Effects of body composition on the procoagulant imbalance in obese patients.

Obesity is associated with increased thrombotic risk and hypercoagulability whose main driver is an excess of coagulation factor VIII relative to protein C. The aims of this study were to evaluate the association between factor VIII, protein C, factor VIII-to-protein C ratio and bioimpedance parameters of body composition in obese patients. We analysed blood from 69 obese patients and 23 non-obese healthy controls. Plasma levels of factor VIII, protein C, and factor VIII-to-protein C ratio were correlated with total fat, visceral fat, and muscle mass. Compared to controls, obese patients had significantly higher factor VIII (110.5% vs 78.05%, p < 0.001), protein C (120.99% versus 110.51%, p = 0.014), and factor VIII-to-protein C ratio (0.93 versus 0.73, p = 0.002). In obese patients, factor VIII correlated with body-mass index, body fat percentage, muscle mass percentage, and fat-to-muscle ratio, whereas protein C had significant relationships with body fat percentage, muscle mass percentage and fat-to-muscle ratio, but not with body-mass index. Factor VIII-to-protein C ratio > 1 was significantly associated with body-mass index (odds ratio 1.08, 95% CI 1.02 to 1.14) and fat-to-muscle ratio (odds ratio 2.47, 95% CI 1.10 to 5.55). Factor VIII-to-protein C ratio strongly correlated with D-dimer levels in the overall population (rho 0.44, p < 0.001) and obese patients (rho 0.41, p < 0.001). In obese patients, bioimpedance measures of body fat and muscle mass percentage were associated with factor VIII and protein C. Factor VIII-to-protein C ratio was strongly associated with fat-to-muscle ratio and only modestly related to BMI.

Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases.

BACKGROUND: Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. METHODS: In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. RESULTS: The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n = 24) and orthopaedic limitations (n = 19). CONCLUSIONS: Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.

Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Relationship between type of unprovoked venous thromboembolism and cancer location: An individual patient data meta-analysis.

BACKGROUND: Unprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to assess the period prevalence of occult cancer detection stratified by VTE location (deep vein thrombosis [DVT], pulmonary embolism [PE] or both) and the anatomical relationship between occult cancer and VTE. METHODS: Post-hoc analysis of a systematic review and individual patient data meta-analysis of adults with unprovoked VTE with at least 12 months of follow-up. Cancer types were grouped according to thoracic, abdomino-pelvic, or other locations. RESULTS: A total of 2300 patients were eligible including 1218 with DVT only (53%), 719 with PE only (31%), and 363 with both PE and DVT (16%). The pooled 12-month period prevalence of cancer in DVT only, PE only, and DVT + PE was 5.6% (95% CI, 4.4 to 7.2), 4.3% (95% CI, 2.7 to 6.9), and 5.6% (95% CI, 1.7 to 15.5), respectively. Most occult cancers were located in the abdomen (68.4%). The proportion of patients with an abdomino-pelvic cancer was not different in patients with DVT + PE (81%; 95% CI, 54 to 96) than in those with DVT (68%; 95% CI, 57 to 78) or PE alone (65%; 95% CI, 48 to 79). CONCLUSION: The 12-month prevalence of occult cancer was similar in patients with DVT only, PE only, or both. Most cancers were located in the abdomen, and there was no relationship between VTE type and cancer location.

Residual vein obstruction in patients diagnosed with acute isolated distal deep vein thrombosis associated with active cancer.

After acute proximal deep vein thrombosis (DVT) the thrombotic mass decreases, especially during the first months of anticoagulation. The persistence of residual vein obstruction (RVO) may predict future recurrence in patients with cancer-associated DVT. We aimed to evaluate the proportion of patients with RVO after an episode of cancer associated isolated distal DVT (IDDVT), to identify variables associated with RVO, and to provide initial evidence of its association with recurrent VTE. We performed a post-hoc analysis of a multicenter cohort study of patients with isolated cancer-associated acute IDDVT. We included patients who underwent a control ultrasonography at the end of the anticoagulant treatment between day 30 and day 365 after index IDDVT, given that no recurrent VTE had already occurred on anticoagulant treatment. A total of 153 patients had ultrasonographic follow-up after a median of 92 days from index IDDVT: 45.8% had RVO and 54.2% exhibited complete recanalization. Female sex, Body Mass Index > 30 Kg/m2 and involvement of axial calf veins showed the strongest association with RVO. The risk of recurrence was twofold higher in patients with (versus without) RVO. RVO persisted in approximately half of patients with an episode of cancer-associated IDDVT at anticoagulant discontinuation. Patients with RVO appeared to be at a higher risk for recurrent events.

Venous thromboembolism in cancer patients receiving neoadjuvant chemotherapy: a systematic review and meta-analysis.

Essentials Cancer patients are at risk for venous thromboembolism (VTE). The risk of VTE in less advanced stage cancer on neoadjuvant chemotherapy is unclear. In over 7800 patients, we found a 7% pooled incidence of VTE during neoadjuvant therapy. Highest VTE rates were observed in patients with bladder and esophageal cancer. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in cancer patients receiving adjuvant treatment. The risk of VTE during neoadjuvant chemo-radiotherapy remains unclear. Objectives This systematic review evaluated the incidence of VTE in patients with cancer receiving neoadjuvant treatment. Methods MEDLINE and EMBASE databases were searched from inception to October 2017. Search results were supplemented with screening of conference proceedings of the American Society of Clinical Oncology (2009-2016) and the International Society of Thrombosis and Haemostasis (2003-2016). Two review authors independently screened titles and abstracts, and extracted data onto standardized forms. Results Twenty-eight cohort studies (7827 cancer patients, range 11 to 1398) were included. Twenty-five had a retrospective design. Eighteen cohorts included patients with gastrointestinal cancer, representing over two-thirds of the whole study population (n = 6002, 78%). In total, 508 of 7768 patients were diagnosed with at least one VTE during neoadjuvant treatment, for a pooled VTE incidence of 7% (95% CI, 5% to 10%) in the absence of substantial between-study heterogeneity. Heterogeneity was not explained by site of cancer or study design characteristics. VTE presented as pulmonary embolism in 22% to 96% of cases (16 cohorts), and it was symptomatic in 22% to 100% of patients (11 cohorts). The highest VTE rates were observed in patients with bladder (10.6%) or esophageal (8.4%) cancer. Conclusions This review found a relatively high incidence of VTE in cancer patients receiving neoadjuvant therapy in the presence of some between-study variation, which deserves further evaluation in prospective studies.

Non-O blood group and outcomes of in vitro fertilization.

PURPOSE: Retrospective and cross-sectional studies suggested that non-O blood group may be associated with failures of in vitro fertilization (IVF), but data remain controversial. The aim of this observational cohort study was to prospectively evaluate the effect of non-O blood type on clinical outcomes of IVF. METHODS: Women < 40 years who underwent IVF and had ABO blood type recorded as part of the routine workup were eligible. The primary study outcome was live birth. Secondary outcomes included spontaneous abortion, positive pregnancy test, and clinical pregnancy. RESULTS: A total of 497 women with a mean age of 34.6 (standard deviation 3.2) years were included. The mean number of embryos transferred was 2.3 (standard deviation 0.6). The most common ABO blood types were O (n = 213, 42.9%) and A (n = 203, 40.8%), while 63 (12.7%) and 18 (3.6%) women had the B and AB blood types, respectively. Differences in live birth (21.8 vs. 24.3%, odds ratio [OR] 1.17; 95% confidence intervals [CI], 0.76 to 1.78), positive pregnancy test (37.9 vs. 36.6%, OR 0.96; 95% CI, 0.66 to 1.38), clinical pregnancy (35.1 vs. 33.8%, OR 0.95; 95% CI, 0.66 to 1.39), and spontaneous abortion (12.3 vs. 9.2%, OR 0.72; 95% CI, 0.41 to 1.29) between women with O and non-O blood type were not statistically significant. CONCLUSIONS: In a prospective cohort study, we confirmed the lack of a significant association between non-O blood type and clinical outcomes of IVF. Further studies are needed to clarify whether non-O blood group has any prognostic relevance in women undergoing IVF.

Clinical course of isolated distal deep vein thrombosis in patients with active cancer: a multicenter cohort study.

Essentials Isolated distal deep vein thrombosis (IDDVT) is frequently associated with cancer. No study has specifically evaluated the long-term clinical course of cancer-associated IDDVT. Patients with cancer-associated IDDVT are at very high risk of symptomatic recurrence and death. We observed low rates of major bleeding during anticoagulation. SUMMARY: Background Although isolated distal deep vein thrombosis (IDDVT) is frequently associated with cancer, no study has specifically evaluated the long-term clinical course of IDDVT in this setting. Aim To provide data on the rate of recurrent venous thromboembolism (VTE), major bleeding events and death in IDDVT patients with active cancer. Patients and Methods Consecutive patients with active cancer and an objective IDDVT diagnosis (January 2011 to September 2014) were included from our files. We collected information on baseline characteristics, IDDVT location and extension, VTE risk factors, and type and duration of anticoagulant treatment. Results A total of 308 patients (mean age 66.2 [standard deviation (SD), 13.2 years]; 57.1% female) with symptomatic IDDVT and a solid (n = 261) or hematologic (n = 47) cancer were included at 13 centers. Cancer was metastatic in 148 (48.1%) patients. All but three (99.0%) patients received anticoagulant therapy, which consisted of low-molecular-weight heparin in 288 (93.5%) patients. Vitamin K antagonists were used for the long-term treatment in 46 (14.9%) patients, whereas all others continued the initial parenteral agent for a mean treatment duration of 4.2 months (SD, 4.6 months). During a total follow-up of 355.8 patient-years (mean, 13.9 months), there were 47 recurrent objectively diagnosed VTEs for an incidence rate of 13.2 events per 100 patient-years. During anticoagulant treatment, the annual incidence of major bleeding was 2.0 per 100 patient-years. Conclusions Cancer patients with IDDVT have a high risk of VTE recurrence. Additional studies are warranted to investigate the optimal intensity and duration of anticoagulant treatment for these patients.

Improving the diagnostic management of upper extremity deep vein thrombosis.

Essentials The Constans score and D-dimer can rule out upper extremity deep vein thrombosis without imaging. We evaluated the performance of an extended Constans score and an age-adjusted D-dimer threshold. The extended Constans score did not increase the efficiency compared to the original score. Age-adjusted D-dimer testing safely increased the efficiency by 4%, but this needs validation. SUMMARY: Background Among patients with clinically suspected upper extremity deep vein thrombosis (UEDVT), a clinical decision rule based on the Constans score combined with D-dimer testing can safely rule out the diagnosis without imaging in approximately one-fifth of patients. Objectives To evaluate the performance of the original Constans score, an extended Constans score and an age-adjusted D-dimer positivity threshold. Methods Data of 406 patients with suspected UEDVT previously enrolled in a multinational diagnostic management study were used. The discriminatory performance, calibration and diagnostic accuracy of the Constans score were evaluated. The Constans score was extended by selecting clinical variables that may have incremental value in detecting UEDVT, conditional on the original Constans score items. The performance of the Constans rule was evaluated in combination with fixed and age-adjusted D-dimer thresholds. Results The original Constans score showed good discriminatory performance (c-statistic, 0.81; 95% confidence interval [CI], 0.76-0.85). An extended Constans score with five additional clinical items improved discriminatory performance and calibration, but this did not translate into a higher efficiency in avoiding imaging tests. Compared with a fixed threshold, age-adjusted D-dimer testing increased the proportion of patients for whom imaging and anticoagulation could be withheld from 21% to 25% (gain, 3.7%; 95% CI, 2.3-6.0%). Conclusions The Constans score has good discriminatory performance in the diagnosis of UEDVT. Age-adjusted D-dimer testing is likely to safely increase the efficiency of the diagnostic algorithm, but this approach needs prospective validation.

Is stand-alone D-dimer testing safe to rule out acute pulmonary embolism?

Essentials A stand-alone D-dimer below 750 µg/L has been proposed to rule out acute pulmonary embolism (PE). This was a post-hoc analysis on data from 6 studies comprising 7268 patients with suspected PE. The negative predictive value of a D-dimer <750 µg/L ranged from 79% to 96% in various subgroups. Stand-alone D-dimer testing seems to be unsafe to rule out PE in all patients. SUMMARY: Background Recently, stand-alone D-dimer testing at a positivity threshold of 750 µg L-1 has been proposed as a safe and efficient approach to rule out acute pulmonary embolism (PE), without additional imaging, but this approach needs validation. Objectives To evaluate stand-alone D-dimer testing at a positivity threshold of 750 µg L-1 to rule out PE. Methods Individual data from 7268 patients with suspected PE previously enrolled in six prospective management studies were used. Patients were assessed by the Wells rule followed by quantitative D-dimer testing in those with a 'PE unlikely' score. Patients were classified post hoc as having a negative (< 750 µg L-1 ) or positive (≥ 750 µg L-1 ) D-dimer. Using a one-stage meta-analytic approach, the negative predictive value (NPV) of stand-alone D-dimer testing was evaluated overall and in different risk subgroups. Results The pooled incidence of PE was 23% (range, 13-42%). Overall, 44% of patients had a D-dimer < 750 µg L-1 , of whom 2.8% were diagnosed with PE at baseline or during 3-month follow-up (NPV, 97.2%; 95% confidence interval [CI], 94.9-98.5). The NPV was highest in patients with a low probability of PE according to the Wells rule (99.2%; 95% CI, 98.6-99.5%) and lowest in those with a high probability of PE (79.3%; 95% CI, 53.0-92.8%). The NPVs in patients with active cancer, patients with previous venous thromboembolism and inpatients were 96.2% (95% CI, 85.6-99.1%), 94.7% (95% CI, 88.6-97.6%) and 92.7% (95% CI, 79.3-97.7%), respectively. Conclusions Our findings suggest that stand-alone D-dimer testing at a positivity threshold of 750 µg L-1 is not safe to rule out acute PE.

Incidental pulmonary embolism in cancer patients: Interobserver agreement on the diagnosis and extent with a focus on distal clots.

BACKGROUND: The incidence of incidental pulmonary embolism (IPE) in cancer patients is increasing. There is scant information on the interobserver agreement among radiologists about the diagnosis of distal incidental clots and the actual radiologic extension of IPE. METHODS: A total of 88 contrast-enhanced computed tomography (CT) scans of cancer patients with IPE were reassessed blindly by two expert thoracic radiologists. First, 62 scans were reassessed and the interobserver agreement on most proximal extent of IPE was calculated between the two expert radiologists as well as between the initial and expert reading, using the kappa statistic. The sample was enriched with 26 additional scans for a total of 30 segmental and 29 subsegmental IPE to determine the interobserver agreement on distal clots. RESULTS: The level of agreement regarding the most proximal extent of IPE between the expert radiologists was very good (kappa 0.84; 95% CI, 0.73-0.95) and poor between the original radiologist and expert radiologists (kappa 0.39; 95% CI, 0.22-0.56). In the patients with segmental or subsegmental IPE on initial reading, the expert radiologists agreed with the segmental location in 12 out of 30 patients (40%) and with the subsegmental location in 17 out of 29 patients (59%). The interobserver agreement between the expert radiologists was good (kappa 0.68; 95% CI, 0.46-0.90) and moderate (kappa 0.48; 95% CI, 0.25-0.71), respectively. CONCLUSIONS: While the interobserver agreement between radiologists on the most proximal location of IPE in cancer patients appears to be fairly good, it decreases significantly for more distally located incidental clots.

Current management strategies and long-term clinical outcomes of upper extremity venous thrombosis.

UNLABELLED: Essentials Few data exist on outcome of upper extremity deep and superficial vein thrombosis (UEDVT and UESVT). We followed 102 and 55 patients with UEDVT or UESVT, respectively, for a median of 3.5 years. Risk of recurrent venous thromboembolism was low in both diseases, and the mortality high. Postthrombotic symptoms were infrequent and cancer patients had a higher risk of recurrent VTE. SUMMARY: Background There is scant information on the optimal management and clinical outcome of deep and superficial vein thrombosis of the upper extremity (UEDVT and UESVT). Objectives To explore treatment strategies and the incidence of recurrent venous thromboembolism (VTE), mortality, postthrombotic symptoms, and bleeding in patients with UEDVT and UESVT and to assess the prognosis of cancer patients with UEDVT. Patients/methods Follow-up of patients with UEDVT or UESVT, who were enrolled previously in a diagnostic management study. Results We followed 102 and 55 patients with UEDVT and UESVT, respectively, both for a median of 3.5 years. Anticoagulant treatment was started in 100 patients with UEDVT (98%) and in 40 (73%) with UESVT. Nine patients with UEDVT (9%) developed recurrent VTE, 26 (26%) died, 6 (8%) of 72 patients had moderate postthrombotic symptoms, and 5 (5%) experienced major bleeding. One patient with UESVT had a recurrent VTE, 18 (33%) died, none had moderate postthrombotic symptoms, and none had major bleeding. Of the cancer patients with UEDVT, 18% had recurrent VTE vs. 7.5% in non-cancer patients (adjusted hazard ratio 2.2, 95%CI 0.6-8.2). The survival rate was 50% in cancer patients with UEDVT vs. 60% in those without (adjusted HR 0.8, 95%CI 0.4-1.4). Conclusions The risk of recurrent VTE was low in patients with UEDVT, and negligible for UESVT. Mortality was high for both diseases. Postthrombotic symptoms were infrequent and mild. Anticoagulant therapy of UEDVT carried a substantial risk of major bleeding. Cancer patients had a significant risk of recurrent VTE.

ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer.

UNLABELLED: ESSENTIALS: Cancer patients are at high risk of venous thromboembolism (VTE). In this study, cases and controls were cancer patients who did or did not develop VTE. von Willebrand factor (VWF) levels were higher if compared with controls and correlated with cancer stage. VWF and ADAMTS-13 are associated with the occurrence of VTE in cancer. BACKGROUND: Patients with cancer are at high risk of venous thromboembolism (VTE). ADAMTS-13 regulates von Willebrand factor (VWF) activity, which plays a role in the development of cancer and in VTE. OBJECTIVES: The aim of this study was to search for an association between the levels of VWF and ADAMTS-13 and VTE in patients with cancer and to compare current scoring systems for prediction of VTE before and after addition of these parameters. PATIENTS/METHODS: In a case-control study, in which patients with recently diagnosed cancer were followed-up for 6 months, we compared 20 patients who developed VTE (cases) and 140 patients with cancer without VTE (controls), matched for sex, age, and type and stage of cancer. We measured VWF, ADAMTS-13 (activity and antigen), P-selectin, D-dimer and F1 + 2 levels at baseline, and calculated both the Khorana score and the Khorana score expanded after addition of P-selectin and D-dimer levels. RESULTS: VWF levels were significantly higher in cases when compared with controls (326 ± 185% vs. 242 ± 158%) and correlated with advanced stage of cancer: localized, 185 [142; 222]; locally advanced, 240 [146; 257]; metastatic, 267 [153; 324] (mean [interquartile range]). The addition of two biomarkers, ADAMTS-13 activity and F1 + 2 levels, to the Khorana score improved receiver operating curves. CONCLUSIONS: von Willebrand factor and ADAMTS-13 are associated with the occurrence of VTE in patients with cancer. Moreover, addition of ADAMTS-13 and F1 + 2 levels to the Khorana score considerably increases the predictive value for VTE.

Anticoagulant treatment of cancer patients with pulmonary embolism in the real world. Actual use of low-molecular-weight heparin in cancer.

BACKGROUND: Since 2004, guidelines recommend long-term treatment with low-molecular-weight heparin (LMWH) in patients with cancer and pulmonary embolism (PE). We assessed the proportion of cancer patients with PE actually treated with LMWH and the duration of anticoagulant treatment in the Netherlands. METHODS: A retrospective cohort study in patients that were hospitalised for PE between 1998-2008. Patients with PE were selected from national hospital discharge records, after linkage to a national pharmacy database. Cancer patients with PE were matched for age, sex and year of diagnosis of PE to subjects with PE without cancer. RESULTS: 600 cancer patients with PE were matched to 1200 patients with PE without cancer. Long-term LMWH was prescribed in 82 (13.7%) of the cancer patients and in eight (0.7%) of the cancer-free patients (p < 0.001); all the other patients received vitamin K antagonists (VKA). From 1998-2008, there was an increase in the use of LMWH in cancer patients: in 2007-2008, LMWH was prescribed in 42 (32%) cases, compared with one (1.7%) of the cancer patients with PE in 1998-1999. Median duration of treatment was 5.8 months (interquartile range 3.1-8.8) in cancer patients, compared with 7.0 months (4.9-11) in patients without cancer (p < 0.001), a difference that persisted after adjustment for mortality. CONCLUSIONS: Although the use of LMWH in patients with cancer and PE is increasing, in 2008, patients in the Netherlands are still mostly treated with VKA, and not with LMWH as recommended by guidelines. Cancer patients with PE on average receive shorter treatment than matched patients without cancer.