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1.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 
PLoS Medicine  2012;9(9):e1001310.
A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
Background
It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.
Methods and Findings
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out.
Please see later in the article for the Editors' Summary.
Conclusions
The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Editors' Summary
Background
Blood normally flows smoothly throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Occasionally, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood towards the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the leg) include pain, swelling, and redness in the affected limb. DVT is treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a pulmonary embolism (PE), a life-threatening condition characterized by chest pain, breathlessness, coughing, and dizziness. Little is known about how to prevent DVTs and PEs but risk factors for these venous thromboembolic events include having an inherited blood clotting disorder, oral contraceptive use, having surgery, and prolonged inactivity (on long-haul plane flights, for example).
Why Was This Study Done?
In 2009, a secondary (add-on) analysis of data from a randomized controlled trial (RCT, a study that randomly assigns individuals to receive different treatments and compares the outcomes associated with each treatment) called the JUPITER trial reported that rosuvastatin—a cholesterol-lowering drug (statin)—halved the risk of venous thromboembolic events among apparently healthy adults. The JUPITER trial was initiated to test whether statins reduce the risk of strokes, heart attacks, and other cardiovascular diseases (conditions that involve the heart and the blood vessels) among adults with raised levels of a predictor for these diseases called C-reactive protein; statins reduce the levels of this protein as well as those of cholesterol. Because fewer than 100 of the participants in the JUPITER trial developed a DVT or PE, the reduction in the risk of a venous thromboembolic event among the participants who took rosuvastatin could have happened by chance. In this systematic review and meta-analysis of 29 RCTs of statins that collected information on many more venous thromboembolic events, the researchers test the hypothesis that statins substantially reduce the risk of such events. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 RCTs (105,759 participants) that compared the effects of statins with control (dummy) tablets and seven (40,594 participants) that compared an intensive statin regimen with a standard regimen. They then obtained largely unpublished information about the venous thromboembolic events that occurred during these trials (about 1,000 DVTs and PEs) from the original investigators. In the trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events. Thus, although events occurred in 465 participants who were given statins (0.9% of the participants) and in 521 participants who were given control tablets (1% of the participants), this difference in outcomes was not statistically significant—it could have happened by chance. Exclusion of the JUPITER trial results from the meta-analysis did not alter this finding. The researchers also found no evidence that intensive statin therapy reduced the risk of venous thromboembolic events compared to standard therapy.
What Do These Findings Mean?
The findings of this meta-analysis do not support the suggestion that statins, either at the standard dose or at higher doses, reduce the risk of venous thromboembolic events substantially among healthy adults. It is possible that the effect of statins has been underestimated in this meta-analysis because of missing data or because of some other source of bias. Furthermore, because the total number of events in this meta-analysis is still relatively modest, these findings do not rule out the possibility that statins may reduce the risk of venous thromboembolic events by up to about one-fifth in some or all individuals. Additional large RCTs are now needed to investigate whether statin treatment does in fact reduce the risk of venous thromboembolic events in adults and, if it does, whether all statins have a similar effect and whether statin treatment is beneficial in everyone or only in specific subgroups of people.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001310.
This study is further discussed in a PLOS Medicine Perspective by Frits Rosendaal
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, on pulmonary embolism, and on statins; a Behind the Headlines article describes the JUPITER trial and its implications
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and statins (in English and Spanish)
doi:10.1371/journal.pmed.1001310
PMCID: PMC3445446  PMID: 23028261
2.  Synergistic Effects of Hypofibrinolysis and Genetic and Acquired Risk Factors on the Risk of a First Venous Thrombosis 
PLoS Medicine  2008;5(5):e97.
Background
Previously, we demonstrated that hypofibrinolysis, a decreased capacity to dissolve a blood clot as measured with an overall clot lysis assay, increases the risk of venous thrombosis. Here, we investigated the combined effect of hypofibrinolysis with established risk factors associated with hypercoagulability.
Methods and Findings
Fibrinolytic potential was determined with a plasma-based clot lysis assay in 2,090 patients with venous thrombosis and 2,564 control participants between 18 and 70 y of age enrolled in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based case-control study on venous thrombosis. Participants completed a standardized questionnaire on acquired risk factors.
Hypofibrinolysis alone, i.e., clot lysis time (CLT) in the fourth quartile (longest CLT) (in absence of the other risk factor of interest) increased thrombosis risk about 2-fold relative to individuals with CLT in the first quartile (shortest CLT). Oral contraceptive use in women with CLT in the first quartile gave an odds ratio (OR) of 2.6 (95% confidence interval [CI] 1.6 to 4.0), while women with hypofibrinolysis who used oral contraceptives had an over 20-fold increased risk of venous thrombosis (OR 21.8, 95% CI 10.2 to 46.7). For immobilization alone the OR was 4.3 (95% CI 3.2 to 5.8) and immobilization with hypofibrinolysis increased the risk 10.3-fold (95% CI 7.7 to 13.8). Factor V Leiden alone increased the risk 3.5-fold (95% CI 2.3 to 5.5), and hypofibrinolysis in factor V Leiden carriers gave an OR of 8.1 (95% CI 5.3 to 12.3). The combination of hypofibrinolysis and the prothrombin 20210A mutation did not synergistically increase the risk. All ORs and 95% CIs presented are relative to individuals with CLT in the first quartile and without the other risk factor of interest.
Conclusions
The combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Frits Rosendaal and colleagues show that the combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Editors' Summary
Background.
When a blood vessel is injured, proteins in the blood called clotting factors “coagulate” (solidify) the blood at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. When the injury has healed, other proteins dissolve the clot, a process called “fibrinolysis.” Sometimes, however, a thrombus develops inside an undamaged blood vessel and partly or completely blocks the blood flow. A clot that occurs in one of the veins (vessels that take the blood to the heart) deep within the body (usually in the leg) is a deep vein thrombosis (DVT). Some DVTs have no symptoms; others cause pain, swelling, and tenderness in one leg. They are usually treated with heparin and warfarin, anticoagulant drugs that stop the clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called a pulmonary embolism (PE).
Why Was This Study Done?
Most people are very unlikely to develop venous thrombosis (the collective term for DVT and PE), but anything that makes blood “hypercoagulable” (prone to clotting) increases this risk. Genetic risk factors can be inherited changes in blood clotting proteins (for example, a mutation in a gene coding for one protein, factor V, which is involved in clotting, is known as factor V Leiden—Leiden, The Netherlands, was where it was first described). There are also acquired risk factors such as taking oral contraceptives or being immobilized (for example, during bed rest). These risk factors often act in such a way that the risk of developing venous thrombosis for a person with multiple risk factors is greater than the sum of the individual risks. Another recently identified but little studied risk factor for venous thrombosis is “hypofibrinolysis,” a decreased capacity to dissolve blood clots. In this study (part of the “MEGA” study on risk factors for venous thrombosis), the researchers investigate the combined effect of hypofibrinolysis and established risk factors associated with hypercoagulability on the risk of developing venous thrombosis.
What Did the Researchers Do and Find?
The researchers collected blood from more than 2,000 individuals after their first DVT or PE and from a similar number of persons without venous thrombosis (controls). For each blood sample, they measured the time it took to dissolve a clot generated from that blood in a test tube (the clot lysis time or CLT) and determined which participants had the factor V Leiden mutation or a genetic change in the clotting factor prothrombin that also increases blood coagulability. The study participants also completed a questionnaire about acquired risk factors for venous thrombosis. The researchers divided the participants into four equal-sized groups (quartiles) based on their CLT and used the quartile with the lowest CLT as the reference group for their statistical analyses; hypofibrinolysis was defined as a CLT in the highest quartile (the longest times). Participants with hypofibrinolysis alone were twice as likely to develop venous thrombosis as those with a CLT in the lowest quartile (the shortest times). Oral contraceptive use alone increased the risk of venous thrombosis 2.5-fold, whereas the combination of oral contraceptive use and hypofibrinolysis increased the risk 20-fold. The researchers also found synergistic effects on thrombosis risk for hypofibrinolysis combined with immobilization or with the factor V Leiden mutation but not with the prothrombin mutation.
What Do These Findings Mean?
These findings confirm that persons with hypofibrinolysis and hence longer CLTs have a greater risk of developing venous thrombosis than those with short CLTs. Because CLTs were measured after venous thrombosis had occurred, hypofibrinolysis could be an effect rather than a cause of this condition. However, this is unlikely because there was no association between how long after the venous thrombosis the blood sample was taken and the measured CLT. These findings also show that the combination of hypofibrinolysis with immobilization, the factor V Leiden mutation, and oral contraceptive use greatly increases the risk of venous thrombosis. This new information about the risk factors for venous thrombosis should help physicians to advise patients about reducing their chances of developing this life-threatening condition.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050097.
The MedlinePlus encyclopedia has pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis, including an animation about how DVT causes pulmonary embolisms
The UK National Health Service Direct health encyclopedia provides information for patients on deep vein thrombosis (in several languages)
More information about the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study is available on the Leiden University Medical Center Web site
Wikipedia has pages on coagulation and on fibrinolysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050097
PMCID: PMC2365975  PMID: 18462012
3.  Risk of Venous Thromboembolism in Patients Infected with HIV: A Cohort Study 
Introduction Human immunodeficiency virus (HIV) patients are at risk of developing thrombosis than general population. There are several intersecting mechanisms associated with HIV infection and antiviral therapy that are emerging, which may lead to vasculopathy and hypercoagulability in these patients.
Methods We analyzed the HIV patients who followed up with our Vascular Medicine outpatient clinic with venous thromboembolism (VTE) over the past 3 years and followed them prospectively. The patients included were those who had minimum, regular follow-up of 3 months, with a Doppler scan in the beginning and last follow-up. Patients were analyzed for age, gender, race, site of thrombosis, coagulation factors, lipid panel, type of antiretroviral treatment, past or present history of infections or malignancy, CD4 absolute and helper cell counts at the beginning of thrombosis, response to treatment and outcome. Patients with HIV with arterial thrombosis were excluded.
Results A total of eight patients were analyzed. The mean age was 49.87 years (range, 38-58 years). All were male patients with six patients having lower limb thrombosis, one patient with upper limb thrombosis related to peripheral inserted central catheter (PICC), and one patient had pulmonary embolism with no deep vein thrombosis. Most common venous thrombosis was popliteal vein thrombosis, followed by common femoral, superficial femoral and external iliac thrombosis. Two patients had deficiency of protein S, two had high homocysteine levels, one had deficiency of antithrombin 3, and one had increase in anticardiolipin Immunoglobulin antibody. All patients were taking nucleoside and nonnucleoside inhibitors but only two patients were taking protease inhibitors. There was history of lymphoma in one and nonsmall cell lung carcinoma in one patient. Three patients had past history of tuberculosis and one of these patients also had pneumocystis carinii pneumonia. The mean absolute CD4 counts were 383.25 cells/UL (range, 103-908 cells/UL) and helper CD4 counts were 22.5 cells/UL (range, 12-45 cells/UL). All were anticoagulated with warfarin or enoxaparin. There was complete resolution of deep vein thrombosis in two patients (one with PICC line thrombosis in 3 months and other with popliteal vein thrombosis in 1 year). There was extension of clot in one patient and no resolution in others. Seven patients are still alive and on regular follow-up.
Conclusion Thrombosis in HIV patients is seen more commonly in middle aged, community ambulant male patients. Left lower limb involvement with involvement of popliteal vein is most common. Deficiency of protein S and hyperhomocystenaemia were noted in these patients. Most of these patients did not respond to therapeutic anticoagulation, but the extension of the thrombosis was prevented in majority of cases.
doi:10.1055/s-0033-1333866
PMCID: PMC3709953  PMID: 24436591
anticoagulation; protein C; protein S; homocysteine; antithrombin 3; duplex; enoxaparin; risk factors
4.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Background
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Conclusions
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Blood normally flows throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001515.
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
The World Health Organization provides information about the dangers of tobacco (in several languages)
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
doi:10.1371/journal.pmed.1001515
PMCID: PMC3775725  PMID: 24068896
5.  Long-Term Survival in a Large Cohort of Patients with Venous Thrombosis: Incidence and Predictors 
PLoS Medicine  2012;9(1):e1001155.
Linda Flinterman and colleagues report on the long-term mortality rate for individuals who have experienced a first venous thrombosis or pulmonary embolism. They describe an ongoing elevated risk of death for individuals who had experienced a venous thrombosis or pulmonary embolism as compared to controls, for up to eight years after the event.
Background
Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis.
Methods and Findings
4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well.
736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0–24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0–5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7–4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0–6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories.
Conclusions
Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The term venous thrombosis describes the clinical situation—more common during pregnancy, after surgery, or serious illness—in which a blood clot lodges in a vein. One specific type, which is more serious, involves the clot forming in a major vein in the lower leg and thigh and is termed a deep venous thrombosis. The clot can block blood flow and cause swelling and pain, but more seriously, can break off and move through the bloodstream, causing an embolism. An embolism can get stuck in the brain (and cause a stroke), lungs (and cause a pulmonary embolism), heart (to cause a heart attack), and/or other areas of the body, leading to severe damage.
Venous thrombosis is known to be associated with considerable short-term morbidity and mortality: the mortality rate after venous thrombosis is about 20% within one year and studies to date have suggested that the mortality rate is two to four times higher for patients with pulmonary embolism, of whom 10%–20% die within three months after the event. Many factors are associated with venous thrombosis, and the underlying cause of the thrombosis affects survival; for example, those with thrombotic events provoked by surgery or trauma have a lower mortality risk than patients with thrombosis caused by malignancy. Furthermore, about 10%–20% of patients who have had a venous thrombosis develop a recurrence within five years and up to 50% develop post-thrombotic syndrome—long-term swelling, pain, and changes in skin color.
Why Was This Study Done?
It is currently unknown whether the poor prognosis associated with venous thrombosis is limited to the months following the thrombotic event, or persists for years afterwards. So in this study, the researchers sought to answer this question by analyzing the long-term survival in a large cohort of patients who had experienced a first venous thrombosis and who were all followed for up to eight years.
What Did the Researchers Do and Find?
The researchers used the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study (MEGA study), which was a case-control study involving 4,965 consecutive patients aged 18 to 70 years who were objectively diagnosed with a deep venous thrombosis or pulmonary embolism and recruited from six anticoagulation clinics in the Netherlands between March 1999 and September 2004. The control group consisted of partners of patients (n = 3,297) and a random control group matched on age and sex (n = 3,000). The researchers obtained causes of death from the Central Bureau of Statistics and for the observation period (30 days after the venous thrombosis, to either death or end of follow-up between February 2007 and May 2009) compared cause-specific death rates of the patients to those of the general Dutch population. The researchers devised specialist survival models (called Kaplan-Meier life-tables) and calculated standardized mortality ratios (SMRs—the ratio of the observed number of deaths over the number of deaths expected) to estimate relative rates of all cause mortality by type of the initial thrombosis and the underlying cause.
Using these methods, the researchers found that the overall mortality rate in patients with thrombosis was substantially greater than in the control group (22.7 per 1,000 person-years compared to 4.7 per 1,000 person-years). Apart from malignancies, the researchers found that the main causes of death were diseases of the circulatory and respiratory system. Patients with venous thrombosis and malignancy had the highest risk of mortality: 55% died during follow-up. Patients with venous thrombosis without malignancy had an overall 2-fold increased risk of mortality compared to the control group and this risk was comparable for patients with different forms of thrombosis (such as deep venous thrombosis and pulmonary embolus). According to the researchers' calculations, the relative risk of death was highest during the first three years after thrombosis, but for those with thrombosis of unknown cause, the risk of death increased by two-fold up to eight years after the thrombosis. Furthermore, the researchers found that the highly increased risk of death for those with pulmonary embolism is mainly only for the first month as long-term survival is similar to that of patients with a deep venous thrombosis.
What Do These Findings Mean?
These findings show that patients who have experienced a venous thrombosis for the first time have an increased risk of death, which may last up to eight years after the event. These findings have important clinical implications and suggest that long-term clinical follow-up could be beneficial in patients who have experienced a venous thrombosis for the first time.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001155.
Wikipedia provides information about venous thrombosis note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Medline has patient-friendly information about deep venous thrombosis and pulmonary embolism
doi:10.1371/journal.pmed.1001155
PMCID: PMC3254666  PMID: 22253578
6.  The Absolute Risk of Venous Thrombosis after Air Travel: A Cohort Study of 8,755 Employees of International Organisations 
PLoS Medicine  2007;4(9):e290.
Background
The risk of venous thrombosis is approximately 2- to 4-fold increased after air travel, but the absolute risk is unknown. The objective of this study was to assess the absolute risk of venous thrombosis after air travel.
Methods and Findings
We conducted a cohort study among employees of large international companies and organisations, who were followed between 1 January 2000 and 31 December 2005. The occurrence of symptomatic venous thrombosis was linked to exposure to air travel, as assessed by travel records provided by the companies and organisations. A long-haul flight was defined as a flight of at least 4 h and participants were considered exposed for a postflight period of 8 wk. A total of 8,755 employees were followed during a total follow-up time of 38,910 person-years (PY). The total time employees were exposed to a long-haul flight was 6,872 PY. In the follow-up period, 53 thromboses occurred, 22 of which within 8 wk of a long-haul flight, yielding an incidence rate of 3.2/1,000 PY, as compared to 1.0/1,000 PY in individuals not exposed to air travel (incidence rate ratio 3.2, 95% confidence interval 1.8–5.6). This rate was equivalent to a risk of one event per 4,656 long-haul flights. The risk increased with exposure to more flights within a short time frame and with increasing duration of flights. The incidence was highest in the first 2 wk after travel and gradually decreased to baseline after 8 wk. The risk was particularly high in employees under age 30 y, women who used oral contraceptives, and individuals who were particularly short, tall, or overweight.
Conclusions
The risk of symptomatic venous thrombosis after air travel is moderately increased on average, and rises with increasing exposure and in high-risk groups.
In a cohort study of 8,755 employees of large international organizations followed for 38,910 person-years, Suzanne Cannegieter and colleagues find a risk of one thrombosis per 4,656 long-haul flights.
Editors' Summary
Background.
Blood normally flows smoothly throughout the human body, supplying the brain and other vital organs with oxygen and nutrients. When an injury occurs, proteins called clotting factors make the blood gel or coagulate at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Sometimes, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood to the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the deep veins of the leg) include pain, swelling, and redness in one leg. DVT is usually treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called pulmonary embolism (PE). Fortunately, DVT and PE are rare but having an inherited blood clotting disorder, taking an oral contraceptive, and some types of surgery are all risk factors for them. In addition, long-haul plane travel increases the risk of DVT and PE, known collectively as venous thrombosis (VT) 2- to 4-fold, in part because the enforced immobilization during flights slows down blood flow.
Why Was This Study Done?
Although the link between air travel and VT was first noticed in the 1950s, exactly how many people will develop DVT and PE (the absolute risk of developing VT) after a long flight remains unknown. This information is needed so that travelers can be given advice about their actual risk and can make informed decisions about trying to reduce that risk by, for example, taking small doses of anticoagulant medicine before a flight. In this study, the researchers have determined the absolute risk of VT during and after long-haul air travel in a large group of business travelers.
What Did the Researchers Do and Find?
The researchers enrolled almost 9,000 employees from several international companies and organizations and followed them for an average of 4.4 years. The details of flights taken by each employee were obtained from company records, and employees completed a Web-based questionnaire about whether they had developed VT and what risk factors they had for the condition. Out of 53 thrombi that occurred during the study, 22 occurred within eight weeks of a long-haul flight (a flight of more than four hours). From this and data on the total time employees spent on long-haul flights, the researchers calculated that these flights tripled the risk of developing VT, and that the absolute risk (the probability of something occurring in a certain time period) of a VT occurring shortly after such travel was one event per 4,656 flights. They also calculated that the risk of VT was increased by exposure to more flights during a short period and to longer flights and was greatest in the first two weeks after a flight. In addition, the risk of VT was particularly high in young employees, women taking oral contraceptives, and people who were short, tall or overweight.
What Do These Findings Mean?
The main finding of this study is that the absolute risk of VT after of a long-haul flight is low—only one passenger out of nearly 5,000 is likely to develop VT because of flying. However, the study included only healthy people without previous VT whose average age was 40 years, so the absolute risk of VT after long-haul flights might be higher in the general traveling population. Even so, this finding strongly suggests that prophylactic (preventative) use of anticoagulants by all long-haul travelers may not be justified because these drugs have potentially dangerous side effects (for example, they can cause uncontrolled bleeding). Subgroups of travelers with additional risk factors for VT might, however, benefit from the use of this and other prophylactic measures, but randomized trials are needed to find out who would benefit most from which prophylactic measure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040290.
MedlinePlus encyclopedia pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
Information from the US National Heart Lung and Blood Institute on deep vein thrombosis, including an animation of how DVT causes pulmonary embolisms
Information for patients from the UK National Health Service Direct health encyclopedia on deep vein thrombosis (in several languages)
Information for travelers on DVT from the US Centers for Disease Control and Prevention and from the UK National Travel Health Network and Centre
This study came out of the WHO Research Into Global Hazards of Travel (WRIGHT) project, and WHO's WRIGHT project on Air Travel and Venous Thromboembolism, of which his study forms a part, has a Web site
doi:10.1371/journal.pmed.0040290
PMCID: PMC1989755  PMID: 17896862
7.  New oral antithrombotics: focus on dabigatran, an oral, reversible direct thrombin inhibitor for the prevention and treatment of venous and arterial thromboembolic disorders 
Venous thromboembolism, presenting as deep vein thrombosis or pulmonary embolism, is a major challenge for health care systems. It is the third most common vascular disease after coronary heart disease and stroke, and many hospitalized patients have at least one risk factor. In particular, patients undergoing hip or knee replacement are at risk, with an incidence of asymptomatic deep vein thrombosis of 40%–60% without thromboprophylaxis. Venous thromboembolism is associated with significant mortality and morbidity, with patients being at risk of recurrence, post-thrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Arterial thromboembolism is even more frequent, and atrial fibrillation, the most common embolic source (cardiac arrhythmia), is associated with a five-fold increase in the risk of stroke. Strokes due to atrial fibrillation tend to be more severe and disabling and are more often fatal than strokes due to other causes. Currently, recommended management of both venous and arterial thromboembolism involves the use of anticoagulants such as coumarin and heparin derivatives. These agents are effective, although have characteristics that prevent them from providing optimal anticoagulation and convenience. Hence, new improved oral anticoagulants are being investigated. Dabigatran is a reversible, direct thrombin inhibitor, which is administered as dabigatran etexilate, the oral prodrug. Because it is the first new oral anticoagulant that has been licensed in many countries worldwide for thromboprophylaxis following orthopedic surgery and for stroke prevention in patients with atrial fibrillation, this compound will be the main focus of this review. Dabigatran has been investigated for the treatment of established venous thromboembolism and prevention of recurrence in patients undergoing hip or knee replacement, as well as for stroke prevention in atrial fibrillation patients with a moderate and high risk of stroke.
doi:10.2147/VHRM.S26482
PMCID: PMC3273411  PMID: 22323896
dabigatran etexilate; venous thromboembolism; stroke; prevention; treatment
8.  Assessment of specific risks for the recurrence of deep vein thrombosis: a case report 
Cases Journal  2009;2:7024.
Introduction
Venous thromboembolism is a multifactorial disease defined by multiple interactions between genetic and environmental components. It is managed by oral anticoagulation with warfarin sodium (Coumadin), a drug that targets the vitamin K epoxide reductase to prevent the recycling of vitamin K epoxide to the reduced form of vitamin K. The reduced form of vitamin K is an essential cofactor in the formation of active clotting factors II, VII, IX, X and regulatory factors protein C, and cofactor protein S through gamma-glutamyl carboxylation. The duration of Coumadin treatment, three to six months or life-long, should be based on the individual risk for recurrent deep vein thrombosis and on the associated increased risk for bleeding complications.
Case Presentation
A previously healthy 50-year-old white male developed a deep vein thrombosis consequent to surgical placement of a titanium rod to correct a fracture of the femur and he was maintained for over a year on daily oral doses of Coumadin 9 mg and aspirin 325 mg. When he began to bruise spontaneously with multiple large hematomas appearing without provocation, he requested that his primary care physician reconsider the anticoagulation. Because of his age, sex, and the possibility of an inherited or acquired anticoagulant protein deficiency he was maintained on Coumadin and a thrombophilia work up was ordered. Test results were interpreted as deficiencies in both protein C and protein S and he was instructed that life-long therapy with Coumadin was necessary. Is this a correct evaluation by his primary care physician?
Conclusion
This case illustrates that Coumadin, a vitamin K agonist, was exerting a therapeutically acceptable negative influence on plasma activity levels of vitamin K-dependent protein C and protein S. Relying on the outcome of a thrombophilia work-up for a decision to maintain or cease Coumadin treatment of patients at risk for recurrent deep vein thrombosis has pitfalls that can be avoided. The use of real-time B-mode venous ultrasonography to verify complete restoration of venous flow before ceasing Coumadin treatment is not always considered in the long-term management of a patient with a first thrombosis, despite the well documented significant risk of deep vein thrombosis recurrence associated with an unresolved thrombosis.
doi:10.4076/1757-1626-2-7024
PMCID: PMC2769333  PMID: 19918503
9.  A Case Series of HIV-Seropositive Patients and Hypercoagulable State—Is It Difficult to Treat Even with Therapeutic Anticoagulation? 
Patients with human immunodeficiency virus (HIV) are at risk of developing thrombosis and are 8 to 10 times more likely to develop thrombosis than the general population. Moreover, if they have hypercoagulable state they can have severe thrombosis and life-threatening thrombotic events. The purpose of this retrospective study is to analyze hypercoagulable state in HIV-seropositive patients who have been diagnosed with venous thromboembolism (VTE). This study is a subgroup study of a larger cohort group of HIV-seropositive patients with VTE followed up with our vascular medicine outpatient clinic. The patients included for this study were HIV-seropositive patients with hypercoagulable state, analyzed over the past 3 years, and followed prospectively. HIV-seropositive patients with arterial thrombosis were excluded. These patients had minimum, regular follow-up of 3 months, with a Doppler scan in the beginning and last follow-up. All the patients were analyzed for hypercoagulable state and the patients selected in this study were those who were tested positive for hypercoagulable state. All patients were analyzed for age, gender, race, site of thrombosis, coagulation factors, lipid panel, type of antiretroviral treatment, past or present history of infections or malignancy, CD4 absolute and helper cell counts at the beginning of thrombosis, and response to treatment and outcome. Patients with HIV with arterial thrombosis were excluded. The study was approved by the ethics committee. Five patients were included in this study. The mean age was 47.8 years (range 38 to 58 years). All were male patients with lower limb thrombosis. Most common venous thrombosis was popliteal vein thrombosis, followed by common femoral, superficial femoral, and external iliac thrombosis. Two patients had deficiency of protein S, two had high homocysteine levels, one had deficiency of antithrombin 3, and one had increase in anticardiolipin immunoglobulin G antibody. All the patients were taking nucleoside and nonnucleoside inhibitors but only one patient was taking protease inhibitors. There was no history of malignancy but two patients had past history of tuberculosis. The mean absolute CD4 counts were 244 cells/UL (range 103 to 392 cells/UL) and helper CD4 counts were 19.6 cells/UL (range 15 to 30 cells/UL). All were anticoagulated with warfarin or enoxaparin. There was complete resolution of deep vein thrombosis only in one patient on long-term anticoagulation but there was no resolution of thrombosis in the other four patients despite of therapeutic anticoagulation for more than 6 months. All the patients are alive and on regular follow-up. Thrombosis in HIV patients is seen more commonly in middle aged, community ambulant male patients. The most common hypercoagulable state was noted as deficiency of protein S and hyperhomocysteinemia. Eighty percent of the patients did not respond to therapeutic anticoagulation.
doi:10.1055/s-0033-1334868
PMCID: PMC3709978  PMID: 24436593
deep vein thrombosis; duplex; DVT; enoxaparin; factor V Leiden; low molecular weight heparin; proximal
10.  Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials 
Objective To determine how length of anticoagulation and clinical presentation of venous thromboembolism influence the risk of recurrence after anticoagulant treatment is stopped and to identify the shortest length of anticoagulation that reduces the risk of recurrence to its lowest level.
Design Pooled analysis of individual participants’ data from seven randomised trials.
Setting Outpatient anticoagulant clinics in academic centres.
Population 2925 men or women with a first venous thromboembolism who did not have cancer and received different durations of anticoagulant treatment.
Main outcome measure First recurrent venous thromboembolism after stopping anticoagulant treatment during up to 24 months of follow-up.
Results Recurrence was lower after isolated distal deep vein thrombosis than after proximal deep vein thrombosis (hazard ratio 0.49, 95% confidence interval 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (1.19, 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (0.55, 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio 1.52, 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (1.19, 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment.
Conclusion Three months of treatment achieves a similar risk of recurrent venous thromboembolism after stopping anticoagulation to a longer course of treatment. Unprovoked proximal deep vein thrombosis and pulmonary embolism have a high risk of recurrence whenever treatment is stopped.
doi:10.1136/bmj.d3036
PMCID: PMC3100759  PMID: 21610040
11.  Thromboembolism 
Clinical Evidence  2010;2010:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low-molecular-weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin.Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC2907619
12.  Thromboembolism 
Clinical Evidence  2011;2011:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low molecular weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low molecular weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT compared with placebo or no treatment.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin. Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC3217723  PMID: 21385473
13.  A Randomized Trial of Rosuvastatin in the Prevention of Venous Thromboembolism: the JUPITER Trial 
The New England journal of medicine  2009;360(18):1851-1861.
Background
Controversies persist on whether arterial and venous thrombosis share common pathways and whether treatments of known efficacy for one disease process have consistent benefits for the other. Observational studies have yielded variable estimates of the effect of statin therapy on risk of venous thromboembolism, and randomized evidence is lacking.
Methods
Symptomatic venous thromboembolism was a pre-specified endpoint of Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg/dL and high-sensitivity C-reactive protein levels of 2.0 mg/L or higher to rosuvastatin, 20 mg/d, or placebo. Intention-to-treat analyses followed participants for the first occurrence of pulmonary embolism or deep vein thrombosis.
Results
During a median follow-up of 1.9 years (maximum 5.0), symptomatic venous thromboembolism occurred in 94 participants, 34 in the rosuvastatin group and 60 in the placebo group. The rates of venous thromboembolism were 0.18 and 0.32 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin 0.57; 95% confidence interval [CI], 0.37 to 0.86; P=0.007), with corresponding rates of 0.10 and 0.17 for unprovoked venous thromboembolism (hazard ratio 0.61; 95% CI, 0.35 to 1.09; P=0.089) and 0.08 and 0.16 for provoked venous thromboembolism (hazard ratio 0.52; 95% CI, 0.28 to 0.96; P=0.033). Corresponding rates of pulmonary embolism were 0.09 and 0.12 (hazard ratio 0.77; 95% CI, 0.41 to 1.45; P=0.42), whereas rates of deep vein thrombosis only were 0.09 and 0.20 (hazard ratio 0.45; 95% CI, 0.25 to 0.79; P=0.004). Consistent effects were observed in all subgroups examined. No differences were seen between treatment groups in rates of bleeding.
Conclusions
In this trial of apparently healthy persons, rosuvastatin significantly reduced the occurrence of symptomatic venous thromboembolism. (ClinicalTrials.gov number, NCT00239681.)
doi:10.1056/NEJMoa0900241
PMCID: PMC2710995  PMID: 19329822
14.  Risk of Venous Thromboembolism in Patients with Cancer: A Systematic Review and Meta-Analysis 
PLoS Medicine  2012;9(7):e1001275.
Venous thromboembolism in patients with cancer is common, but precise incidence rates in different cancers are not known, making it difficult to target prevention strategies. This study summarizes the existing literature to determine the risk of venous thromboembolism in high- and average-risk groups of patients with different cancers.
Background
People with cancer are known to be at increased risk of venous thromboembolism (VTE), and this risk is believed to vary according to cancer type, stage of disease, and treatment modality. Our purpose was to summarise the existing literature to determine precisely and accurately the absolute risk of VTE in cancer patients, stratified by malignancy site and background risk of VTE.
Methods and Findings
We searched the Medline and Embase databases from 1 January 1966 to 14 July 2011 to identify cohort studies comprising people diagnosed with one of eight specified cancer types or where participants were judged to be representative of all people with cancer. For each included study, the number of patients who developed clinically apparent VTE, and the total person-years of follow-up were extracted. Incidence rates of VTE were pooled across studies using the generic inverse variance method. In total, data from 38 individual studies were included. Among average-risk patients, the overall risk of VTE was estimated to be 13 per 1,000 person-years (95% CI, 7 to 23), with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk (due to metastatic disease or receipt of high-risk treatments), the risk of VTE was 68 per 1,000 person-years (95% CI, 48 to 96), with the highest risk among patients with brain cancer (200 per 1,000 person-years; 95% CI, 162 to 247). Our results need to be considered in light of high levels of heterogeneity, which exist due to differences in study population, outcome definition, and average duration of follow-up between studies.
Conclusions
VTE occurs in greater than 1% of cancer patients each year, but this varies widely by cancer type and time since diagnosis. The absolute VTE risks obtained from this review can aid in clinical decision-making about which people with cancer should receive anticoagulant prophylaxis and at what times.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
A venous thrombosis is the medical term for a blood clot that forms in a vein, often completely blocking the vessel. The most common type is a deep vein thrombosis of the lower leg, which apart from causing pain and immobility, can break off (embolize), flow through the blood stream back to the heart, get caught in one of the blood vessels supplying the lungs, and cause a life-threatening pulmonary embolism. The term venous thromboembolism (VTE) refers to both a deep venous thrombosis and a pulmonary embolism and is a common cause of death, responsible for at least 300,000 deaths a year in the United States alone. There are many risk factors for developing a VTE, including age, immobility, certain medications, and some conditions, such as cancer: an estimated 20% of deaths from VTE occur among patients with cancer, and importantly, cancer patients with VTE have a much higher risk of death than those who do not have a VTE. The increased risk of developing a VTE is due to the treatments and surgery involved in the management of cancer, in addition to the risks associated with the condition itself.
Why Was This Study Done?
Previous studies have suggested that certain types of cancer, such as brain and pancreatic cancer, are associated with an increased risk of developing a VTE, but to date, clinical guidelines recommend preventative treatment of VTE only for cancer patients during hospital admissions for medical treatment and surgery, not for those patients receiving outpatient care. In this study, the researchers systematically reviewed the available published evidence to quantify the risks of developing a VTE in patients with cancer according to the type of cancer, and to determine whether certain patient groups are at particularly high risk of developing a VTE.
What Did the Researchers Do and Find?
The researchers used a comprehensive keyword search of two medical literature databases to identify relevant studies published between 1966 and 2011. Then they examined these studies according to certain criteria, such as the type of study and the type of cancer: the researchers were specifically looking for cohort studies of adult patients with one of eight cancer types—breast, lung, colorectal, prostate, brain, bone, pancreatic, and hematologic (including all leukemias, lymphomas, and multiple myeloma). The selected studies also had to include follow-up of more than 30 days and VTE outcomes. Then the researchers categorized selected studies according to the risk of developing a VTE—the researchers judged high-risk patients to be those with metastatic disease or receiving certain types of high-risk treatments, and judged average-risk patients to be representative of all patients with a cancer diagnosis. The researchers then pooled all the data from these studies and did a separate statistical analysis for high and average risk and for each cancer type.
Using these methods, the researchers identified 7,274 potentially relevant articles, of which 46 reports from 38 individual cohorts met the criteria to be included in their review. Of the 38 cohorts, the researchers categorized 31 as high risk and seven as average risk. In the pooled analysis the researchers found that among average-risk patients, the overall risk of VTE was 13 per 1,000 person-years, with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk, the researchers found that the risk of VTE was 68 per 1,000 person-years, with the highest risk among patients with brain cancer (200 per 1,000 person-years).
What Do These Findings Mean?
These findings suggest that the annual incidence rate of VTE in patients with cancer is between 0.5% and 20%, depending on the cancer type, background risk, and time since diagnosis. Cancers of the brain and pancreas have the highest risk of VTE for both high- and average-risk patient groups. Based on these more accurate data on the risks of VTE in different groups of cancer patients, future updates of clinical guidelines can now include more information about categories of risk to help guide clinicians when they make decisions about which patients should receive preventative treatment for VTE and when they should receive such treatment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10. 1371/journal.pmed.1001275.
Wikipedia gives more information about VTE (note that Wikipedia is a free online encyclopedia that anyone can edit)
Information about VTE for patients and health professionals is available from the American Cancer Society, the US National Cancer Institute, and the UK-based thrombosis charity Lifeblood
doi:10.1371/journal.pmed.1001275
PMCID: PMC3409130  PMID: 22859911
15.  Prevalence of thrombophilic mutations in patients with unprovoked thromboembolic disease. A comparative analysis regarding arterial and venous disease 
Hippokratia  2012;16(3):250-255.
Background: Thromboembolic disease (TED) represents one of the main reasons of morbitity and mortality in Western World. Venous and arterial thrombotic disorders have long been viewed as separate pathophysiological entities. However, in recent times the separate nature of arterial and venous thrombotic events has been challenged. Although inherited thrombophilia’s predominant clinical manifestation is venous thrombosis, its contribution to arterial thrombosis remains controversial. Purpose  of  the  study  was  to  evaluate  the  prevalence  of  the  most common  thrombophilic  mutations, FV Leiden G1691A-FVL and FII G20210A-PTM and to assess  the  differences between venous, arterial and mixed thrombotic events. Testing  for polymorphism MTHFR C677T and  antithrombin,  protein  C  and  protein  S was also performed. Correlations with  dyslipidemia, smoking, obesity, homocysteine and antiphospholipid antibodies were made.
Methods: 515 patients with unprovoked TED, 263 males, median age 44 years, were studied. Patients were divided into three groups: 258 with venous thrombosis (group A), 239 with arterial (group B) and 18 with mixed episodes (group C). All patients were interviewed regarding family history of TED, origin, smoking and dyslipidemia. Body mass index (BMI) had been calculated. Molecular assessment of the FVL, PTM and MTHFR C677T was performed. Antithrombin, protein C, protein S, APCR, homocysteine, antiphospholipid antibodies and lipid profile were also measured.
Results: The population studied was homogenous among three groups as regards age (p=0.943), lipid profile (p=0.271), BMI (p=0.506), homocysteine (p=0.177), antiphospholipid antibodies (p=0.576), and positive family history (p=0.099). There was no difference in the prevalence of FVL between venous and arterial disease (p=0.440). Significant correlation of PTM with venous TED was found (p=0.001). The number of positive and negative for MTHFR presented statistically significant difference with a support in arterial disease (p=0.05). Moreover, a 2-fold increase in the risk of venous thrombosis in FVL positive patients (odds ratio: 2.153) and a positive correlation of homocysteine levels with MTHFR C677T (p<0.001) was found.
Conclusions: Correlation of PTM with venous thrombosis was established. Analysis showed no difference in prevalence of FVL between venous and arterial thrombosis, indicating that FVL might be a predisposing factor for arterial disease. A significant increase in MTHFR C677T prevalence in arterial disease was found. In conclusion, young patients with unprovoked arterial disease should undergo evaluation for thrombophilic genes. Identification of these mutations is important in the overall assessment and management of patients at high risk. Findings will influence the decisions of stratified approaches for antithrombotic therapy either primary or secondary thromboprophylaxis, the duration of therapy, the potential for avoiding clinical thrombosis by risk factor modification and the genetic counselling of family members. However, further studies are needed to clarify the nature of the association regarding venous and arterial thrombotic events.
PMCID: PMC3738733  PMID: 23935293
thrombophilic mutations; unprovoked thromboembolic disease; arterial thromboembolic disease; venous thromboembolic disease
16.  Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging 
Background:
Compression ultrasonography performed serially over a 7-day period is recommended for the diagnosis of deep vein thrombosis in symptomatic pregnant women, but whether this approach is safe is unknown. We evaluated the safety of withholding anticoagulation from pregnant women with suspected deep vein thrombosis following negative serial compression ultrasonography and iliac vein imaging.
Methods:
Consecutive pregnant women who presented with suspected deep vein thrombosis underwent compression ultrasonography and Doppler imaging of the iliac vein of the symptomatic leg(s). Women whose initial test results were negative underwent serial testing on 2 occasions over the next 7 days. Women not diagnosed with deep vein thrombosis were followed for a minimum of 3 months for the development of symptomatic deep vein thrombosis or pulmonary embolism.
Results:
In total, 221 pregnant women presented with suspected deep vein thrombosis. Deep vein thrombosis was diagnosed in 16 (7.2%) women by initial compression ultrasonography and Doppler studies; none were identified as having deep vein thrombosis on serial testing. One patient with normal serial testing had a pulmonary embolism diagnosed 7 weeks later. The overall prevalence of deep vein thrombosis was 7.7% (17/221); of these, 65% (11/17) of cases were isolated to the iliofemoral veins and 12% (2/17) were isolated iliac deep vein thromboses. The incidence of venous thromboembolism during follow-up was 0.49% (95% confidence interval [CI] 0.09%–2.71%). The sensitivity of serial compression ultrasonography with Doppler imaging was 94.1% (95% CI 69.2%–99.7%), the negative predictive value was 99.5% (95% CI 96.9%–100%), and the negative likelihood ratio was 0.068 (95% CI 0.01–0.39).
Interpretation:
Serial compression ultrasonography with Doppler imaging of the iliac vein performed over a 7-day period excludes deep-vein thrombosis in symptomatic pregnant women.
doi:10.1503/cmaj.120895
PMCID: PMC3589327  PMID: 23318405
17.  Risk factors and recurrent thrombotic episodes in patients with cerebral venous thrombosis 
Blood Transfusion  2014;12(Suppl 1):s337-s342.
Background
The prevalence of thrombophilic abnormalities in patients with cerebral vein thrombosis has been reported to be similar to that in patients with deep vein thrombosis of the lower limb. The role of gender-specific risk factors (pregnancy, oral contraceptives) is well established, whereas that of other acquired risk conditions is debated.
Materials and methods
We screened 56 patients with cerebral vein thrombosis and 184 age- and sex-matched apparently healthy controls for prothrombin (factor II, FII) G20210A and factor V Leiden polymorphisms; protein S, protein C, and antithrombin deficiency; anticardiolipin antibodies; hyperhomocysteinaemia and other putative risk factors.
Results
The G20210A polymorphism was found in 29.1% of patients and in 5.7% of controls (odds ratio [OR] 7.1; P <0.0001; adjusted OR 12.67, P <0.0001). Frequencies of factor V Leiden and hyperhomocysteinaemia were not significantly different in patients and controls, nor were the other thrombophilic tests and some established cardiovascular risk factors, such as smoking, obesity or overweight and arterial hypertension. Conversely, 53.7% of the women who developed cerebral vein thrombosis did so while assuming oral contraceptives (OR 6.12; P <0.0001), with a further increase of risk in FII G20210A carriers (OR 48.533). Some associated diseases (onco-haematological disorders and infections) also had a significant role. Over a median 7-year follow-up, irrespective of the duration of antithrombotic treatment, 9/56 (16%) patients had further episodes of venous/arterial thrombosis. No significant risk factor for recurrent thrombosis was identified.
Discussion
In spite of the limitations of the sample size, our data confirm the role of FII G20210A mutation in this setting and its interactions with acquired risk factors such as oral contraceptives, also highlighting the risk of recurrent thrombosis in cerebral vein thrombosis patients.
doi:10.2450/2013.0196-12
PMCID: PMC3934282  PMID: 23399370
risk factors; cerebral venous thrombosis; recurrences
18.  Protected Iliofemoral Venous Thrombectomy 
Texas Heart Institute Journal  2002;29(2):130-132.
Although thromboembolism is uncommon during pregnancy and the postpartum period, physicians should be alert to the possibility because the complications, such as pulmonary embolism, are often life threatening. Pregnant women who present with thromboembolic occlusion are particularly difficult to treat because thrombolysis is hazardous to the fetus and surgical intervention by any of several approaches is controversial.
A 22-year-old woman, in her 11th week of gestation, experienced an episode of pulmonary embolism and severe ischemic venous thrombosis of the left lower extremity. The cause was determined to be a severe protein S deficiency in combination with compression of the left iliac vein by the enlarged uterus.
The patient underwent emergency insertion of a retrievable vena cava filter and surgical iliofemoral venous thrombectomy with concomitant creation of a temporary femoral arteriovenous fistula. The inferior vena cava filter was inserted before the venous thrombectomy to prevent pulmonary embolism from clots dislodged during thrombectomy. When the filter was removed, medium-sized clots were found trapped in its coils, indicating the effectiveness of this approach. The operation resolved the severe ischemic venous thrombosis of the left leg, and the patency of the iliac vein was maintained throughout the pregnancy without embolic recurrence. At full term, the woman spontaneously delivered an 8-lb, 6-oz, healthy male infant. (Tex Heart Inst J 2002;29:130–2)
PMCID: PMC116741  PMID: 12075871
Femoral vein/surgery; heparin/therapeutic use; iliac vein/surgery; pregnancy complications, cardiovascular/surgery; pulmonary embolism/prevention & control; thrombectomy; thrombosis/therapy; vena cava filters; venous thrombosis/therapy
19.  Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: prospective study 
Objective To assess the safety of using single complete compression ultrasonography in pregnant and postpartum women to rule out deep vein thrombosis.
Design Prospective outcome study.
Setting Two tertiary care centres and 18 private practices specialising in vascular medicine in France and Switzerland.
Participants 226 pregnant and postpartum women referred for suspected deep vein thrombosis.
Methods A single proximal and distal compression ultrasonography was performed. All women with a negative complete compression ultrasonography result did not receive anticoagulant therapy and were followed up for a three month period.
Main outcome measures Symptoms of venous thromboembolism, second compression ultrasonography or chest imaging, a thromboembolic event, and anticoagulant treatment.
Results 16 women were excluded, mainly because of associated suspected pulmonary embolism. Deep vein thrombosis was diagnosed in 22 out of the 210 included women (10.5%). 10 patients received full dose anticoagulation despite a negative test result during follow-up. Of the 177 patients without deep vein thrombosis and who did not receive full dose anticoagulant therapy, two (1.1%, 95% confidence interval 0.3% to 4.0%) had an objectively confirmed deep vein thrombosis during follow-up.
Conclusions The rate of venous thromboembolic events after single complete compression ultrasonography in pregnant and postpartum women seems to be within the range of that observed in studies in the non-pregnant population. These data suggest that a negative single complete compression ultrasonography result may safely exclude the diagnosis of deep vein thrombosis in this setting.
Trial registration clinicaltrials.gov NCT00740454.
doi:10.1136/bmj.e2635
PMCID: PMC3339806  PMID: 22531869
20.  Trial Protocol: A randomised controlled trial of extended anticoagulation treatment versus routine anticoagulation treatment for the prevention of recurrent VTE and post thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (The ExACT Study) 
Background
Venous thromboembolism comprising pulmonary embolism and deep vein thrombosis is a common condition with an incidence of approximately 1 per 1,000 per annum causing both mortality and serious morbidity. The principal aim of treatment of a venous thromboembolism with heparin and warfarin is to prevent extension or recurrence of clot. However, the recurrence rate following a deep vein thrombosis remains approximately 10% per annum following treatment cessation irrespective of the duration of anticoagulation therapy. Patients with raised D-dimer levels after discontinuing oral anticoagulation treatment have also been shown to be at high risk of recurrence.
Post thrombotic syndrome is a complication of a deep vein thrombosis which can lead to chronic venous insufficiency and ulceration. It has a cumulative incidence after 2 years of around 25% and it has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure.
Methods/design
Patients with a first idiopathic venous thromboembolism will be recruited through anticoagulation clinics and randomly allocated to either continuing or discontinuing warfarin treatment for a further 2 years and followed up on a six monthly basis. At each visit D-dimer levels will be measured using a Roche Cobas h 232 POC device. In addition a venous sample will be taken for laboratory D-dimer analysis at the end of the study. Patients will be examined for signs and symptoms of PTS using the Villalta scale and complete VEINES and EQ5D quality of life questionnaires.
Discussion
The primary aim of the study is to investigate whether extending oral anticoagulation treatment (prior to discontinuing treatment) beyond 3–6 months for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism prevents recurrence. The study will also determine the role of extending anticoagulation for patients with elevated D-dimer levels prior to discontinuing treatment and identify the potential of D-dimer point of care testing for identification of high risk patients within a primary care setting.
Trial registration
ISRCTN73819751
doi:10.1186/1471-2261-13-16
PMCID: PMC3602651  PMID: 23497371
Venous thromboembolism; Deep vein thrombosis; Pulmonary embolism; Extended warfarin; Post thrombotic syndrome; D-dimer
21.  An Economic Evaluation of Venous Thromboembolism Prophylaxis Strategies in Critically Ill Trauma Patients at Risk of Bleeding 
PLoS Medicine  2009;6(6):e1000098.
Using decision analysis, Henry Stelfox and colleagues estimate the cost-effectiveness of three venous thromboembolism prophylaxis strategies in patients with severe traumatic injuries who were also at risk for bleeding complications.
Background
Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.
Methods and Findings
Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies—pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF)—in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.
Conclusions
The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs.
Please see later in the article for Editors' Summary
Editors' Summary
Background
For patients who have been seriously injured in an accident or a violent attack (trauma patients), venous thromboembolism (VTE)—the formation of blood clots that limit the flow of blood through the veins—is a frequent and potentially fatal complication. The commonest form of VTE is deep vein thrombosis (DVT). “Distal” DVTs (clots that form in deep veins below the knee) affect about half of patients with severe trauma; “proximal” DVTs (clots that form above the knee) develop in one in five trauma patients. DVTs cause pain and swelling in the affected leg and can leave patients with a painful condition called post-thrombotic syndrome. Worse still, part of the clot can break off and travel to the lungs where it can cause a life-threatening pulmonary embolism (PE). Distal DVTs rarely embolize but, if untreated, half of patients who present with a proximal DVT will develop a PE, and 2%–3% of them will die as a result.
Why Was This Study Done?
VTE is usually prevented by using heparin, a drug that stops blood clotting, but clinicians treating critically ill trauma patients have a dilemma. Many of these patients are at high risk of serious bleeding complications so cannot be given heparin to prevent VTE. Nonpharmacological ways to prevent VTE include the use of pneumatic compression devices to keep the blood moving in the legs (clots often form in patients confined to bed because of the sluggish blood flow in their legs), repeated screening for blood clots using Doppler ultrasound, and the insertion of a “vena cava filter” into the vein that takes blood from the legs to the heart. This last device catches blood clots before they reach the lungs but increases the risk of DVT. Unfortunately, no-one knows which VTE prevention strategy works best in trauma patients who cannot be given heparin. In this study, therefore, the researchers use decision analysis (the systematic evaluation of the most important factors affecting a decision) to estimate the costs and likely clinical outcomes of these strategies.
What Did the Researchers Do and Find?
The researchers used cost and clinical data from patients admitted to a Canadian trauma center with severe head/neck and/or abdomen/pelvis injuries (patients with a high risk of bleeding complications likely to make heparin therapy dangerous for up to two weeks after the injury) to construct a Markov decision analysis model. They then fed published data on the chances of patients developing DVT or PE, and on the effectiveness of the three VTE prevention strategies, into the model to obtain estimates of the costs and clinical outcomes of the strategies at 12 weeks after the injury and over the patients' lifetime. The estimated incidence of DVT at 12 weeks was 15% for the pneumatic compression device and Doppler ultrasound strategies, but 25% for the vena cava filter strategy. By contrast, the estimated incidence of PE was 2.9% with the pneumatic compression device, 1.5% with Doppler ultrasound, but only 0.3% with the vena cava filter. The expected mortality with all three strategies was similar. Finally, the estimated health care costs per patient at 12 weeks were Can$55,334 and Can$55,831 for the Doppler ultrasound and pneumatic compression device strategies, respectively, but Can$57,377 for the vena cava filter strategy; similar trends were seen for lifetime health care costs.
What Do These Findings Mean?
As with all mathematical models, these findings depend on the data fed into the model and on the assumptions included in it. For example, because data from one Canadian trauma unit were used to construct the model, these findings may not be generalizable. Nevertheless, these findings suggest that, although VTE is common among patients with severe injuries, PE is not a major cause of death among these patients. They also suggest that the use of vena cava filters for VTE prevention in patients who cannot receive heparin should not be routinely used because it is expensive and increases the risk of DVT. Finally, these results suggest that, compared with the other strategies, serial Doppler ultrasound is associated with better clinical outcomes and lower costs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000098.
The US National Heart Lung and Blood Institute provides information (including an animation) on deep vein thrombosis and pulmonary embolism
MedlinePlus provides links to more information about deep vein thrombosis and pulmonary embolism (in several languages)
The UK National Health Service Choices Web site has information on deep vein thrombosis and on embolism (in English and Spanish)
The Eastern Association for the Surgery of Trauma working group document Practice Management Guidelines for the Management of Venous Thromboembolism in Trauma Patients can be downloaded from the Internet
doi:10.1371/journal.pmed.1000098
PMCID: PMC2695771  PMID: 19554085
22.  Advances in oral anticoagulation treatment: the safety and efficacy of rivaroxaban in the prevention and treatment of thromboembolism 
Arterial and venous thromboembolic diseases are a clinical and economic burden worldwide. In addition to traditional agents such as vitamin K antagonists and heparins, newer oral agents – such as the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, and the direct thrombin inhibitor dabigatran – have been shown to be effective across several indications. Rivaroxaban has been shown to have predictable pharmacokinetic and pharmacodynamic properties, including a rapid onset of action. In addition, there is no requirement for routine coagulation monitoring; and no dose adjustment is necessary for age alone, sex, or body weight. Rivaroxaban has successfully met primary efficacy and safety endpoints in large, randomized phase III trials across several indications, including: prevention of venous thromboembolism in orthopedic patients undergoing elective hip or knee replacement surgery; treatment of deep vein thrombosis and secondary prevention of deep vein thrombosis and pulmonary embolism; stroke prevention in patients with atrial fibrillation; and secondary prevention of acute coronary syndrome. Rivaroxaban and the other newer oral anticoagulants are likely to improve outcomes in the prevention and treatment of thromboembolic events, and will offer patients and physicians alternative treatment options.
doi:10.1177/2040620712453067
PMCID: PMC3546633  PMID: 23365716
acute coronary syndrome; atrial fibrillation; orthopedics; pulmonary embolism; rivaroxaban; stroke; venous thromboembolism; venous thrombosis
23.  Advances in oral anticoagulation treatment: the safety and efficacy of rivaroxaban in the prevention and treatment of thromboembolism 
Arterial and venous thromboembolic diseases are a clinical and economic burden worldwide. In addition to traditional agents such as vitamin K antagonists and heparins, newer oral agents – such as the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, and the direct thrombin inhibitor dabigatran – have been shown to be effective across several indications. Rivaroxaban has been shown to have predictable pharmacokinetic and pharmacodynamic properties, including a rapid onset of action. In addition, there is no requirement for routine coagulation monitoring; and no dose adjustment is necessary for age alone, sex, or body weight. Rivaroxaban has successfully met primary efficacy and safety endpoints in large, randomized phase III trials across several indications, including: prevention of venous thromboembolism in orthopedic patients undergoing elective hip or knee replacement surgery; treatment of deep vein thrombosis and secondary prevention of deep vein thrombosis and pulmonary embolism; stroke prevention in patients with atrial fibrillation; and secondary prevention of acute coronary syndrome. Rivaroxaban and the other newer oral anticoagulants are likely to improve outcomes in the prevention and treatment of thromboembolic events, and will offer patients and physicians alternative treatment options.
doi:10.1177/2040620712453067
PMCID: PMC3546633  PMID: 23365716
acute coronary syndrome; atrial fibrillation; orthopedics; pulmonary embolism; rivaroxaban; stroke; venous thromboembolism; venous thrombosis
24.  Lower extremity venous thrombosis in patients younger than 50 years of age 
Aim
Lower extremity deep venous thrombosis in the young adult is uncommon and has not been well studied in the literature. The aim of this study is to define risk factors for deep venous thrombosis among patients younger than 50 years of age, to compare them with a control group, and to suggest recommendations for the management and treatment of venous thrombosis in this particular group of patients.
Methods
From January 2003 to January 2011, 66 consecutive Lebanese patients (29 males and 37 females) younger than 50 years, diagnosed in an academic tertiary-care center with lower extremity deep venous thrombosis by color flow duplex scan, were retrospectively reviewed. Their age varied between 21 and 50 years (mean 38.7 years). The control group included 217 patients (86 males and 131 females) older than 50 years (range: 50–96 years; mean 72.9 years).
Results
The most commonly reported risk factors in the younger age group were inherited thrombophilia (46.9% compared with 13.8% in the control group; P < 0.001), pregnancy (18.2% compared with 0.5%; P < 0.001), treatment with estrogen drugs (13.6% compared with 2.3%; P = 0.001), and family history of venous thromboembolism (9.1% compared with 3.8%; P = 0.084).
Conclusion
Inherited thrombophilia is the most commonly observed risk factor among patients younger than 50 years, with a prevalence of three times more than the control group. Young adults should be screened for thrombophilia even in the presence of transient acquired risk factors. Pregnancy and treatment with estrogen drugs essentially when associated with inherited thrombophilia represent a frequent cause of venous thrombosis among young female patients. Inferior vena cava abnormalities should be excluded in young patients with spontaneous proximal venous thrombosis especially when recurrent venous thrombosis or resistance to anticoagulation are observed.
doi:10.2147/VHRM.S29457
PMCID: PMC3310360  PMID: 22454560
venous thrombosis; lower extremities; young patient; risk factors; genetics
25.  Postpartum deep vein thrombosis and pulmonary embolism in twin pregnancy: undertaking of clinical symptoms leading to massive complications 
Thrombosis Journal  2013;11:4.
Background
Deep Vein Thrombosis (DVT) is an important cause of morbidity and is the first cause of maternal death after delivery in Western Nations. The risk of venous thromboembolism is present throughout the pregnancy and is maximal during postpartum, especially after twin delivery. Many of the signs and symptoms of DVT overlap those of a normal pregnancy causing difficulty for diagnosis.
Case report
We report the case of a 33 year-old woman transferred to our Department one week after caesarean section for twin delivery. She presented with severe abdominal pain, fever, abdominal distension and shortness of breath. She had no personal or family history of thromboembolism. Computerized Tomography Scan revealed right ovarian vein thrombosis, left renal vein thrombosis extending up to the Inferior Vena Cava and pulmonary embolism with bilateral pleural effusion. Caval filter was positioned and anticoagulation therapy associated with antibiotics was instituted. Pancreatitis showed up two days after and was promptly treated. Three months after discharge the caval filter was removed and oral anticoagulation was stopped. During a 12-months follow-up, she remained stable and symptom free.
Results
Ovarian vein thrombosis is rare but recognition of signs and symptoms is fundamental to start adequate therapy and avoid potential serious sequelae. The risk for maternal postpartum ovarian vein thrombosis is increased by caesarean section delivery of twins. Such patients should be closely monitored. We illustrated how an underestimated condition can lead to massive complications.
doi:10.1186/1477-9560-11-4
PMCID: PMC3629711  PMID: 23433174
Twin delivery; Postpartum ovarian vein thrombosis; Pulmonary emboli

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