Deep Vein Thrombosis In Cancer Patients Research Articles

Usefulness of low-dose direct oral anticoagulants for peripheral deep vein thrombosis of the lower extremities in cancer patients with cancer bleeding lesions

Abstract Background Venous thromboembolism (VTE) is a frequent complication in cancer patients. VTE is often detected as asymptomatic peripheral deep vein thrombosis (DVT). Standard doses of anticoagulants are generally considered difficult to administer in cancer patients due to the high risk of bleeding. However, it has been reported that peripheral DVT worsening to proximal DVT in cancer patients due to increased coagulation tendency, and some strategy for peripheral DVT is required. And the adverse bleeding effects of DOACs have been reported to be dose-dependent. Purpose The aim of this study was to determine the optimal treatment strategy of peripheral DVT in patients with bleeding cancer lesions. In order to do this we compared no anticoagulation, low-dose direct oral anticoagulants (DOACs) and standard-dose DOACs in patients with and without bleeding cancer lesions. Methods A total of 224 consecutive patients with peripheral DVT of the lower extremities (excluding pulmonary thromboembolism or proximal DVT) were included from April 2019 to March 2020. Of these, 172 patients could be followed up by repeated ultrasound examinations for up to 2 years. We investigated retrospectively the change in ultrasound findings between first and second examinations (median interval 44 days). 163 patients were studied, excluding 9 patients who used warfarin or heparin. In 119 of these DOACs were applied, and 44 were without anticoagulation. If the treatment procedure had changed between the first and second ultrasound examinations main treatment procedure was selected and categorized. Results All the patients of low-dose and standard-dose DOACs groups had no major bleeding during follow up period. In the group with cancer bleeding lesion (n=45) there were 12 patients (70.1%) worsening DVT in the group without anticoagulation, 1 patient (4.3%) in the low-dose DOACs and 0 (0%) in the standard-dose DOACs group. There was significant worsening of DVT in the no anticoagulant group compared with low-dose DOACs (P<0.0001), but no significant difference between low-dose DOACs and standard-dose DOACs (P=0.63) in the group with bleeding (see Figure 1). In the group without cancer bleeding (n=118), worsening of DVT occurred in 16 patients (59.3%) without anticoagulation, in 6 patients (16.7%) with low-dose DOACs and in 4 patients (7.3%) with standard-dose DOACs. There was significant worsening of DVT in the no anticoagulant group compared with low-dose DOACs (P<0.0001), but no significant difference between the low-dose and standard-dose DOACs (P=0.16) in the group without bleeding (see Figure 2). Conclusion Low-dose DOACs were found to be as effective as standard-dose DOACs in treating peripheral DVT in cancer patients, with or without bleeding of the cancer lesion. Peripheral DVT treatment with low-dose DOACs can reduce worsening of DVT and should be one of the supportive treatments for the completion of cancer management.DVT in 3 groups with cancer bleedingDVT in 3 groups without cancer bleeding

Low-dose anticoagulation for peripheral deep vein thrombosis of the lower extremities in cancer patients

Abstract Background Venous thromboembolism (VTE) is a frequent complication in cancer patients and is often detected as asymptomatic peripheral deep vein thrombosis (DVT). However, guidelines for peripheral DVT have not been established in either general cardiology or onco-cardiology. Furthermore, in cancer patients, it is generally considered difficult to administer standard doses of anticoagulants due to the high risk of bleeding caused by thrombocytopenic tendency during chemotherapy, as well as bleeding lesions such as gastrointestinal and gynecological cancers. Treatment of peripheral DVT with direct oral anticoagulants (DOACs) may minimize the worsening of bleeding and prevent the transition to proximal DVT. Objective The purpose of this study was to investigate the optimal treatment for peripheral DVT in cancer patients. Methods 242 consecutive patients with peripheral DVT of the lower extremities (excluding complications of pulmonary thromboembolism or proximal DVT) were examined by venous ultrasound from April 2019 to March 2020. 190 patients could be followed up by ultrasound examination, for up to 2 years. The course of the DVT was retrospectively examined. In cases of anticoagulant therapy, standard and low dosage of DOACs were evaluated. Results 142 patients were treated with anticoagulant (AC) therapy (group AC(+)), 48 patients were without AC therapy (group AC(−)). (4 of the 142 patients were treated with warfarin and the rest with DOACs). DVT worsened in 8 patients (5.6%) in the AC(+) group and 23 patients (47.9%) in the AC(−) group. DVT worsening was significantly less in the AC(+) group (p<0.0001). There were no cases of worsening to proximal type in the AC(+) group and 4 cases (17.4%) in the AC(−) group. Of the 138 patients who used DOACs as AC therapy, 62 used half or less than the standard dose for maintenance (low-dose DOAC group), and 76 used the standard dose as maintenance (standard-dose DOAC group). In the low-dose DOAC group, DVT worsened in 5 cases, remained unchanged in 7 cases, and improved in 50 cases. In the standard-dose DOAC group, there were 4 cases of worsening DVT, 3 cases of no change, and 69 cases of improvement. There was no significant difference in the DVT treatment effect between the two groups. There were no thrombus-related deaths. Conclusion Peripheral DVT worsens in about half of cancer patients without anticoagulation, and 17% of these worsen to proximal VTE. In addition, low-dose DOACs are found to be as effective as standard-dose DOACs in treating peripheral DVT in cancer patients. Peripheral DVT treatment with low-dose DOACs can reduce the risk of bleeding complications and thrombus-related mortality in cancer patients and should be one of the supportive treatments for the completion of cancer management. Funding Acknowledgement Type of funding sources: None.

Correlation of Inflammation and Coagulation Markers with the Incidence of Deep Vein Thrombosis in Cancer Patients with High Risk of Thrombosis.

BackgroundDeep vein thrombosis (DVT) is a common complication and the second leading cause of death in cancer patients. Pro-inflammatory stimuli in the cancer microenvironment induce nuclear factor kappa B (NF-κB) signaling pathway that plays an integral role in immunothrombosis mechanism.ObjectiveTo investigate the role of inflammatory and coagulation biomarkers in the development of DVT in cancer patients with high risk of thrombosis (Khorana score ≥2).Subjects and methodsThis study was a cross-sectional study at Dr. Kariadi General Hospital. The serum levels of proinflammatory cytokines, ie, NF-κB, interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and coagulation biomarkers, ie, tissue factor (TF), prothrombin fragment F1+2 (F1+2), fibrinogen and D-dimer were measured in newlydiagnosed cancer patients with a highrisk of thrombosis. Color duplex sonography was used for DVT screening.ResultsFrom January to November 2021, there were 83 eligible patients. DVT was confirmed in 8 subjects (9.63%). Univariate analysis revealed a significant difference between the median age of patients with DVT compared to non-DVT patients, 49.5 years (range: 23–60 years) and 42 years (range: 19–60 years), with p=0.046. D-dimer level was higher in DVT patients [(6.020 µg/L, range 2.090–20.000) vs (1.940 µg/L, range 270–20.000), p=0.005]. Multivariate analysis revealed age and D-dimer were significantly correlated with DVT incidence. In all patients, there were significant positive correlations between several inflammatory and coagulation activation parameters, which were IL-6 with D-dimer and F1+2, CRP with F1+2 and D-dimer as well as TNF-α with F1+2. However, these findings were not shown in DVT patients.ConclusionIn cancer patients with a high risk of thrombosis, age and D-dimer level are the significant variables towards the incidence of DVT. In patients with DVT, there was no significant correlation between inflammatory and coagulation activation parameters.

Particular aspects in patients with paraneoplastic deep vein thrombosis: from a shadowy diagnosis to a routinely met pathology

The oncological patient presents many pathophysiological particularities, including a hypercoagulable state, which causes frequent thromboembolic complications. Furthermore, the side effects of chemotherapy, laborious surgical interventions and the poor performance status favor the occurrence of deep vein thrombosis (DVT). The aim of this retrospective study is to identify the prevalence of paraneoplastic DVT in patients admitted in the Cardiology Department of the “Sf. Spiridon” County Clinical Emergency Hospital from Iași and to establish the correlations between the DVT, type of neoplasia and certain particularities of the patients. Material and methods: The current retrospective study was conducted over a two-year period and enrolled 100 patients divided into two groups based on the presence or absence of a neoplasia (25 patients having a tumoral pathology and 75 patients without such a comorbidity). All study participants underwent a complete clinical examination and were assessed through biochemical and echocardiographic parameters. Results: Various tumor locations were identified in the 25 patients with a malignancy, the most prevalent being the colorectal cancer (6 cases, 24% of total), followed by the lung cancer (4 cases, 16%) and, with a similar occurrence, the brain, ovarian and breast cancer (2 cases each, 8%). Among the patients with neoplasia, 13 had a history of cancer (52% of cases from the neoplasia group), while for the remaining 12 patients it was a de novo diagnosis. Conclusions: Patients with DVT showed a significant cancer prevalence, either previously diagnosed or incidentally discovered. The increased risk of DVT in cancer patients is multifactorial and represents a diagnosis and therapeutic challenge. In our study, we recorded a slightly increased prevalence of cancer in women (56% vs. 44%), who had cervical cancer as the most common etiology (35.7%). On the other hand, male sex was associated with an increased frequency of colorectal cancer (36.4% of all cancers diagnosed in men), followed by lung cancer (27.3%).

Von Willebrand factor:antigen and ADAMTS-13 level, but not soluble P-selectin, are risk factors for the first asymptomatic deep vein thrombosis in cancer patients undergoing chemotherapy

BackgroundThere is a high incidence of deep vein thrombosis (DVT) among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is characterized by increased plasma levels of von Willebrand factor (vWF) and soluble P-selectin (sP-selectin), leading to the activation of endothelial cells and signaling cascades. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) is to control the activity of vWF and consequently the risk of thrombosis. The objective of this study was to investigate the roles of sP-selectin, vWF, and ADAMTS-13 as risk factors for the first episode of DVT in cancer patients undergoing chemotherapy.MethodsThis prospective cohort study was conducted at Dr. Kariadi Hospital, Indonesia, on 40 cancer patients. Prechemotherapy (baseline) and postchemotherapy sP-selectin, vWF antigen (vWF:Ag), and ADAMTS-13 plasma levels were determined with ELISAs before and 3 months after chemotherapy. The clinical characteristics of the patients, cancer type, cancer stage, chemotherapy regimen, ABO blood type, D-dimer level and Khorana risk score were also analyzed using logistic regression. Patients were observed for the possibility of developing DVT during chemotherapy.ResultsDVT was confirmed in 5 patients (12.5%) after a period of 3 months. In patients with DVT, sP-selectin and vWF were significantly higher while ADAMTS-13 was lower than in their counterparts. The levels of baseline vWF:Ag and ADAMTS-13, with cut-off points ≥ 2.35 IU/mL and ≤ 1.03 IU/mL, respectively, were found to independently predict the incidence of DVT. In the multivariate logistic regression analysis, the relative risk (RR) for DVT in patients with high vWF:Ag was 3.80 (95% CI 1.15–12.48, p = 0.028), and that for patients with low ADAMTS-13 was 2.67 (95% CI 1.22–23.82, p = 0.005). The vWF:Ag/ADAMTS-13 ratio and both vWF:Ag and ADAMTS-13 dynamics during treatment were also able to differentiate those with prospective DVT. However, sP-selectin and other covariates showed no statistical significance.ConclusionWe found that prechemotherapy plasma levels of vWF:Ag ≥ 2.35 IU/mL and ADAMTS-13 ≤ 1.03 IU/mL are independent risk factors for DVT incidence among cancer patients.

Diagnosing deep vein thrombosis in cancer patients with suspected symptoms: An individual participant data meta‐analysis

BackgroundA previous individual participant data (IPD) meta‐analysis showed that the Wells rule and D‐dimer testing cannot exclude suspected deep vein thrombosis (DVT) in cancer patients. ObjectivesTo explore reasons for this reduced diagnostic accuracy and to optimize the diagnostic pathway for cancer patients suspected of DVT. Patients and MethodsUsing IPD from 13 studies in patients with suspected DVT, DVT prevalence and the predictive value of the Wells rule items and D‐dimer testing were compared between patients with and without cancer. Next, we developed a prediction model with five variables selected from all available diagnostic predictors. ResultsAmong the 10 002 suspected DVT patients, there were 834 patients with cancer. The median prevalence of DVT in these patients with cancer was 37.5% (interquartile range [IQR], 30.8‐45.5), whereas it was 15.1% (IQR, 11.5‐16.7) in patients without cancer. Diagnostic performance of individual Wells rule items and D‐dimer testing was similar across patients with and without cancer, except “immobility” and “history of DVT.” The newly developed rule showed a pooled c‐statistic 0.80 (95% confidence interval [CI], 0.75‐0.83) and good calibration. However, using this model, still only 4.3% (95% CI, 3.0‐5.7) of the suspected patients with cancer could be identified with a predicted DVT posttest probability of <2%. ConclusionsLikely because of the high prevalence of DVT, clinical models followed by D‐dimer testing fail to rule out DVT efficiently in cancer patients suspected of DVT. Direct referral for compression ultrasonography appears to be the preferred approach for diagnosis of suspected DVT in cancer patients.

Biomarkers and Clinical Prediction Rules in the Diagnosis of Suspected Deep Vein Thrombosis: A Comparison of Cancer and Non-Cancer Patients

Introduction: Despite efforts toward prevention, thousands of patients suffer from venous thromboembolic disease (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE), each year; this results in significant morbidity and mortality. Clinical prediction rules, such as the Wells score, in conjunction with biomarkers like the D-dimer, are suggested by national guidelines to aide in evaluating for DVT. Substantial interest exists in developing improved diagnostic testing strategies and algorithms to limit the need for more costly, time consuming, and/or invasive testing. Novel biomarkers, like the soluble P selectin (sP-Sel), a cell adhesion molecule that functions to mediate thrombus formation and amplification, have shown promise in this area.While cancer patients suffer from a high burden of VTE, the D-dimer and Wells score are less helpful in this group. This is due to non-specific D-dimer elevations in these patients, and cancer being part of the Wells risk stratification schema. We sought to identify a more specific combination of biomarkers and Wells score, for the diagnosis of DVT that would apply to cancer patients as well.Methods: We previously performed a prospective cohort study of adults presenting with symptoms of DVT afflicting the upper or lower extremities (Vandy et al. J Vasc Surg Venous Lymphat Disord., 2013). Patients were enrolled from December 2008 to July 2013. Those with isolated calf DVT, superficial venous thrombosis, pregnant or breastfeeding, on therapeutic anticoagulation, or with symptoms of simultaneous upper and lower DVT were excluded. After informed consent was obtained, clinical characteristics and biomarkers (D-dimer, C-reactive protein (CRP), Von Willebrand Factor activity (VWF), and sP-Sel) were collected, and duplex ultrasonography was performed to determine if DVT was present. In this subset analysis, cancer patients were compared to non-cancer patients with regards to thrombotic risk factors, biomarker values, and to assess the test characteristics of various combinations of biomarkers and Wells score.Results: A total of 373 patients were enrolled, 151 (40%) in the cancer group, compared to 222 (60%) in the non-cancer group. Cancer patients were more likely to have a DVT on confirmatory testing (58.9% vs. 43.2%). Cancer patients tended to be older, male, have a lower BMI, more recent acute illness, and more central lines, relative to the non-cancer group. Non-cancer patients were more likely to have other potential risk factors for thrombosis, i.e. recent surgery, oral contraceptive use, and a family history of thrombosis. Biomarker values for CRP and sP-Sel were similar, however VWF and D-dimer values were significantly higher in the cancer patients (see table).D-Dimer > 500 with Wells score ≥ 2 was less specific for the diagnosis of DVT among cancer patients compared to non-cancer patients (p=0.003). However, D-Dimer ≥ 500 with sP-Sel ≥ 90 showed not only high specificity, but that specificity was not different between the cancer and non-cancer populations (p=0.88). sP-Sel ≥ 90 and Wells ≥ 2 had similar performance characteristics in both groups as well (p=0.54 for specificity, p=0.14 for positive predictive value (PPV)).Conclusion: Co-morbid risk factors for thrombosis among cancer patients included an older age, male gender, and an increased use of central lines. This group was less likely to have other potential thrombotic risk factors like family history or recent surgery.Our results concur with the finding that the D-dimer, combined with a clinical prediction rule, is not as helpful for DVT in cancer patients. Moreover, this study further supports sP-Sel as a specific test for DVT, that can be combined with clinical information (Wells score) or other laboratory data (D-dimer) to reflect the presence of DVT and potentially rule in clot; the test seems equally useful for both cancer and non-cancer populations. This could potentially be used to guide initial patient management in scenarios where imaging or further testing is not immediately available, such as in an outpatient clinic or rural area. Further exploration of the optimal strategy for utilizing biomarkers and clinical prediction rules in the diagnosis of DVT in cancer is needed. [Display omitted] DisclosuresSood:Bayer: Research Funding.

Increased Levels of NF-kB-Dependent Markers in Cancer-Associated Deep Venous Thrombosis.

Several studies highlight the role of inflammatory markers in thrombosis as well as in cancer. However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations. In the present study, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), matrix metalloproteases-9 (MMP-9), vascular endothelial growth factor (VEGF), tissue factor (TF), fibrinogen and soluble P-selectin, were analyzed in plasma and in monocyte samples from 385 cancer patients, of whom 64 were concomitantly affected by DVT (+). All these markers were higher in cancer patients DVT+ than in those DVT-. Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-. Significant correlation between data obtained in plasma and monocyte samples was observed. NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-. To further demonstrate the involvement of NF-kB activation by the above mentioned molecules, we treated monocyte derived from healthy donors with a pool of sera from cancer patients with and without DVT. These set of experiments further suggest the significant role played by some molecules, regulated by NF-kB, and detected in cancer patients with DVT. Our data support the notion that NF-kB may be considered as a therapeutic target for cancer patients, especially those complicated by DVT. Treatment with NF-kB inhibitors may represent a possible strategy to prevent or reduce the risk of DVT in cancer patients.

IL-6-174 G > C and MMP-9-1562 C > T polymorphisms are associated with increased risk of deep vein thrombosis in cancer patients

BackgroundA growing body of evidence shows an increased risk of deep vein thrombosis (DVT) among cancer patients. Novel markers are needed to identify patients prone to develop DVT. The aim of the present study was to determine whether IL-6-174 G>C and MMP-9-1562 C>T polymorphisms may influence the development of DVT in cancer patients. MethodsPolymorphisms of IL-6 and MMP-9 were analyzed in 320 DNA samples from cancer patients (DVT+ and DVT−) and in 215 healthy donors. IL-6 and MMP-9 plasma levels were also measured by ELISA. ResultsDistribution of −174 IL-6 genotype and −1562 MMP-9 were similar between healthy controls and DVT− cancer cases (OR=0.98 and 1.04, respectively). Different results were obtained by compared healthy controls with DVT+ cancer patients. −174 IL-6 GG polymorphism was associated to DVT (OR=2.07; 95% CI: 1.30–3.30), as well as −1562 MMP-9 CC polymorphism (OR=2.60; 95% CI: 1.48–4.57). ConclusionThe results of the present study support a model in which the GG and CC genotypes, respectively for IL-6-174 G>C and MMP-9-1562 C>T polymorphisms, are associated with a risk of DVT in cancer patients by inducing the release of IL-6 with subsequent increment of MMP-9. Overall, these findings may contribute to the management of DVT in cancer patients.

Soluble P-Selectin for the Diagnosis of Deep Vein Thrombosis (DVT) in Cancer Patients

AbstractAbstract 3406 Background:Accurate and early diagnosis of DVT is crucial to prevent untreated DVT from progressing to fatal PE. Clinical scoring systems used in combination with D-dimer for DVT diagnosis can exclude but not confirm DVT, and vascular ultrasound is still needed. Diagnostic algorithms are challenging in cancer, where the burden of VTE is higher, clinical scores less accurate and baseline D-dimer frequently elevated. Soluble P-selectin (sPsel) is expressed upon activation of platelets and endothelial cells by a thrombotic stimulus. sPsel is known to be important in predicting VTE in cancer patients. We previously showed that elevated sPsel in combination with Wells’ score can confirm lower extremity (LE) DVT with a positive predictive value (PPV) of 100% in a general patient cohort (Clin Appl Thromb Hemost, 2011; 17:425–31). To date, no validated biomarker can establish VTE in cancer patients. The primary objective of this analysis was to identify a biomarker that alone or in combination confirms the presence of acute DVT in cancer patients. Secondary objective was to apply the previously derived model to patients with active cancer. Methods:Patients referred to the diagnostic vascular ultrasound lab with signs or symptoms concerning for acute LE DVT were enrolled in a prospective cohort study. Following informed consent, patients underwent LE doppler, clinical assessment, and blood draw for biomarkers sPsel, D-dimer, and CRP. Exclusion criteria were age < 18, isolated calf vein DVT, pregnant, nursing, or on therapeutic anticoagulation. Only subjects with active cancer, defined as actively receiving anti-tumor therapy, or with physical or radiological evidence of malignancy within 6 months of enrollment, were included in this subset analysis of previously published data. Continuous and categorical values were compared with t-test and chi-squared test, respectively. PPV and NPV were estimated from cut points. Results:Between 2006 to 2012, 442 patients with LE DVT were eligible for analysis; 99 had active cancer. 60 cases (63% male) had a confirmed proximal LE DVT; 39 controls (56% male) had leg pain but negative for VTE. Cases had increased prior history (p=0.001) and family history of VTE (p=0.039). No difference in mean age (62.4 vs. 61.8 years), BMI, or active chemotherapy was seen. Cancer types (%) included: breast (4), lung (10), hematologic (22), melanoma (3), GI (16), GU (16), Gyn (11), brain (4), other (6). sPsel, D-dimer, CRP, and Wells' score were all elevated in cases versus controls at time of DVT diagnosis.BiomarkerPositive DVT Mean (SE)Negative DVT Mean (SE)p-valuePsel (ng/mL)86.70 (4.33)53.20 (5.34)<0.0001D-dimer (mg/L)6.31 (0.43)2.35 (0.50)<0.0001CRP (μg/mL)4.87 (0.63)2.86 (0.77)0.044Wells' score3.53 (0.16)2.80 (0.19)0.003Application of our previously derived model of sPsel + Wells' with cut point of 2 yielded a similar PPV but lower NPV in active cancer versus non-cancer patients. Had imaging not been available, we could have ruled in or out 27.5% (27/98) patients for LE-DVT with this rule. D-dimer + Wells' had a superior NPV, albeit in a low number of patients. Raising the Wells' cut point to 3 (to accommodate a point assigned in the score for active cancer) improved the PPV for both the sPsel and D-dimer models, at the expense of the NPV in the D-dimer model. 38% (37/98) cancer patients could be ruled in or out for LE-DVT without imaging in this sPsel model.Non-cancerActive cancerRules to confirm DVTPPVsPsel ≥ 90 ng/mL + Wells’ ≥ 284%87%D-dimer ≥ 0.5 mg/L + Wells’ ≥ 257%60%sPsel ≥ 90 ng/mL + Wells’ ≥ 391%95%D-dimer ≥ 0.5 mg/L + Wells’ ≥ 362%66%Rules to exclude DVTNPVsPsel ≤ 60 ng/mL + Wells’ < 288%50%D-dimer < 0.5 mg/L + Wells’ < 294%100%sPsel ≤ 60 ng/mL + Wells’ < 381%53%D-dimer < 0.5 mg/L + Wells’ < 387%40% Conclusions:D-dimer is the most commonly used marker to rule out acute DVT. However, due to its low specificity and elevated baseline value in patients with cancer, it cannot be used to confirm clot presence. In patients with active cancer presenting with potential symptoms of LE DVT, sPsel, D-dimer, CRP and Wells’ criteria were all elevated in cases versus controls. A combination of sPsel ≥ 90 ng/mL + Wells’ ≥ 3 was superior to the D-dimer + Wells score to rule in clot at the time of presentation. D-dimer remained superior to rule out clot in this population. In the future, rapid VTE diagnosis through the use of novel biomarkers such as sPsel may help improve morbidity and mortality. Disclosures:No relevant conflicts of interest to declare.

Epidemiologic analysis of proximal deep vein thrombosis in thai patients: Malignancy, the predominant etiologic factor

From January 1995 to December 2000, 1555 patients (585 males, 970 females, with a mean age of 52.3 years) with acute limb swelling underwent diagnostic duplex venous ultrasonagraphy at the Vascular Surgery Unit, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. Of these 1555 patients, 514 (188 males, 326 females, with a mean age of 53 years) were diagnosed with deep vein thrombosis (DVT). DVT was found mainly in the lower extremities, occurring in 506 of these 514 cases (98.4%). The affected vein in the lower extremity was found more commonly in the left side (359 limbs) than in the right side (184 limbs) (p < 0.001). DVT also occurred in the upper extremities in 8 of the 514 cases (1.6%). In this study, out of 308 patients with DVT in their lower limbs, DVT was associated with malignancy in 123 cases (39.9%), with postoperation in 48 cases (15.6%), and with limb immobilization in 38 cases (12.3%). Malignancy-related DVT was found to be more extensive and virulent and was associated with high morbidity and mortality. Further study should be conducted to investigate the role of anticoagulant drugs for the prevention of DVT in cancer patients. Perhaps the spectrum of DVT as presented in this series is characteristic not only of the Thai population but also of the populations of other Asian countries.

Incidence and Predictive Factors of Symptomatic Thrombosis Related to Peripherally Inserted Central Catheters In Chemotherapy Patients

AbstractAbstract 4206 Background:The use of peripherally inserted central catheter (PICC) lines has significantly enhanced the management of chemotherapy patients. While deep vein thrombosis (DVT) of a catheterized vein is a common and potentially serious complication, such thromboses are frequently asymptomatic. Indeed, the true incidence of symptomatic catheter-related DVT in cancer patients remains unclear, and there is a lack of reliable data on the risk factors of catheter-related thrombosis. Moreover, little work has focused on predictive factors of symptomatic events related specifically to PICC lines in chemotherapy patients. Methods:We performed a retrospective cohort study of consecutive cancer patients who received an ultrasound guided PICC line for the administration of chemotherapy at The Ottawa Hospital between September 1, 2009 and December 31, 2009. Relevant demographic, clinical and laboratory characteristics were collected, including factors previously suggested as being predictive of catheter-related DVT. Univariate and multivariate logistic regression analyses were performed for symptomatic PICC-related DVT, defined as a clot in one or more of the deep veins of the catheterized arm leading to and confirmed by Doppler ultrasound. Results:In total, 340 cancer patients obtained PICC lines for the administration of chemotherapy. Of these patients, 19 (5.6%; 95% CI: 3.6–8.6) developed symptomatic PICC-related DVT. In the univariate analysis, demographic factors were not significant predictors of PICC-related DVT, including gender, age, body mass index and smoking status. Interestingly, factors previously suggested as being associated with central venous catheter-related clots in prior studies were not significant determinants in our analysis; in particular, side of line placement (p=0.281), catheter tip location (p=0.539), number of lumens (p=0.911), number of insertion attempts (p=0.964), and catheter repositioning (p=0.731) were not predictive. Importantly, patients with diabetes were three times more likely to develop PICC-related DVT (OR 3.0, p=0.039), while the presence of chronic obstructive pulmonary disease (COPD) or metastatic cancer increased the odds of developing PICC-related DVT (OR 3.3, p=0.078; OR 2.3, p=0.083 respectively). Diabetes remained a significant risk factor after adjustment for effect of metastases and COPD (OR 3.175, p=0.039). Further, the presence of metastases was a significant predictor (OR 3.34, p=0.024) in our multivariate model. Conclusion:Symptomatic PICC-related DVT are frequent in cancer patients receiving chemotherapy. Previously described factors associated with catheter-related thrombosis, such as tip location, lumen size, and side of catheter, were not predictive of PICC-related DVT in our study. In addition, known risk factors for DVT, including gender and obesity, were not predictive, which may suggest an alternate pathophysiologic process in this particular population. Diabetes, advanced disease and COPD appear to increase the risk of developing PICC-related DVT in chemotherapy patients, although the biologic mechanism of this result is not clear. To our knowledge, this is the largest study to date to exclusively examine PICC-associated DVT in cancer patients. Further studies with larger number of patients are required to better characterize risk factors and their relative impact in developing PICC-related DVT. Disclosures:Tay:Ortho-Biotech:Honoraria;Pfizer: Honoraria.

Addressing the Issue of the Pathogenesis of Deep Vein Thrombosis In Cancer

AbstractAbstract 4220The risk of thrombotic complications during tumor development has been the focus of several clinical studies over the past decades. Thrombotic disease is a common cause of death in cancer patients and almost one in five of all symptomatic cases of Deep Vein Thrombosis (DVT) are thought to be cancer related. Tumor cells generate and profit from a local and systemic hypercoagulable state, which promotes tumor growth, angiogenesis, and metastasis. The resulting procoagulant state is responsible for the heightened risk for thrombotic complications and the etiology of the resulting DVT event. However, despite the fact that some molecules, such as tissue factor, have recently been described as potential modulators of clot formation in DVT, the true trigger of DVT in cancer patients remains unknown. To determine whether the presence of cancer cells can trigger formation of a thrombus in a deep vein in vivo, we combined a murine model of Trousseau's Syndrome with a model of DVT. First, we induced the development of a tumor by subcutaneous injection of syngeneic pancreatic tumor cells in C57BL/6 mice. It was previously demonstrated that these mice have significantly reduced tail bleeding time and time to occlusion in injured mesenteric arteries and veins compared to control vessels. After 3 hours of partial flow restriction of the inferior vena cava, we observed that all tumor-bearing mice developed an occlusive thrombus (n=8) while only 29% of the control mice (n=7) formed occlusive thrombi. Interestingly, perfusion of cancer-derived microparticles in mice also induced thrombus formation in this DVT model, reproducing the tumor-bearing mice phenotype. This new approach showed that microparticles shed by cancer cells have a key role in the pathogenesis of cancer-associated DVT, and they may become a reasonable pharmaceutical target to prevent thrombosis associated with cancer development. Disclosures:No relevant conflicts of interest to declare.

A pilot study of central venous catheter survival in cancer patients using low-molecular-weight heparin (dalteparin) and warfarin without catheter removal for the treatment of upper extremity deep vein thrombosis (The Catheter Study).

Central venous catheters in patients with cancer are associated with development of deep vein thrombosis (DVT); however, there is no accepted standard treatment. To assess the safety and effectiveness of a management strategy for central venous catheter-related DVT in cancer patients consisting of dalteparin and warfarin without the need for line removal. Patients older than 18 years of age with an active malignancy and who had symptomatic, acute, objectively documented UEDVT were eligible. Patients were treated with dalteparin 200 IU kg(-1) per day for 5-7 days and warfarin with a target International Normalized Ratio of 2.0-3.0. Patients were followed for 3 months for recurrent venous thromboembolism, major hemorrhage and survival of the central venous catheter. There were 74 patients (48 males). The average age was 58 years. There were no episodes of recurrent venous thromboembolism and three (4%) major bleeds. No lines were removed because of infusion failure or recurrence/extension of DVT. Treatment of UEDVTs secondary to central catheters in cancer patients with standard dalteparin/warfarin can allow the central line to remain in situ with little risk of line failure or recurrence/extension of the DVT.

Long-term Low-Molecular-Weight Heparin versus Usual Care in Proximal-Vein Thrombosis Patients with Cancer

Purpose A substantial clinical need exists for an alternative to vitamin K antagonists for treating deep-vein thrombosis in cancer patients who are at high risk of both recurrent venous thromboembolism and bleeding. Low-molecular-weight heparin, body-weight adjusted, avoids anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy. Subjects and Methods Subjects were patients with cancer and acute symptomatic proximal-vein thrombosis. We performed a multi-centre randomized, open-label clinical trial using objective outcome measures comparing long-term therapeutic tinzaparin subcutaneously once daily with usual-care long-term vitamin-K-antagonist therapy for 3 months. Outcomes were assessed at 3 and 12 months. Results Of 200 patients, 100 received tinzaparin and 100 received usual care. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin ( P = .044; risk ratio = .44; absolute difference −9.0; 95% confidence interval [CI], −21.7 to −0.7). Bleeding, largely minor, occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference −3.0; 95% CI, −9.1 to 15.1). In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 0 of 51 patients (0%) receiving tinzaparin and 1 of 48 patients (2.1%) receiving usual care. Mortality at 1 year was high, reflecting the severity of the cancers; 47% in each group died. Conclusion Our findings confirm the limited but benchmark data in the literature that long-term low-molecular-weight heparin is more effective than vitamin-K-antagonist therapy for preventing recurrent venous thromboembolism in patients with cancer and proximal venous thrombosis.

Epidemiologic analysis of proximal deep vein thrombosis in thai patients: Malignancy, the predominant etiologic factor

From January 1995 to December 2000, 1555 patients (585 males, 970 females, with a mean age of 52.3 years) with acute limb swelling underwent diagnostic duplex venous ultrasonagraphy at the Vascular Surgery Unit, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. Of these 1555 patients, 514 (188 males, 326 females, with a mean age of 53 years) were diagnosed with deep vein thrombosis (DVT). DVT was found mainly in the lower extremities, occurring in 506 of these 514 cases (98.4%). The affected vein in the lower extremity was found more commonly in the left side (359 limbs) than in the right side (184 limbs) (p < 0.001). DVT also occurred in the upper extremities in 8 of the 514 cases (1.6%). In this study, out of 308 patients with DVT in their lower limbs, DVT was associated with malignancy in 123 cases (39.9%), with postoperation in 48 cases (15.6%), and with limb immobilization in 38 cases (12.3%). Malignancy-related DVT was found to be more extensive and virulent and was associated with high morbidity and mortality. Further study should be conducted to investigate the role of anticoagulant drugs for the prevention of DVT in cancer patients. Perhaps the spectrum of DVT as presented in this series is characteristic not only of the Thai population but also of the populations of other Asian countries.

Heparins and Venous Thromboembolism: Current Practice and Future Directions

Unfractionated heparin (UFH) in adjusted doses and low-molecular-weight heparins (LMWH) in fixed doses are the chosen therapy for the initial treatment of venous thromboembolism. The use of UFH protocols ensures that virtually all patients will promptly achieve the therapeutic range for the activated partial thromboplastin time. However, proper use of UFH requires considerable expertise, can cause inconvenience and has limitations. Unmonitored therapy with subcutaneous LMWH is at least as effective and safe as adjusted-dose UFH, is associated with a considerable reduction of mortality in cancer patients, and permits the treatment of suitable patients in an outpatient setting. LMWH in high prophylactic doses is more effective than UFH and oral anticoagulants for prevention of postoperative venous thrombosis in major orthopedic surgery. Whether thromboprophylaxis should be continued for a few additional weeks after hospital discharge is controversial. LMWH and UFH are equally effective for prevention of postoperative deep-vein thrombosis in cancer patients. In a recent controlled randomized trial, enoxaparin in high prophylactic doses was an effective and safe measure of thromboprophylaxis in ordinary bedridden patients. The efficacy and safety of pentasaccharide (the smallest antithrombin binding sequence of heparin) in the treatment and prevention of venous thromboembolic disorders is currently under investigation.

Effect of water coagulation by seeds of Moringa oleifera on bacterial concentrations

A growing body of evidence shows an increased risk of deep vein thrombosis (DVT) among cancer patients. Novel markers are needed to identify patients prone to develop DVT. The aim of the present study was to determine whether IL-6-174 G > C and MMP-9-1562 C > T polymorphisms may influence the development of DVT in cancer patients.Polymorphisms of IL-6 and MMP-9 were analyzed in 320 DNA samples from cancer patients (DVT+ and DVT−) and in 215 healthy donors. IL-6 and MMP-9 plasma levels were also measured by ELISA.Distribution of −174 IL-6 genotype and −1562 MMP-9 were similar between healthy controls and DVT− cancer cases (OR = 0.98 and 1.04, respectively). Different results were obtained by compared healthy controls with DVT+ cancer patients. −174 IL-6 GG polymorphism was associated to DVT (OR = 2.07; 95% CI: 1.30–3.30), as well as −1562 MMP-9 CC polymorphism (OR = 2.60; 95% CI: 1.48–4.57).The results of the present study support a model in which the GG and CC genotypes, respectively for IL-6-174 G > C and MMP-9-1562 C > T polymorphisms, are associated with a risk of DVT in cancer patients by inducing the release of IL-6 with subsequent increment of MMP-9. Overall, these findings may contribute to the management of DVT in cancer patients.