Search

Subjects undergoing major orthopedic surgery and acutely ill hospitalized medical patients represent a population at medium-high risk for venous thromboembolism (VTE). They are treated with low molecular weight heparin (LMWH) and direct oral anticoagulants [DOACs] for VTE prevention. We conducted a meta-analysis of phase III randomized clinical trials evaluating LMWH enoxaparin versus DOACs for prophylaxis of VTE by combining studies including patients undergoing elective total hip and knee replacement surgery, and acutely ill hospitalized medical subjects. Studies were searched using PubMed, MEDLINE, and EMBASE databases until December 2016. Differences in clinical outcomes for efficacy and safety endpoints between treatment groups were expressed as risk differences with 95% confidence intervals (95% CI), using random effects regression models. Fourteen RCTs were considered (60,467 subjects). Overall mortality, symptomatic deep venous thrombosis, non-fatal pulmonary embolism (PE) major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) are not different between treatment regimens. Treatment with LMWH enoxaparin is associated with a lower risk of fatal PE plus VTE-related death compared therapy with DOACs (RD = 0.040%, 95% CI 0.001-0.080%, p = 0.0434). Subgroup analysis shows an incidence of MB (RD = 0.181%, 95% CI 0.029-0.332%, p = 0.0033) and CRNMB (RD = 0.546%, 95% CI 0.009-1.082%, p = 0.0462) in patients treated with 40 mg OD enoxaparin compared to DOACs. In major orthopedic surgery and acutely ill hospitalized medical patients, DOACs do not offer clear advantages in terms of clinical efficacy compared to enoxaparin. The advantage of the latter in terms of major and CRNMB, when used at a dose of 40 mg, is statistically significant, but small in terms of clinical relevance.

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA 2 DS 2 VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Atrial fibrillation (AF) is a major arrhythmia in clinical practice, and its frequency rises rapidly from the sixth decade onward. Its most serious clinical consequence is ischemic stroke. Patients with AF have a five-fold increased risk of stroke compared to those in sinus rhythm. Advancing age, prior stroke or transient cerebral ischemia, diabetes, hypertension, and impaired function of the left ventricle are known risk factors. On the basis of data from several randomized controlled clinical trials and pooled analyses, several guidelines have been published to promote the use of anticoagulant treatment to prevent stroke in patients with AF. The management of oral anticoagulant therapy needs regular monitoring of INR, which should be kept in the narrow therapeutic range of 2.0-3.0 most of the time, with adjustments of the dose as required. Only a small proportion of patients with AF whom best-practice guidelines identify as eligible for oral anticoagulant therapy actually receive it. Inconvenience of monitoring and frequent dose adjustments, together with fear of major hemorrhage associated with oral anticoagulants, contribute to this underuse. In particular, conventional intensity of anticoagulation increases the risk of intracranial hemorrhage, and patients with advanced age are more prone to cerebral bleeding than younger patients. Up to date, the efficacy of aspirin, an antiplatelet agent, for stroke prevention in AF patients is less clear and remains controversial and alternative pharmacological treatment options have failed to demonstrate their superiority over vitamin K antagonists.

Background: Idraparinux is a synthetic pentasaccharide that binds to antithrombin with high affinity. In view of its long half-life, it is suitable for once-a-week administration., Objective: To review the evidence favoring the use of idraparinux for the acute and long-term treatment of patients with venous thromboembolism (VTE) and for the prevention of thromboembolic events in patients with atrial fibrillation (AF)., Methods: All preclinical and clinical studies carried out with the use of idraparinux were sought through electronic searches of MEDLINE from January 1, 1999 up to December 31, 2007., Results: The administration of idraparinux in subcutaneous fixed doses of 2.5 mg once weekly was found to be as effective and safe as conventional antithrombotic therapy in the initial treatment of patients with deep vein thrombosis, but less effective than standard therapy in the initial treatment of patients with primary pulmonary embolism. During a 6-month extension of thromboprophylaxis, idraparinux was effective in preventing recurrent VTE but was associated with an increased risk of bleeding versus placebo. Finally, in patients with AF the long-term treatment with idraparinux was as effective as vitamin K antagonists, but caused more bleeding., Conclusions: In its current formulation, idraparinux can be recommended only for the initial treatment of patients with deep vein thrombosis. The bioequipotency of a biotinylated version of idraparinux (idrabiotaparinux), whose effects can be reversed by a neutralizing agent (avidin), is under investigation in the treatment of VTE at present, as is the use of lower doses in patients with AF.

Background: Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of idraparinux with vitamin K antagonists., Methods: Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous idraparinux (2.5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1.5. This trial is registered with ClinicalTrials.gov, number NCT00070655., Findings: The trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10.7 (SD 5.4) months because of excess clinically relevant bleeding with idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p<0.0001). There were 21 instances of intracranial bleeding with idraparinux and nine with vitamin K antagonists (1.1 vs 0.4 per 100 patient-years; p=0.014); elderly patients and those with renal impairment were at greater risk of such complications. There were 18 cases of thromboembolism with idraparinux and 27 cases with vitamin K antagonists (0.9 vs 1.3 per 100 patient-years; hazard ratio 0.71, 95% CI 0.39-1.30; p=0.007), satisfying the non-inferiority criterion. There were 62 deaths with idraparinux and 61 with vitamin K anatagonists (3.2 vs 2.9 per 100 patient-years; p=0.49)., Interpretation: In patients with atrial fibrillation at risk for thromboembolism, long-term treatment with idraparinux was no worse than vitamin K antagonists in terms of efficacy, but caused significantly more bleeding.

An increasing body of evidence suggests the likelihood of a link between arterial and venous disease. According to the results of recent studies, atherosclerosis and venous thromboembolism (VTE) share common risk factors, including age, obesity, diabetes mellitus and metabolic syndrome. Atherosclerosis has the potential to promote the development of thrombotic disorders in the venous system. Another scenario assumes that the two clinical conditions are simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system. Several recent studies have consistently shown that patients with VTE of unknown origin are at a higher risk of cardiovascular diseases, including atherosclerotic complications, than patients with secondary VTE and matched control individuals. Future studies are needed to clarify the nature of this association, to assess its extent and to evaluate its implications for clinical practice.

Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous thromboembolism (VTE). However, whether these thrombophilic abnormalities are also risk factors for recurrent VTE is unclear. We conducted a systematic review of prospective studies to assess the risk of recurrent VTE associated with heterozygous carriage of each of these mutations. All randomized controlled trials and prospective cohort studies that reported the incidence of recurrent VTE in patients with and without FVL and PTM after discontinuation of anticoagulant treatment were collected and analyzed. The risk ratios (RR) and their 95% confidence intervals (CI) for recurrent VTE were calculated in heterozygous carriers of FVL or PTM and compared to those of non-carriers. Eleven studies fulfilled the inclusion criteria. Recurrent VTE occurred in 114 out of 557 heterozygous carriers of FVL (20.5%) as compared to 382 out of 2,646 non-carriers (14.4%); and in 38 out of 212 heterozygous carriers of PTM (17.9%) compared to 428 of 2,996 non-carriers (14.3%). The RR of VTE recurrence conferred by the heterozygous carriage of FVL and PTM was 1.39 (95% CI, range 1.15 to 1.67) and 1.20 (range 0.89 to 1.61), respectively, using the Mantel-Haenszel fixed-effects model; 1.45 (1.13 to 1.85) and 1.36 (1.02 to 1.82), respectively, using the Der Simonian and Laird random effects method. In symptomatic patients with VTE, heterozygous carriage of FVL is clearly associated with a definitely increased risk of recurrent thromboembolism. The risk is lower with PTM and is difficult to interpret since it varies according to the assessment method used.

After the initial demonstration provided 4 years ago by a case-control study in the New England Journal of Medicine, numerous investigations have addressed the association between venous and arterial thrombotic disorders. According to the results of recent studies, the two conditions are likely to share common risk factors, including age, obesity, cigarette smoking, diabetes mellitus, arterial hypertension, hyperlipemia and metabolic syndrome. The nature of this association is unclear. On the one hand, atherosclerosis has the potential to promote the development of thrombotic disorders in the venous system. On the other hand, the two clinical conditions can be simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system. Based on the results of two population-based studies carried out in the USA, atherosclerosis is unlikely to constitute a risk factor for venous thromboembolic (VTE) disorders. Several recent studies have consistently shown that subjects with VTE of unknown origin are at a higher risk of subsequent arterial cardiovascular events than subjects with secondary VTE and matched control individuals. In conclusion, the separate nature of arterial and venous disorders has been challenged. Future studies are needed to clarify the nature of this association, to assess its extent, and to evaluate its implications for clinical practice.

Background and Objectives: A high incidence of atherosclerotic lesions and cardiovascular events has been reported in patients with spontaneous venous thromboembolism. Endothelial dysfunction is an early marker of atherosclerosis and has predictive value for ischemic events. We have evaluated endothelial function in patients with a history of spontaneous venous thromboembolism., Design and Methods: Patients with a history of symptomatic, objectively confirmed, spontaneous venous thromboembolism were included in a case-control study. Exclusion criteria were any known risk factors for cardiovascular diseases, other conditions associated with endothelial dysfunction, estro-progestinic therapy or pregnancy. Controls were age- (+/-5 years) and sex-matched subjects with the same exclusion criteria but without previous venous thromboembolism. Endothelial function was evaluated by the non-invasive measurement of flow-mediated vasodilation of the brachial artery and of plasma markers of endothelium activation; platelet activation parameters were also measured., Results: Twenty-eight cases (8 females; mean age 59+/-15 years) and 28 controls (8 females; mean age 58+/-15) were studied. Flow-mediated vasodilation was 3.5+/-0.6% in cases (95% CIs: 2.2 to 4.8) and 5.7+/-0.6% (4.2 to 6.8) in controls (p=0.015). Brachial artery blood flow and hyperemic blood flow did not differ between the two groups. Plasma von Willebrand factor and soluble P-selectin levels were significantly higher in patients with venous thromboembolism, while plasma soluble CD40 ligand and urinary 11-dehydro-TxB2 levels were similar in cases and controls., Interpretation and Conclusions: Patients with spontaneous venous thromboembolism have endothelial dysfunction, unlike age- and sex- matched controls. This finding suggests that spontaneous venous thromboembolism may be a condition associated with an enhanced risk of atherosclerosis.

Background and Objectives: While it has long been recognized that patients with acute unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) have a higher risk of recurrent venous thromboembolism (VTE) than that of patients with secondary thrombosis, whether other clinical parameters can help predict the development of recurrent events is controversial. The aim of this investigation was to assess the rate of recurrent VTE after withdrawal of vitamin K antagonists, and to identify clinical parameters associated with a higher likelihood of recurrence., Design and Methods: We followed, up to a maximum of 10 years, 1626 consecutive patients who had discontinued anticoagulation after a first episode of clinically symptomatic proximal DVT and/or PE. All patients with clinically suspected recurrent VTE underwent objective tests to confirm or rule out the clinical suspicion., Results: After a median follow-up of 50 months, 373 patients (22.9%) had had recurrent episodes of VTE. The cumulative incidence of recurrent VTE was 11.0% (95% CI, 9.5-12.5) after 1 year, 19.6% (17.5-21.7) after 3 years, 29.1% (26.3-31.9) after 5 years, and 39.9% (35.4-44.4) after 10 years. The adjusted hazard ratio for recurrent VTE was 2.30 (95% CI, 1.82-2.90) in patients whose first VTE was unprovoked, 2.02 (1.52-2.69) in those with thrombophilia, 1.44 (1.03-2.03) in those presenting with primary DVT, 1.39 (1.08-1.80) for patients who received a shorter (up to 6 months) duration of anticoagulation, and 1.14 (1.06-1.12) for every 10-year increase of age. When the analysis was confined to patients with unprovoked VTE the results did not change., Interpretation and Conclusions: Besides unprovoked presentation, other factors independently associated with a statistically significant increased risk of recurrent VTE are thrombophilia, clinical presentation with primary DVT, shorter duration of anticoagulation, and increasing age.

In recent years, new opportunities have emerged that have the potential to change rapidly the therapeutic scenario of patients with acute venous thromboembolism (VTE). Selected patients with deep vein thrombosis (DVT) can be treated effectively and safely at home with fixed doses of low molecular weight heparins. The prompt administration of compression elastic stockings in addition to anticoagulant drugs in patients with acute DVT has the potential to halve the rate of late postthrombotic sequelae. The long-term use of low molecular weight heparins is likely to be more effective than oral anticoagulants for the secondary prevention of VTE in patients with advanced malignancy. Patients with pulmonary embolism and right ventricular dysfunction might benefit from the early administration of thrombolytic drugs in combination with heparin to a greater extent than from heparin alone. Despite an impressive amount of clinical information on the proper duration of oral anticoagulants in patients with unprovoked VTE, the optimal long-term treatment of these patients remains undefined. Finally, new categories of drugs are emerging that have the potential to replace conventional anticoagulants in the near future. They include compounds that inhibit factor Xa or thrombin.

The association between cancer and activation of blood coagulation has been described since Trousseau's time. The hypercoagulable state often encountered in cancer patients not only acts as an important risk factor for thrombosis, but also may play a role in tumor progression and metastasization. An antineoplastic effect of anticoagulants in this setting has often been hypothesized. The results of recently conducted clinical trials suggest that cancer patients could have a benefit from administration of low molecular weight heparin, particularly in those with nonadvanced disease. Additional clinical trials are needed to provide an important step forward in this challenging setting.

The evidence of the important two-way clinical correlation between cancer and venous thromboembolism (VTE) dates back to Trousseau's time. Over time it has been established that cancer patients not only exhibit a higher risk of developing VTE when compared with noncancer patients, but also that VTE, especially in its idiopathic presentation, sometimes acts as an epiphenomenon of a hidden cancer, offering possible chances for anticipated diagnosis of the pathology. Research has contributed greatly to the progression of this field through the identification of VTE risk factors in this setting, and through the assessment of the most adequate thromboprophylaxis and treatment modalities as well as secondary prophylaxis management. Anticoagulant drugs appear to be an attractive strategy in cancer treatment because there is growing evidence for their possible benefits in terms of cancer prognosis and patient survival.

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.

Thromboembolic complications represent one of the most important cause of morbidity and mortality in cancer patients. Although several data have been published demonstrating the strong association between cancer and venous thromboembolism (VTE), there is poor perception, among oncologists, of the level of risk of thrombosis and of relevance of managing VTE in these patients. The Associazione Italiana di Oncologia Medica (AIOM) has provided some recommendations to direct clinical practice according to evidence-based data concerning cancer and VTE. In fact, we conducted an extensive literature review (1996-2005) to produce evidence-based recommendations to improve perceptions of the magnitude of this risk among Italian medical and surgical oncologists and alert on the new approaches to prophylaxis and treatment of VTE in cancer patients. Levels of evidence are given according to a five-point rating system, and similarly for each key recommendation a five-point rating system suggests if the evidence is strong and indicate that the benefits do, or do not, outweigh risks and burden.

Purpose of Review: The aim of this review is to explore the state of the art knowledge on the possible association between venous thromboembolism, especially idiopathic venous thromboembolism, and occult cancer, and to speculate on its implications., Recent Findings: Venous thromboembolism, especially idiopathic venous thromboembolism, is sometimes associated with a subsequent increased risk of newly discovered cancers during the follow-up period. Its incidence approximates 10%. The performance of extensive screening procedures for cancer identification when venous thromboembolism is diagnosed appears advisable if it provides an impact on cancer-related mortality. Recent prospective trials have observed that, thanks to extensive screening procedures, most hidden cancers are detected at baseline or at an earlier stage. Data from these studies do not conclusively demonstrate that earlier diagnosis ultimately prolongs life, but the collective observation makes such a beneficial effect likely., Summary: Venous thromboembolism, especially in its idiopathic presentation, may sometimes be a marker for a hidden cancer. With extensive screening procedures, the earlier discovery of cancer, which might mean identification of the disease at an attachable stage, may be crucial, because innovations in treatment protocols provide increasing chances of success and the eradication of cancer.

Recent data have shown a higher incidence of arterial events in patients with venous thromboembolism (VTE) of unknown origin than in those with the secondary form of disease. Whether patients with idiopathic VTE have a higher risk of subsequent arterial events than the general population is unknown. The aim was to evaluate the rates of subsequent arterial events in patients with idiopathic VTE and control subjects. In a retrospective cohort study we compared the rates of subsequent arterial events (i.e. acute myocardial infarction, ischemic stroke and peripheral arterial disease) in 151 consecutive patients with objectively confirmed spontaneous VTE and 151 control subjects randomly selected from the database of two family physicians. We collected information about cardiovascular risk-factors (hypertension, hypercholesterolemia, diabetes, obesity and smoke) at the time of VTE episode, or corresponding date for the controls, and considered the follow-up from this time. Patients and controls who had suffered from arterial events before the index date were excluded. During a mean follow-up of 43.1 (+/- 21.7) months there were 16 arterial events in the VTE patients and six in the control group (HR, 2.84;95% CI,1.11 to 7.27; p = 0.03). The difference remained significant after adjusting for age and other cardiovascular risk factors (HR 2.86;95% CI,1.07 to 7.62). Overall mortality was also higher in the VTE patients (12 vs.4 deaths). In conclusion, arterial events are more common in patients with previous idiopathic VTE than in the general population. These findings may have practical implications.

Background: The SOMIT trial randomized patients with idiopathic venous thromboembolism (IVTE) and without signs of cancer at routine medical examination, to extensive screening for cancer plus 2 years of follow-up or to just 2-year follow-up., Methods: The data of the SOMIT-trial were used to perform a decision analysis. The screening tests were divided in several possible strategies. The number of detected cancer patients and the number of patients investigated further for an eventually benign condition were calculated for each strategy. The total costs for the screening strategy and for each detected cancer patient were determined. Based on the tumor type, stage, age and gender of the individual cancer patient, the difference in live years gained (LYG) was calculated between the two study groups., Results: Computed tomography (CT) of the abdomen combined with sputum cytology and mammography detected 12 of the 14 patients with cancer and had one false-positive result. In general, screening strategies including abdominal/pelvic ultrasonography (US) or tumor markers yielded a higher number of patients needed to screen in comparison with those using abdominal/pelvic CT. Furthermore, the strategies which included colonoscopy, tumor markers, and abdominal/pelvic US were significantly more costly, had inferior LYG and higher costs per LYG, when compared with strategies using abdominal/pelvic CT., Conclusions: Despite the limitations of this analysis, the screening for cancer with a strategy including abdominal/pelvic CT with or without mammography and/or sputum cytology appears potentially useful for cancer screening in patients with IVTE. The cost-effectiveness analysis of this strategy needs confirmation in a large trial.

Venous thromboembolism occurs commonly in patients with cancer. The pathogenetic mechanisms of thrombosis involve a complex interaction between tumour cells, the haemostatic system, and characteristics of the patient. Among risk factors for thromboembolism are long-term immobilisation, especially in hospital, surgery, and chemotherapy with or without adjuvant hormone therapy. Although prophylaxis and treatment of thromboembolism in patients with cancer draw on the agents that are commonly used in those without cancer, there are many special features of patients with cancer that make use of these drugs more challenging. Low-molecular-weight heparins are the cornerstone of prophylaxis and treatment of venous thromboembolism in patients with cancer. These drugs have the potential to increase survival, at least in patients with more favourable outlook. About 10% of patients with idiopathic venous thromboembolism have an underlying malignant disorder that can be detected by extensive diagnostic investigation. However, the issue of whether screening for occult malignant disease ultimately improves prognosis and survival remains to be resolved.

Although considerable progress has been made in the treatment of venous thromboembolism (VTE), many unanswered questions remain, which are awaiting proper solution. Furthermore, new opportunities are emerging, which have the potential to rapidly change the therapeutic scenario. Selected patients with deep-vein thrombosis can be effectively and safely treated at home with fixed-dose low-molecular-weight heparins. The long-term use of low-molecular-weight heparins is likely to be more effective than and as safe as oral anticoagulants for the secondary prevention of VTE in cancer patients with venous thrombosis. Recent publications have unexpectedly raised a renewed interest on the use of thrombolytic drugs in patients with pulmonary embolism, at least in those who present with heart ventricular dysfunction. The optimal long-term treatment of VTE is still undefined. Finally, new categories of drugs are emerging, which have the potential to replace conventional anticoagulants in the near future. They include anti-Xa inhibitors, such as pentasaccharide, and antithrombin inhibitors, such as ximelagatran.

Introduction: Whether patients with hereditary or acquired thrombophilia have an increased risk for recurrence of venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) is still controversial. The aim of this study was to evaluate the incidence of recurrence of venous thromboembolism in patients with and without thrombophilic abnormalities treated with standardized anticoagulant treatment., Material and Methods: Database was from a prospective multicenter randomized study aimed at evaluating the long-term clinical benefit of extending to 1 year the 3-month oral anticoagulant treatment after a first episode of idiopathic proximal deep vein thrombosis. The screening for thrombophilia included antithrombin, protein C, protein S deficiencies, resistance to activated protein C and/or factor V R506Q mutation, the mutation 20210GA of the prothrombin gene, hyperhomocysteinemia and antiphospholipid antibodies. The diagnosis of venous thromboembolism recurrence was done by objective tests and adjudicated by a panel unaware of the results of the thrombophilia screening., Results: A screening for thrombophilic abnormalities was performed in 195 patients. Twenty of 57 (35.1%) thrombophilic patients experienced a recurrence of venous thromboembolism as compared with 29 of 138 (21.0%) patients without thrombophilia (HR=1.78, 95% CI 1.002-3.140, p=0.046). The difference in VTE recurrence between patients with and without thrombophilia was accounted for by those who received 3 months of oral anticoagulation (HR=3.21, 95% CI 1.349-7.616, p=0.008). No difference between thrombophilic and non-thrombophilic patients was observed in the time interval from the index episode to recurrent venous thromboembolism (29.1+/-23.9 and 30.6+/-19.8 months, respectively)., Conclusions: Thrombophilic abnormalities are associated with an increased risk of venous thromboembolism recurrence. The role of thrombophilia in the long-term management of venous thromboembolism should be addressed in prospective management studies.

The association between cancer and venous thromboembolism (VTE) is well established. Importantly, VTE is a significant cause of mortality in cancer patients. Although long-term warfarin (Coumadin(trade mark); Bristol-Myers Squibb; New York, NY) therapy is the mainstay of treatment for cancer patients with VTE, there are many practical problems with its use in this population. In particular, achieving therapeutic drug levels is difficult in cancer patients due to the increased risk of drug interactions, malnutrition, vomiting, and liver dysfunction in these patients. Moreover, cancer patients are at an increased risk of adverse effects of warfarin therapy. In contrast, low-molecular-weight heparins (LMWHs) are associated with a lower risk of adverse events compared with warfarin in patients with cancer. These agents also offer practical advantages compared with warfarin, including more predictable anticoagulant effects and ease of administration in addition to possible antineoplastic effects. Several LMWHs have demonstrated superior efficacy to warfarin in the secondary prevention of VTE. In particular, the LMWH, dalteparin (Fragmin; Pfizer; New York, NY), has recently been shown to have superior efficacy to warfarin in a large trial of patients with cancer and VTE without increasing the risk of bleeding. A randomized trial of dalteparin has also shown improved response rates and survival in patients with small cell lung cancer. In view of the availability of more effective and reliable alternatives to warfarin therapy in cancer patients, it is appropriate to reassess the role of warfarin therapy in patients with cancer and VTE. Further evaluation of the LMWHs for effects on cancer outcome is indicated.

Patients with symptomatic idiopathic venous thromboembolism and apparently cancer-free have an approximate 10% incidence of subsequent cancer. Apparently cancer-free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2-year follow-up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow-up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3-36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer-related mortality during the 2 years follow-up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of the 102 control patients [absolute difference, 1.9% (95% CI, -5.5-10.9)]. Although early detection of occult cancers may be associated with improved treatment possibilities, it is uncertain whether this improves the prognosis.

The role of antiprothrombin (aPT) antibodies in the development of venous thromboembolism (VTE) is still uncertain. The aim of this study was to evaluate the potential role of aPT antibodies in the development of recurrent thromboembolism. Out of 236 consecutive symptomatic patients with an episode of acute VTE, antiphospholipid antibodies were found in 85 (36.0%), of whom 24 were carriers of aPT antibodies (10.2% of the entire cohort). A history of previous thromboembolism was identified in 56 patients (23.7%). The prevalence of previous thromboembolism was significantly higher in carriers than in non-carriers of antiphospholipid antibodies (OR=2.4; 95% CI, 1.3 to 4.4). Of the 24 patients with aPT antibodies, 12 had a history of previous thromboembolism. In a multivariate logistic regression analysis, in which the other categories of antiphospholipid antibodies were taken into account, as well as the patient's age, sex, and the modality of clinical presentation, it was found that the presence of aPT antibodies was significantly associated with the prevalence of prior thromboembolism (OR=3.3; 95% CI, 1.3 to 8.6). Since aPT antibodies are more commonly identifiable in patients with multiple thrombotic episodes, they are a likely risk factor for recurrent thromboembolism.

In contrast with the paucity of data on the risk of a first episode of thrombosis in cancer patients, the frequency of recurrent thromboembolism in patients with malignancy has been extensively investigated, both during anticoagulation and after its cessation. Cancer patients are more likely to develop recurrent thromboembolism and major bleeding during anticoagulation than patients without malignancies. These events are more pronounced during the first weeks of treatment and increase with cancer severity. Since they are not associated with anticoagulant intensities outside the therapeutic range, possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed. In this regard, the use of low-molecular-weight heparins for initial treatment and long-term anticoagulation in cancer patients with venous thrombosis seems promising. Furthermore, patients with active cancers exhibit a particularly high risk of recurrent venous thromboembolism after the cessation of anticoagulation. In view of the persisting high risk for recurrent thrombotic events in cancer patients, and the acceptable risk of bleeding, prolonged warfarin treatment should be considered in such patients for as long as the cancer is active.

Background: A prolonged treatment with oral anticoagulants has been claimed to reduce the incidence of newly diagnosed cancer in the long-term follow-up of patients with venous thromboembolism., Objectives: In a multicenter prospective study we assessed the incidence of newly diagnosed clinically overt cancer in patients with a first episode of idiopathic venous thromboembolism (VTE) treated with oral anticoagulants for 3 months or 1 year., Patients and Methods: Consecutive patients with an idiopathic venous thromboembolism who had completed 3 months of oral anticoagulant therapy without having a recurrence, bleeding or newly diagnosed cancer were randomized to discontinue oral anticoagulant therapy or to continue it for nine additional months. Idiopathic venous thromboembolism was defined as thrombosis occurring in the absence of known cancer, known thrombophilia, or temporary risk factors for venous thromboembolism. All patients were followed up for at least 1 year after randomization., Results: A total of 429 patients, 265 patients with DVT and 164 with PE, were followed up for an average of 43.7 months after randomization. A newly diagnosed cancer occurred in 32 patients (7.5%), 13 (6.2%) of the 210 patients treated for 3 months and 19 (8.7%) of the 219 patients treated for 1 year (RR = 0.71, 95% confidence interval 0.36-1.41)., Conclusions: The incidence of newly diagnosed clinically overt cancer is not reduced in patients with idiopathic venous thromboembolism treated with 1-year anticoagulant treatment compared with patients treated for 3 months.

Except for selected patients requiring aggressive therapies, the large majority of patients with acute venous thromboembolism are currently treated with full doses of unfractionated or low-molecular-weight heparins (LMWH) followed by oral anticoagulants for variable periods of time. LMWHs present a number of potential advantages over unfractionated heparin: a longer plasma half-life, improved subcutaneous bioavailability, and a more predictable dose-response relationship. As a result of these pharmacokinetic properties, these compounds have the potential to greatly simplify the initial treatment of venous thromboembolism, making the treatment of suitable patients feasible in an outpatient setting with considerable saving in costs and improvement in patients' quality of life. The use of unfractionated heparin is still desirable in the initial treatment of acute pulmonary embolism in non-critically ill patients. The use of heparin protocols assures that virtually all patients will promptly achieve the therapeutic range for the activated partial thromboplastin time. Although the optimal duration of anticoagulation in patients suffering an episode of venous thromboembolism is presently unknown, it seems reasonable to administer a short-term course of coumarin drugs to patients with thrombosis associated with transient risk factors, while a longer course should be considered in patients with idiopathic thrombosis and in those with permanent risk factors. At present, indefinite anticoagulant therapy remains a clinical judgment in the individual patient. The efficacy and safety of emerging drugs (pentasaccharide, ximelagatran) in the treatment and secondary prevention of venous thromboembolic disorders is currently under investigation.

Background: To simplify the diagnostic strategy of patients suspected for venous thromboembolism, the use of D-dimer tests has been advocated. Very important for the safety of such diagnostic strategies would be the capacity to recognise false-normal D-dimer results, in order to prevent inadequately withholding anticoagulant treatment in patients who actually have the disease. Insight in the causes of false-normal D-dimer results would therefore be necessary. We hypothesised that certain patient characteristics are associated with relatively low plasma D-dimer levels and, therefore, could increase the risk of false-normal results., Methods: Consecutive patients with an objectively confirmed venous thromboembolic event and an independently obtained false-normal SimpliRED D-dimer test result were included in the study. For each patient, two controls with objectively confirmed venous thromboembolism and an adequate abnormal D-dimer result were selected. Baseline patient characteristics, obtained by standardised questionnaires, were compared between the two groups of patients., Results: In total, 686 patients had a venous thromboembolic event and 47 of these patients had a false-normal SimpliRED result. Therefore, the overall sensitivity of the SimpliRED test for venous thromboembolism was 94% (95% CI: 92-95%). Although the prevalence of certain clinical characteristics was significantly higher in patients with a false-normal D-dimer result than in the controls [odds ratios for (LMW)heparin treatment and symptoms lasting more than 10 days: 5.1 (95% CI: 1.5-18.7) and 3.2 (95% CI:1.4-7.4), respectively], the prevalence of these characteristics was also high in the control group with an adequate abnormal D-dimer. Combining two or more of these characteristics had a low prevalence and did not further improve the ability to identify those patients with a false-normal D-dimer test at presentation., Conclusions: Although these findings clearly indicate an association between certain baseline clinical characteristics and the occurrence of a false-normal SimpliRED test, the clinical utility for these characteristics is limited.

A small proportion of patients with deep vein thrombosis develop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment. These complications may occur more frequently if these patients have concomitant cancer. This prospective follow-up study sought to determine whether in thrombosis patients those with cancer have a higher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer. Of the 842 included patients, 181 had known cancer at entry. The 12-month cumulative incidence of recurrent thromboembolism in cancer patients was 20.7% (95% CI, 15.6%-25.8%) versus 6.8% (95% CI, 3.9%- 9.7%) in patients without cancer, for a hazard ratio of 3.2 (95% CI, 1.9-5.4) The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%-18.2%) in patients with cancer and 4.9% (95% CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of 2.2 (95% CI, 1.2-4.1). Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation. Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy. These risks correlate with the extent of cancer. Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed.

Antithrombin and protein C and S defects, factor V Leiden mutation, and G20210A prothrombin gene mutation are well-recognized risk factors for venous thromboembolism (VTE) in adults, especially during circumstantial situations such as trauma, immobilization, surgery, or oral contraceptive treatment. The relevance of these defects in predisposing children to VTE is still undefined. In a prospective cohort study we assessed the incidence of spontaneous and risk period-related VTE in asymptomatic children (aged 1-14 years), who were family members of a proband with an objectively diagnosed venous thromboembolic event and a documented single thrombophilic abnormality. We enrolled 143 children from 63 families. Of them, 81 (56.6%) were carriers of an inherited defect, whereas the remaining 62 were free from known genetic or acquired causes of thrombophilia. The mean observation period was 5 years (range, 1-8 years) in each group. Thirty-one risk periods occurred in the carriers group and 20 in noncarriers. Neither spontaneous nor risk period-related VTE occurred in either group during 395 and 296 observation years, respectively. However, circumstances where most of the pediatric thromboses occur (insertion of central venous lines, cancer, and cardiovascular surgery) were not encountered. In conclusion, the thrombotic risk in otherwise healthy children with a single identified thrombophilic defect appears to be very low. Common triggering conditions for VTE in thrombophilic adults do not seem to increase the thrombotic risk in children carrying the same inherited defect. Accordingly, screening for thrombophilia in otherwise healthy children younger than 15 years who belong to families with inherited defects predisposing to thrombosis seems unjustified.

The overall incidence of postoperative DVT in patients with cancer is twice as high as in cancer-free patients. Immobilisation and chemotherapy increase the risk of thrombosis as does the insertion of central venous lines. Patients with cancer who have established thrombosis exhibit a remarkably high risk of recurrent thromboembolism, particularly in the first months after the interruption of anticoagulant treatment: the risk is double that of non-cancer patients. Even during anticoagulant treatment, the cumulative incidence of recurrent thromboembolism is 3.5 times higher in patients with malignancy than in cancer-free patients. Conversely, there is a high rate of cancer detection in patients with idiopathic VTE: the risk of concomitant cancer is approximately four times higher in these patients than in those with thrombosis triggered by known factors. Extensive screening for cancer in patients with idiopathic venous thrombosis allows early detection of malignancies and identification of malignancy at an early stage.

In a prospective cohort study, we assessed the incidence of spontaneous and risk period-related venous thromboembolism (VTE) in asymptomatic family members of patients who experienced VTE and had the factor V Leiden mutation. In all, 561 family members of 131 probands were included, 313 of whom were carriers (299 heterozygous and 14 homozygous) and 248 of whom were noncarriers of the factor V Leiden mutation. Average follow-up was 4 years (range, 4 months-6 years). There were 1255 and 984 observation-years of follow-up in carriers and noncarriers, respectively. Eight episodes of VTE occurred in heterozygous carriers, resulting in an annual incidence of 0.67% (95% confidence interval [CI], 0.29-1.33). Two events occurred in the absence of associated risk factors, determining an annual incidence of spontaneous VTE of 0.17% (95% CI, 0.02-0.6). Only one VTE (risk period-related) occurred in noncarriers, with an annual incidence of 0.1% (95% CI, 0.003-0.56). Relative risk for VTE in heterozygous carriers compared with noncarriers of the factor V Leiden mutation was 6.6 (95% CI, 1.1-39.8). Risk period-related VTE occurred with an incidence of 18% and 5% per risk period in heterozygous carriers and in noncarriers, respectively. Thus, the low rate of VTE in asymptomatic family members carrying the mutation did not justify continuous anticoagulant prophylaxis. Screening families of symptomatic probands with the factor V Leiden mutation has the potential to identify those asymptomatic carriers who might benefit from thromboprophylaxis during risk periods.

Background and Objectives: In this retrospective, single center, cohort study we assessed the risk of pregnancy-related venous thromboembolism (VTE) in women belonging to a large number of families identified because of a symptomatic proband with single identified factor V Leiden mutation., Design and Methods: Female family members who had experienced at least one full-term pregnancy were enrolled in the study. Two hundred and seventy pregnancies occurred in 105 carriers and 215 pregnancies in 81 non-carriers of factor V Leiden mutation., Results: The frequency of VTE was 6.4% for heterozygous, 16.7% for homozygous, 20% for double heterozygous carriers of thrombophilic defects, and 1.2% for non-carriers. The majority of VTE events related to pregnancy occurred in the post-partum period. The relative risks of developing pregnancy-related VTE in women who were carriers of heterozygous and homozygous (or combined heterozygous) factor V Leiden mutation as compared to non-carriers were 5.3 (95% CI, 0.6 to 43.9) and 15.4 (95% CI, 1.4 to 164), respectively., Interpretation and Conclusions: Factor V Leiden mutation is a risk factor for pregnancy-related VTE, especially in its homozygous form and in combination with other thrombophilic abnormalities. Screening of families with this mutation might be useful for women of fertile age, as they may take advantage from thromboprophylaxis during pregnancy and the post-partum period.

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

Carriers of a mutation in the prothrombin (clotting factor II) or factor V gene have a 2- to 4-fold greater risk for venous thromboembolism than subjects without the mutations. Whether both mutations also predispose to recurrent venous thromboembolism is unclear. Outpatients who had a first episode of proven symptomatic deep-vein thrombosis and a long-term follow-up were studied. The outcome measure was the cumulative incidence of confirmed venous thromboembolic complications. Two hundred fifty-one patients were enrolled in the study. Mean duration of follow-up was 8.3 years. The prothrombin gene mutation was demonstrated in 27 patients (prevalence, 10.8%; 95% CI, 6.9 to 14.6), and the factor V gene mutation was demonstrated in 41 patients (prevalence, 16.3%; 95% CI, 11.8 to 20.9). The cumulative incidence of venous thromboembolic complications after 10 years was 61.3% (95% CI, 35.7 to 87.9), and the hazard ratio was 2.4 (95% CI, 1.3 to 4.7; P =.004) in patients with the prothrombin gene mutation); the cumulative incidence of venous thromboembolic complications after 10 years was 55.2% (95% CI, 36.4 to 74.0), and the hazard ratio was 2.4 (95% CI, 1.4 to 4.1; P =.001) in patients with the factor V gene mutation. In comparison, the cumulative incidence of venous thromboembolic complications after 10 years was 23.1% (95% CI, 16.2 to 30.1) in patients without the mutations. Prothrombin and factor V gene mutations occur frequently in patients with venous thrombosis and are associated with an increased risk for recurrent venous thromboembolic complications.

Despite the availability of low-molecular-weight heparins, unfractionated heparin (UFH) still remains the drug of choice for the initial treatment of acute venous thromboembolism in many countries. When appropriately employed, UFH treatment results in a degree of efficacy and safety that is fully comparable with that obtained with the use of heparin derivatives. The use of nomograms for the intravenous or subcutaneous administration of UFH assures that virtually all patients will promptly achieve adequate levels of anticoagulation, thus decreasing the likelihood of recurrent venous thromboembolism without extra bleeding-risk. In this article we reviewed clinical studies on the implementation and validation of UFH dosing nomograms, and attempted a quantitative analysis of their performance. According to the results of our analysis, a statistically significantly higher proportion of patients treated on the basis of a nomogram reached a therapeutic anticoagulant level within 24 h of treatment, as compared to patients treated following the standard practice (odds ratio, 3.6; 95% CI, 2.6 to 4.9). The rate of recurrent thromboembolic events was significantly lower for patients treated according to a nomogram (odds ratio, 0.3; 95% CI, 0.1 to 0.8), while no significant differences in terms of either major or minor bleedings were detected between nomogram patients and controls.

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, is a major cause of morbidity and mortality. In most cases, one or more risk factors for removable or persistent venous thromboembolism can be identified. Persistent risk factors include inherited or acquired abnormalities of the hemostatic system and cancer. As Armand Trousseau first suggested, venous thromboembolism may be the first clinical manifestation of an occult cancer. This relationship has recently been confirmed by methodologically well designed studies. Furthermore, venous thromboembolism is the second cause of death in patients with clinically overt cancer. This review summarizes the state of the art of this association. The clinical trials described focus on the need to perform screening for occult cancer in patients with idiopathic venous thromboembolism. How extensive this screening should be is still matter of debate. On the other hand, patients with clinically overt cancer should be considered at high risk for developing venous thromboembolism, and adequate prophylaxis should be used.

To establish the prevalence of antibodies against beta2-glycoprotein I (beta2GPI) in unselected patients with venous thromboembolism, as well as the association with antiphospholipid antibodies (aPL) and a history of previous thromboembolism, we investigated the presence of these antibodies in 227 consecutive patients with acute deep vein thrombosis or pulmonary embolism, of whom 63 were carriers of aPL with or without lupus anticoagulant (LA), and seven were carriers of LA alone. The presence of antibodies against beta2GPI was demonstrated in 19 patients [8.4%; 95% confidence interval (CI), 4.5-11.3%]. All of them belonged to the group of 63 patients with aPL (30.2%). A history of a previous thromboembolism was identified in 11 of the 19 patients with anti-beta2GPI antibodies (57.9%) and in 45 of the 208 patients without these antibodies [21.6%; odds ratio (OR)=4.98; 95% CI, 1.89-13.1; p<0.0005]. In the subgroup of patients with aPL and/or LA, the rate of recurrent thromboembolism among patients with anti-beta2GPI antibodies (11 of 19, 57.9%) was significantly higher than that observed in patients without these antibodies (15 of 51, 29.4%; OR=3.3; 95% CI, 1.1-9.83; p=0.28). We conclude that in patients with acute venous thromboembolism the prevalence of antibodies against beta2GPI is unexpectedly high. The presence of these antibodies seems to identify a subgroup of patients with antiphospholipid antibodies who have a peculiarly high risk of thrombotic recurrences. Further prospective studies are indicated to better define the role of anti-beta2GPI antibodies in the development of recurrent thromboembolism.

Background and Objective: Although the relationship between malignant diseases and venous thromboembolism has been convincingly demonstrated, the clinical implications of this association still have to be thoroughly elucidated. The aim of this study was to review briefly the mechanisms by which cancer may induce the development of thrombosis and to analyze critically the most recent clinical advances in this field., Evidence and Information Sources: The material examined in the present review includes articles published in journals covered by the Science Citation Index and Medline ., State of the Art: Neoplastic cells can activate the clotting system directly, thereby generating thrombin, or indirectly, by stimulating mononuclear cells to synthesize and express various procoagulants. Cancer cells and chemotherapeutic agents can injure endothelial cells, thereby intensifying hypercoagulability. Currently, primary prevention of venous thrombosis should be considered for cancer patients during and immediately after chemotherapy, when long-term indwelling central venous catheters are placed, during prolonged immobilization from any cause, and following surgical interventions. Secondary prevention of recurrent venous thromboses usually necessitates long-term anticoagulation. In some patients with cancer the condition is resistant to warfarin, and long-term adjusted high-dose heparin is required. The diagnosis of venous thromboembolism may help to uncover previously occult carcinoma by prompting a complete physical examination and a few routine tests., Perspectives: Further investigations are required to evaluate the cost-benefit ratio of extensive diagnostic screening for occult malignancy in all patients presenting with idiopathic venous thromboembolism, and to explore the potential of low molecular weight heparins for improving survival in patients with cancer.

Background: Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience., Objective: To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed., Methods: For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed., Results: For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%)., Conclusions: The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.

In recent years, a growing body of evidence has provided the convincing demonstration of a strong association between cancer and venous thromboembolism. This relationship is further supported by the risk of developing overt malignancy in patients with idiopathic venous thromboembolism. However, the cost-to-benefit ratio of an extensive diagnostic work-up aimed at identifying an occult cancer in patients with spontaneous thromboembolism still has to be demonstrated. During prolonged immobilization from any cause, and following surgical interventions, patients with cancer are at a remarkably higher risk of venous thromboembolism than patients free from malignant disorders. Standard heparin in adjusted doses or a low-molecular-weight heparin in doses commonly recommended for high risk surgical patients represent the prophylactic treatment of choice for cancer patients undergoing an extensive abdominal or pelvic intervention. Furthermore, the risk of thrombotic episodes is increased in cancer patients by chemotherapy and by the use of indwelling central venous catheters. Recent data suggest a positive benefit-to-risk ratio with the systematical use of fixed mini-dose of warfarin in both conditions. After experiencing an episode of thrombosis, cancer patients remain at risk of recurrence for as long as the cancer is active. Therefore, they should be protected by a long-term course of oral anticoagulation. The risk of recurrent thrombotic events despite adequate anticoagulation is higher in patients with cancer than in those without cancer. The routine use of long-term subcutaneous heparin therapy rather than oral anticoagulants should be reserved for patients in whom warfarin has been ineffective. Can antithrombotic drugs improve survival in cancer patients? In cancer patients affected by deep-vein thrombosis, the treatment with low-molecular-weight heparins has been reported to lower mortality at a higher extent than the standard heparin therapy. Such an observation suggests that these agents might develop an antineoplastic activity.