri A, Fonseca R, Geyer SM et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia 2003; 17: 775–779.

    CAS  Google Scholar 

  31. 31

    Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R . Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21: 16–19.

    CAS  Google Scholar 

  32. 32

    Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98: 492–494.

    CAS  Google Scholar 

  33. 33

    Neben K, Moehler T, Benner A, Kraemer A, Egerer G, Ho AD et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin Cancer Res 2002; 8: 3377–3382.

    CAS  Google Scholar 

  34. 34

    Schey SA, Cavenagh J, Johnson R, Child JA, Oakervee H, Jones RW . An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment. Leuk Res 2003; 27: 909–914.

    CAS  Google Scholar 

  35. 35

    Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P et al. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 2004; 89: 826–831.

    CAS  Google Scholar 

  36. 36

    Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20: 4319–4323.

    CAS  Google Scholar 

  37. 37

    Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R . Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol 2003; 121: 768–771.

    CAS  Google Scholar 

  38. 38

    Palumbo A, Bertola A, Falco P, Rosato R, Cavallo F, Giaccone L et al. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J 2004; 5: 318–324.

    CAS  Google Scholar 

  39. 39

    Dimopoulos MA, Anagnostopoulos A, Terpos E, Repoussis P, Zomas A, Katodritou E et al. Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma. Haematologica 2006; 91: 252–254.

    CAS  Google Scholar 

  40. 40

    Offidani M, Corvatta L, Marconi M, Olivieri A, Catarini M, Mele A et al. Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma. Hematol J 2004; 5: 312–317.

    CAS  Google Scholar 

  41. 41

    Osman K, Comenzo R, Rajkumar SV . Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med 2001; 344: 1951.

    CAS  Google Scholar 

  42. 42

    Schutt P, Ebeling P, Buttkereit U, Brandhorst D, Opalka B, Poser M et al. Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma. Eur J Haematol 2005; 74: 40–46.

    CAS  Google Scholar 

  43. 43

    Zervas K, Dimopoulos MA, Hatzicharissi E, Anagnostopoulos A, Papaioannou M, Mitsouli Ch et al. Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study. Ann Oncol 2004; 15: 134–138.

    CAS  Google Scholar 

  44. 44

    Baz R, Li L, Kottke-Marchant K, Srkalovic G, McGowan B, Yiannaki E et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005; 80: 1568–1574.

    CAS  Google Scholar 

  45. 45

    Sidra G, Williams CD, Russell NH, Zaman S, Myers B, Byrne JL . Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma. Haematologica 2006; 91: 862–863.

    CAS  Google Scholar 

  46. 46

    Wu P, Davies FE, Horton C, Jenner MW, Krishnan B, Alvares CL et al. The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide–vincristine–doxorubicin–methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis. Leuk Lymphoma 2006; 47: 2335–2338.

    CAS  Google Scholar 

  47. 47

    Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V et al. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J 2004; 5: 112–117.

    CAS  Google Scholar 

  48. 48

    Garcia-Sanz R, Gonzalez-Porras JR, Hernandez JM, Polo-Zarzuela M, Sureda A, Barrenetxea C et al. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004; 18: 856–863.

    CAS  Google Scholar 

  49. 49

    Kropff MH, Lang N, Bisping G, Dominé N, Innig G, Hentrich M et al. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma. Br J Haematol 2003; 122: 607–616.

    CAS  Google Scholar 

  50. 50

    Suvannasankha A, Fausel C, Juliar BE, Yiannoutsos CT, Fisher WB, Ansari RH et al. Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: a Hoosier Oncology Group Trial, HEM01-21. Oncologist 2007; 12: 99–106.

    CAS  Google Scholar 

  51. 51

    Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354: 1021–1030.

    CAS  Google Scholar 

  52. 52

    Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A et al. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 2002; 100: 1168–1171.

    CAS  Google Scholar 

  53. 53

    Lee C-K, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol 2003; 21: 2732–2739.

    CAS  Google Scholar 

  54. 54

    Zonder JA . Thrombotic complications of myeloma therapy. Hematology Am Soc Hematol Educ Program 2006; 1: 348–355.

    Google Scholar 

  55. 55

    Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100: 3063–3067.

    CAS  Google Scholar 

  56. 56

    Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B . Results of phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy. Blood 2001; 98: 775a (abstract [3226]).

    Google Scholar 

  57. 57

    Zonder JA, Barlogie B, Durie BG, McCoy J, Crowley J, Hussein MA . Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. Blood 2006; 108: 403.

    CAS  Google Scholar 

  58. 58

    Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Williams M et al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2007; 25: 447s (abstract [8025]).

    Google Scholar 

  59. 59

    Dimopoulos MA, Spencer A, Attal M, Prince M, Harousseau J, Dmoszynska A et al. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study (MM-010). Blood 2005; 106: 6a (abstract [6]).

    Google Scholar 

  60. 60

    Weber D, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer E et al. Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): results of a North American phase III study (MM-009). J Clin Oncol 2006; 24: 427s (abstract [7521]).

    Google Scholar 

  61. 61

    Morgan GJ, Schey SA, Wu P, Srikanth M, Phekoo KJ, Jenner M et al. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients. Br J Haematol 2007; 137: 268–269.

    Google Scholar 

  62. 62

    Richardson P, Schlossman R, Munshi N, Avigan D, Jagannath S, Alsina M et al. A phase 1 trial of lenalidomide (REVLIMID(R)) with bortezomib (VELCADE(R)) in relapsed and refractory multiple myeloma. Blood 2005; 106: 110a (abstract [365]).

    Google Scholar 

  63. 63

    Zangari M, Barlogie B, Thertulien R, Jacobson J, Eddleman P, Fink L et al. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma 2003; 4: 32–35.

    CAS  Google Scholar 

  64. 64

    Galli M, Elice F, Crippa C, Comotti B, Rodeghiero F, Barbui T . Recombinant human erythropoietin and the risk of thrombosis in patients receiving thalidomide for multiple myeloma. Haematologica 2004; 89: 1141–1142.

    CAS  Google Scholar 

  65. 65

    Knight R, DeLap RJ, Zeldis JB . Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006; 354: 2079–2080.

    CAS  Google Scholar 

  66. 66

    Cohen AT, Alikhan R, Arcelus JI, Bergmann JF, Haas S, Merli GJ et al. Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients. Thromb Haemost 2005; 94: 750–759.

    Google Scholar 

  67. 67

    Haas SK . Venous thromboembolic risk and its prevention in hospitalized medical patients. Semin Thromb Hemost 2002; 28: 577–584.

    Google Scholar 

  68. 68

    Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA . Meta-anlaysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146: 278–288.

    Google Scholar 

  69. 69

    Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341: 793–800.

    CAS  Google Scholar 

  70. 70

    Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ, PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110: 874–879.

    CAS  Google Scholar 

  71. 71

    Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. BMJ 2006; 332: 325–329.

    CAS  Google Scholar 

  72. 72

    Mismetti P, Laporte-Simitsidis S, Tardy B, Cucherat M, Buchmuller A, Juillard-Delsart D et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomized clinical trials. Thromb Haemost 2000; 83: 14–19.

    CAS  Google Scholar 

  73. 73

    Francis CW . Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007; 356: 1438–1444.

    CAS  Google Scholar 

  74. 74

    Geerts WH, Pineo GF, Heit JA, Berggvist D, Lassen MR, Colwell CW et al. Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 338–400.

    Google Scholar 

  75. 75

    Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: III. reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994; 308: 235–246.

    Google Scholar 

  76. 76

    Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295–1302.

  77. 77

    Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Fibrinolysis 2003; 12: 341–346.

    Google Scholar 

  78. 78

    Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A et al. Double-bind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: 886–889.

    CAS  Google Scholar 

  79. 79

    Taube J, Halsall D, Baglin T . Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816–1819.

    CAS  Google Scholar 

  80. 80

    Wang M, Weber D, Delasalle K, Alexanian R . Thalidomide–dexamethasone as primary therapy for advanced multiple myeloma. Am J Hematol 2005; 79: 194–197.

    CAS  Google Scholar 

  81. 81

    Minnema MC, Breitkreutz I, Auwerda JJ, van der Holt B, Cremer FW, van Marion AM et al. Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy. Leukemia 2004; 18: 2044–2046.

    CAS  Google Scholar 

  82. 82

    Offidani M, Corvetta L, Piersantelli MN, Visani G, Alesiani F, Brunori M et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood 2006; 108: 2159–2164.

    CAS  Google Scholar 

  83. 83

    Zangari M, Barlogie B, Anaissie E, Saghafifar F, Eddlemon P, Jacobson J et al. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation. Br J Haematol 2004; 126: 715–721.

    CAS  Google Scholar 

  84. 84

    Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106: 4050–4053.

    CAS  Google Scholar 

  85. 85

    Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma. J Clin Oncol 2007; 25: 4459–4465.

    CAS  Google Scholar 

  86. 86

    Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol 2006; 17: 1766–1771.

    CAS  Google Scholar 

  87. 87

    Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C . Low-dose aspirin for the prevention for atherothrombosis. N Engl J Med 2005; 353: 2373–2383.

    CAS  Google Scholar 

  88. 88

    US Food and Drug Administration Web site. Thalidomide package insert.,020785s031lbl.pdf. Accessed September 6 2006.

  89. 89

    US Food and Drug Administration Web site. Lenalidomide package insert. Accessed September 6 2006.

  90. 90

    Zangari M, Barlogie B, Lee CK, Tricot AE, Fassas A, Anaissie E et al. Protective effect of VELCADE® on thalidomide-associated deep vein thrombosis (DVT). Blood 2004; 104: 13a (abstract [4914]).

    Google Scholar 

  91. 91

    Cestac P, Bagheri H, Lapeyre-Mestre M, Sie P, Fouladi A, Maupas E et al. Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients. Drug Saf 2003; 26: 197–207.

    CAS  Google Scholar 

  92. 92

    Nagge J, Crowther M, Hirsh J . Is impaired renal function a contraindication to the use of low-molecular-weight heparin? Arch Intern Med 2002; 162: 2605–2609.

    Google Scholar 

  93. 93

    Thromboembolic Risk Factors (THRIFT) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. BMJ 1992; 305: 567–574.

    Google Scholar 

  94. 94

    Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P . Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl 3): 483S–512S.

    CAS  Google Scholar 

  95. 95

    Lagerstedt CI, Olsson CB, Fagher BO, Oqvist BW, Albrechtsson U . Need for long term anticoagulant treatment in patients with symptomatic calf-vein thrombosis. Lancet 1985; 2: 515–518.

    CAS  Google Scholar 

  96. 96

    Moser KM, Fedullo PF, LittleJohn JK, Crawford R . Frequent asymptomatic pulmonary embolism in patients with deep venous thrombosis. JAMA 1994; 271: 223–225.

    CAS  Google Scholar 

  97. 97

    Bozlar U, Gaughen JR, Nambiar AP, Hagspiel KD . Imaging diagnosis of acute pulmonary embolism. Expert Rev Cardiovasc Ther 2007; 5: 519–529.

    Google Scholar 

  98. 98

    Baglin T, Luddington R, Brown K, Baglin C . Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523–526.

    Google Scholar 

  99. 99

    Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Martin Prins MB et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146–153.

    CAS  Google Scholar 

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Palumbo, A., Rajkumar, S., Dimopoulos, M. et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 22, 414–423 (2008).

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  • thrombosis
  • prophylaxis
  • risk factors
  • thalidomide
  • lenalidomide

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