Dees P. M. Brandjes

Detection of Deep-Vein Thrombosis by Real-Time B-Mode Ultrasonography

In 220 consecutive outpatients with clinically suspected deep-vein thrombosis of the leg, we compared contrast venography with real-time B-mode ultrasonography, using the single criterion of vein compressibility with the ultrasound transducer probe. The common femoral and popliteal veins were evaluated for full compressibility (no thrombosis) and noncompressibility (thrombosis). Both veins were fully compressible in 142 of the 143 patients with normal venograms (specificity, 99 percent; 95 percent confidence interval, 97 to 100). All 66 patients with proximal-vein thrombosis had noncompressible femoral veins, popliteal veins, or both (sensitivity, 100 percent; 95 percent confidence interval, 95 to 100). For all patients (including 11 with calf-vein thrombi), sensitivity and specificity were 91 (95 percent confidence interval, 82 to 96) and 99 percent, respectively. The sensitivity for isolated calf-vein thrombosis was only 36 percent. The compression ultrasound test was repeated in a subset of 45 consecutive patients by a second examiner, unaware of the results of the first test, whose results agreed in all patients with those of the first examiner (kappa = 1). We conclude that ultrasonography with the single criterion of vein compressibility is a highly accurate, simple, objective, and reproducible noninvasive method for detecting proximal-vein thrombosis in outpatients with clinically suspected deep-venous thrombosis.

Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis

BACKGROUND Post-thrombotic syndrome varies from mild oedema to incapacitating swelling with pain and ulceration. We investigated the rate of post-thrombotic syndrome after a first episode of deep-vein thrombosis and assessed the preventive effect of direct application of a sized-to-fit graded compression stocking. METHODS Patients with a first episode of venogram-proven proximal deep-vein thrombosis were randomly assigned no stockings (the control group) or made-to-measure graded compression elastic stockings for at least 2 years. Post-thrombotic syndrome was assessed with a standard scoring system that combined clinical characteristics and objective leg measurements. Patients were assessed every 3 months during the first 2 years, and every 6 months thereafter for at least 5 years. The cumulative incidence of mild-to-moderate post-thrombotic syndrome was the primary outcome measure. FINDINGS Of the 315 consecutive outpatients considered for inclusion, 44 were excluded and 77 did not consent to take part. 194 patients were randomly assigned compression stockings (n = 96) or no stockings (n = 98). The median follow-up was 76 months (range 60-96) in both groups. Mild-to-moderate post-thrombotic syndrome (score > or = 3 plus one clinical sign) occurred in 19 (20%) patients in the stocking group and in 46 (47%) control-group patients (p < 0.001). 11 (11%) patients in the stocking group developed severe post-thrombotic syndrome (score > or = 4), compared with 23 (23%) patients in the control group (p < 0.001). In both groups, most cases of post-thrombotic syndrome occurred within 24 months of the acute thrombotic event. INTERPRETATION About 60% of patients with a first episode of proximal deep-vein thrombosis develop post-thrombotic syndrome within 2 years. A sized-to-fit compression stocking reduced this rate by about 50%.

Thyroid Diseases and Cerebrovascular Disease

Background and Purpose— Acute cerebral ischemia has been described in different diseases of the thyroid gland, and not only as a result of thyrotoxic atrial fibrillation and cardioembolic stroke. The purpose of this review is to summarize the studies on the relationship between thyroid diseases and cerebrovascular diseases, discussing the main findings for overt hyperthyroidism and hypothyroidism, as well as for subclinical thyroid dysfunction. Summary of Review— In overt hyperthyroidism, cardioembolic stroke is clearly associated to thyrotoxic atrial fibrillation, and in subclinical hyperthyroidism with serum thyroid-stimulating hormone levels <0.1 mU/L, the incidence of atrial fibrillation is increased. Although in vitro and in vivo studies indicate a hypercoagulability state in hyperthyroidism, there is insufficient evidence to prove that this state leads to an increased risk of cardiac emboli. However, the hypothesis that overt hyperthyroidism may cause acute cerebral venous thrombosis is intriguing. Possible associations between hyperthyroidism and Moyamoya or Giant cell arteritis have only been described in case reports. There is enough evidence that overt hypothyroidism is associated with several traditional and newer atherosclerotic risk factors, especially hypertension, hyperlipidemia, and hyperhomocysteinemia. For subclinical hypothyroidism, these associations are less certain. Hypothyroidism has been associated with signs of aortic or coronary atherosclerosis, but no case-control or cohort studies have ever investigated hypothyroidism as a possible risk factor for atherothrombotic stroke. Conclusions— Hyperthyroidism is associated with atrial fibrillation and cardioembolic stroke. Hypothyroidism is associated with a worse cardiovascular risk factor profile and leads to progression of atherosclerosis. Associations between hyperthyroidism and acute cerebral venous thrombosis, Moyamoya, and Giant cell arteritis have been suggested, but sound evidence is lacking. Additional studies are needed to clarify these issues.

Hypercoagulable State in Cushing's Syndrome: A Systematic Review

CONTEXT It has been debated whether an increased risk of venous thromboembolism (VTE) exists in patients with Cushings syndrome. OBJECTIVE We aimed to summarize published literature on the effects of endogenous hypercortisolism on coagulation and fibrinolysis, as well as on the clinical outcome of VTE. DATA SOURCES We searched the MEDLINE and EMBASE databases up to July 2008. Review of reference lists further identified candidate studies. STUDY SELECTION Two investigators independently performed study selection and data extraction. Eligible studies had to include Cushings syndrome patients and either evaluate hemostatic parameters in comparison with control persons or posttreatment levels or describe the occurrence of VTE. DATA EXTRACTION The Newcastle-Ottawa Scale was used to assess study quality. A scoring system divided studies into categories of low, medium and high quality. DATA SYNTHESIS Of 441 identified publications, 15 reports were included. They contained information on eight cross-sectionals, two intervention, and eight cohort studies. No high-quality studies were identified. Hypercoagulability was suggested by high levels of factor VIII, factor IX, and von Willebrand factor and by evidence of enhanced thrombin generation. A risk of 1.9 and 2.5% was reported for VTE not provoked by surgery, whereas risk of postoperative VTE varied between 0 and 5.6%, with one outlier of 20%. VTE was reported as the cause of death in 0-1.9% of Cushings syndrome patients. CONCLUSIONS Available studies suggest a high risk of venous thrombosis in patients with Cushings syndrome. Glucocorticoid-induced hypercoagulability as well as surgery and obesity almost certainly contribute to this thrombotic tendency.

Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management

Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolytic anemia, increased susceptibility to infections and vaso‐occlusion leading to a reduced quality of life and life expectancy. Oxidative stress is an important feature of SCD and plays a significant role in the pathophysiology of hemolysis, vaso‐occlusion and ensuing organ damage in sickle cell patients. Reactive oxygen species (ROS) and the (end‐)products of their oxidative reactions are potential markers of disease severity and could be targets for antioxidant therapies. This review will summarize the role of ROS in SCD and their potential implication for SCD management. Am. J. Hematol. 2011.

Infections and endothelial cells

Systemic infection by various pathogens interacts with the endothelium and may result in altered coagulation, vasculitis and atherosclerosis. Endothelium plays a role in the initiation and regulation of both coagulation and fibrinolysis. Exposure of endothelial cells may lead to rapid activation of coagulation via tissue factor (TF) expression and the loss of anticoagulant properties by impairment of antithrombin III, TF pathway inhibitor (TFPI) and the protein C system. Endothelial-derived plasminogen activator inhibitor (PAI) is essential for the regulation of fibrinolysis and impaired endothelial function leads to imbalance in fibrinolysis, resulting in a procoagulant state. The interaction between inflammation and coagulation, soluble adhesion molecules and circulation endothelial cells is important in the pathogenesis of an unbalanced haemostatic system. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation appears to be significant. In the crosstalk, the endothelium is playing a pivotal role.

Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors.

Summary.  Background: Whether glucocorticoid use contributes to a hypercoagulable state, and thereby enhances the thrombotic risk, is controversial. Objective: We aimed to examine the effects of glucocorticoid use on coagulation and fibrinolysis. Methods: MEDLINE and EMBASE databases were searched to identify published studies comparing glucocorticoid treatment with a glucocorticoid‐free control situation. Subjects could be either patients or healthy volunteers. Two investigators independently performed study selection and data extraction. Results were expressed as standardized mean difference, if possible; data were pooled with a random‐effects model. Results: Of the 1967 identified publications, 36 papers were included. In healthy volunteers, a clear rise in factor (F)VII, VIII and XI activity was observed after glucocorticoid treatment, but these data alone provided insufficient evidence to support hypercoagulability. However, during active inflammation, glucocorticoids significantly increased levels of plasminogen activator inhibitor‐1 (PAI‐1), whereas levels of von Willebrand factor (VWF) and fibrinogen decreased. Peri‐operative use of glucocorticoids inhibited the increase in tissue‐type plasminogen activator induced by surgery. Conclusions: The present study showed differential effects of glucocorticoids depending on the clinical situation in which it is given, most likely as a result of their disease modifying properties. Clinical outcome studies are needed to adequately assess the risk‐benefit of glucocorticoid use per population when thrombotic complication is the focus.

Effects on Coagulation and Fibrinolysis Induced by Influenza in Mice With a Reduced Capacity to Generate Activated Protein C and a Deficiency in Plasminogen Activator Inhibitor Type 1

Influenza infections increase the risk of diseases associated with a prothrombotic state, such as venous thrombosis and atherothrombotic diseases. However, it is unclear whether influenza leads to a prothrombotic state in vivo. To determine whether influenza activates coagulation, we measured coagulation and fibrinolysis in influenza-infected C57BL/6 mice. We found that influenza increased thrombin generation, fibrin deposition, and fibrinolysis. In addition, we used various anti- and prothrombotic models to study pathways involved in the influenza-induced prothrombotic state. A reduced capacity to generate activated protein C in TMpro/pro mice increased thrombin generation and fibrinolysis, whereas treatment with heparin decreased thrombin generation in influenza-infected C57Bl/6 mice. Thrombin generation was not changed in hyperfibrinolytic mice, deficient in plasminogen activator inhibitor type-1 (PAI-1−/−); however, increased fibrin degradation was seen. Treatment with tranexamic acid reduced fibrinolysis, but thrombin generation was unchanged. We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin. The fibrinolytic system appears not to be important for thrombin generation. These findings suggest that influenza leads to a prothrombotic state by coagulation activation. Heparin treatment reduces the influenza induced prothrombotic state.

Additional value of procalcitonin for diagnosis of infection in patients with fever at the emergency department

Objective: First, to determine whether procalcitonin (PCT) significantly adds diagnostic value in terms of sensitivity and specificity to a common set of markers of infection, including C-reactive protein (CRP), at the Emergency Department. Second, to create a simple scoring rule implementing PCT values. Third, to determine and compare associations of CRP and PCT with clinical outcomes. Design: The additional diagnostic value of PCT was determined using multiple logistic regression analysis. A score was developed to help distinguish patients with a culture-proven bacterial infection from patients not needing antibiotic treatment using 16 potential clinical and laboratory variables. The prognostic value of CRP and PCT was determined using Spearmans correlation and logistic regression. Setting: Emergency Department of a 310-bed teaching hospital. Patients: Patients between 18 and 85 years old presenting with fever to the Emergency Department. Interventions: None. Measurements and Main Results: A total of 211 patients were studied (infection confirmed, n = 73; infection likely, n = 58; infection not excluded, n = 46; no infection, n = 34). CRP and chills were the strongest predictors for the diagnosis of bacterial infection. After addition of PCT to these parameters, model fit significantly improved (p = .003). The resulting scoring rule (score = 0.01 * CRP + 2 * chills + 1 * PCT) was characterized by an AUC value of 0.83 (sensitivity 79%; specificity of 71%), which was more accurate than physician judgment or SIRS (systemic inflammatory response syndrome). PCT levels were significantly associated with admission to a special care unit, duration of intravenous antibiotic use, total duration of antibiotic treatment, and length of hospital stay, whereas CRP was related only to the latter two variables. Conclusions: These data suggest that PCT may be a valuable addition to currently used markers of infection for diagnosis of infection and prognosis in patients with fever at the Emergency Department.

Cerebrovascular reserve capacity is impaired in patients with sickle cell disease

Sickle cell disease (SCD) is associated with a high incidence of ischemic stroke. SCD is characterized by hemolytic anemia, resulting in reduced nitric oxide-bioavailability, and by impaired cerebrovascular hemodynamics. Cerebrovascular CO2 responsiveness is nitric oxide dependent and has been related to an increased stroke risk in microvascular diseases. We questioned whether cerebrovascular CO2 responsiveness is impaired in SCD and related to hemolytic anemia. Transcranial Doppler-determined mean cerebral blood flow velocity (V(mean)), near-infrared spectroscopy-determined cerebral oxygenation, and end-tidal CO2 tension were monitored during normocapnia and hypercapnia in 23 patients and 16 control subjects. Cerebrovascular CO2 responsiveness was quantified as Delta% V(mean) and Deltamicromol/L cerebral oxyhemoglobin, deoxyhemoglobin, and total hemoglobin per mm Hg change in end-tidal CO2 tension. Both ways of measurements revealed lower cerebrovascular CO2 responsiveness in SCD patients versus controls (V(mean), 3.7, 3.1-4.7 vs 5.9, 4.6-6.7 Delta% V(mean) per mm Hg, P < .001; oxyhemoglobin, 0.36, 0.14-0.82 vs 0.78, 0.61-1.22 Deltamicromol/L per mm Hg, P = .025; deoxyhemoglobin, 0.35, 0.14-0.67 vs 0.58, 0.41-0.86 Deltamicromol/L per mm Hg, P = .033; total-hemoglobin, 0.13, 0.02-0.18 vs 0.23, 0.13-0.38 Deltamicromol/L per mm Hg, P = .038). Cerebrovascular CO2 responsiveness was not related to markers of hemolytic anemia. In SCD patients, impaired cerebrovascular CO2 responsiveness reflects reduced cerebrovascular reserve capacity, which may play a role in pathophysiology of stroke.