High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses

BACKGROUND: Diabetes mellitus is generally not recognized as an important risk factor for venous thromboembolism (VTE). However, clinical observations and case reports have suggested that patients with diabetes and hyperosmolarity may be at increased risk for VTE. Objectives: To determine the risk of VTE in patients hospitalized for diabetes with hyperosmolar state compared to patients with other acute medical illnesses. PATIENTS/METHODS: The California Patient Discharge Data Set was used to determine the incidence of first-time VTE in all patients admitted between 1995 and 2000 for diabetes with hyperosmolarity and 11 other acute medical conditions. Proportional hazard modeling was used to adjust for age, race, gender, and prior hospitalization within 3 months. RESULTS: Among 2859 patients with diabetes and hyperosmolarity, 34 (1.2%) developed VTE during the hospitalization and 14 (0.5%) developed VTE within 91 days after discharge. In an adjusted multivariate model comparing the risk of VTE to cases with depression, patients with hyperosmolarity had a significantly higher risk of VTE [hazard ratio (HR) = 16.3; 95% confidence interval (CI): 10-25] comparable to the risk associated with sepsis (HR = 19.3; 95% CI: 13-29) or acute connective tissue disease (HR = 21; 95% CI: 15-31). Compared to uncomplicated diabetes, patients with hyperosmolarity had a significantly higher risk of VTE (HR = 3.0; 95% CI: 2.1-4.5) whereas patients with ketoacidosis were not at higher risk (HR = 1.2; 95% CI: 0.8-1.7). CONCLUSIONS: Patients hospitalized for diabetes with hyperosmolarity are at increased risk for developing VTE both during their inpatient stay and in the 3 months after discharge. Thromboprophylaxis in these patients appears warranted, and extended prophylaxis for after hospital discharge should be studied.     

The metabolic syndrome and the risk of venous thrombosis: a case–control study

OBJECTIVE: The results of recent studies have suggested that patients with idiopathic venous thromboembolism (VTE) might be at increased risk of asymptomatic atherosclerosis and cardiovascular events. The metabolic syndrome is a cluster of risk factors for atherosclerosis. Its impact on VTE is unknown. METHODS: In a case-control study, consecutive patients with objectively confirmed deep vein thrombosis (DVT) and control subjects with objectively excluded DVT underwent clinical assessment for the presence of the metabolic syndrome according to the National Cholesterol Education Program criteria. The presence of known risk factors for DVT was documented. Patients with DVT secondary to cancer were excluded. The prevalence of the metabolic syndrome was compared between patients with idiopathic DVT and controls. RESULTS: We enrolled 93 patients with a first episode of idiopathic DVT and 107 controls. The mean age was 65.1 and 63.7 years, respectively. The metabolic syndrome was diagnosed in 50.5% of patients with idiopathic DVT and in 34.6% of controls [odds ratio (OR) 1.93; 95% confidence interval (CI) 1.05, 3.56]. After adjustment for age, sex, body mass index, and smoke, the metabolic syndrome remained independently associated with idiopathic DVT (OR 1.94; 95% CI 1.04, 3.63). In patients with secondary DVT, the prevalence of the metabolic syndrome was 27%. CONCLUSIONS: The metabolic syndrome may play a role in the pathogenesis of idiopathic DVT and may act as link between venous thrombosis and atherosclerosis.     

Prospective study of subclinical atherosclerosis as a risk factor for venous thromboembolism

BACKGROUND: Whether atherosclerotic disease predisposes to venous thrombosis is uncertain. OBJECTIVE: To determine whether subclinical atherosclerosis, manifested as increased carotid intima-media thickness (IMT) or presence of carotid plaque, is associated with increased incidence of venous thromboembolism (VTE). PATIENTS AND METHODS: The Atherosclerosis Risk in Communities study is a prospective cohort of adults aged 45-64 years, examined at baseline (1987-89) and followed for cardiovascular events. Bilateral carotid ultrasound for IMT measurements was done at baseline for portions of the common and internal carotid arteries, and carotid bifurcation and also to detect the presence of carotid plaque. Exclusion criteria included baseline anticoagulant use, history of coronary heart disease, stroke, or VTE, and incomplete data. First VTE during follow-up was validated using abstracted medical records. RESULTS: Among 13,081 individuals followed for a mean of 12.5 years, 225 first VTE events were identified. Unadjusted hazard ratios (HR) (95% CI) of VTE across quartiles of baseline IMT were 1.0, 1.16 (0.77-1.75), 1.64 (1.12-2.40), and 1.52 (1.03-2.25). However, this association disappeared after adjustment for age, sex, and ethnicity (HRs: 1.0, 1.06, 1.40, and 1.18). Further adjustment for body mass index and diabetes weakened the relative risks even further. Presence of carotid plaque at baseline also was not associated with VTE occurrence; adjusted HR = 0.97, 95% CI = 0.72-1.29. CONCLUSION: Increased carotid IMT or presence of carotid plaque was not associated with an increased incidence of VTE in this middle-aged cohort, suggesting subclinical atherosclerosis itself is not a VTE risk factor.     

The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study

In order to assess whether the HR2 haplotype of the factor V gene (HR2) increases the risk of venous thromboembolism (VTE) in carriers of antithrombin (AT), protein C (PC) or S (PS) defects, we performed this determination in 336 subjects, who were family members of 66 symptomatic patients with clotting inhibitors defects. We first assessed the presence of previous VTE, and then followed prospectively subjects without prior VTE. VTE episodes had occurred in 26 individuals: 18 in 139 carriers of clotting inhibitors defects alone (annual incidence, 0.55%), four in 33 carriers of clotting inhibitors defects combined with HR2 (0.52%) and four in 151 non-carriers (0.1%), resulting in a relative risk (RR) for VTE of 4.9 (95% CI: 1.7-14.4) and 4.62 (95% CI: 1.2-18.4), respectively. After an overall follow-up of 2557 patient-years, VTE episodes developed in 12 subjects: nine in 121 carriers of clotting inhibitors defects alone (annual incidence, 0.92%), three in 29 carriers of clotting inhibitors defects combined with HR2 (1.0%) and none in 147 non-carriers. In family members of patients with AT, PC or PS defects the coinheritance of HR2 haplotype does not seem to increase the thromboembolic risk.     

A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score

Summary. Background: Prophylaxis of venous thromboembolism (VTE) in hospitalized medical patients is largely underused. We sought to assess the value of a simple risk assessment model (RAM) for the identification of patients at risk of VTE. Methods: In a prospective cohort study, 1180 consecutive patients admitted to a department of internal medicine in a 2‐year period were classified as having a high or low risk of VTE according to a predefined RAM. They were followed‐up for up to 90 days to assess the occurrence of symptomatic VTE complications. The primary study outcome was to assess the adjusted hazard ratio (HR) of VTE in high‐risk patients who had adequate in‐hospital thromboprophylaxis in comparison with those who did not, and that of VTE in the latter group in comparison with low‐risk patients. Results: Four hundred and sixty‐nine patients (39.7%) were labelled as having a high risk of thrombosis. VTE developed in four of the 186 (2.2%) who received thromboprophylaxis, and in 31 of the 283 (11.0%) who did not (HR of VTE, 0.13; 95% CI, 0.04–0.40). VTE developed also in two of the 711 (0.3%) low‐risk patients (HR of VTE in high‐risk patients without prophylaxis as compared with low‐risk patients, 32.0; 95% CI, 4.1–251.0). Bleeding occurred in three of the 186 (1.6%) high‐risk patients who had thromboprophylaxis. Conclusions: Our RAM can help discriminate between medical patients at high and low risk of VTE. The adoption of adequate thromboprophylaxis in high‐risk patients during hospitalization leads to longstanding protection against thromboembolic events with a low risk of bleeding.     

Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study

Summary. Background: Recent studies indicate that arterial cardiovascular diseases and venous thromboembolism (VTE) share common risk factors. A family history of myocardial infarction (MI) is a strong and independent risk factor for future MI. Objectives: The purpose of the present study was to determine the impact of cardiovascular risk factors, including family history of MI, on the incidence of VTE in a prospective, population‐based study. Patients and methods: Traditional cardiovascular risk factors and family history of MI were registered in 21 330 subjects, aged 25–96 years, enrolled in the Tromsø study in 1994–95. First‐lifetime VTE events during follow‐up were registered up to 1 September 2007. Results: There were 327 VTE events (1.40 per 1000 person‐years), 138 (42%) unprovoked, during a mean of 10.9 years of follow‐up. In age‐ and gender‐adjusted analysis, age [hazard ratio (HR) per decade, 1.97; 95% confidence interval (CI), 1.82–2.12], gender (men vs. women; HR, 1.25; 95% CI, 1.01–1.55), body mass index (BMI; HR per 3 kg m^?2, 1.21; 95% CI, 1.13–1.31), and family history of MI (HR, 1.31; 95% CI, 1.04–1.65) were significantly associated with VTE. Family history of MI remained a significant risk factor for total VTE (HR, 1.27; 95% CI, 1.01–1.60) and unprovoked VTE (HR, 1.46; 95% CI, 1.03–2.07) in multivariable analysis. Blood pressure, total cholesterol, HDL‐cholesterol, triglycerides, and smoking were not independently associated with total VTE. Conclusions: Family history of MI is a risk factor for both MI and VTE, and provides further evidence of a link between venous and arterial thrombosis.     

Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology

Summary.  Background:  In a recent case–control study, the odds of metabolic syndrome (MetSyn) among deep vein thrombosis cases were almost twice those among controls. We tested the hypothesis that the incidence of non-cancer-related venous thromboembolism (VTE) is higher among adults with MetSyn and further, that associations are stronger for idiopathic than secondary VTE. Methods:  A total of 20 374 middle-aged and elderly adults were followed for over 12 years for incident VTE in the Longitudinal Investigation of Thromboembolism Etiology (LITE). All hospitalizations were identified and VTEs validated by chart review. Baseline MetSyn was defined using ATP III guidelines, including ≥3 of the following components: abdominal obesity, elevated blood pressure, low HDL-cholesterol, high triglycerides and high glucose. Because sex modified the relation between MetSyn and VTE (p_interaction = 0.001), proportional hazards regression analyses were stratified by sex to assess the associations of MetSyn and its components with risk of incident non-cancer-related VTE, adjusting for potential confounders. Results:  Incident VTE ( n  = 358) included 196 idiopathic events. Baseline MetSyn was associated with risk of total VTE (hazard ratio (HR) = 1.84, 95% CI = 1.30, 2.59) and idiopathic VTE (HR = 1.59, 95% CI = 1.02, 2.47) among men, but not women. The association was largely attributable to abdominal obesity (HR of VTE = 2.10, 95% CI = 1.51, 2.93, in men; HR of VTE = 1.70, 95% CI = 1.24, 2.34, in women), with no additional contribution by the other MetSyn components. Conclusion:  Although abdominal obesity was associated with increased risk of VTE in both men and women, MetSyn and its other components do not seem important in VTE etiology.     

High risk of recurrent venous thromboembolism in men

BACKGROUND: We have analyzed the influence of gender on risk of recurrence after a first episode of venous thromboembolism (VTE). METHODS: The Cambridge Venous Thromboembolism Study (CVTE) is a single-center study of a cohort of unselected patients with a first episode of objectively proven VTE. RESULTS: Recurrence rates were significantly higher in men compared with women [log rank chi2=11.82; hazard ratio (HR) 2.66; 95% confidence interval (CI) 1.49, 4,77; P=0.0006]. The cumulative recurrence rate at 2 years was 19.2% in men and 7.7% in women. There was no evidence of a difference in recurrence between men with or without thrombophilia (log rank chi2=0.03; HR 1.08; 95% CI 0.49, 2.37; P=0.855). The high recurrence rate in men compared with women was still observed when only patients with idiopathic VTE were analyzed (log rank chi2=4.38; HR 2.31; 95% CI 1.027, 5.20; P=0.0363). The recurrence risk was highest in men with a first idiopathic event at 25.7% compared with 11.7% for women in the same category. CONCLUSION: The risk of recurrent VTE is higher in men than in women.     

Venous thromboembolism after spinal cord injury: incidence, time course, and associated risk factors in 16,240 adults and children

OBJECTIVE: To analyze the incidence of venous thromboembolism (VTE) after spinal cord injury (SCI). DESIGN: Retrospective cohort analysis of all SCI cases (16,240) in California from 1991 through 2001. SETTING: All public hospitals in California. PARTICIPANTS: Subjects (cases) coded as having complete or incomplete SCI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Diagnosis of VTE or death within 91 days of the day of hospital admission. RESULTS: For all cases, the 91-day cumulative incidence of VTE was 5.4%. In a multivariate model, significant predictors of VTE included male sex (odds ratio [OR]=1.4; 95% confidence interval [CI], 1.2-1.7), African-American race (OR=1.6; 95% CI, 1.3-1.9), complete paraplegia versus tetraplegia (OR=1.8; 95% CI, 1.4-2.3), and presence of 3 or more comorbid conditions versus none (OR=1.6; 95% CI, 1.3-2.1). Age less than 14 years was predictive of not developing VTE (OR=0.2; 95% CI, 0.1-0.7). The incidence of VTE did not change significantly over the 11-year time period (P=.07), and VTE was not a significant predictor of death in the first 91 days after hospitalization. CONCLUSIONS: The incidence of VTE in SCI patients in California did not change between 1991 and 2001. We identified specific risk factors for VTE. Further studies are needed to determine if prompt initiation of medical prophylaxis in high risk subjects reduces the incidence of symptomatic VTE.     

D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism

BACKGROUND: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE). OBJECTIVES: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5-2.0) in preventing recurrence by biomarker level. PATIENTS AND METHODS: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc. RESULTS: One-third of participants had elevated baseline D-dimer (> or = 500 ng mL(-1)) and one-fourth, elevated FVIIIc (> or = 150 IU dL(-1)). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2-3.4] and 1.5 (95% CI 0.8-2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3-8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7-2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers. CONCLUSIONS: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.     

Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

Essentials

• Chronic kidney disease (CKD) is associated with procoagulant and inflammatory biomarkers.
• We studied the association of CKD and venous thromboembolism (VTE) in a case‐cohort study.
• Factor VIII, D‐dimer and C‐reactive protein appeared to explain the association of CKD and VTE.
• Statin use was protective against VTE in those with and without CKD.

Summary

Background

Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown.

Objectives

To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients.

Methods

Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non‐cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged ≥45 years with 4.3 years of follow‐up. The hazard ratio (HR) of VTE per 10 mL min^?1 1.73 m^?2 decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD.

Results

The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02–1.25), and VTE risk was attenuated by 23% (95% CI 5–100) by D‐dimer, by 100% (95% CI 50–100) by factor VIII, and by 15% (95% CI 2–84) by C‐reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32–0.70), but not in those with CKD (HR 1.07, 95% CI 0.51–2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups.

Conclusions

Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients.

     

Safety and efficacy of low‐dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study

Summary. Background: Renal impairment is common, affecting around 40% of acutely ill medical patients, and is associated with an increased risk of both venous thromboembolism (VTE) and bleeding. The clinical benefit of effective thromboprophylactic strategies may be outweighed in these patients by an excessive rate of hemorrhage. Objective: To assess the safety and efficacy of lower prophylactic doses of fondaparinux in acutely ill medical patients with renal impairment. Patients/Methods: We carried out a multicenter, investigator‐initiated, prospective cohort study. Patients at risk of VTE with a creatinine clearance between 20 and 50 mL min^?1 were treated with fondaparinux 1.5 mg qd for a minimum of 6 to a maximum of 15 days. The primary outcome was the incidence of major bleeding; secondary outcomes were clinically relevant non‐major bleeding (CRNMB) and symptomatic VTE. Results: We enrolled 206 patients with a mean age of 82 years, mean creatinine clearance of 33 mL min^?1, and a mean Charlson co‐morbidity index of 8.2. One patient had major bleeding (0.49%, 95% confidence interval [CI] 0.03–3.10), eight had CRNMB (3.88%, 95% CI 1.81–7.78) and three developed symptomatic VTE (1.46%, 0.38–4.55). Twenty‐three patients (11.17%, 7.36–16.48) died. No independent predictors of bleeding were found at univariate analysis. Conclusions: The addition of moderate to severe renal impairment to patients with traditional risk factors for VTE identified a population of very elderly acutely ill medical patients potentially at high risk of both VTE and bleeding complications. The recently approved lower prophylactic dose of fondaparinux appears to be a safe and relatively effective strategy in these patients.     

Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient‐level meta‐analysis

Summary. Aim: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. Methods: We carried out a patient‐level meta‐analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan‐Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. Results: The 5‐year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5‐year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5‐year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1‐fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9–5.1). Patients with proximal DVT had a 4.8‐fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1–11.0). Conclusion: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.     

Venous thromboembolic events and organ-specific occult cancers: a review and meta-analysis

Summary.  Background:  Despite a recognized association between venous thromboembolic events (VTE) and cancer, little is known about the strength and the features of this association. We performed a meta-analysis in order to clarify this issue. Methods:  We retrieved data from 40 reports published between 1982 and 2007: 12 contained cancer risk estimates for patients with either idiopathic or secondary VTE vs. subjects without VTE and 17 for patients with idiopathic vs. secondary VTE. We also pooled risk estimates from four cohort studies to assess the association between VTE and specific forms of cancer and conducted a proportional incidence study, based on the remaining 28 reports, which did not provide risk estimates. Results:  The pooled relative risk (RR) of cancer was 3.2 [95% confidence interval (95% CI) 2.4–4.5] for patients with any form of VTE vs. no VTE, 2.7 (95% CI 1.9–3.9) for patients with idiopathic vs. no VTE and 3.8 (95% CI 2.6–5.4) for patients with idiopathic vs. secondary VTE. In the pooled cohort studies, RRs for VTE vs. no VTE were significantly elevated for cancers of the ovary (RR 7.0), pancreas (RR 6.1), liver (RR 5.6), blood (4.2), brain (RR 3.8), kidney (RR 3.4), lung (3.1), colon (2.9), and esophagus (2.1). In the proportional incidence study, cancers of the pancreas, colon, and blood were significantly more frequently observed than in the general population. Conclusions:  Overall we found a 3-fold excess risk of occult cancer in patients with VTE. The risk varies according to tumor site and is highest for cancers of the ovary, pancreas, and liver.     

Clinical outcome in patients with venous thromboembolism and hidden cancer: findings from the RIETE Registry

Summary.  Introduction:  Although extensive screening in patients with venous thromboembolism (VTE) may result in early identification of hidden cancer, it is unknown whether the prognosis of these patients may be favorably influenced. Patients and methods:  RIETE is an ongoing, prospective registry of consecutive patients with objectively confirmed, symptomatic, acute VTE. We compared the 3-month outcome of patients with hidden cancer with that in patients in whom no symptoms of cancer were noted. Results:  Of 17 475 patients with acute VTE, 2852 (16%) had cancer diagnosed before VTE or during admission. Hidden cancer was detected in 178 (1.2%) of the remaining 14 623 patients. The most common sites were lung, prostate, colorectum, or hematologic, and 51% had metastases. As compared with patients in whom no symptoms of cancer were noted, those with hidden cancer had an increased incidence of recurrent VTE (11.4% vs. 2.1%; P  <   0.001), major bleeding (5.1% vs. 2.1%; P  =   0.007), and mortality (20% vs. 5.4%; P  <   0.001). In the multivariate analysis, patients aged 60–75 years [odds ratio 1.8; 95% CI 1.2–2.7], with idiopathic VTE (odds ratio 3.0; 95% CI 2.2–4.2), with bilateral thrombosis (odds ratio 2.3; 95% CI 1.3–4.1) or with anemia (odds ratio 1.9; 95% CI 1.4–2.6) were at an increased risk for hidden cancer. Conclusions:  VTE patients with hidden cancer have an increased incidence of recurrences, major bleeding or death during the first 3 months of therapy. With four simple, easily obtainable variables, it is possible to identify a subgroup of VTE patients with a higher risk for hidden cancer.     

High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS)

Summary.  Background:  In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Increased platelet count has been found to be a risk factor for VTE in cancer patients receiving chemotherapy (CHT). We have assessed high platelet count as a risk predictor for VTE in patients with cancer undergoing discriminative anti-cancer treatments and investigated whether platelet count correlates with thrombopoietin (TPO) levels. Design and methods:  The Cancer and Thrombosis Study (CATS) is an ongoing prospective observational study of patients with newly diagnosed cancer or progression of disease, which started in October 2003. Occurrence of VTE and information on the patients' anti-cancer treatment during follow-up were recorded. Results: Between October 2003 and February 2008, 665 patients with solid tumors were included (314 female/351 male, mean age 62 years). VTE occurred in 44 patients (18 female/26 male, mean age 62 years). The cumulative probability of VTE after 1 year was 34.3% in patients with a platelet count (PC) above the 95th percentile representing 443 × 10⁹/L compared with 5.9% in those below 443 × 10⁹/L. High platelet count [hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.52–8.06, P  = 0.0032], soluble P-selectin [HR: 2.66, 95% CI: 1.42–4.96, P  = 0.0021] and surgery [HR: 4.05, 95% CI: 1.74–9.46, P  = 0.0012] were statistically significant risk factors for VTE in multivariable analysis along with leucocyte count, age, gender, radio- and CHT. We found no correlation between platelet count and TPO levels. Conclusions:  High PC is a clinically important, independent risk predictor for VTE in cancer patients. PC was not found to be associated with TPO levels.     

Insulin resistance and risk of venous thromboembolism: results of a population‐based cohort study

Summary. Background: Obesity is an established risk factor for venous thromboembolism (VTE), but it is uncertain how this is mediated. Insulin resistance has a central role in the pathophysiology of the metabolic effects of obesity. Objective: We aimed to investigate whether insulin resistance is a risk factor for VTE. Methods: For this analysis we used the PREVEND prospective community‐based observational cohort study. Insulin resistance was measured as HOMA‐IR (homeostasis model assessment of insulin resistance) and fasting insulin. VTE was assessed using databases of the national registries of hospital discharge diagnoses, death certificates and the regional anticoagulation clinic. Results: Out of 7393 subjects, 114 developed VTE during a median follow‐up of 10.5 years. High HOMA‐IR was associated with increased risk of VTE after adjustment for traditional cardiovascular risk factors, CRP and markers of endothelial dysfunction (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 1.09–1.75; P = 0.007). When body mass index (BMI) was added to the model, BMI was a strong risk predictor for VTE (HR, 1.53; 95% CI, 1.24–1.88; P < 0.001) whereas HOMA‐IR no longer showed such an association (HR, 1.11; 95% CI, 0.85–1.43; P = 0.45). Results were similar for fasting insulin. Conclusion: Our population‐based cohort study shows an increased risk of VTE in subjects with increasing insulin resistance but not independently of BMI.     

Acute venous thromboembolism in patients with recent major bleeding. The influence of the site of bleeding and the time elapsed on outcome

BACKGROUND: Patients with major bleeding who subsequently develop clinically apparent venous thromboembolism (VTE) present a particularly difficult therapeutic dilemma. METHODS: RIETE is a prospective registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. We retrospectively studied those who had experienced recent major bleeding (<30 days prior to VTE) to assess the influence of the site of bleeding and the time elapsed to VTE on their 3 month outcome. RESULTS: Of 12,294 patients enrolled up to July 2005, 306 (2.5%) had recent major bleeding: gastrointestinal (GI) tract, 116 (38%); intracranial, 94 (31%); other, 96 (31%). During the study period, 19 patients [6.2%; 95% confidence interval (CI) 3.5-8.9] with recent bleeding rebled (eight died): 13 of them (68%) during the first 2 weeks. Multivariate analysis confirmed that patients with recent GI bleeding had an increased risk for both major rebleeding (hazard ratio 2.8; 95% CI 1.4-5.3) and death (hazard ratio 1.9; 95% CI 1.2-3.1) compared to those with no recent bleeding. Those who bled in other sites had an increased risk only for death (hazard ratio 2.0; 95% CI 1.2-3.3). An elapsed time of <2 weeks from bleeding to the index VTE event was also associated with an increased risk for major rebleeding (hazard ratio 2.4; 95% CI 1.2-5.0) and death (hazard ratio 2.8; 95% CI 1.8-4.5). CONCLUSION: The incidence of new bleeding or death depends on the site of prior bleeding and the time elapsed until VTE. This information may help to identify the best therapeutic approach for these high-risk patients.     

High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism

Summary.  Background:  The assessment of the risk of recurrent venous thromboembolism (VTE) is important to determine the optimal duration of secondary prophylaxis. The risk can be estimated by measuring individual parameters reflecting hypercoagulability. Because of the large numbers of such putative parameters, the assessment in individual patients is complex. Application of global assays reflecting the pro-/anti-coagulant balance in vivo would be desirable. Objectives:  To investigate the relationship between recurrent VTE and thrombin generation (TG). Patients-methods:  Two hundred and fifty-four patients were followed-up after a first episode of unprovoked, objectively documented VTE for a period of 2.7 years after discontinuation of treatment with vitamin K antagonists. TG was measured 1 month after discontinuation of treatment as endogenous thrombin potential (ETP), peak thrombin and lag-time in the presence or absence of thrombomodulin. The study outcome was objectively documented symptomatic recurrent VTE. Results:  Patients with ETP or peak (measured in the presence of thrombomodulin) of >960 n m _*min or >193 n m had hazard ratios (HR) (95% CI) for recurrent VTE of 3.41 (1.34–8.68) or 4.57 (1.70–12.2) as compared with those with an ETP <563 n m _*min or peak <115 n m . Patients with lag-time <14.5 min had HR of 3.19 (1.29–7.89) as compared with those with lag-time >20.8 min. HR for ETP, peak or lag-time measured in the absence of thrombomodulin were smaller than those measured in the presence of thrombomodulin. Conclusions:  The measurement of TG helps to identify patients at higher risk of VTE recurrence. The increased risk may be better appreciated if the test is performed in the presence of thrombomodulin.     

The incidence of venous thromboembolism among patients with primary lung cancer

Background:  The incidence of venous thromboembolism (VTE) by lung cancer histology and stage is unknown. Objectives:  To determine the incidence of VTE and the risk factors associated with development of VTE in a large population-based study of patients with non-small cell and small cell lung cancer. Methods:  The California Cancer Registry was merged with the Patient Discharge Data Set to determine the incidence of VTE among lung cancer cases diagnosed between 1993 and 1999. Results:  Among 91 933 patients with newly diagnosed lung cancer, the 1-year and 2-year cumulative VTE incidences were 3.0% and 3.4%, respectively, with a person-time rate of 7.2 events/100 patient-years during the first 6 months. The 1-year incidence of VTE was significantly increased in comparison to the general population [standardized incidence ratio = 21.2, 95% confidence interval (CI) = 20.4–22.0]. In a multivariate model, significant predictors of developing VTE within 1 year of non-small cell lung cancer (NSCLC) diagnosis were: younger age, the number of chronic medical comorbidities [hazard ratio (HR) = 2.8 if 3 vs. 0, 95% CI = 2.5–3.1], advancing cancer stage (HR = 4.0 for metastatic vs. local disease, 95% CI = 3.4–4.6) and adenocarcinoma histology (HR = 1.9 vs. squamous cell, 95% CI = 1.7–2.1). In multivariate models, VTE was a significant predictor of death within 2 years for both NSCLC and small cell lung cancer (SCLC), HR = 2.3, 95% CI = 2.2–2.4, and HR = 1.5, 95% CI = 1.3–1.7, respectively. Conclusions:  Approximately 3% of lung cancer patients developed VTE within 2 years. The diagnosis of VTE was associated with a higher risk of death within 2 years for NSCLC and SCLC.