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1.  Implementing Thrombosis Guidelines in Cancer Patients: A Review 
Venous thromboembolism is a frequent and serious complication in patients with cancer. It is an independent prognostic factor of death in cancer patients and the second leading cause of death, but physicians often underestimate its importance, as well as the need for adequate prevention and treatment. Management of venous thromboembolism in patients with cancer requires the coordinated efforts of a wide range of clinicians, highlighting the importance of a multidisciplinary approach. However, a lack of consensus among various national and international clinical practice guidelines has contributed to knowledge and practice gaps among practitioners, and inconsistent approaches to venous thromboembolism. The 2013 international guidelines for thrombosis in cancer have sought to address these gaps by critically re-evaluating the evidence coming from clinical trials and synthesizing a number of guidelines documents. An individualized approach to prophylaxis is recommended for all patients.
doi:10.5041/RMMJ.10175
PMCID: PMC4222430  PMID: 25386357
Anticoagulants; cancer; guidelines; thrombosis; venous thromboembolism
2.  Improving stroke prevention in patients with atrial fibrillation 
Trials  2013;14:193.
Background
Patients with atrial fibrillation (AF) are at increased risk for stroke. Antithrombotic treatment reduces this risk. Antithrombotic treatment consists of either administration of oral anticoagulants (OAC) or the provision of an antiplatelet drug. International guidelines provide advice on the preferred treatment, thereby balancing the risks and benefits of OAC. However, adherence to these guidelines is reported to be as low as 50%. There is paucity in research on why adherence rates are low. Recent studies have shown decision support systems can improve guideline adherence. We investigate the use of a clinical decision support system to improve guideline adherence among general practitioners (GPs) treating patients with AF and study reasons for guideline non-adherence.
Methods/Design
The study is a randomized controlled trial, which is performed among Dutch general practitioners. Initially, GPs in the vicinity of the Academic Medical Center (AMC) in Amsterdam will be included, after which other practices will be recruited. We have developed a novel decision support system that displays a list with pending messages for the on-screen medical record in real time. Messages are generated on a server that evaluates a decision rule based on the atrial fibrillation guideline of the Dutch College of General Practitioners. By interacting with the list, messages can be opened for a description and explanation, or be ignored. GPs are allocated into three groups: 1) control group; 2) intervention group A, in which messages can be ignored without justification; and 3) intervention group B, in which messages can only be ignored with justification.
Our main outcome measure is the between-group difference in the proportion of patients receiving antithrombotic prescriptions in adherence to the Dutch GP guideline for atrial fibrillation. Secondary outcomes are reasons GPs state for deviating from the guideline and the effect on guideline adherence of requiring justification when ignoring a message.
Discussion
This paper describes the protocol for a cluster randomized trial to study the effects of a clinical decision support system in patients with atrial fibrillation. The system is characterized by a non-interruptive presentation and real-time messages that are updated after each relevant action the GP performs.
Trial registration
This trial is registered with the Dutch Trial Register under registration number 3570.
doi:10.1186/1745-6215-14-193
PMCID: PMC3703259  PMID: 23815891
Atrial fibrillation; Decision support; Stroke prevention; Anti-thrombotic treatment; Clinical decision support system; General practice
3.  Benchmark for Time in Therapeutic Range in Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS ONE  2012;7(9):e42269.
Introduction
The percentage of time within the target INR range 2.0 to 3.0 (TTR) in patients treated with vitamin K antagonists varies considerably among efficacy-studies of novel anticoagulants. In order to properly asses the quality of anticoagulant control in upcoming cost-effectiveness studies and real life registries this systematic review reports a benchmark of TTR for different treatment durations in patients with venous thromboembolism and discusses ways to calculate TTR.
Methods
Medline and Embase were searched for studies published between January 1990 and May 2012. Randomized controlled trials and cohort studies reporting the TTR in patients with objectively confirmed venous thromboembolism treated with vitamin K antagonists (VKA) were eligible. Duplicate reports, studies only reporting INR during initial treatment or with VKA treatment less than 3 months were excluded. Three authors assessed trials for inclusion and extracted data independently. Discrepancies were resolved by discussion between the reviewers. A meta-analysis was performed by calculating a weighted mean, based on the number of participants in each included study, for each time-period in which the TTR was measured since the confirmation of the diagnosis of VTE.
Results
Forty studies were included (26064 patients). The weighted means of TTR were 54.0% in the first month since the start of treatment, 55.6% in months 1 to 3, 60.0% in months 2 to 3, 60.0% in the months1 to 6+ and 75.2% in months 4 to 12+. Five studies reported TTR in classes. The INR in these studies was ≥67% of time in therapeutic range in 72.0% of the patients.
Conclusion
Reported quality of VKA treatment is highly dependent on the time-period since the start of treatment, with TTR ranging from approximately 56% in studies including the 1st month to 75% in studies excluding the first 3 months.
doi:10.1371/journal.pone.0042269
PMCID: PMC3458058  PMID: 23049730
4.  Applicability of the ankle-brachial-index measurement as screening device for high cardiovascular risk: an observational study 
Background
Screening with ankle-brachial index (ABI) measurement could be clinically relevant to avoid cardiovascular events in subjects with asymptomatic atherosclerosis. To assess the practical impact of guidelines regarding the use of ABI as a screening tool in general practice, the corresponding number needed to screen, including the required time investment, and the feasibility of ABI performance, was assessed.
Methods
An observational study was performed in the setting of 955 general practices in the Netherlands. Overall, 13,038 subjects of ≥55 years presenting with symptoms of intermittent claudication and/or presenting with ≥ one vascular risk factor were included. Several guidelines recommend the ABI as an additional measurement in selected populations for risk assessment for cardiovascular morbidity.
Results
Screening of the overall population of ≥50 years results in ≈862 subjects per general practice who should be screened, resulting in a time-requirement of approximately 6 weeks of full time work. Using an existing clinical prediction model, 247 patients per general practice should be screened for PAD by ABI measurement.
Conclusion
Screening the entire population of ≥50 years will in our opinion not be feasible in general practice. A more rationale and efficient approach might be screening of subsets of the population of ≥55 years based on a clinical prediction model.
doi:10.1186/1471-2261-12-59
PMCID: PMC3444328  PMID: 22846150
5.  Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular-weight heparin: results of a retrospective cohort study 
BMJ Open  2011;1(2):e000257.
Background
Low-molecular-weight heparin (LMWH) is the drug of choice to prevent venous thrombosis in pregnancy, but the optimal dose for prevention while avoiding bleeding is unclear. This study investigated whether therapeutic doses of LMWH increase the incidence of postpartum haemorrhage (PPH) in a retrospective controlled cohort.
Methods
All pregnant women who received therapeutic doses of LMWH between 1995 and 2008 were identified in the Academic Medical Center, Amsterdam, The Netherlands. The controls were women registered for antenatal care in the same hospital who did not use LMWH during pregnancy, matched by random electronic selection for age, parity and delivery date to LMWH users. The incidence of PPH (blood loss >500 ml), severe PPH (blood loss >1000 ml) and median blood loss were compared in two cohorts of LMWH users and non-users.
Results
The incidence of PPH was 18% in LMWH users (N=95) and 22% in non-users (N=524) (RR 0.8; 95% CI 0.5 to 1.4). The incidence of severe PPH was 6% in both groups (RR 1.2; 0.5 to 2.9). The median amount of blood loss differed only in normal vaginal deliveries. It was 200 ml in LMWH users and 300 ml in non-users (difference −100 ml; 95% CI −156 to −44).
Conclusion
Therapeutic doses of LMWH in pregnancy were observed not to be associated with a clinically meaningful increase in the incidence of PPH or severe PPH in women delivered in this hospital, although this observation may be confounded by the differential use of strategies to prevent bleeding. A randomised controlled trial is necessary to provide a definite answer about the optimal dose of LMWH in pregnancy.
Article summary
Article focus
To compare the incidence of PPH (ie, blood loss >500 ml in the first 24 h of delivery) in two cohorts of pregnant women who were treated with therapeutic doses of LMWH and those who were not.
To compare the incidence of severe PPH (blood loss >1000 ml) in two cohorts of pregnant women who were treated with therapeutic doses of LMWH and those who were not.
To compare the median blood loss in two cohorts of pregnant women who were treated with therapeutic doses of LMWH and those who were not.
Key message
Therapeutic doses of LMWH in pregnancy were not associated with a clinically meaningful increase in the incidence of PPH (RR 0.8; 95% CI 0.5 to 1.4) or severe PPH (RR 1.2; 0.5 to 2.9) in women delivered in our hospital.
The median amount of blood loss differed only in normal vaginal deliveries. It was lower in LMWH users (200 ml) than in non-users (300 ml) (difference −100 ml; 95% CI −156 to −44).
Strength and limitation of this study
This is the largest cohort of pregnancies treated with high doses of LMWH.
Although this was a controlled cohort study, it is likely that strategies to decrease the risk of PPH differed between women who were treated with LMWH and controls.
doi:10.1136/bmjopen-2011-000257
PMCID: PMC3221289  PMID: 22102641
6.  Excluding pulmonary embolism in primary care using the Wells-rule in combination with a point-of care D-dimer test: a scenario analysis 
BMC Family Practice  2010;11:64.
Background
In secondary care the Wells clinical decision rule (CDR) combined with a quantitative D-dimer test can exclude pulmonary embolism (PE) safely. The introduction of point-of-care (POC) D-dimer tests facilitates a similar diagnostic strategy in primary care.
We estimated failure-rate and efficiency of a diagnostic strategy using the Wells-CDR combined with a POC-D-dimer test for excluding PE in primary care.
We considered ruling out PE safe if the failure rate was <2% with a maximum upper confidence limit of 2.7%.
Methods
We performed a scenario-analysis on data of 2701 outpatients suspected of PE. We used test characteristics of two qualitative POC-D-dimer tests, as derived from a meta-analysis and combined these with the Wells-CDR-score.
Results
In scenario 1 (SimpliRed-D-dimer sensitivity 85%, specificity 74%) PE was excluded safely in 23.8% of patients but only by lowering the cut-off value of the Wells rule to <2. (failure rate: 1.4%, 95% CI 0.6-2.6%)
In scenario 2 (Simplify-D-dimer sensitivity 87%, specificity 62%) PE was excluded safely in 12.4% of patients provided that the Wells-cut-off value was set at 0. (failure rate: 0.9%, 95% CI 0.2-2.6%)
Conclusion
Theoretically a diagnostic strategy using the Wells-CDR combined with a qualitative POC-D-dimer test can be used safely to exclude PE in primary care albeit with only moderate efficiency.
doi:10.1186/1471-2296-11-64
PMCID: PMC2944151  PMID: 20831834
7.  Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts 
Objectives In older patients, the the D-dimer test for pulmonary embolism has reduced specificity and is therefore less useful. In this study a new, age dependent cut-off value for the test was devised and its usefulness with older patients assessed.
Design Retrospective multicentre cohort study.
Setting General and teaching hospitals in Belgium, France, the Netherlands, and Switzerland.
Patients 5132 consecutive patients with clinically suspected pulmonary embolism.
Intervention Development of a new D-dimer cut-off point in patients aged >50 years in a derivation set (data from two multicentre cohort studies), based on receiver operating characteristics (ROC) curves. This cut-off value was then validated with two independent validation datasets.
Main outcome measures The proportion of patients in the validation cohorts with a negative D-dimer test, the proportion in whom pulmonary embolism could be excluded, and the false negative rates.
Results The new D-dimer cut-off value was defined as (patient’s age×10) μg/l in patients aged >50. In 1331 patients in the derivation set with an “unlikely” score from clinical probability assessment, pulmonary embolism could be excluded in 42% with the new cut-off value versus 36% with the old cut-off value (<500 μg/l). In the two validation sets, the increase in the proportion of patients with a D-dimer below the new cut-off value compared with the old value was 5% and 6%. This absolute increase was largest among patients aged >70 years, ranging from 13% to 16% in the three datasets. The failure rates (all ages) were 0.2% (95% CI 0% to 1.0%) in the derivation set and 0.6% (0.3% to 1.3%) and 0.3% (0.1% to 1.1%) in the two validation sets.
Conclusions The age adjusted D-dimer cut-off point, combined with clinical probability, greatly increased the proportion of older patients in whom pulmonary embolism could be safely excluded.
doi:10.1136/bmj.c1475
PMCID: PMC2847688  PMID: 20354012
8.  Dutch orthopedic thromboprophylaxis: a 5-year follow-up survey 
Acta Orthopaedica  2009;80(1):109-112.
Background and purpose Previous surveys in the Netherlands have revealed that guidelines regarding orthopedic thromboprophylaxis were not followed and that a wide variation in protocols exists. This survey was performed to assess the current use of thromboprophylactic modalities and to compare it with the results of a previous survey.
Methods All departments of orthopedic surgery in the Netherlands were sent a follow-up survey on venous thromboprophylaxis, and the data obtained were compared to the results of a survey performed 5 years earlier.
Results All departments used pharmacological thromboprophylaxis following arthroplasties of the hip and knee. Low-molecular-weight heparin (LMWH) was used most frequently (79%) of the departments, followed by fondaparinux (13%). 5 years earlier, coumarin treatment was the predominant prophylaxis (79%). All departments prescribed pharmacological prophylaxis after femoral and tibial fractures; 78% used LMWH. Prophylaxis was continued for 6 weeks in 85% of cases. LMWH treatment was initiated on the day before surgery in 31% of cases (65% in the previous survey), perioperatively in 55%, and in the evening following surgery in 24%. In general, for daycare surgery and arthroscopies either no prophylaxis was given or a LMWH was given for 1 day. After anterior cruciate ligament reconstruction, 94% of departments prescribed some form of pharmacological prophylaxis.
Interpretation The use of pharmacological prophylaxis after arthroplasty of the hip and knee and also after fracture surgery around the hip and knee is common practice in the Netherlands. In 5 years, the widely used coumarin derivates have been largely replaced with LMWH.
doi:10.1080/17453670902807441
PMCID: PMC2823229  PMID: 19234891
9.  Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule 
Background
If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index.
Aim
To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease.
Design of study
An observational study.
Setting
General practice in The Netherlands.
Method
This observational study included patients of ≥55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease.
Results
Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category.
Conclusion
This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.
PMCID: PMC1934053  PMID: 17132381
ankle brachial index; atheroscelerosis; clinical decision rule; Edinburgh Claudication Questionnaire; intermittent claudication; peripheral vascular disease
10.  Influenza infection and risk of acute pulmonary embolism 
Thrombosis Journal  2007;5:16.
Background
Influenza infections have been associated with procoagulant changes. Whether influenza infections lead to an increased risk of pulmonary embolism remains to be established.
Methods
We conducted a nested case control study in a large cohort of patients with a clinical suspicion of having pulmonary embolism. Blood samples were collected to investigate the presence of influenza A and B by complement fixation assay (CFA). We compared case patients, in whom pulmonary embolism was proven (n = 102), to controls, in whom pulmonary embolism was excluded (n = 395). Furthermore, we compared symptoms of influenza-like illness in both patient groups 2 weeks prior to inclusion in the study, using the influenza-like illness (ILI) score, which is based on a questionnaire. We calculated the risk of pulmonary embolism associated with influenza infection.
Results
The percentage of patients with influenza A was higher in the control group compared to the case group (4.3% versus 1.0%, respectively, odds ratio 0.22; 95% CI: 0.03–1.72). Influenza B was not detectable in any of the cases and was found in 3 of the 395 controls (0.8%). The ILI score was positive in 24% of the cases and 25% in the control persons (odds ratio 1.16, 95% CI: 0.67–2.01). We did not observe an association between the ILI score and proven influenza infection.
Conclusion
In this clinical study, influenza infection was not associated with an increased risk of acute pulmonary embolism. The ILI score is non-specific in this clinical setting.
doi:10.1186/1477-9560-5-16
PMCID: PMC2104525  PMID: 17939867
11.  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
12.  A C1173T Dimorphism in the VKORC1 Gene Determines Coumarin Sensitivity and Bleeding Risk 
PLoS Medicine  2005;2(10):e312.
Background
A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes.
Methods and Findings
We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6–3.2], CT genotype 2.6 mg/d [95% CI: 2.1–3.1], TT genotype 1.4 mg/d [95 % CI: 1.1–1.7]) or acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9–3.5], CT genotype 2.3 mg/d [95% CI: 2.1–2.5], TT genotype 1.7 mg/d [95% CI: 1.3–2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2–5.7), but not in acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6–2.3).
Conclusion
These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.
A polymorphism in the VKORC1 gene may affect the dose of vitamin K antagonists needed and the risk of bleeding after anticoagulation in some patients.
doi:10.1371/journal.pmed.0020312
PMCID: PMC1251635  PMID: 16201835
13.  Recombinant human activated protein C resets thrombin generation in patients with severe sepsis – a case control study 
Critical Care  2005;9(5):R490-R497.
Introduction
Recombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls.
Methods
In this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 μg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation.
Results
Sepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group.
Conclusion
Sepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation.
doi:10.1186/cc3774
PMCID: PMC1297612  PMID: 16277710
14.  Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study 
Objective To validate the use of the Wells clinical decision rule combined with a point of care D-dimer test to safely exclude pulmonary embolism in primary care.
Design Prospective cohort study.
Setting Primary care across three different regions of the Netherlands (Amsterdam, Maastricht, and Utrecht).
Participants 598 adults with suspected pulmonary embolism in primary care.
Interventions Doctors scored patients according to the seven variables of the Wells rule and carried out a qualitative point of care D-dimer test. All patients were referred to secondary care and diagnosed according to local protocols. Pulmonary embolism was confirmed or refuted on the basis of a composite reference standard, including spiral computed tomography and three months’ follow-up.
Main outcome measures Diagnostic accuracy (sensitivity and specificity), proportion of patients at low risk (efficiency), number of missed patients with pulmonary embolism in low risk category (false negative rate), and the presence of symptomatic venous thromboembolism, based on the composite reference standard, including events during the follow-up period of three months.
Results Pulmonary embolism was present in 73 patients (prevalence 12.2%). On the basis of a threshold Wells score of ≤4 and a negative qualitative D-dimer test result, 272 of 598 patients were classified as low risk (efficiency 45.5%). Four cases of pulmonary embolism were observed in these 272 patients (false negative rate 1.5%, 95% confidence interval 0.4% to 3.7%). The sensitivity and specificity of this combined diagnostic approach was 94.5% (86.6% to 98.5%) and 51.0% (46.7% to 55.4%), respectively.
Conclusion A Wells score of ≤4 combined with a negative qualitative D-dimer test result can safely and efficiently exclude pulmonary embolism in primary care.
doi:10.1136/bmj.e6564
PMCID: PMC3464185  PMID: 23036917

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