Kruip, M.J.H.A.

Obesity in haemophilia patients: Effect on bleeding frequency, clotting factor concentrate usage, and haemostatic and fibrinolytic parameters (Article)

2013-05-15T00:00:00Z

The prevalence of obesity in patients with haemophilia (PWH) is increasing. We investigated the effect of obesity on bleeding frequency and clotting factor concentrate (CFC) usage in PWH and assessed whether prothrombotic changes observed in obesity differ between controls and PWH. Number of bleeds and CFC usage were compared between obese (N = 51) and non-obese (N = 46) haemophilia A patients. Markers of haemostasis and fibrinolysis were compared between PWH, and gender-, age- and body mass index (BMI)-matched non-haemophilic controls (N = 91). Median number of bleeds/patient-month was comparable between obese and non-obese patients with severe haemophilia (P = 0.791). Obese patients with severe haemophilia used 1.4 times more CFC/patient-month than non-obese patients (P = 0.036). When adjusting for weight this difference disappeared (P = 0.451). von Willebrand factor plasma concentration (VWF:Ag), factor VIII activity and endogenous thrombin potential were higher in obese than in non-obese controls. Obesity did not influence these markers in PWH. Plasminogen activator inhibitor type 1 levels were higher in obese vs. non-obese PWH (P < 0.001), whereas levels were comparable between PWH and controls (P = 0.912). Plasmin-α2-antiplasmin complex (PAP) levels appeared to be lower in obese vs. non-obese subjects, both within controls (P = 0.011) and PWH (P = 0.008). However, in PWH, PAP levels were higher than in controls (P < 0.001). Obesity is associated with an increase in net CFC usage in PWH, but has no effect on bleeding frequency. In addition, obesity attenuates hyperfibrinolysis in PWH. Future research investigating whether obese PWH need CFC treatment dosed on weight or whether a lower dosage would suffice to prevent and treat bleedings is needed.

Factor VIII deficiency does not protect against atherosclerosis (Article)

2012-01-01T00:00:00Z

Summary. Background: Hemophilia A patients have a lower cardiovascular mortality rate than the general population. Whether this protection is caused by hypocoagulability or decreased atherogenesis is unclear. Objectives: To evaluate atherosclerosis and endothelial function in hemophilia A patients with and without obesity as well as in matched, unaffected controls. Methods: Fifty-one obese (body mass index [BMI]≥30kgm-2) and 47 non-obese (BMI≤25kgm-2) hemophilia A patients, and 42 obese and 50 matched non-obese male controls were included. Carotid and femoral intima-media thickness [IMT] and brachial flow-mediated dilatation (FMD) were measured as markers of atherogenesis and endothelial function. Results: The overall population age was 50±13 years. Carotid IMT was increased in obese subjects (0.77±0.22mm) as compared with non-obese subjects (0.69±0.16mm) [mean difference 0.07mm (95% confidence interval [CI] 0.02-0.13, P=0.008)]. No differences in mean carotid and femoral IMT between obese hemophilic patients and obese controls were found (mean difference of 0.02mm [95% CI -0.07-0.11, P=0.67], and mean difference of 0.06mm [95% CI -0.13-0.25, P=0.55], respectively). Thirty-five per cent of the obese hemophilic patients and 29% of the obese controls had an atherosclerotic plaque (P=0.49), irrespective of the severity of hemophilia. Brachial FMD was comparable between obese hemophilic patients and obese controls (4.84%±3.24% and 5.32%±2.37%, P=0.45). Conclusion: Hemophilia A patients with obesity develop atherosclerosis to a similar extent as the general male population. Detection and treatment of cardiovascular risk factors in hemophilic patients is equally necessary.

Outpatient treatment in patients with acute pulmonary embolism: The Hestia Study (Article)

2011-08-01T00:00:00Z

Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non-randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. Patients and Methods: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow-up. Results: Of 297 included patients, who all completed the follow-up, six (2.0%; 95% confidence interval [CI] 0.8-4.3) had recurrent VTE (five PE [1.7%] and one DVT [0.3%]). Three patients (1.0%, 95% CI 0.2-2.9) died during the 3 months of follow-up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08-2.4). Conclusion: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319;).

Hypercoagulability and hypofibrinolysis and risk of deep vein thrombosis and splanchnic vein thrombosis: Similarities and differences (Article)

2011-03-01T00:00:00Z

In this review, we provide an overview of the risk factors for venous thromboembolism, focusing on hypercoagulability and hypofibrinolysis. In the first part of this review, we discuss the risk factors for commonly occurring venous thrombosis, in particular deep vein thrombosis and pulmonary embolism. In the second part, we provide an overview of the risk factors for the Budd-Chiari syndrome and portal vein thrombosis. These are rare, life-threatening forms of venous thromboembolism located in the splanchnic veins. There are many similarities in the risk profiles of patients with common venous thrombosis and splanchnic vein thrombosis. Inherited thrombophilia and hypofibrinolysis increase the risk of both common venous thrombosis and splanchnic vein thrombosis. However, there are also apparent differences. Myeloproliferative neoplasms and paroxysmal nocturnal hemoglobinuria have a remarkably high frequency in patients with thrombosis at these unusual sites but are rarely seen in patients with common venous thrombosis. There are also clear differences in the underlying risk factors for Budd-Chiari syndrome and for portal vein thrombosis, suggesting site specificity of thrombosis even within the splanchnic venous system. These clear differences in underlying risk factors provide leads for further research on the site specificity of venous thrombosis and the development of thrombosis at these distinct sites. Copyright

Cardiovascular risk assessment in haemophilia patients (Article)

2011-02-01T00:00:00Z

Haemophilia patients have a reduced cardiovascular mortality, which may be the result of a lifelong deficiency of factor VIII or IX. On the other hand, the prevalence of risk factors may differ in these chronically ill patients compared to the general population. The prevalence of risk factors and expected risk of cardiovascular disease was compared in haemophilia patients and healthy controls. In adult haemophilia A and B patients, body mass index, blood pressure, cholesterol levels and fasting glucose levels were measured and compared to healthy age-matched males. The expected risk of mortality due to cardiovascular disease was calculated using a European risk prediction algorithm (SCORE). A total of 100 haemophilia A and B patients and 200 healthy controls were analysed. The mean age of the patients was 47 years (range 18-83). The number of haemophiliacs with hyperglycaemia (24%) and hypertension (51%) was higher than in the controls (p-values 0.001 and 0.03, respectively). The mean low-density lipoprotein (LDL) cholesterol level in cases was lower than the controls (3.02 mM (0.69-6.57) and 3.60 mM (1.68-5.95), respectively, p < 0.001). Fewer cases had increased LDL levels (p=0.045). No difference was found in the 10-year cardiovascular mortality risk >10% between cases and controls (12% and 7%, respectively, p = 0.18). The prevalence of risk factors and expected risk of cardiovascular disease in haemophilia patients is comparable to the general population. This strengthens the hypothesis that hypocoagulability may reduce cardiovascular mortality in haemophilia patients.

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 (Article)

2010-05-07T00:00:00Z

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 agex10) 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% CI0%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.

Comparison of risk profile and clinical outcome of patients after acute pulmonary embolism in university and non-university hospitals (Article)

2010-02-01T00:00:00Z

Reversible renal failure due to bilateral renal sarcoma in a patient with acute myeloid leukemia (Article)

2009-12-30T00:00:00Z

A 68-year-old male presented with acute myeloid leukemia, renal failure, hypokalemia, and enlarged kidneys on renal ultrasound. Renal biopsy revealed massive leukemic infiltration of the kidney. After systemic chemotherapy, the patient developed tumor lysis syndrome followed by a phase of proximal tubule dysfunction presenting as polyuria and diverse electrolyte abnormalities. In time, renal function returned to normal, as did kidney size. This report shows that renal failure, enlargement of the kidneys, and tubule dysfunction in the course of AML infiltrating the kidneys can be reversed by treatment of the hematological disease.

Elevated fibrinogen γ′ ratio is associated with cardiovascular diseases and acute phase reaction but not with clinical outcome (Article)

2009-11-12T00:00:00Z

Comparison of the clinical usefulness of two quantitative D-Dimer tests in patients with a low clinical probability of Pulmonary Embolism (Article)

2009-03-01T00:00:00Z

Background: Quantitative D-Dimer tests are established methods in the non-invasive diagnostic management to rule out venous thromboembolism (VTE). The diagnostic performance and the clinical efficiency different D-Dimer assays in the exclusion of pulmonary embolism (PE) have not yet been compared in a clinical outcome study. Objective: Evaluation of the efficiency and safety of excluding the diagnosis of PE with two different quantitative D-Dimer assays in consecutive patients with clinically suspected PE. Patients and Methods: We studied the VTE-failure rate of 2206 consecutive patients with an unlikely clinical probability in whom VIDAS or Tinaquant D-Dimer tests were performed. Results: The prevalence of PE in 1238 patients whose D-Dimer level was analyzed with Tinaquant assay was 11%. The VIDAS assay group consisted of 968 patients with a PE prevalence of 13%. The VIDAS assay had a sensitivity of 99.2% (95%CI; 96- > 99.9%), the Tinaquant assay of 97.3% (95%CI; 93 -99%). The negative predictive value (NPV) in the Tinaquant assay group was 99.4% (95%CI 98-99.8%) in comparison to 99.7% (95%CI 99-> 99.9%) in the VIDAS assay group. During 3 month of follow-up, there were no fatal cases of PE among patients with normal D-Dimer and unlikely clinical probability in both D-Dimer assay groups. In addition, the test efficiency of Tinaquant assay was significantly higher in comparison to VIDAS assay (52% vs 42%, p < 0.001). Conclusion: Both Tinaquant and VIDAS D-Dimer tests perform equally well in combination with an unlikely clinical probability in excluding PE. The Tinaquant test was shown to be more efficient.

Excluding pulmonary embolism without imaging tests - Can our diagnostic algorithm be optimized? (Article)

2008-12-01T00:00:00Z

Further validation and simplification of the Wells clinical decision rule in pulmonary embolism (Article)

2008-01-01T00:00:00Z

The Wells rule is a widely applied clinical decision rule in the diagnostic work-up of patients with suspected pulmonary embolism (PE).The objective of this study was to replicate, validate and possibly simplify this rule.We used data collected in 3,306 consecutive patients with clinically suspected PE to recalculate the odds ratios for the variables in the rule, to calculate the proportion of patients with PE in the probability categories,the area under the ROC curve and the incidence of venous thromboembolism during follow-up. We compared these measures with those for a modified and a simplified version of the decision rule. In the replication, the odds ratios in the logistic regression model were found to be lower for each of the seven individual variables (p=0.02) but the proportion of patients with PE in the probability categories in our study group were comparable to those in the original derivation and validation groups.The area under the ROC of the original, modified and simplified decision rule was similar: 0.74 (p=0.99; p=0.07).The venous thromboembolism incidence at three months in the group of patients with a Wells score ≤ 4 and a normal D-climer was 0.5%, versus 0.3% with a modified rule and 0.5% with a simplified rule.The proportion of patients safely excluded for PE was 32%, versus 31 % and 30%, respectively.This study further validates the diagnostic utility of the Wells rule and indicates that the scoring system can be simplified to one point for each variable.

Clinically suspected acute recurrent pulmonary embolism: A diagnostic challenge (Article)

2007-06-01T00:00:00Z

It is unknown whether strategies validated for diagnosing pulmonary embolism (PE) are valid in patients with a history of PE. It was the objective of this study to investigate whether a diagnostic algorithm consisting of sequential application of a clinical decision rule (CDR), a quantitative D-dimer test and computed tomography (CT) safely ruled out a clinical suspicion of acute recurrent PE. Data were obtained from a diagnostic outcome study of patients suspected of PE. Acute recurrent PE was ruled out by an unlikely probability of PE (CDR score ≤4 points) combined with a normal D-dimer test (≤500 ng/ml) or by a normal CT in all other patients. The primary outcome was the incidence of acute recurrent venous thromboembolism during three months of follow-up in patients with normal tests and not treated with anticoagulants. Of 3,306 patients suspected of acute PE, 259 patients (7.8%) had a history of PE of whom 234 were not treated with anticoagulants. The probability of PE was unlikely in 82 of 234 patients (35%), and 42 had a normal D-dimer test (18%), excluding recurrent PE. None of these patients had a thrombotic event during follow-up (0%, 95%Cl: 0-6.9). A CT was indicated in all other patients (192) and ruled out recurrent PE in 127 patients (54%). Only one patient with a negative CT had a fatal recurrent PE during follow-up (0.8%; 95%Cl: 0.02-4.3). In conclusion, this prospective study demonstrates the safety of ruling out a clinical suspicion of acute recurrent PE by a simple diagnostic algorithm in patients with a history of PE.

Evaluation of the AutoDimer D-dimer assay for the exclusion of pulmonary embolism [3] (Article)

2007-02-01T00:00:00Z

Improving the diagnostic strategy of pulmonary embolism (Doctoral Thesis)

2006-12-15T00:00:00Z

Pulmonary embolism is a common clinical disorder that is associated with high morbidity and mortality if untreated. In the only randomized study comparing anticoagulant therapy with no treatment in patients with pulmonary embolism, 26% of untreated patients had a fatal embolic event and another 26% developed nonfatal recurrent emboli1. With a course of anticoagulant treatment, the recurrence rate of thromboembolic events decreases to approximately 2% to 9% over 3 to 6 months2, 3. However, anticoagulation always carries a risk for bleeding (annual rate of major bleeding, 7%)4, 5. To avoid unnecessary anticoagulant therapy, it is therefore important to rapidly confirm or exclude pulmonary embolism in patients who present with suspicion of the disorder. Diagnosing or excluding pulmonary embolism on the basis of clinical manifestations alone is difficult because such manifestations are nonspecific6. Approximately 25% of patients with suspected pulmonary embolism have the disease confirmed by objective testing7-9. The goal of the first diagnostic strategies introduced was to confirm rather than exclude the presence of pulmonary emboli. The more recently evaluated diagnostic approaches have focused on identifying patients who probably do not have pulmonary embolism and therefore do not require anticoagulant therapy. Various invasive and noninvasive diagnostic methods have been advocated for excluding the disease. We performed a systematic review of the literature to evaluate diagnostic strategies designed to exclude pulmonary embolism. Our objective was to investigate whether clinical outcome evaluation properly documented the safety of withholding anticoagulant treatment in patients in whom pulmonary embolism was excluded according to a given diagnostic strategy. We assessed the accuracy of the various diagnostic strategies by examining the number of symptomatic thromboembolic events (deep venous thrombosis or pulmonary embolism) that occurred without anticoagulant treatment during a follow-up period of at least 3 months. Studies were grouped according to the number of rounds of diagnostic testing performed before pulmonary embolism was ruled out.