Onset Of Venous Thromboembolism Research Articles

High Plasma Level of Factor VIII - An Important Risk Factor for Venous Thromboembolism -

Elevated levels of factor VIII (FVIII) have been suggested as important for the pathogenesis of venous thromboembolism (VTE). The objective of this study was to explore the association between elevated FVIII level and VTE in Japan. 68 patients with objectively documented VTE and 40 controls were included. In the patients, the FVIII level was measured for a mean follow-up period of 52.6 months (3-348 months) after the onset of VTE, in order to avoid an acute-phase response. The VTE patients had a higher mean FVIII level than the controls (154.5 ± 55.8 IU/dl vs. 114.3 ± 16.0 IU/dl, P < 0.0001). According to multivariate analysis, FVIII levels above the 50(th) percentile (124 IU/dl) conferred an odds ratio of 4.9 (95% confidence intervals (CI) 1.9-12.4; P < 0.001) and those above the 75(th) percentile (150 IU/dl) conferred an odds ratio of 31.9 (95%CI 4.0-252.3; P < 0.001). Elevated plasma FVIII level is a risk factors for VTE in Japanese people, and FVIII levels above the 75(th) percentile are associated with a significant odds ratio for the occurrence of VTE.

The Association of Active Cancer With Venous Thromboembolism Location: A Population-Based Study

To test active cancer for an association with venous thromboembolism (VTE) location. Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN, residents with incident VTE during the 35-year period 1966-2000 (N = 3385). We restricted analyses to residents with objectively diagnosed VTE during the 17-year period from January 1, 1984, to December 31, 2000 (N = 1599). For each patient, we reviewed the complete medical records in the community for patient age, gender, and most recent body mass index at VTE onset; VTE event type and location; and previously identified independent VTE risk factors (ie, surgery, hospitalization for acute medical illness, active cancer, leg paresis, superficial venous thrombosis, and varicose veins). Using logistic regression we tested active cancer for an association with each of 4 symptomatic VTE locations (arm or intra-abdominal deep venous thrombosis [DVT], intra-abdominal DVT, pulmonary embolism, and bilateral leg DVT), adjusted for age, gender, body mass index, and other VTE risk factors. In multivariate analyses, active cancer was independently associated with arm or intra-abdominal DVT (odds ratio [OR], 1.76; P = .01), intra-abdominal DVT (OR, 2.22; P = .004), and bilateral leg DVT (OR, 2.09; P = .02), but not pulmonary embolism (OR, 0.93). Active cancer is associated with VTE location. Location of VTE may be useful in decision making regarding cancer screening.

Usefulness of antithrombin deficiency phenotypes for risk assessment of venous thromboembolism: type I deficiency as a strong risk factor for venous thromboembolism

Inherited antithrombin deficiency, an established risk factor for venous thromboembolism (VTE), can be classified into type I (quantitative deficiency) or type II (qualitative deficiency). In the present study, we assessed the VTE risk associated with the phenotypes of antithrombin deficiency in patients admitted to our hospital. We found that patients with type I deficiency (n = 21) had more VTE events and earlier onset of VTE than those with type II deficiency (n = 10). The VTE-free survival analysis showed that the risk for VTE in patients with type I deficiency was sevenfold greater than that in patients with type II deficiency (hazard ratio: 7.3; 95% confidence interval: 1.9-12.2; P = 0.0009). The prevalence of type I deficiency in the VTE group (5.6%, 6/108) was higher than that in the general population (0.04%, 2/4,517) (odds ratio: 132.8; 95% confidence interval: 26.5-666.1; P < 0.0001). However, the prevalence of type II deficiency was not different between the VTE group and the general population. Our study indicated that the risk for VTE in patients with type I deficiency was much higher than that in patients with type II deficiency. Thus, simple phenotypic classification of antithrombin deficiency is useful for assessment of VTE risk in Japanese.

Lack of prophylaxis before the onset of acute venous thromboembolism among hospitalized cancer patients: the SWIss Venous ThromboEmbolism Registry (SWIVTER)

Background: Venous thromboembolism (VTE) prophylaxis remains underutilized, particularly in cancer patients. We explored clinical predictors of prophylaxis in hospitalized cancer patients before the onset of acute VTE.Methods: In the SWiss Venous ThromboEmbolism Registry, 257 cancer patients (61 ± 15 years) with acute VTE and prior hospitalization for acute medical illness or surgery within 30 days (91% were at high risk with Geneva VTE risk score ≥3) were enrolled.Results: Overall, 153 (60%) patients received prophylaxis (49% pharmacological and 21% mechanical) before the onset of acute VTE. Outpatient status at the time of VTE diagnosis [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.18–0.53], ongoing chemotherapy (OR 0.51, 95% CI 0.31–0.85), and recent chemotherapy (OR 0.53, 95% CI 0.32–0.88) were univariately associated with the absence of VTE prophylaxis. In multivariate analysis, intensive care unit admission within 30 days (OR 7.02, 95% CI 2.38–20.64), prior deep vein thrombosis (OR 3.48, 95% CI 2.14–5.64), surgery within 30 days (OR 2.43, 95% CI 1.19–4.99), bed rest >3 days (OR 2.02, 95% CI 1.08–3.78), and outpatient status (OR 0.38, 95% CI 0.19–0.76) remained the only independent predictors of thromboprophylaxis.Conclusions: Although most hospitalized cancer patients were at high risk, 40% did not receive any prophylaxis before the onset of acute VTE. There is a need to improve thromboprophylaxis in cancer patients, particularly in the presence of recent or ongoing chemotherapy.

Unusual onset of venous thromboembolism and heparin-induced thrombocytopenia in a patient with essential thrombocythemia

Essential thrombocythemia is a hematological disorder characterized by clonal hemopoiesis in the bone marrow and increased number of circulating platelets. It is usually discovered accidentally at the time of routine blood examinations or can become clinically evident with either thrombotic or hemorrhagic complications. In the present article, we describe the case of a 66-year-old woman with pneumonia due to Pneumocystis carinii, who experienced deep vein thrombosis and pulmonary embolism during hospitalization with a subsequent heparin-induced thrombocytopenia. Bone marrow examination performed after clinical improvement revealed the patient to be affected by essential thrombocythemia.

A Phase III Study of Enoxaparin vs Aspirin vs Low-Dose Warfarin as Thromboprophylaxis for Newly Diagnosed Myeloma Patients Treated with Thalidomide Based-Regimens.

Abstract 492 Background.The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens. Anticoagulant prophylaxis is recommended. Controversies exist on the best thromboprophylactic regimen to adopt. Aims. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. End-points were incidence of VTE, acute cardiovascular events, sudden death, major and minor bleeding. Methods.In a GIMEMA study, 991 newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m2 d 1,4,8,11; Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=223) or ASA (Aspirin 100 mg/d, N=227) or WAR (Warfarin 1.25 mg/d, N=223) for the duration of the induction therapy; 61 patients were excluded from sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Patients treated with VMP (N=257) did not receive any prophylaxis and were used as controls. Results.Patient characteristics and distribution of major risk factors were similar in all groups. The incidence of VTE was 5% in the LMWH group, 6% in the ASA group and 8% in the WAR group (p not significant). VTEs were 2% in the VMP group. Median time to onset of VTE for patients who received LMWH or ASA or WAR were 4.7, 2.4 and 2.4 months, respectively. Patients who received higher doses of both steroids and thalidomide (VTD and TD) had a higher VTE incidence (7%) in comparison with those who received lower doses (VMPT, 3%, p=0.06). Patients treated with bortezomib (VTD and VMPT) had a lower VTE incidence (5%) in comparison with patients on TD (8%, p=0.08). The rates of cardiovascular events were 2% in the LMWH group, 1% in the ASA group and 0.5% in the WAR group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group and 1% in the WAR group (p not significant). The incidence of combined thrombosis, bleeding and cardiovascular events was 9% in the LMWH group, 10% in the ASA group and 9% in the WAR group (p not significant). Conclusion.The overall incidence of VTE was less than 10% in all groups and was not superior to that expected during the natural course of MM. The LMWH patients had lower risk of VTE, although no statistical difference was observed. LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens. The final analysis on 991 patients will be presented at the meeting.Table 1Incidence of thrombotic events, acute cardiovascular events, sudden death and bleeding events.EventsLMWH (N = 217)ASA (N = 225)WAR (N = 219)VMP (N = 238)Grade 3-4 thrombotic events, (%)5682Acute cardiovascular events, (%)210.51Sudden deaths, (%)0000Major and minor bleeding, (%)2314Total events, (%)91097 Disclosures:No relevant conflicts of interest to declare.

Critical role of von Willebrand factor and platelet interaction in venous thromboembolism.

It has been generally considered that platelets are less important in venous thrombus formation. However, clinical studies have shown an association between venous thromboembolism (VTE) and von Willebrand factor (VWF). We therefore investigated the contribution of VWF and platelet interaction to the onset of VTE using tissues from autopsies and from an animal model. An immunohistochemical study revealed that glycoprotein (GP) IIb/IIIa, fibrin, glycophorin A (erythrocyte-specific protein) and VWF were consistently localized in ilio-femoral venous thrombi and in pulmonary thromboemboli from 8 autopsied cases who died of VTE, and VWF was closely associated with GPIIb/IIIa and fibrin. Venous thrombi and pulmonary emboli contained significant amounts of GPIIb/IIIa and VWF, in addition to glycophorin A and fibrin, and the factors did not significantly differ between them. A rabbit model of VTE was developed by inserting a polyethylene tube into the iliac vein. The constituents of the induced thrombi were quite similar to those of human VTE. An antibody against VWF (AJW200), which inhibits interactions between the VWF A1 domain and platelet GPIb, significantly reduced venous thrombus formation and pulmonary thromboembolism in the model. These results suggest that VWF A1-platelet GPIb interaction plays a significant role in venous thrombus formation.

A Phase III Study of Enoxaparin Versus Low-Dose Warfarin Versus Aspirin as Thromboprophylaxis for Patients with Newly Diagnosed Multiple Myeloma Treated up-Front with Thalidomide-Containing Regimens

Thalidomide-containing regimens are currently being used as standard initial therapy for both younger and elderly pts with multiple myeloma (MM), but are associated with an increased risk of venous thromboembolism (VTE) which necessitates routine thromboprophylaxis. Controversies exist concerning the best thromboprophylactic regimen to be used in these pts. To address this issue, the Italian Myeloma Network GIMEMA designed a phase III sub-study aimed at prospectively investigating the efficacy and safety of low molecular weight heparin (LMWH) or fixed low-dose warfarin (WAR) or low-dose aspirin (ASA) as prophylaxis against VTE in newly diagnosed MM pts who were randomized to receive primary induction therapy with thalidomide-containing regimens in the context of 2 phase III studies conducted by the same group. In one of these studies, pts with ≤65 years of age were randomly assigned to receive Velcade-Thalidomide-Dexamethasone (VTD) or Thalidomide-Dexamethasone (TD) before autologous transplantation. In the other study, Velcade-Melphalan-Prednisone (VMP) was compared with VMP plus thalidomide (VMPT) for elderly patients aged >65 years. The daily dose of Thalidomide was 200 mg in both VTD and TD, and 50 mg in VMPT. Pts randomized to VTD or TD received a total Dexamethasone dose of 320 mg/cycle, while those assigned to VMP or VMPT were given a total Prednisone dose of 240 mg/m2/cycle. By sub-study design, pts treated on VTD or TD or VMPT were randomly assigned to receive thromboprophylaxis with LMWH (Enoxaparin, 40 mg/d) or WAR (1.25 mg/d) or ASA (100 mg/d) for the duration of induction therapy. At the opposite, pts randomized to VMP did not receive any prophylaxis and were used as controls. Sub-study end points included incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. At the time of the present analysis, 703 pts who received at least 3 cycles of induction therapy were evaluated. Of these pts, 164 treated on VMP were the control group, while the remaining 539 pts (of whom, 209 treated on VTD, 211 on TD and 119 on VMPT) were randomized to receive either LMWH (n=178) or WAR (n=180) or ASA (n=181). Baseline pts characteristics and risk factors for VTE were comparable in all sub-groups. Overall, the risk of VTE was 3.9% with WAR vs 4.5% with LMWH vs 5.5% with ASA (P values not significant for comparisons between different sub-groups), whereas it was 1.8% among the controls. Median times to onset of VTE for pts treated on LMWH or WAR or ASA were 2.66 vs 2.96 vs 2.10 months, respectively. Pts receiving Velcade-containing regimens (VTD or VMPT) had a VTE frequency in the range of approximately 3%, as compared to 5.8% for pts on TD (P value not significant). The rates of cardiovascular events were 0.6% in each of sub-groups including LMWH, WAR and controls, vs 1.1% for pts treated on ASA. No sudden deaths were reported. The incidence of all grades bleeding was 0.6% with LMWH vs 1.1% with WAR vs 3.3% with ASA (P values not significant for comparisons between different sub-groups), while it was 3.7% among the controls. In conclusion, results of the present analysis show that the overall risk of VTE among sub-groups of pts treated with different thalidomide-containing regimens was not superior to that expected during the natural course of MM. No significant relationship was found between the frequency of VTE and thromboprophylactic regimens, induction treatments (e.g. containing or not Velcade) and age of pts (e.g. young vs elderly). In comparison with LMWH and WAR, there was a higher, albeit marginal, risk of VTE and bleeding complications associated with ASA prophylaxis. Finally, a finding not previously well recognized, fixed low-dose WAR was not inferior to LMWH in reducing the risk of VTE among newly diagnosed MM pts receiving thalidomide-containing regimens. For these pts, LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens.

Influence of the factor II G20210A variant or the factor V G1691A mutation on symptomatic recurrent venous thromboembolism in children: an international multicenter cohort study.

To determine the relative importance of the factor (F) II G20210A or FV G1691A mutations as risk factors or predictors for fatal/non-fatal recurrent venous thromboembolism (VTE) in children. In the present cohort, the rate of VTE recurrence and the time to recurrence in relation to FII, FV, age, and sex was determined in consecutively enrolled patients with VTE aged newborn to <or=18 years carrying the FII (n = 64) or FV (n = 194) mutation. 158 children with VTE without thrombophilia served as controls. Patients were followed for a median of 58 months. Data were pooled across participating sites to increase power and to enhance the generalizability of the data. Incidence rates were given as events per 1000 person-years. Of the 416 children enrolled, 44 had recurrent VTE at a median of 12 months following VTE onset. The overall incidence rate of recurrence was 19.8, 57.9 in patients with the FII variant, 17.9 for FV carriers, and 11.8 in the control cohort. When comparing FII patients, FV children and the control cohort multivariate analysis (Cox regression) adjusted for age and sex showed that the FII variant (hazard ratio 2.6; 95% confidence interval 1.1-5.9) influenced the hazard for recurrent VTE. Based on multivariate analysis, the presence of the FII variant was associated with an increased risk of VTE recurrence.

Impact of Inherited Thrombophilia on Venous Thromboembolism in Children

The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a). The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.

Impact of Inherited Thrombophilia on Symptomatic Venous Thrombo-Embolism (VTE) in Children: A Systematic Review & Meta-Analysis of 37 Studies Including 2470 Pediatric Patients.

Background: Inherited thrombophilia (IT) has been described as a risk factor for venous thromboembolism (VTE) in children. So far the majority of studies performed in the field were either retrospective or prospective on small numbers of patients. Thus, the results are contradictory or inconclusive mainly due to lack of statistical power. The aim of this study was to better estimate the impact of IT on early VTE onset and recurrence in children as a prerequisite to develop primary and secondary treatment options.Methods: A systematic search of publications listed in the electronic databases (Pubmed, Medline, EMBASE, Web of Science, The Cochrane Library) up to August 2007 using key words in combination both as MeSH terms and text words, was conducted. Citations were screened by two independent group members and those meeting the inclusion criteria were retained. Articles were included if published after 1990, when pediatric VTE was started to be systematically investigated.Findings: Twenty case-control and 17 cohort studies from 13 countries met the inclusion criteria. In these studies > 70% of patients had at least one clinical risk factor. The summary odds ratios (OR) and 95% confidence intervals (CI) of included studies under a fixed-effects and random-effects model showed statistically significant associations between the IT traits investigated and VTE onset (table). For the rare event of VTE recurrence, 1227 patients (eight studies) were evaluated: at the present state due to high heterogeneity, a trend towards association with recurrent VTE was found for ≥2 IT traits in the fixed-effects model (0R/CI: 2.8/1.6–4.8).Interpretation: The present meta-analysis gives evidence that the detection of inherited thrombophilia is clincially meaningful in children with VTE and underlines the importance of a pediatric thrombophilia screening program.Summary of DataRisk FactorsOR/CI:fixed modelOR/CI:random modelpatients/controls2470/4119N/AFV G1691A3.5/2.9–4.23.2/2.3–4.4FII G20210A2.2/1.5–3.32.2/1.5–3.4Protein C defiiciency9.8/5.9–169.9/6.1–16.1Protein S deficiency7.1/3.9–13.26.8/3.7–12.7Antithrombin deficiency7.9/3.8–16.67.3/3.4–15.3Lipoprotein(a)4.4/3,2–5.94/2.4–6.6≥ 2 risk factors12.6/7.3–21.811.6/6.2–20.2

High incidence of silent venous thromboembolism before treatment in ovarian cancer

Venous thromboembolism (VTE) such as deep-vein thrombosis (DVT) and pulmonary thromboembolism (PTE) often occurs after surgery and rarely occurs even before surgery in patients with ovarian cancer. It is well known that levels of plasma D-dimer (DD) before treatment in most ovarian cancer patients are increased. This study therefore examined whether increased levels of DD are associated with presence of VTE before treatment of ovarian cancer. Between November 2004 and March 2007, DD levels prior to initial treatment were measured in 72 consecutive patients with presumed epithelial ovarian cancer (final diagnosis: epithelial ovarian cancer, n=60; and epithelial ovarian borderline malignancy, n=12). Venous ultrasound imaging (VUI) of the lower extremity was conducted for all patients except for two patients in whom DVT was detected by pelvic computed tomography (CT). When DVT was found, pulmonary scintigraphy was subsequently performed to ascertain presence of PTE. D-dimer levels were above the cut-off value (0.5 μg ml−1) in 65 of 72 patients (90.2%). Venous ultrasound imaging or CT revealed DVT in 18 of 72 patients (25.0%) and pulmonary scintigraphy found PTE in 8 patients (11.1%). All patients with VTE were asymptomatic when VTE was found. D-dimer levels were associated with incidence of VTE (0–1.4 μg ml−1; 0 of 26 (0%), 1.5–7.4 μg ml−1; 9 of 30 (30%) and ⩾7.5 μg ml−1; 9 of 16 (56.3%), P for trend=0.0003). However, even if 1.5 μg ml−1 was used as a cut-off value, this had low specificity and positive predictive value (47.2, 38.3%), though it had high sensitivity and negative predictive value (100, 100%). Therefore, ovarian cancer patients with DD level ⩾1.5 μg ml−1 should be examined using VUI to detect silent DVT. Patients with VTE underwent preventive managements including anticoagulant therapy before initial treatment, chemotherapy or surgery, and after surgery. There was no clinical onset of postoperative VTE in all 72 patients. Measurement of DD levels and subsequent ultrasonography revealed that silent or subclinical VTE frequently occurs before surgery in ovarian cancer. The usefulness of preoperative assessment of VTE needs further confirmation in randomised controlled trials.

Intensity of Heparin Anticoagulation as an Independent Predictor of 14-Day Recurrence after Deep Vein Thrombosis or Pulmonary Embolism: A Population-Based Cohort Study.

Background: Most trials of standard heparin and warfarin therapy used the 3- to 6-month cumulative incidence of venous thromboembolism (VTE) recurrence as the primary efficacy outcome. Consequently, the effect of heparin anticoagulation intensity on short-term VTE recurrence after controlling for other predictors of recurrence (e.g., active cancer, neurological disease with extremity paresis) is uncertain.Objectives: To test standard heparin anticoagulation intensity, using activated partial prothrombin time (APTT) data, as an independent predictor of 14-day VTE recurrence.Measurements: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis or pulmonary embolism over the 14-year period, 1984–1997 (n=1165). We followed each case (conditional on surviving one day) forward in time through their complete medical records in the community for first VTE recurrence. We collected date of incident VTE onset, start and stop dates of heparin and warfarin, and date, time and result of all APTT and platelet count values. Using these and other measures of standard heparin therapy as time-dependent variables, we tested the intensity of heparin anticoagulation as an independent predictor of 14-day VTE recurrence while controlling for other baseline characteristics using Cox proportional hazards modeling.Results: Of the 1165 patients, 1026 (88%) and 989 (85%) received heparin and warfarin, respectively, and 254 (22%) developed recurrent VTE over 5461 person-years of follow-up; 23 recurred within 14 days. In the multivariate analysis, the independent predictors of 14-day recurrence included female gender (HR=3.06, 95%CI: 1.05, 8.91; p=0.04) and neurologic disease with extremity paresis (HR=6.01, 95%CI: 1.93, 18.66; p<0.01); the hazard of recurrence was marginally increased for active cancer (HR=2.21, p=0.13). Warfarin therapy (HR=0.44, p=0.11) and a therapeutic APTT within the first 24 hours of therapy (HR=0.41, p=0.08) were marginally protective, but age, body mass index, time interval between VTE onset and start of heparin, and other measures of heparin anticoagulation intensity (e.g., proportion of time in therapeutic APTT range, etc) were not predictors of recurrence. Three patients developed new and persistent thrombocytopenia beginning 2, 4 and 5 days after starting heparin, respectively and prior to VTE recurrence.Conclusions: VTE recurrence is uncommon within 14 days after starting heparin therapy. Female gender and neurologic disease with extremity paresis are independent predictors of 14-day recurrence, and active cancer may be an additional predictor. Warfarin therapy and a therapeutic APTT within the first 24 hours may predict a reduced recurrence risk. However, other measures of heparin anticoagulation intensity were non-predictive. Heparin-induced thrombocytopenia may partially account for early VTE recurrence.

Intensity of Warfarin Anticoagulation as an Independent Predictor of 6-Month Recurrence after Deep Vein Thrombosis or Pulmonary Embolism: A Population-Based Cohort Study.

Background: Most trials of standard heparin and warfarin therapy used the 3- to 6-month cumulative incidence of venous thromboembolism (VTE) recurrence as the primary efficacy outcome. However, the independent effect of warfarin anticoagulation intensity on VTE recurrence after controlling for other predictors of recurrence (e.g., active cancer, neurological disease with extremity paresis) is uncertain.Objectives: To test warfarin anticoagulation intensity, using international normalized ratio (INR) data, as an independent predictor of 6-month VTE recurrence. Measurements: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis or pulmonary embolism over the 14-year period, 1984–1997 (n=1165). We followed each case (conditional on surviving 14 days without VTE recurrence) forward in time through their complete medical records in the community for first VTE recurrence. We collected date of incident VTE onset, start and stop dates of heparin and warfarin, and date, time and result of all INR values. Using these and other measures of standard warfarin therapy as time-dependent variables, we tested the intensity of warfarin anticoagulation (expressed as the cumulative percent of time with an INR at or above 2.0 [or at or above 1.5] while on warfarin) as an independent predictor of 6-month VTE recurrence while controlling for other baseline characteristics using Cox proportional hazards modeling.Results: Of the 1165 patients, 1026 (88%) and 989 (85%) received heparin and warfarin, respectively, and 254 (22%) developed recurrent VTE over 5461 person-years of follow-up; 52 recurred within 15–180 days. In the multivariate analysis, the independent predictor of 6-month recurrence was active cancer (HR=3.98, 95% CI: 2.12, 7.45; p<0.01); age, gender, body mass index and neurologic disease with extremity paresis were not predictors of VTE recurrence. In models that included presence or absence of warfarin therapy along with proportion of time with an INR ≥2, this latter intensity variable was protective (HR=0.16 for 100% versus 0% of time, p=0.02) against recurrence, while mere presence of warfarin therapy (HR =0.72, p= 0.56) was not. Similar results were obtained when intensity was represented as proportion of time with an INR ≥1.5 (HR=0.17, p=0.02). Interestingly, a therapeutic APTT within the first 24 hours of heparin therapy also was protective against 6-month recurrence (HR=0.45, p=0.02).Conclusions: Active cancer is an independent predictor of 6-month VTE recurrence. Warfarin therapy with a higher proportion of time with an INR ≥1.5 or ≥2 offers similar protection against recurrence. A rapid heparin-response (as reflected by a therapeutic APTT within 24 hours of heparin therapy) also is a predictor of reduced 6-month recurrence, possibly reflecting lower factor VIII activity at the acute incident VTE event. Gender is not a predictor of long-term recurrence.

Reply

Sir, We would like to respond to the letter from Shukunami et al. A report by Zotz et al. described that ETP-based normalized APC sensitivity ratio (nAPC-sr) in patients with a past history of venous thromboembolism (VTE) in pregnancy or puerperium was not elevated significantly compared with nAPC-sr in healthy women in the blood samples obtained at least six months after thromboembolic events. However, unfortunately they did not show the changes in nAPC-sr in patients with VTE prior to the onset of VTE. On the contrary, we reported that ETP-based nAPC-sr in women during late pregnancy and puerperium was significantly elevated compared with that in non-pregnant women and women during early pregnancy. An animal experiment suggests that hormonal changes enhance ETP, as the changes in ETP in pregnant women and OC users 1. Also, we demonstrated that nAPC-sr in patients with VTE right after onset during puerperium was elevated significantly compared with that in healthy women during puerperium 2. Furthermore, we detected the marked elevation of nAPC-sr prior to the onset of suprasagittal thrombosis during puerperium without marked changes in other coagulation variables 3. These observations suggest that reduced sensitivity to APC in pregnancy and puerperium is related with the onset of thrombotic events although the changes are partly related to thrombosis and/or inflammation. As Zotz et al. pointed out, the retrospective study design does not allow information to be given about possible temporary pregnancy-associated changes in ETP-based nAPC-sr prior to the thrombotic event. At present, we have not concluded that ETP-based nAPC-sr is not a risk marker for pregnancy-associated VTE as far as the temporary changes are determined in sensitivity to APC prior to thrombosis in the future. Furthermore, they also demonstrated that nAPC-sr in normal healthy OC users was elevated significantly compared with that in controls. If nAPC-sr in normal healthy OC users is elevated compared with that in control, nAPC-sr in normal healthy pregnant women should be elevated because the hormonal changes in OC users are similar to those in pregnant women, as we have shown.

Prevention of Venous Thromboembolism Among Hospitalized Medical Patients

Case presentation : A 79-year-old woman was noted by staff at her skilled nursing facility to have increasing shortness of breath during the previous 24 to 48 hours. She had been receiving daily physical therapy, occupational therapy, and 6 prescription medications to manage underlying congestive heart failure with preserved systolic function. The woman was hospitalized. After being transferred to the emergency department, she underwent further workup, which showed no pulmonary embolism on chest CT scan. The chest x-ray, however, revealed a new right lobar infiltrate and consolidation, which are consistent with pneumonia. On examination, she was alert, with a respiratory rate of 24 per minute, heart rate of 96 bpm, blood pressure of 154/76 mm Hg, temperature of 38°C, distended neck veins, right lower lung zone posterior musical rales, regular heart rhythm, normal S1, single S2, and grade II/VI systolic murmur at the left lower sternal border. The diagnosis of pneumonia was made, and levofloxacin was initiated in the emergency department. Specific evaluation of her medical regimen, including furosemide, potassium chloride, metoprolol, candesartan, simvastatin, and baby aspirin, was recommended. Prevention of venous thromboembolism has been neglected in hospitalized patients with medical illnesses such as congestive heart failure, chronic lung disease, cancer, and infectious diseases. In the Medical Intensive Care Unit (MICU) at Brigham and Women’s Hospital, we found a combination of omitted and ineffective prophylaxis. When we performed venous ultrasound examinations on 100 patients admitted to the MICU with an anticipated stay of >48 hours, we detected deep vein thrombosis (DVT) in 33%.1 Almost 50% of the patients with DVT …

The Seasonal Incidence of Venous Thromboembolism (VTE): A Population-Based Cohort Study.

If the incidence of VTE varies by season, then the etiology of VTE could be related to seasonal exposures. However, the few studies that estimated VTE incidence by season reached conflicting conclusions.Objective: To estimate the incidence of VTE by month and by season of the year.Methods: Using the resources of the Rochester Epidemiology Project, we identified the inception cohort of Olmsted County, MN, residents with a first lifetime VTE over the 30-year period, 1966–1995 (n=2761). For each case, we reviewed the complete medical records in the community for the date of VTE onset, date of birth, gender and 48 baseline clinical characteristics commonly accepted as risk factors for VTE. We categorized cases as idiopathic (n=305) if no such characteristics were present; remaining cases were categorized as secondary. Incidence rates were calculated using the number of overall, idiopathic or secondary VTE cases by month of onset as the numerator, and age- and sex-specific estimates of the monthly population of Olmsted County as the denominator (yearly population estimates divided by 12).Results: The incidence of VTE did not vary appreciably by month of the year for overall, idiopathic or secondary VTE (all p-values >0.2). However, the overall incidence of VTE was higher in the 3 summer months (June, July, August) compared to the 3 winter months (December, January, February; 132.6 vs. 116.9 per 100,000 person-years, respectively, both age- and sex-adjusted to year 2000 U.S. Whites; p-value = 0.026). The same general pattern was true for both idiopathic and secondary VTE, but separately neither was statistically significant (p-value=0.48 and 0.15, respectively).Conclusions: The incidence of VTE is higher in the summer compared to the winter months, suggesting the hypothesis that vector-borne (e.g., mosquito, tick) and/or enteroviral infection may play a role in the etiology of VTE.

Incidence of Venous Thromboembolism in Hospitalized Patients vs Community Residents

To estimate the incidence rates of deep venous thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients and to compare these with incidence rates in community residents. We performed a retrospective review of the complete medical records from a population-based inception cohort of patients who resided in Olmsted County, Minnesota, and had an incident DVT or PE from 1980 through 1990. From 1980 through 1990, 911 Olmsted County residents experienced their first lifetime event of definite, probable, or possible venous thromboembolism. Of these residents, 253 had been hospitalized for some reason other than a diagnosis of DVT or PE (in-hospital cases), and 658 were not hospitalized at onset of venous thromboembolism (community residents). The average annual age- and sex-adjusted incidence of in-hospital venous thromboembolism was 960.5 (95% confidence interval, 795.1-1125.9) per 10,000 person-years and was more than 100 times greater than the incidence among community residents at 7.1 (95% confidence interval, 6.5-7.6) per 10,000 person-years. The incidence of venous thromboembolism rose markedly with increasing age for both groups, with PE accounting for most of the age-related increase among in-hospital cases. Incidence rates in the 2 groups changed little over time despite a reduction in the average length of hospital stay between 1980 and 1990. Venous thromboembolism is a major national health problem, especially among elderly hospitalized patients. This finding emphasizes the need for accurate identification of hospitalized patients at risk for venous thromboembolism and a better understanding of the mechanisms involved so that safe and effective prophylaxis can be implemented.

New Onset of Venous Thromboembolism Among Hospitalized Patients at Brigham and Women’s Hospital Is Caused More Often by Prophylaxis Failure Than by Withholding Treatment

Guidelines to prevent venous thromboembolism (VTE) have been widely distributed and generally have been assumed to be effective. Therefore, among hospitalized patients, the development of VTE is thought to occur in the context of omitted prophylaxis. To describe hospitalized patients who develop VTE and to determine whether they received antecedent prophylaxis. Case series. Brigham and Women's Hospital. Three hundred eighty-four patients who developed in-hospital deep venous thrombosis or pulmonary embolism or who developed VTE within 30 days of prior hospital discharge. The relationship of developing new-onset VTE to the use or omission of antecedent in-hospital prophylaxis. Of the 384 identified patients, 272 had deep venous thrombosis alone, 62 had pulmonary embolism alone, and 50 had deep venous thrombosis and pulmonary embolism. Most were medical service patients; fewer than one fourth were general or orthopedic surgery patients. Overall, 52% had received antecedent VTE prophylaxis. Thirteen deaths (3.4%) were ascribed to pulmonary embolism, and prophylaxis was omitted in only 1 of those 13 patients. Most deaths from pulmonary embolism among patients hospitalized for other conditions occurred in the setting of failed prophylaxis rather than omitted prophylaxis. High-risk patients, especially medical service patients, warrant intensive VTE prophylaxis and close follow-up to ensure successful outcomes.

Activated protein c resistance (APC) and inherited factor V (FV) mis‐sense mutation in patients with venous and arterial thrombosis in a haematology clinic

Inherited factor V (FV) mis-sense point mutation has recently been identified as a major cause of familial venous thrombosis. The incidence of this congenital haemostatic disorder in Australia is unknown. To examine the incidence of this congenital defect in patients with thrombosis attending a haematology clinic. Individuals investigated or treated for venous and arterial thrombosis over a four month period, as well as those who were on anticoagulant for valvular replacement or arrhythmia were studied for the presence of FV mis-sense point mutation, FV Q506 (G to A at nucleotide position 1691) by a polymerase chain reaction based test, and activated protein C (APC) resistance using an APTT based coagulation assay. Forty-five patients with venous thromboembolism (VTE), 20 patients with coronary artery disease and 25 patients with valvular replacement or arrhythmia who were on anticoagulant were examined. The frequency of FV mis-sense point mutation in these three groups was 26.7%, 15% and 4% respectively. In this study, patients with FV Q506 were of a younger age and had a higher incidence of extensive thrombosis or recurrence as compared to those with the normal factor V gene. This mutation was found in a diverse group of people (four of the 12 patients were of non-European origin). Nearly 50% of these patients had other risk factors for VTE. The number of patients with a family history of VTE was similar for those with the FV mutation and the normal FV. This study confirms the high incidence of FV Q506 mutation in patients with VTE reported overseas. Several clinical features, i.e. young age of onset of VTE, high recurrence rate, diverse ethnic background and importance of associated risk factors are highlighted. The findings in this study also raise the possibility that this mutation may be a risk factor for arterial thrombosis. Large studies are required to substantiate these findings.