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Relationship between fibrinopeptide A and fibrinogen/fibrin fragment E in thromboembolism, DIC and various non-thromboembolic diseases.

Increased fibrinopeptide A (FPA) levels have been reported in various non-thrombotic disorders, including cancer, acute myocardial infarction, liver cirrhosis and collagen vascular diseases. To investigate the significance of these findings, the present study combined the radioimmunoassay of FPA with that of fibrinogen/fibrin degradation fragment E (FgE) in the aforementioned disorders and compared the results with those observed in healthy subjects as well as in patients with thromboembolism and overt disseminated intravascular coagulation (DIC). Mean FPA and FgE in malignancy were 6.3 and 305 ng/ml, in myocardial infarction 5.6 and 98 ng/ml, in liver cirrhosis 2.7 and 132 ng/ml and in collagen vascular diseases 5.6 and 142 ng/ml. All these values were significantly higher than in healthy controls (mean FPA 1.6 ng/ml, mean FgE 49 ng/ml) but significantly lower than in thromboembolism (mean FPA 10.7 ng/ml, mean FgE 639 ng/ml). and DIC (mean FPA 22.0 ng/ml, mean FgE 1041 ng/ml). The overall correlation between FPA and FgE was highly significant. However, different disorders showed peculiar patterns in FPA, FgE and fibrinogen levels. In malignancy, a definite increase of FPA, FgE and plasma fibrinogen levels was observed. This finding probably indicates a compensated state of (intra- or extravascular) fibrin formation and lysis. Acute myocardial infarction was characterized by a high FPA to FgE ratio, which is interpreted to reflect acute thrombin generation and fibrin formation. FPA in cirrhosis was only marginally elevated with most single values within the normal range, indicating that intravascular coagulation was infrequent and unimportant in quantitative terms.

Collagen Diseases↗

[C-reactive protein, leukocyte count and D-dimer monitoring after orthopedic surgery: early diagnosis of infectious or thromboembolic complications. Part two: does d-dimer measurement contribute to the diagnosis of postoperative venous thromboembolism?].

OBJECTIVES: To determine the modification in postoperative D-dimer level as a function of the surgical act and to assess the relevance of this measure for diagnosing thromboembolism. METHOD: A cohort of 179 patients was followed: group 1 comprised 128 patients undergoing lower limb arthroplasty, group 2 comprised 29 patients undergoing lower limb surgery without implant, and group 3 comprised 22 patients undergoing spinal or upper limb surgery. D-dimer level was systematically measured on admission and then once a week for 4 weeks. Doppler ultrasonography was performed on clinical suspicion of deep vein thrombosis. D-dimer levels were compared between patients with and without deep vein thrombosis. RESULTS: D-dimer levels were constantly elevated postsurgery (2- to 6-fold above normal) and returned to normal by week 4 in groups 2 and 3 but remained elevated in group 1 (3-fold above normal). Deep vein thrombosis was suspected in 45 cases and confirmed by Doppler ultrasonography in 10 cases. D-dimer level was not significantly different between patients with deep vein thrombosis and those without. DISCUSSION AND CONCLUSIONS: In the postoperative period, measurement of D-dimer level does not aid in diagnosing thromboembolism since its constant high level obviates any negative predictive value.

Adult↗

Clinical characteristics, diagnosis and management of patients with pulmonary thromboembolism who are not diagnosed in the acute phase and not classified as chronic thromboembolic pulmonary hypertension.

BACKGROUND: There have been many cases of pulmonary thromboembolism (PTE) that were not diagnosed in the acute phase and not classified as chronic thromboembolic pulmonary hypertension (CTEPH). The aim of the present study was clarify the clinical characteristics of chronic PTE. METHODS AND RESULTS: The study subjects were 601 patients (chronic PTE = 92, acute PTE = 456, CTEPH = 53) who were clinically diagnosed before their death. Dyspnea and chest pain, which are frequently found in acute PTE, were found less frequently in chronic PTE. The diagnosis of chronic PTE is often delayed in cases of mild to moderate severity with atypical onset. Chronic heart failure and chronic respiratory failure were most frequent in chronic PTE, and cerebrovascular disease was present in approximately 15% of the cases of chronic PTE. Pulmonary angiography and ventilation lung scan were used least frequently in acute PTE. Heparin and thrombolysis were used most frequently in acute PTE. CONCLUSIONS: Besides the atypical onset and reduced severity, the presence of preexisting diseases may be one of the reasons why the diagnosis for chronic PTE is delayed. The diagnostic and management techniques differ according to the type of PTE.

Adult↗

The first ambulatory screening on thromboembolism: a multicentre, cross-sectional, observational study on risk factors for venous thromboembolism.

OBJECTIVES: To assess the prevalence of risk factors for venous thromboembolism (VTE) and the prevalence of recent (<1 year) VTE [including superficial vein thrombosis (SVT), deep vein thrombosis (DVT) and pulmonary embolism (PE)] amongst patients attending general practitioner (GP) surgeries. DESIGN: Multicentre, cross-sectional, observational study. SETTING: A total of 1536 GP surgeries. PARTICIPANTS: A total of 15 180 adult, co-operative subjects, who had consulted their GP for a health disorder and signed the informed consent form. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence of known VTE risk factors graded according to importance and prevalence of recent (<1 year) VTE events (including SVT), based on interviews. RESULTS: About 1:5 patients had at least one strong risk factor and about 1:20 had at least two risk factors, with no difference between sexes. The prevalence of strong risk factors increased with age. Most were related to medical conditions: history of SVT and/or DVT/PE, heart failure and malignancy. About 3:4 women and 2:3 men had at least one moderate to weak risk factor; nearly 1:2 women and 1:3 men had at least two moderate to weak risk factors. The most common were: history of VTE, smoking, history of miscarriage, estrogen therapy, obesity, and varicose veins. Overall, 80% women and 67% men had at least one risk factor, and 50% women and 35% men had at least two risk factors. The prevalence of recent (<1 year) VTE was 3.4% in women and 2.4% in men, and increased with age. The majority of cases were SVT in both sexes (2.5% in women and 1.5% in men). CONCLUSIONS: The prevalence of risk factors for VTE amongst patients attending GP surgeries is high. GPs should bear this in mind during their daily practice.

Adolescent↗

The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism.

BACKGROUND: Factor V (FV) Leiden is a risk factor for venous thrombosis (VT). Data on its influence on the risk of recurrent venous thromboembolism (VTE) are controversial owing to different study designs and patient cohorts. METHODS: We reevaluated the risk of recurrence among heterozygous carriers and noncarriers of FV Leiden with a first spontaneous proximal VT of the leg and/or pulmonary embolism. Patients with secondary VTE, homozygous FV Leiden, natural inhibitor deficiencies, lupus anticoagulant, cancer, or long-term anticoagulation were excluded. The study end point was objectively documented, symptomatic, recurrent VTE. RESULTS: After discontinuation of oral anticoagulant therapy for a first VTE, we prospectively observed 287 patients, 83 (29%) of whom were heterozygous for FV Leiden. Recurrent VTE was seen in 17 (20%) of 83 patients with and 44 (21.6%) of 204 without FV Leiden. The probability of recurrence among heterozygotes was 12% (95% confidence interval [CI], 8%-16%), 27% (95% CI, 21%-33%), and 27% (95% CI, 21%-33%) after 2, 4, and 6 years, respectively, and was not higher than that among patients without the mutation (16%, 23%, and 34%, respectively). The relative risk of recurrence in heterozygotes was 0.9 (95% CI, 0.5-1.6; P =.60) after adjustment for confounding variables. The risk of recurrence among patients with and without FV Leiden was not different when sex distribution or duration of anticoagulation therapy was taken into account. CONCLUSIONS: The risk of recurrence is similar among carriers and noncarriers of FV Leiden. Heterozygous patients should receive secondary thromboprophylaxis for a similar length of time as patients without FV Leiden.

Adult↗

Case-control studies on venous thromboembolism: bias due to design? A methodological study on venous thromboembolism and steroid hormone use.

This study addressed methodological issues of epidemiologic studies on venous thromboembolism (VTE) to show how design decisions can affect the results. It examines the influence of a restricting to hospitalized and to "idiopathic" cases of VTE in case-control studies on VTE risk and oral contraceptive (OC) use and thereby the bias potential. The diagnostic processes and OC exposures of 1068 suspected cases of VTE were followed in 21 German centers from 1994 to 1999 and evaluated compared to population and hospital controls. Of 606 confirmed cases, 385 (65.5%) were hospitalized, 168 (27.7%) were "idiopathic." Comparing users versus nonusers of OCs, the odds ratio (OR) for VTE risk for all cases and controls was 3.38 and 5.44 for "idiopathic" VTE. For hospital cases and controls, the OR was 3.72 and 9.1 for "idiopathic" VTE. The risk ratio for third- vs. second-generation OCs was increased in the hospital base but not in the population base. It was concluded that restriction to hospitalized events and exclusions of certain cases overestimate the VTE risk of OCs. An evidence-based consensus on methodological standards and definitions in case-control studies on VTE and steroid hormone use is required.

Adult↗

Factor Xa inhibition in the prevention of venous thromboembolism and treatment of patients with venous thromboembolism.

Venous thromboembolism (VTE) is a life-threatening complication following orthopedic surgery. Selective factor Xa inhibition is a new antithrombotic approach designed to avoid difficulties associated with heparins and other current anticoagulants. Several antifactor Xa compounds are in early investigation, but fondaparinux (Arixtra; NV Organon, Oss, The Netherlands; Sanofi-Synthelabo, Paris, France) is the first and most advanced compound in the development of a new class of synthetic antithrombotic agents--the selective factor Xa inhibitors. Fondaparinux has a highly favorable pharmacokinetic profile; four large phase 3 trials comparing subcutaneous fondaparinux 2.5 mg once daily with the low molecular weight heparin (LMWH) enoxaparin in doses approved by regulatory bodies showed that fondaparinux reduced the overall risk of VTE in major orthopedic surgery by > 50% without increasing clinically relevant bleeding. Fondaparinux also appears to be a very promising candidate for the treatment of patients with existing VTE.

Animals↗

Genetic heterogeneity in hereditary thrombophilia.

Venous thromboembolism is a multifactorial disease that depends on variable combinations of acquired and genetic risk factors. The genetic risk factors include loss-of-function mutations in the genes that encode proteins with clot-restraining function, and gain-of-function mutations in procoagulant factors. The loss-of-function mutations are heterogeneous and comprise any mutation that impairs gene function. On the whole, these mutations are rare, with fewer than 1/200--500 individuals affected. This low prevalence in the population is probably caused by the loss of mutant alleles from the gene pool through critically ill homozygous subjects. The gain-of-function mutations in procoagulant proteins differ from the loss-of-function mutations in at least three important respects: these are more homogeneous (factor V Leiden and PT 20210), homozygous individuals are relatively mildly affected, and these are relatively prevalent (3--15%) in Caucasian populations.

3' Untranslated Regions↗

Venous thromboembolism in medical inpatients: prophylaxis with low-weight heparin in a university hospital and prevalence of thromboembolic events.

The aim of this study was to determine the prevalence of venous thromboembolism (VT) in current prophylactic practice with low-molecular-weight heparin (LMWH) among medical inpatients and to analyze associated risk factors for VT. A cross-sectional survey on five given days was conducted in the medical departments of a university hospital. The prevalence of prophylaxis and confirmed VT was measured. Risk markers for receiving high doses of LMWH and for VT under prophylaxis were assessed by logistic regression models. Of 1,194 inpatients, 1.4% suffered VT. The mean proportion of patients with LMWH prophylaxis was 24% (range: 4-64%). The prevalence of VT was higher among inpatients receiving prophylaxis than among those patients not receiving prophylaxis (3.5% vs. 0.7%, p = 0.002). Under prophylaxis, independent risk markers for thrombosis were history of vein thrombosis (odds ratio [OR]: 4.03; confidence interval [95%CI]: 1.04-15.62) and age (OR: 1.08; 95%CI: 1.01-1.15). Two factors were independently associated with the prescription of high doses of LMWH: obesity was positively associated (OR: 7.50; 95%CI: 2.97-18.92; p < 0.0001) and respiratory insufficiency was negatively associated. In medical departments, current prophylaxis practice leads to many patients being given LMWH. LMWH doses and other preventive measures should be adapted in high-risk inpatients.

Age Factors↗

Rationale and design of a clinical trial of a low-molecular-weight heparin in preventing clinically important venous thromboembolism in medical patients: the prospective evaluation of dalteparin efficacy for prevention of venous thromboembolism in immobilized patients trial (the PREVENT study).

The utility of low-molecular-weight heparin (LMWH) in the prophylaxis of venous thromboembolic disease has been examined using the surrogate endpoint of venographically identified thrombi. The largest portion of these thrombi were asymptomatic calf-vein thrombi. The clinical relevance of this observation is a matter of debate. The present study is designed to evaluate the impact of an LMWH on clinically important endpoints. The current study is a randomized, prospective, double-blinded, multicenter, multinational, controlled clinical trial comparing dalteparin with placebo in moderately high-risk hospitalized medical patients. A total of 3300 patients will be randomized to receive either 5,000 IU per day of dalteparin or placebo for 14 days. Patients will undergo appropriate evaluation for any symptomatic episodes and all patients will undergo a bilateral compression ultrasound (CUS) on day 21 to search for asymptomatic proximal thrombi. The primary endpoint is the combination of objectively confirmed symptomatic deep vein thrombi (DVT), fatal or non-fatal pulmonary emboli, all proximal DVT, and sudden death. This study will be the first study to examine clinically important endpoints in evaluating the effect of a LMWH in hospitalized medical patients. This study also is the first study to use CUS rather than venography in concordance with contemporary medical practice. This trial is thus designed to address this important question in a clinically relevant manner.

Adult↗

Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET).

Recent observational studies suggest a 2-4 fold increased risk of venous thromboembolism (VTE) in women taking hormone replacement therapy (HRT). The present study was started before publication of these studies, and the aim was to determine if HRT alters the risk of VTE in high risk women. The study was a randomized. double-blind, and placebo-controlled clinical trial with a double-triangular sequential design. Females with previously verified VTE were randomized to 2 mg estradiol plus 1 mg norethisterone acetate, 1 tablet daily (n = 71) or placebo (n = 69). The primary outcome was recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE). Between 1996 and 1998 a total of 140 women were included. The study was terminated prematurely based on the results of circumstantial evidence emerging during the trial. Eight women in the HRT group and one woman in the placebo group developed VTE. The incidence of VTE was 10.7% in the HRT group and 2.3% in the placebo group. In the HRT group, all events happened within 261 days after inclusion. The sequential design did not stop the study, but strongly indicated a difference between the two groups. Our data strongly suggests that women who have previously suffered a VTE have an increased risk of recurrence on HRT. This treatment should therefore be avoided in this patient group if possible. The results also support those of recent epidemiological studies, which also indicate increased risk of VTE in non-selected female populations during HRT.

Actuarial Analysis↗

Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology.

BACKGROUND: The association between traditional cardiovascular risk factors and risk of venous thromboembolism (VTE) has not been extensively examined in prospective studies. METHODS: To determine whether atherosclerotic risk factors are also associated with increased incidence of VTE, we conducted a prospective study of 19 293 men and women without previous VTE in 6 US communities between 1987 and 1998. RESULTS: There were 215 validated VTE events (1.45 per 1000 person-years) during a median of 8 years of follow-up. The age-adjusted hazard ratio was 1.4 (95% confidence interval [CI], 1.1-1.9) for men vs women, 1.6 (95% CI, 1.2-2.2) for blacks vs whites, and 1.7 (95% CI, 1.5-2.0) per decade of age. Cigarette smoking, hypertension, dyslipidemia, physical inactivity, and alcohol consumption were not associated with risk of VTE. Age-, race-, and sex-adjusted hazard ratios for body mass index categories (calculated as the weight in kilograms divided by the height in meters squared) of less than 25, 25 to less than 30, 30 to less than 35, 35 to less than 40, and 40 or more were 1.0, 1.5, 2.2, 1.5, and 2.7, respectively (P<.001 for the trend). Diabetes was also associated with an increased risk of VTE (adjusted hazard ratio, 1.5 [95% CI, 1.0-2.1]). CONCLUSIONS: Our data showing no relationship of some arterial risk factors with VTE corroborate the view that the etiology of VTE differs from atherosclerotic cardiovascular disease. In addition, the findings suggest a hypothesis that avoidance of obesity and diabetes or vigilance in prophylaxis in patients with those conditions may prevent some venous thromboses.

Aged↗

Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).

We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.

Aged↗

Venous thromboembolism in malignancy and malignancy in venous thromboembolism.

The activation of coagulation in patients with cancer contributes significantly to morbidity and mortality rates and may play a fundamental role in the host response to growing tumours. Patients with cancer are clearly at high risk for the development of venous thromboembolism (VTE), particularly during chemotherapy and surgery. This situation is aggravated by the use of venous access catheters and possibly growth factors. Data derived from large, randomized, controlled trials have been used to determine the true incidence of this complication of cancer and its treatment. The incidence based on the analyses of these randomized controlled trials varies from 1% for limited stage patients with breast cancer treated with tamoxifen to 60% for patients with any type of cancer who are subjected to orthopaedic surgery and do not receive prophylactic therapy. In view of the morbidity and mortality attributable to VTE in cancer, widespread utilization of prophylactic anticoagulation therapy, which has proven safe and effective in a variety of situations, should be considered. While migratory thrombophlebitis is a clear indicator of an underlying neoplasm, the risk of cancer in patients with the more typical form of VTE has been the subject of intense debate over recent years. Some investigators have suggested that the relative risk of being diagnosed with an occult cancer within 6 months of an episode of VTE (particularly recurrent VTE) could be up to 10-fold. However, the cost-effectiveness of aggressive screening for cancer in patients with VTE has not yet been defined adequately.

Antineoplastic Agents↗

Longitudinal evaluation of health plan cost per venous thromboembolism or bleed event in patients with a prior venous thromboembolism event during hospitalization.

OBJECTIVE: To measure the per-event health plan costs for acute and follow-up treatment not directed by a clinical study protocol in a group of commercially insured patients in 2 managed care organizations following an incident hospitalization that included a diagnosis for a venous thromboembolism (VTE) event. METHODS: A cohort of patients with an incident in-hospital VTE event, consisting of deep vein thrombosis (DVT), or pulmonary embolism (PE), or both DVT + PE, was retrospectively identified from the administrative claims databases of 2 large U.S. health care plans. Inclusion criteria were (a) an inpatient VTE event between January 1, 1998, and December 31, 2000, (b) no VTE diagnosis or anticoagulation therapy 3 months prior to the incident VTE in-hospital event, (c) at least 1 anticoagulation pharmacy fill following the incident hospital VTE, and (d) continuous health plan enrollment 3 months prior to and 6 months following the incident hospital VTE event. Total costs were reported on a per-event basis and consisted of the aggregated amount paid by the health plan to the provider after subtraction of member cost-share. Costs were collected separately, first for the incident VTE event for all patients identified and second for patients who had at least 1 of the following events in the follow-up period: bleed requiring or not requiring hospitalization, a recurrent VTE event requiring hospitalization, or a recurrent VTE and bleed (VTE + bleed) event requiring hospitalization. Costs were compared between incident diagnosis groups using multivariate generalized linear model techniques. RESULTS: A total of 2,147 patients (DVT=1,499 [69.8%], PE=373 [17.4%], DVT+PE= 275 [12.8%]) were identified (mean age=61.6standard deviation [SD] 16 years; 46.3% male) and were followed for an average of 21.3 (median, 19.2) months. Disease severity was high in these patients, including 59.2% with a history of or active malignancy. The prevalence of VTE was 2.04 per 100,000 study-eligible health plan members. For the incident VTE events, average costs were 7,712+/-18,339 US dollars (median, 3,131 US dollars) per incident DVT event; 9,566+/-13,512 US dollars (median, 6,424 US dollars) per PE incident event; and 12,200+/-24,038 US dollars (median, 6,678 US dollars) per incident DVT+PE event. Warfarin treatment following the incident VTE event was administered to 97.3% of patients for an average of 6.7 (median, 5.0) months at an average cost of 19.40 US dollars per patient per month. During the average period of 21.3 months, 534 patients (24.9%) experienced an average of 1.24 bleed or recurrent VTE events per patient that required hospitalization at a mean cost of 14,975 US dollars per event or 2,101 US dollars per patient per year. For patients with a bleed in the follow-up period that required hospitalization, average costs were 12,326+/-24,448 US dollars (median, 5,736 US dollars) per recurrent VTE; 15,339+/-52,029 US dollars (median, 4,999 US dollars) per bleed; or 24,085+/-65,411 US dollars (median, 10,185 US dollars) per recurrent VTE + bleed event. During the follow-up period, a total of 612 patients (28.5%) experienced 1,489 recurrent bleed events that did not require hospitalization, at an average cost of 239+/-386 US dollars (median, 95 US dollars) per event. There were no significant differences in mean total costs for all pair-wise comparisons between the 3 incident diagnosis groups. CONCLUSIONS: Of patients who experienced a VTE event during the incident hospital stay for any diagnosis, 1 in 4 experienced an average of 1.24 bleed or recurrent VTE events that required hospitalization in the 21 months of follow-up and incurred an average health plan cost of 14,957 US dollars per event. These data may be of interest to managed care decision makers when evaluating the cost impact of new therapies or providing more comprehensive anticoagulation management services for existing therapies.

Age Distribution↗

Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism.

Factor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.

3' Untranslated Regions↗