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1.  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
2.  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
3.  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
4.  Retrograde Blood Flow in the Aortic Arch Determined by Transesophageal Doppler Ultrasound 
Background
Aortic arch atheromas may be important sources of cerebral embolism. Aortic plaques are frequently found somewhat distal to the origin of the cerebral arteries, implying that cerebral embolization from such plaques depends on local retrograde blood flow components in this area. Therefore, we investigated the occurrence of blood flow reversal in this part of the aorta. Furthermore, since the presence and magnitude of retrograde flow might be influenced by aortic wall properties, we also studied the relationship between plaque size and distribution, aortic strain and degree of retrograde flow.
Methods
We evaluated aortic arch ante- and retrograde blood flow velocities in 56 patients by transesophageal echocardiography using color-Doppler-guided pulsed-Doppler techniques. The velocity-time integrals (VTI) were measured and the diastolic/systolic VTI ratio was calculated.
Results
Retrograde diastolic blood flow was noted in all subjects, and diastolic/systolic VTI ratios were higher (p < 0.05) in patients with plaque ≥4 mm (n = 17) compared to those (n = 39) without. Patients exhibiting plaques exclusively in the aortic arch showed the highest VTI ratios (p < 0.01) and tended to have the lowest strain values. Aortic strain was also reduced in patients >50 years of age (p < 0.01).
Conclusions
Our findings demonstrate retrograde aortic flow in all subjects and its proportion increases in subjects with atherosclerosis, particularly in the aortic arch. Aortic plaques situated distally to the origin of the cerebral arteries are therefore possible sources of cerebral emboli.
doi:10.1159/000172630
PMCID: PMC2813812  PMID: 19018134
Secondary prevention; Ischemic stroke; Ultrasonography; Doppler ultrasound
5.  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
6.  Fibrin Architecture in Clots: A Quantitative Polarized Light Microscopy Analysis 
Fibrin plays a vital structural role in thrombus integrity. Thus, the ability to assess fibrin architecture has potential to provide insight into thrombosis and thrombolysis. Fibrin has an anisotropic molecular structure, which enables it to be seen with polarized light. Therefore, we aimed to determine if automated polarized light microscopy methods of quantifying two structural parameters; fibrin fiber bundle orientation and fibrin's optical retardation (OR: a measure of molecular anisotropy) could be used to assess thrombi. To compare fibrin fiber bundle orientation we analyzed picrosirius red-stained sections obtained from clots formed: (A) in vitro, (B) in injured and stenotic coronary arteries, and (C) in surgically created aortic aneurysms (n = 6 for each group). To assess potential changes in OR, we examined fibrin in picrosirius red-stained clots formed after ischemic preconditioning (10 minutes ischemia + 10 minutes reflow; a circumstance shown to enhance lysability) and in control clots (n = 8 each group). The degree of fibrin organization differed significantly according to the location of clot formation; fibrin was most aligned in the aneurysms and least aligned in vitro whereas fibrin in the coronary clots had an intermediate organization. The OR of fibrin in the clots formed after ischemic preconditioning was lower than that in controls (2.9 ± 0.5 nm versus 5.4 ± 1.0 nm, P < 0.05). The automated polarized light analysis methods not only enabled fibrin architecture to be assessed, but also revealed structural differences in clots formed under different circumstances.
doi:10.1016/j.bcmd.2008.10.014
PMCID: PMC2649791  PMID: 19054699
birefringence; blood coagulation; fibrin; polarization microscopy; thrombosis
7.  Mediastinal leiomyosarcoma concurrent with intra-aortic thrombosis 
BMJ Case Reports  2013;2013:bcr2012007527.
We report a case of a large intra-aortic thrombosis in an 83-year-old woman concurrent with metastatic mediastinal leiomyosarcoma. Imaging studies incidentally detected a mediastinal malignant tumour metastasising to bilateral adrenals and an extensive intra-aortic mass that was suspected to be intra-aortic thrombosis. One month later massive embolism developed in the lower limb and her condition deteriorated rapidly resulting in death. Autopsy revealed diffused proliferation of highly pleomorphic atypical cells accompanied by necrosis in the mediastinum tumours and bilateral adrenal glands. Leiomyosarcoma metastasising to bilateral adrenals was confirmed by the results of immunostaining. The intra-aortic mass suggested that the fragmented thrombus might be the cause of a sudden lower-limb embolism. Microscopic examination showed that the mass lesion in the aortic arch was composed of a blood clot containing neutrophils. We report this case because leiomyosarcoma arising from the mediastinum and, especially, associated with an extraordinarily large intra-aortic thrombosis is very rare.
doi:10.1136/bcr-2012-007527
PMCID: PMC3603919  PMID: 23429014
8.  Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery 
Critical Care  2014;18(5):549.
Introduction
Thromboembolic complications contribute substantially to perioperative morbidity and mortality. Routine laboratory tests do not detect patients with acquired or congenital hypercoagulability who may be at increased risk of perioperative thromboembolism. Rotational thromboelastometry (ROTEM) is a digitized modification of conventional thromboelastography that is stable and technically easy to use. We designed a prospective observational study to evaluate whether preoperative ROTEM can identify patients at increased risk for postoperative thromboembolic complications after major non-cardiac surgery.
Methods
Preoperative ROTEM analysis using extrinsic rotational thromboelastometry (EXTEM), intrinsic rotational thromboelastometry (INTEM), and fibrinogen rotational thromboelastometry (FIBTEM) activators was performed on 313 patients undergoing major non-cardiac surgery. Patients’ medical records were reviewed after discharge for results of standard coagulation studies - partial thromboplastin time (PTT), international normalized ratio (INR), platelet count - and evidence of thromboembolic complications during their hospital stay. A thromboembolic complication was defined as a new arterial or deep venous thrombosis, catheter thrombosis, or pulmonary embolism diagnosed by ultrasound or spiral chest computed tomography.
Results
Ten patients developed postoperative thromboembolic complications, of whom 9 had received standard prophylaxis with subcutaneous enoxaparin or heparin. There was no indication of by PTT, INR, or platelet count. Preoperative EXTEM and INTEM activators that assess fibrin clot formation and platelet interaction indicated that these patients had significantly lower clot formation time (CFT) and significantly higher alpha angle (α) and maximum clot firmness (MCF), compared to patients without thromboembolic complications. There was no significant difference for any parameter using FIBTEM activator, which excludes platelet interaction. Receiver operating characteristic (ROC) curves were constructed for these variables. INTEM clot firmness at 10 min (A10) was the best predictor of thromboembolic complications, with an ROC area under the curve of 0.751.
Conclusions
Our results indicate that preoperative ROTEM assays that include fibrin clot and platelet interaction may detect patients at increased risk for postoperative thromboembolic complications after major non-cardiac surgery. Future studies need to evaluate the clinical utility and cost effectiveness of preoperative ROTEM and better define the association between ROTEM values and specific hypercoagulable conditions.
doi:10.1186/s13054-014-0549-2
PMCID: PMC4200117  PMID: 25292221
9.  Atherosclerotic Aortic Arch Plaques in Acute Ischemic Stroke 
Background:
Atherosclerotic aortic arch plaques (AAP) have been linked to an increased risk of thrombo-embolic events as a cause of acute ischemic stroke of undetermined etiology.
Objectives:
To find out the presence of atherosclerotic plaques in aortic arch and their potential role as a source of embolism in cerebral infarction of undetermined etiology.
Methods:
We performed trans-esophageal echocardiography (TEE) and multislice computerized tomography (MSCT) of the aortic arch on 30 patients with acute ischemic stroke of undetermined cause from a total series of 150 non-selected patients with acute ischemic stroke studied prospectively by clinical evaluation, laboratory investigations, cranial computed tomography, color coded duplex ultrasonography of the carotid arteries and transcranial Doppler (TCD).
Results:
Using trans-esophageal echocardiography eight patients (29.6%) had atherosclerotic aortic arch plaques, while using multislice computerized tomography atherosclerotic aortic arch plaques were revealed in twelve patients (40%). Atherosclerotic aortic arch plaques were significantly related to older age, male gender, hypertension, ischemic heart disease and low-grade atherosclerotic carotid lesions. Multislice computerized tomography of the aortic arch was more sensitive than trans-esophageal echocardiography in detecting the site, size and characters of atherosclerotic aortic arch plaques.
Conclusion:
Atherosclerotic aortic arch plaques are a frequent finding in patients with acute ischemic stroke of undetermined cause supporting the hypothesis that aortic plaques have embolic potential. In addition, multislice computerized tomography is more sensitive than trans-esophageal echocardiography in detecting atherosclerotic aortic arch plaques and better characterization of these plaques especially relevant one.
PMCID: PMC3317276  PMID: 22518260
Aorta; Atherosclerotic plaques; Echocardiography; Multislice Computerized Tomography; Stroke
10.  Concealed primary aortic sarcoma induced hypertensive encephalopathy resulting from a thoracic aortic occlusion: a case report 
Primary aortic sarcoma is a rare condition that is frequently associated with distal embolization. In addition, growth characteristics of primary aortic sarcoma lead to the narrowing of the involved aortic lumen. A 72-year-old Korean male with primary aortic sarcoma showed progressive unexplained blood pressure elevation that didn’t improve with additional antihypertensive drug therapy. Because follow-up measures were not taken, the patient ultimately developed hypertensive encephalopathy with concurrent embolic dissemination. Although we successfully performed open transcatheter embolectomy in both legs, the patient died because of multiple organ failure 3 days after surgery. Given the ominous prognosis for this condition, this case report highlights the fact that the value of early detection and prompt evaluation of altered vital signs should not be overemphasized. We describe a rare case of primary aortic sarcoma that showed hypertensive encephalopathy caused by thoracic aortic occlusion and also had embolic metastases to the lower extremities.
doi:10.1186/1749-8090-8-102
PMCID: PMC3658867  PMID: 23597173
Aorta; Sarcoma; Hypertensive encephalopathy
11.  Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease 
Altered fibrin clot structure has been reported both in patients with coronary artery disease (CAD) and those with type 2 diabetes mellitus (DM2). The aim of the present study was to evaluate plasma fibrin clot permeability and susceptibility to lysis in patients with DM2 and CAD. We studied 132 consecutive CAD patients, including 67 subjects with DM2, scheduled for elective coronary artery bypass grafting surgery. Ex vivo plasma fibrin clot permeability (Ks) and lysis time (t50%) induced by 1 μg/mL recombinant tissue plasminogen activator (tPA), along with plasma levels of plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tPA, von Willebrand factor (vWF), P-selectin, soluble CD40 ligand (sCD40L), were measured. Diabetic and non-diabetic patients did not differ in regard to demographics and remaining cardiovascular risk factors. Concomitant DM2 was associated with higher glucose (+24.3 %, p < 0.001), fibrinogen (+9.0 %, p = 0.037), PAI-1 (+58.7 %, p < 0.001), tPA (+24.0 %, p < 0.001) and P-selectin (+12.2 %, p < 0.001). Compared with the non-diabetic group, the CAD patients with DM2 had lower Ks (-6.1 %, p = 0.02) and prolonged t50% (+5.1 %, p = 0.04). Multiple regression analysis of the whole study group showed that vWF, PAI-1, fibrinogen and DM2 were the independent predictors of t50% (R2 = 0.58, p < 0.001), while only vWF was an independent predictor of Ks (R2 = 0.22, p < 0.001). This study indicates that DM2 is potent enough to unfavorably affect plasma fibrin clot characteristics despite abnormal clot phenotype typically observed in CAD. Of note, platelet and endothelial markers appear to contribute to fibrin clot properties in CAD concomitant with DM2.
doi:10.1007/s11239-012-0821-8
PMCID: PMC3549239  PMID: 23086579
Coronary artery disease; Diabetes mellitus; Fibrin clot; Fibrinolysis; Platelet activation
12.  Fibrin Derived from Patients with Chronic Thromboembolic Pulmonary Hypertension Is Resistant to Lysis 
Rationale: Although acute pulmonary embolism is epidemiologically associated with chronic thromboembolic pulmonary hypertension, the factors responsible for resistance to thrombolysis and a shift toward vascular remodeling within the pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension are unknown.
Objective: Determine whether fibrin from patients is more resistant to plasmin-mediated lysis than fibrin from healthy control subjects.
Methods: Fibrinogen purified from patients and control subjects was used to prepare fibrin clots, which were subsequently digested with plasmin for various periods of time. The degradation of the α-, β-, and γ-chains of fibrin and the appearance of peptide fragments over time were assessed by polyacrylamide gel electrophoresis and Western blotting.
Measurements and Main Results: Densitometry of Coomassie-stained gels revealed significantly slower cleavage of all three polypeptide chains of fibrin from patients compared with control subjects (p < 0.05). In particular, release of N-terminal fragments from the β-chain of fibrin, which promote cell signaling, cell migration, and angiogenesis, was retarded in patients compared with control subjects (p < 0.01).
Conclusions: The relative resistance of patient fibrin to plasmin-mediated lysis may be due to alterations in fibrin(ogen) structure affecting accessibility to plasmin cleavage sites. The persistence of structural motifs of fibrin, such as the β-chain N-terminus, within the pulmonary vasculature could promote the transition from acute thromboemboli into chronic obstructive vascular scars.
doi:10.1164/rccm.200506-916OC
PMCID: PMC2662971  PMID: 16514114
blood coagulation factors; fibrinolysis; pulmonary embolism; thrombosis; vascular diseases
13.  THE FIBRINOLYTIC ACTIVITY OF HEMOLYTIC STREPTOCOCCI 
Broth cultures of hemolytic streptococci derived from patients are capable of rapidly liquefying normal human fibrin clot. The active fibrinolytic principle is also contained in sterile, cell-free filtrates of broth cultures. The degree of activity of filtrates parallels the activity of whole broth cultures sufficiently closely to indicate that large amounts of the fibrinolytic substance are freely excreted into the surrounding medium and pass readily through Berkefeld V, Seitz, and Chamberland filters. The occurrence of fibrinolysis is most strikingly observed when plasma or fibrinogen is mixed with active cultural material before clot formation is effected. Under the standard experimental conditions described, complete dissolution of human plasma clot (whole oxalated plasma + CaCl2) occurs in about 10 minutes; complete dissolution of human fibrinogen clot (chemically isolated fibrinogen + thrombin) takes place in about 2 minutes. Titration of filtrate activity is recorded in Table IV. Twenty-eight strains of Streptococcus hemolyticus, isolated from patients suffering from various manifestations of streptococcus infection, have been tested for the capacity to liquefy fibrin clot. Broth cultures of all of the strains induced fibrinolysis. Of 18 strains of Streptococcus hemolyticus of animal origin, only three were capable of causing dissolution of clot. Completely negative results were obtained with 38 strains of other bacterial species. The list is presented on pages 492 and 493. The plasma of many patients recovered from acute hemolytic streptococcus infections, when clotted in the presence of active cultures, is highly resistant to fibrinolysis. Furthermore, serum, derived from patients whose plasma clot is resistant, often confers on normal plasma clot an antifibrinolytic property. One example of the resistance possessed by the blood of convalescent patients is presented in this report. A second paper, now in preparation, will give in detail a large number of observations on the relation of infection to the development of resistance to the fibrinolytic activity of hemolytic streptococci. In contrast to the susceptibility of normal human fibrin clot to liquefaction by active culture, normal rabbit fibrin clot is totally resistant to dissolution when tested under comparable conditions. The insusceptibility of rabbit fibrin clot is manifest provided the coagulum is composed of rabbit constituents. When human thrombin is used to clot rabbit plasma or fibrinogen in the presence of active cultures, fibrinolysis is not prohibited. The rôle of thrombin in determining the resistance or susceptibility of rabbit fibrin to dissolution offers a suggestive approach to problems relating to the underiving mechanism.
PMCID: PMC2132310  PMID: 19870210
14.  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
15.  A Case of Huge Thrombus in the Aortic Arch with Cerebrovascular Embolization 
Pedunculated thrombus in the aortic arch that is associated with cerebral infarction is very rare requires prompt diagnosis and treatment to prevent occurrence of another devastating complication. Transesophageal echocardiography is useful for detecting source of embolism including aortic thrombi. The treatment options of aortic thrombi involves anticoagulation, thrombolysis, thromboaspiration, and thrombectomy. Here we report a case of huge thrombus in the aortic arch, resulting in acute multifocal cerebellar embolic infarct in patient without any risk factors for vascular thrombosis. Thrombi in the aortic arch were diagnosed by transesophageal echocardiography and treated with anticoagulants successfully.
doi:10.4250/jcu.2009.17.4.148
PMCID: PMC2889393  PMID: 20661342
Aortic thrombus; Echocardiography
16.  A novel missense mutation in the FGB g. 3354 T>A (p. Y41N), Fibrinogen Caracas VIII 
Thrombosis and Haemostasis  2011;105(4):627-634.
Summary
A novel dysfibrinogenemia with a replacement of Tyr by Asn at Bβ41 has been discovered (fibrinogen Caracas VIII). An asymptomatic 39 year-old male was diagnosed as having dysfibrinogenemia due to a mildly prolonged thrombin time (+ 5.8 sec); his fibrinogen concentration was in the low normal range, both by Clauss and gravimetric determination, 1.9 g/l and 2.1 g/l, respectively. The plasma polymerization process was slightly impaired, characterized by a mildly prolonged lag time and a slightly increased final turbidity. Permeation through the patients’ clots was dramatically increased, with the Darcy constant around 4 times greater than that of the control (22 ± 2 ×10−9 cm2 compared to 6 ± 0.5 ×10−9 cm2 in controls). The plasma fibrin structure of the patient, by scanning electron microscopy, featured a mesh composed of thick fibers (148 ± 50 nm vs. 120 ± 31 nm in controls, p<0.05) and larger pores than those of the control fibrin clot. The viscoelastic properties of the clot from the patient were also altered, as the storage modulus (G′, 310 ± 30) was much lower than in the control (831 ± 111) (p ≤ 0.005). The interaction of the fibrin clot with a monolayer of human microvascular endothelial cells, by confocal laser microscopy, revealed that the patients’ fibrin network had less interaction with the cells. These results demonstrate the significance of the amino terminal end of the β chain of fibrin in the polymerization process and its consequences on the clot organization on the surface of endothelial cells.
doi:10.1160/TH10-03-0179
PMCID: PMC3337776  PMID: 21301788
mutation; abnormal fibrinogen; clots; permeation; viscoelastic properties; scanning electron microscopy; confocal microscopy
17.  Aortic arch reconstruction in newborns with an autologous pericardial patch: contemporary results 
OBJECTIVES
The incidence of recurrent aortic arch obstruction after Norwood procedure and other types of aortic arch reconstruction in newborns remains high. Biological and synthetic materials are used to enlarge the aorta. We report our experience using autologous pericardium to reconstruct the aortic arch in patients with hypoplastic left heart syndrome, aortic arch interruption and hypoplastic aortic arch.
METHODS
A retrospective analysis of 39 consecutively operated patients evaluated after an initial Norwood and other types aortic arch repair was performed. The presence of recurrent arch obstruction (mean gradient ≥20 mmHg) and its management were noted. The mean weight of our patients was 3.2 ± 0.7 kg.
RESULTS
The mean age at primary surgical correction was 7.4 ± 6.8 (range 1–35 days). All patients were discharged without a significant residual gradient at the aortic arch except 4 who had a peak gradient of ≥30 mmHg. The overall incidence of recurrent arch obstruction was 28.2% (11 patients). Four (12.1%) patients had a distal obstruction, 1 (3%) had proximal obstruction and 1 had a mid-transverse arch obstruction. All patients underwent aortic arch reintervention consisting of balloon dilatation, and only after unsuccessful dilatation, 3 underwent surgical patch aortoplasties.
CONCLUSIONS
The use of autologous pericardium in aortic arch reconstruction procedure is effective and associated with an acceptable incidence of recurrent arch obstruction. Its availability and characteristics make it an attractive alternative to other materials.
doi:10.1093/icvts/ivs510
PMCID: PMC3568820  PMID: 23223671
Congenital heart disease; Aortic arch plasty; Autologous pericardium; Hypoplastic left heart syndrome; Aortic interruption; Hypoplastic aortic arch
18.  Stroke Propensity Is Increased under Atrial Fibrillation Hemodynamics: A Simulation Study 
PLoS ONE  2013;8(9):e73485.
Atrial fibrillation (AF) is the most common sustained dysfunction in heart rhythm clinically and has been identified as an independent risk factor for stroke through formation and embolization of thrombi. AF is associated with reduced cardiac output and short and irregular cardiac cycle length. Although the effect of AF on cardiac hemodynamic parameters has been reported, it remains unclear how the hemodynamic perturbations affect the potential embolization of blood clots to the brain that can cause stroke. To understand stroke propensity in AF, we performed computer simulations to describe trajectories of blood clots subject to the aortic flow conditions that represent normal heart rhythm and AF. Quantitative assessment of stroke propensity by blood clot embolism was carried out for a range of clot properties (e.g., 2–6 mm in diameter and 0–0.8 m/s ejection speed) under normal and AF flow conditions. The simulations demonstrate that the trajectory of clot is significantly affected by clot properties as well as hemodynamic waveforms which lead to significant variations in stroke propensity. The predicted maximum difference in stroke propensity in the left common carotid artery was shown to be about 60% between the normal and AF flow conditions examined. The results suggest that the reduced cardiac output and cycle length induced by AF can significantly increase the incidence of carotid embolism. The present simulations motivate further studies on patient-specific risk assessment of stroke in AF.
doi:10.1371/journal.pone.0073485
PMCID: PMC3764003  PMID: 24039957
19.  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
20.  Enhancement of blood coagulation by soluble fibrin complexes 
We have detected a species of soluble fibrin complexes with significant biological properties. Agarose gel chromatography of normal plasma or purified fibrinogen previously incubated with small amounts of thrombin revealed the presence of a species of high molecular weight soluble fibrin complexes, which contained only small quantities of fibrinogen by immunological assays but which exhibited enhanced sensitivity to thrombin. In addition, these complexes substantially shortened the thrombin-clotting time of normal plasma and enhanced the resistance of normal plasma to heparin action. Similar thrombin-sensitive soluble fibrin complexes were demonstrated in vivo in rabbits for up to 10 min after the infusion of 50 U of thrombin. Thrombin-sensitive soluble fibrin complexes were also demonstrated in 3 of 12 patients with documented thromboembolic disease and in 2 of 20 patients after major surgery. High molecular weight soluble fibrin complexes, which exhibit enhanced thrombin sensitivity and which are capable of increasing the rate of normal fibrinogen-to-fibrin conversion by thrombin, may appear consequent to clinical thrombosis and situations involving trauma (e.g., major surgery). Such soluble complexes, although they have no proven role in the primary pathogenesis of intravascular thrombosis, may contribute to a temporary "hypercoagulable state" and may accelerate the build-up and extension of already existing thrombotic deposits.
PMCID: PMC2189796  PMID: 805207
21.  Pulmonary mucormycosis with embolism: two autopsied cases of acute myeloid leukemia 
Mucormycosis is an increasingly important cause of morbidity and mortality for patients with hematological malignancies. The diagnosis of mucormycosis usually requires mycological evidence through tissue biopsy or autopsy because the signs and symptoms are nonspecific and there are currently no biomarkers to identify the disease. We herein present two autopsied cases of acute myeloid leukemia with prolonged neutropenia who developed invasive mucormycosis accompanied by pulmonary artery embolism. Our cases were featured by unexplained fever and rapidly progressive dyspnea. Computed tomography scan detected nodular lesions or nonspecific consolidations in the lungs. Cultures, cytological study, and serum fungal markers consistently gave negative results. Autopsy revealed embolism of the pulmonary artery which consisted of fibrin clots by filamentous fungi. Genomic DNA was extracted from the paraffin-embedded clots and was applied to polymerase chain reaction amplification, leading to the diagnosis of infection by Rhizopus microsporus. We should carefully search for life-threatening pulmonary embolism when patients with hematological malignancies develop pulmonary mucormycosis.
PMCID: PMC4097268  PMID: 25031775
Rhizopus microsporus; mucormycosis; pulmonary embolism; acute myeloid leukemia; neutropenia
22.  C-reactive protein and fibrin clot strength measured by thrombelastography after coronary stenting 
Inflammation is implicated in the progression of coronary artery disease and the molecular processes of inflammation and thrombosis are closely intertwined. Elevated levels of C-reactive protein (CRP) have been associated with an elevated risk of adverse ischaemic events after coronary stenting and hypercoagulability. Heightened whole blood clot strength measured by thrombelastography (TEG) has been associated with adverse ischaemic events after stenting. We intended to examine the relationship of CRP to plasma fibrin clot strength in patients after coronary stenting. Plasma fibrin clot strength was measured by TEG in 54 patients 16–24 h after undergoing elective percutaneous coronary intervention (PCI). Coagulation was induced in citrated plasma by addition of kaolin and CaCl2. Plasma levels of CRP and fibrinogen were measured by enzyme-linked immunoassay. Increasing quartiles of CRP were associated with increasing levels of maximal plasma fibrin clot strength measured by TEG (P < 0.001) and increasing BMI (P =0.04). Patients in the highest quartile of CRP had significantly higher maximal fibrin clot strength (G) than the patients in the lowest quartile (G: 3438 ± 623 vs. 2184 ± 576 dyn/cm2, P < 0.0001). Fibrinogen concentration was not significantly different across quartiles of CRP (P =0.97). Patients with established coronary artery disease undergoing coronary stenting who have elevated CRP after PCI exhibit heightened maximal plasma fibrin clot strength as compared with those with low CRP. Thrombotic risk associated with elevated CRP may be linked to procoagulant changes and high tensile fibrin clot strength independent of fibrinogen concentration.
doi:10.1097/MBC.0b013e32835cc193
PMCID: PMC4028117  PMID: 23429252
clot strength; coronary artery disease; C-reactive protein; fibrin; thrombelastography
23.  In Vivo Fluorescence Imaging of Large-Vessel Thrombosis in Mice 
Objectives
Experimental studies of large-vessel thrombosis have been adapted for applications in mice, but proffer limited quantifiable information in outcome measures. This study presents a novel approach for evaluating large-vessel thrombogenesis with temporally/spatially quantifiable measures and normalization methods for inter-animal comparisons.
Methods and Results
Shuttered, beam-expanded lasers provided uniform narrow-wavelength illumination of a 100× microsurgical field with large depth of focus. Thrombosis was generated in murine carotid arteries and femoral veins by brief vascular surface electrolytic injury. Thrombus-targeting fluorophores were injected systemically and subsequently localized at the site of thrombus induction. A low-light digital video camera with filter wheel provided target-specific image acquisition over a 60-minute interval. Platelets accumulated with a subsequent fibrin border emerging to stabilize the clot in both arteries and veins. Coagulation enzyme complexes colocalized with fibrin deposition. Large arteries underwent cyclic massive thrombo-embolization, whereas veins showed gradual shedding of microemboli and clot contraction. Systemic administration of fibrin- and platelet-inhibiting compounds reduced their respective targets, but also often inhibited their clotting counterparts (platelets and fibrin, respectively) in both arteries and veins.
Conclusions
Intermediate-level magnified image capture represents a novel approach for analysis of fluorescence-based in vivo imaging, with quantitative application to the study of large-vessel thrombosis.
doi:10.1161/ATVBAHA.111.225334
PMCID: PMC3098306  PMID: 21393581
thrombosis; artery; vein; platelets; fibrin
24.  Cellular procoagulant activity dictates clot structure and stability as a function of distance from the cell surface 
Background
Thrombin concentration modulates fibrin structure and fibrin structure modulates clot stability; however, the impact of localized, cell surface-driven in situ thrombin generation on fibrin structure and stability has not previously been evaluated.
Methods
Human fibroblasts were incubated with factors Xa, Va, prothrombin and fibrinogen, or plasma. Fibrin formation, structure, and lysis were examined using laser scanning confocal microscopy and transmission electron microscopy.
Results:
in situ thrombin generation on the cell surface produced clots with a significantly denser fiber network in a 10-μm region proximal versus distal to (40 – 50 μm) the cell surface. This morphology was not altered by addition of integrin-blocking RGDS peptide and was not apparent in clots made by exogenous thrombin addition, suggesting that spatial morphology was dictated predominantly by localized thrombin generation on the fibroblast surface. The fibrin network lysed more rapidly distal versus proximal to the cell surface, suggesting that the clot’s structural heterogeneity affected its fibrinolytic stability.
Conclusions:
in situ thrombin generation on the cell surface modulates the three-dimensional structure and stability of the clot. Thrombus formation in vivo may reflect the ability of the local cell population to support thrombin generation and therefore, the three-dimensional structure and stability of the fibrin network.
doi:10.1161/ATVBAHA.108.176008
PMCID: PMC2773697  PMID: 18974382
coagulation; fibrin clot structure; thrombin generation; fibrinolysis
25.  Best surgical option for arch extension of type B aortic dissection: the open approach 
Annals of Cardiothoracic Surgery  2014;3(4):406-412.
Arch extension of aortic dissection (AD) is reported to occur in 4-25% of patients presenting with acute type B AD. The DeBakey and Stanford classifications do not specifically account for this subset, however, recent studies have demonstrated that the prognosis of patients with arch extension in acute type B AD is virtually identical to that of others with type B AD. In this sense, it seems reasonable to extend the general management principles that are applied to classic acute type B AD even to patients with arch extension. This may be because even in patients with arch extension, most complications occur at locations distal to the arch, and therefore treatment of these patients is similar to that of complicated type B AD, namely thoracic endovascular aortic repair (TEVAR). Conversely, 10% of patients with acute type B AD and arch extension develop complications that are directly related to the arch pathology. This clinical scenario generally necessitates surgical arch repair through a sternotomy approach. The frozen elephant trunk technique combined with arch repair is a very reasonable option to treat this unique clinical entity that involves relatively distal locations of the aortic diseases. Combined arch and descending aorta replacement through thoracotomy is an alternative option particularly when the anatomical features of the target lesions are not suitable for a sternotomy approach or TEVAR. Nonetheless, the reported mortality associated with this approach has been exceedingly high. Hybrid arch repair is another consideration in treating these patients to reduce the treatment-related mortality and morbidity, especially when the arch pathology is limited to the distal part. Nevertheless, the safety and efficacy of this procedure in cases with more extensive arch involvement needs to be assessed in further studies in comparison with other treatment modalities.
doi:10.3978/j.issn.2225-319X.2014.06.02
PMCID: PMC4128934  PMID: 25133105
Type B aortic dissection (AD); surgery; aortic arch; endovascular stent grafting

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