The value of 64-detector row computed tomography for the exclusion of pulmonary embolism.

Recently, a diagnostic strategy using a clinical decision rule, D-dimer testing and spiral computed tomography (CT) was found to be effective in the evaluation of patients with clinically suspected pulmonary embolism (PE). However, the rate of venous thromboembolic complications in the three-month follow-up of patients with negative CT was still substantial and included fatal events. It was the objective to evaluate the safety of withholding anticoagulants after a normal 64-detector row CT (64-DCT) scan from a cohort of patients with suspected PE. A total of 545 consecutive patients with clinically suspected first episode of PE and either likely pre-test probability of PE (using the simplified Wells score) or unlikely pre-test probability in combination with a positive D-dimer underwent a 64-DCT. 64-DCT scanning was inconclusive in nine patients (1.6%), confirmed the presence of PE in 169 (31%), and ruled out the diagnosis in the remaining 367. During the three-month follow-up of the 367 patients one developed symptomatic distal deep-vein thrombosis (0.27%; 95%CI, 0.0 to 1.51%) and none developed PE (0 %; 95%CI, 0 to 1.0%). We conclude that 64-DCT scanning has the potential to safely exclude the presence of PE virtually in all patients presenting with clinical suspicion of this clinical disorder.

A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score.

BACKGROUND: Prophylaxis of venous thromboembolism (VTE) in hospitalized medical patients is largely underused. We sought to assess the value of a simple risk assessment model (RAM) for the identification of patients at risk of VTE. METHODS: In a prospective cohort study, 1180 consecutive patients admitted to a department of internal medicine in a 2-year period were classified as having a high or low risk of VTE according to a predefined RAM. They were followed-up for up to 90 days to assess the occurrence of symptomatic VTE complications. The primary study outcome was to assess the adjusted hazard ratio (HR) of VTE in high-risk patients who had adequate in-hospital thromboprophylaxis in comparison with those who did not, and that of VTE in the latter group in comparison with low-risk patients. RESULTS: Four hundred and sixty-nine patients (39.7%) were labelled as having a high risk of thrombosis. VTE developed in four of the 186 (2.2%) who received thromboprophylaxis, and in 31 of the 283 (11.0%) who did not (HR of VTE, 0.13; 95% CI, 0.04-0.40). VTE developed also in two of the 711 (0.3%) low-risk patients (HR of VTE in high-risk patients without prophylaxis as compared with low-risk patients, 32.0; 95% CI, 4.1-251.0). Bleeding occurred in three of the 186 (1.6%) high-risk patients who had thromboprophylaxis. CONCLUSIONS: Our RAM can help discriminate between medical patients at high and low risk of VTE. The adoption of adequate thromboprophylaxis in high-risk patients during hospitalization leads to longstanding protection against thromboembolic events with a low risk of bleeding.

Von Willebrand factor propeptide makes it easy to identify the shorter Von Willebrand factor survival in patients with type 1 and type Vicenza von Willebrand disease.

Reduced von Willebrand factor (VWF) half-life has been suggested as a new pathogenic mechanism in von Willebrand disease (VWD). The usefulness of VWF propeptide (VWFpp) in exploring VWF half-life was assessed in 22 type 1 and 14 type Vicenza VWD patients, and in 30 normal subjects, by comparing the findings on post-Desmopressin (DDAVP) VWF t(1/2) elimination (t(1/2el)). The VWFpp/VWF antigen ratio (VWFpp ratio) was dramatically increased in type Vicenza VWD (13.02 +/- 0.49) when compared to normal subjects (1.45 +/- 0.06), whereas it appeared to be normal in all type 1 VWD patients (1.56 +/- 0.7), except for the four carrying the C1130F mutation (4.69 +/- 0.67). A very short VWF t(1/2el) was found in type Vicenza VWD (1.3 +/- 0.2 h), while all type 1 VWD patients had a t(1/2el) similar to that of the controls (11.6 +/- 1.4 and 15.4 +/- 2.5 h respectively), except for the four patients carrying the C1130F mutation, who had a significantly shorter VWF survival (4.1 +/- 0.2 h). A significant inverse correlation emerged between VWFpp ratio and VWF t(1/2el) in both VWD patients and normal subjects. The VWFpp ratio thus seemed very useful for distinguishing between type 1 VWD cases with a normal and a reduced VWF survival, as well as for identifying type Vicenza VWD.

Endothelial dysfunction in haemophilia patients.

Haemophilia patients may develop cardiovascular diseases, suggesting that their clotting defect does not protect them completely from atherosclerosis and its complications. We aimed to evaluate cardiovascular risk factors and, for the first time, the presence of endothelial dysfunction in middle-aged haemophilia patients. We studied 40 patients with haemophilia A and B (24 with moderate-severe disease and 16 with mild disease), and 40 healthy controls. Flow-mediated dilation (FMD), carotid ultrasound (US) intima media thickness (IMT), arterial blood pressure, body mass index (BMI), cholesterol, triglycerides, glucose, insulin, lipoprotein(a) and homocysteine levels were measured, and PAI-1 and t-PA levels before and after venous occlusion (VO), and antibodies to HIV, HBV and HCV were assayed. At least one cardiovascular risk factor was detected in 87.5% of patients, and 2 or more in 47.5% of cases. At US exam, none of the patients had significant carotid stenosis or significant differences in IMT compared to controls. In contrast, all the patients had a significant FMD impairment, associated with a reduced t-PA release after VO in 70% of cases. PAI-1 levels significantly correlated with BMI, triglycerides and insulin values. Fifteen haemophilia patients with chronic viral hepatitis and/or HIV infection showed a significantly lower FMD than patients without active infection. We found an endothelial dysfunction with impaired FMD and t-PA release in our haemophilia patients, usually associated with cardiovascular risk factors. Other pathogenic mechanisms, such as chronic viral infections, are likely to be involved in this endothelial damage, however.

Variations in fibrinolytic parameters and inhibin-A in pregnancy: related hypertensive disorders.

BACKGROUND: The mechanisms leading to pregnancy-related hypertensive disorders, and pregnancy-induced hypertension (PIH) and pre-eclampsia (PE) in particular, are still not clear. Diagnostic criteria are clinical because specific markers of the condition are lacking. A role of the fibrinolytic system has been suggested. OBJECTIVES: We aimed to evaluate the behavior of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), PAI-2, and the placental hormone inhibin-A in women with a normal pregnancy vs. women with pregnancies complicated by PIH or PE. METHODS: Blood samples were drawn between the 25th and 30th gestational week (GW) and between the 31st and 36th GW in order to assay t-PA, PAI-1, PAI-2 and inhibin-A; routine biochemical exams, ultrasonography umbilical artery pulsatility index (PI), placental weight and newborn weight were measured. RESULTS: In pregnancies complicated by hypertensive disorders, PAI-1 levels were higher than in controls and increased significantly after the 25th GW, especially in PE, as did inhibin-A. PAI-2 levels were significantly lower after the 30th GW in patients with PIH and PE. The PAI-1/PAI-2 ratio was significantly higher in PE patients than in controls as of the 25th GW, but only after the 30th GW in patients with PIH. Inhibin-A was significantly correlated with fibrinolytic parameters, and inversely with newborn weight. Receiver-operator characteristic curves for PAI-1 and inhibin-A showed a high sensitivity and specificity for PE. PAI-2 correlated with newborn and placental weight, and inversely with PI of the umbilical artery. CONCLUSIONS: Fibrinolytic tests (especially PAI-1) and inhibin-A monitoring during pregnancy may help in the early diagnosis of pregnancy-related hypertensive disorders.

Porphyrin-photosensitized processes: their applications in the prevention of arterial restenosis.

Photodynamic therapy (PDT) is based on the use of a photozensitising compound which is accumulated by rapidly proliferating cells. Subsequent irradiation with light wavelengths specifically absorbed by the photosensitiser promotes the generation of reactive short-lived oxygen species which cause an irreversible and selective damage. Endovascular interventions to correct obstructive arterial disease have been developed worldwide with excellent short term results. However, long term patency is still limited by the onset of restenosis, due to subsequent intimal hyperplasia (IH). IH is characterized by proliferation and migration of smooth muscle cells (SMC) and extracellular matrix production. Targeting of SMC by photozensitisers can be efficiently achieved by taking advantage of the receptors for low density lipoproteins (LDL) expressed by such cells. Thus, preference is given to hydrophobic compounds which readily partition in the lipid matrix of LDL. We developed a liposomal formulation of a highly hydrophobic photozensitising agent, Zn(II)-phthalocyanine (ZnPc). The liposome-delivered ZnPc was readily taken up by cultured SMC cells and preferentially localized in the Golgi apparatus. Red light irradiation of incubated SMC induced cell death. Extension of these investigations to an in vivo rabbit model showed that ZnPc mainly accumulated in the media layer, where PDT induces the main damage through cellular depletion due to apoptosis of SMC, changes in the extracellular matrix with generation of a barrier to cellular migration, and acceleration of re-endothelization. Initial clinical applications showed that PDT safely and effectively prevents restenosis after angioplasty up to a 6 month follow-up.

Identifying carriers of type 2N von Willebrand disease: procedures and significance.

The defective FVIII carrier function of von Willebrand factor (VWF) identifies type 2N von Willebrand disease (VWD), a variant with a pattern resembling hemophilia A. Type 2N characterization is based on the evaluation of the capacity of VWF to bind exogenous FVIII (VWF:FVIIIB). Here we report on a retrospective evaluation of hemostatic laboratory parameters most useful in detecting type 2N carriers. The diagnostic capacity of aPTT, FVIII, VWF:Ag, FVIII/VWF:Ag ratio, VWF:FVIIIB and VWF:FVIIIB/VWF:Ag ratio was evaluated in 21 type 2N VWD carriers. Twenty subjects were heterozygous for the R854Q mutation, one was heterozygous for the R760C missense mutation, which interferes with cleavage of the VWF propeptide. We found that prolongation of aPTT and decrease in FVIII and FVIII/VWF:Ag ratio were not frequent findings in type 2N carriers. The same was true for VWF:FVIIIB which was not always abnormal. On the contrary, VWF:FVIIIB/VWF:Ag ratio was always defective and its values were not related with FVIII and FVIII/VWF:Ag ratio or influenced by plasma VWF concentration. Given these results, we attribute the greatest significance to VWF:FVIIIB/VWF:Ag ratio in the diagnosis of type 2N defects, and only search for type 2N mutations, to validate the diagnosis, if the ratio proves abnormal.

Cardiovascular risk factors and ultrasound evaluation of intima-media thickness at common carotids, carotid bulbs, and femoral and abdominal aorta arteries in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a tendency for obesity, high insulin, and high 24-h blood pressure levels has been reported in children and adolescents. Increased intima-media thickness (IMT) is considered a measure of subclinical atherosclerosis and a predictor of myocardial infarction and stroke. OBJECTIVE: The objective of the study was to evaluate glucose metabolism, lipid profile, IMT of the abdominal aorta, right and left common carotids, carotid bulbs, and common femoral arteries in adult CAH patients. SUBJECTS: Nineteen (10 females, nine males; 28 +/- 3.5 yr) patients (12 salt wasting and seven simple virilizing) and 19 (10 females, nine males) healthy subjects matched for anthropometric parameters (age, sex, body mass index, smoking habit, waist to hip ratio, and blood pressure). METHODS: Glucose metabolism was studied using the oral glucose tolerance test and the homeostasis model assessment-insulin resistance. The echo-Doppler was used for arterial ultrasound. 17-Hydroxyprogesterone, androstenedione, testosterone, ACTH, plasma renin activity, total and high-density lipoprotein cholesterol, and triglycerides were measured. RESULTS: CAH patients had significantly higher fasting plasma insulin (11.6 +/- 6.20 microU/ml vs 5.18 +/- 2.4 microU/ml; P < 0.0001) and homeostasis model assessment-insulin resistance than controls (2.46 +/- 1.92 vs 1.12 +/- 0.58; P = 0.0033). IMT of the studied arteries was higher in CAH patients than controls. There was no correlation between IMT and cumulative glucocorticoid doses and androgen levels. CONCLUSION: A reduced insulin sensitivity and increased IMT were demonstrated in adults with CAH, who consequently need a follow-up for cardiovascular risk.

Diagnosis and follow-up of thrombotic thrombocytopenic purpura by means of von Willebrand factor collagen binding assay.

Thrombotic thrombocytopenic purpura (TTP) is characterized by intravascular thrombosis leading to consumption of large or unusually large von Willebrand factor (VWF) multimers. The usefulness of VWF collagen binding (VWF:CB) assay was assessed in detecting the decrease/absence of large VWF multimers or the presence of abnormally large forms in patients with TTP. Nine patients with TTP were studied during the acute phase of the disorder and the absence of large VWF multimers was demonstrated by means of the VWF:CB assay. These findings were confirmed by VWF multimer pattern analysis; VWF:CB deficiency appeared to correlate with abnormalities in large VWF multimers. The diagnostic potency of VWF:CB was especially evident when the values were expressed as VWF:CB/VWF:Ag ratio. VWF:CB was also used during the follow-up of the disorder to document improvement or restoration of large VWF multimers. VWF:CB was able to detect the absence or decrease of large VWF multimers better than VWF ristocetin cofactor (VWF:RCo); in fact, VWF:CB was defective when large VWF multimers persisted to be decreased, in contrast with what observed with VWF:RCo. In conclusion, VWF:CB is a simple test that appears to be useful, together with clinical symptoms and reduced platelet count, for the diagnosis and follow-up of TTP.