Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy.

An in-depth focused study of specific cases of patients with recurrent thrombosis may help to identify novel circumstances, genetic and acquired factors contributing to the development of this disorder. The aim of this study was to carry out a detailed and sequential analysis of samples from a patient suffering from early and recurrent venous and arterial thrombosis. We performed thrombophilic tests, biochemical, functional, genetic and glycomic analysis of antithrombin and other plasma proteins. The patient carried a new type I antithrombin mutation (p.Ile218del), whose structural relevance was verified in a recombinant model. Experiments with N-glycosidase F and neuraminidase suggested a nearly full desialylation of plasma proteins, which was confirmed by mass spectrometry analysis of transferrin glycoforms. However, partial desialylation and normal patterns were detected in samples collected at other time-points. Desialylation was noticeable after arterial events and was associated with low antithrombin activity, reduced platelet count and glomerular filtration rate. This is the first description of a global and transient desialylation of plasma proteins associated with thrombosis. The decrease in the strong electronegative charge of terminal glycans may modulate hemostatic protein-protein interactions, which in combination with a strong prothrombotic situation, such as antithrombin deficiency, could increase the risk of thrombosis.

Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.

Age-adjusted D-dimer (AADD) appears to increase the proportion of patients in whom pulmonary embolism (PE) can safely be excluded compared with conventional D-dimer (CDD), according to a limited number of studies. The aim if this study was to assess whether the use of an AADD might safely increase the clinical usefulness of CDD for the diagnosis of PE in our setting. Three hundred and sixty two consecutive outpatients with clinically suspected PE in whom plasma samples were obtained to measure D-dimer were included in this post hoc analysis of a previous study. CDD cutoff value was 500 ng/mL and AADD was calculated as (patient's age × 10) ng/mL in patients aged >50. Sensitivity, specificity, clinical usefulness (i.e., proportion of true-negative tests among all patients with suspected PE), and the proportion of false negatives were calculated for both AADD and CDD among patients with low-to-moderate clinical probability of PE according to Well's criteria. PE was confirmed in 98 patients (27%). Among 331 patients with low-to-moderate clinical probability of PE, sensitivity and clinical usefulness were 100 and 27.8% for CDD, respectively, and 100 and 36.5% for AADD, respectively. In 29 patients aged >50 with CDD >500 ng/mL, AADD showed values under its normal cutoff point, without false negatives for the diagnosis of PE (0%, 95% CI 0-11%). AADD increases clinical usefulness notably with respect to that of CDD in patients with clinical suspected PE without losing sensitivity in our cohort. The use of AADD apparently does not reduce the safety of CDD for the exclusion of PE.

Can the tandem measurement of age adjusted D-dimer and tissue plasminagen activator improve the clinical utility of a conventional D-dimer in the pulmonary embolism diagnosis?

BACKGROUND: The aim of this study was to evaluate if a sequential measurement of age adjust D-dimer (ADD) and tissue plasminogen activator (tPA) could increase the clinical utility in patients with suspected pulmonary embolism (PE) compared to a conventional D-dimer. METHODS: We measured a conventional D-dimer (CDD), an ADD alone and a sequential combination ADD and tPA (ADD/tPA combination) in a prospective sample of 127 outpatients with PE suspected. Diagnosis of PE was based on a strict protocol. Plasma sample to measure levels of tPA and D-dimer was obtained at enrollment, and CDD, ADD and tPA were assessed at the end of study. For CDD the cut-off value was 500 ng/mL and for ADD the cut-off value was defined as (patient's age x10) ng/mL in patients aged >50. We compared the sensitivity, specificity and clinical utility obtained for CDD, ADD alone, and ADD/tPA combination. RESULTS: PE was confirmed in 41 patients (32%). The sensitivity, specificity and clinical utility for CDD were 95%, 36% and 28%, respectively. The ADD/tPA combination and ADD alone demonstrated an increased in specificity of +29% and +12% respectively, and increased in clinical utility of +20% and +8%, respectively, compared to CDD, and this was obtained without loss of sensitivity. CONCLUSION: The ADD/tPA combination substantially increased the clinical utility in the PE diagnosis compared with conventional D-dimer, without reducing the security. The ADD/tPA combination could decrease the need for pulmonary vascular imaging for the PE diagnosis in nearly the half. These promising results should be validated prospectively.

Tissue plasminogen activator as a novel diagnostic aid in acute pulmonary embolism.

BACKGROUND: We evaluated the diagnostic efficacy of tissue plasminogen activator (tPA), using an enzyme-linked immunosorbent assay (ELISA) and compared it with an ELISA D-dimer (VIDAS D-dimer) in acute pulmonary embolism (PE). PATIENTS AND METHODS: We studied 127 consecutive outpatients with clinically suspected PE. The diagnosis of PE was based on a clinical probability pretest for PE and a strict protocol of imaging studies. A plasma sample to measure the levels of tPA and D-dimer was obtained at enrollment. Diagnostic accuracy for tPA and D-dimer was determined by the area under the receiver operating characteristic (ROC) curve. Sensitivity, specificity, predictive values, and the diagnostic utility of tPA with a cutoff of 8.5 ng/mL and D-dimer with a cutoff of 500 ng/mL, were calculated for PE diagnosis. RESULTS: PE was confirmed in 41 patients (32 %). Areas under ROC curves were 0.86 for D-dimer and 0.71 for tPA. The sensitivity/negative predictive value for D-dimer using a cutoff of 500 ng/mL, and tPA using a cutoff of 8.5 ng/mL, were 95 % (95 % CI, 88-100 %)/95 % (95 % CI, 88-100 %) and 95 % (95 % CI, 88-100 %)/94 %), respectively. The diagnostic utility to exclude PE was 28.3 % (95 % CI, 21-37 %) for D-dimer and 24.4 % (95 % CI, 17-33 %) for tPA. CONCLUSIONS: The tPA with a cutoff of 8.5 ng/mL has a high sensitivity and negative predictive value for exclusion of PE, similar to those observed for the VIDAS D-dimer with a cutoff of 500 ng/mL, although the diagnostic utility was slightly higher for the D-dimer.

Association of anaemia and mortality in patients with acute pulmonary embolism.

This study aimed to evaluate the relationship between anaemia and pulmonary embolism (PE) prognosis. We analysed a cohort of 764 patients with acute PE referred to a single center for diagnosis and management. Patients were divided into groups by quartiles of haemoglobin (Hb): Hb < 11.7 g/dl; Hb 11.7 to 12.9 g/dl; Hb 13.0 to 14.1 g/dl; Hb > 14.1 g/dl. Patients had a mean Hb of 12.9 g/dl, and values ranged from to 4.3 to 19.5 g/dl. Lower Hb was associated with recent bleeding, an impaired haemodynamic profile and higher creatinine. Patients in the lower Hb quartiles more commonly had female gender (p < 0.001), a diagnosis of cancer (p < 0.001), and an indication for an inferior vena cava (IVC) filter (p < 0.002), compared to patients in the higher Hb quartiles. Patients in higher Hb quartiles had higher survival at three months (75%, 86%, 90% and 91% for lowest to highest quartiles, respectively). On multivariate analysis, adjusting for known PE prognostic factors, low Hb proved to be an independent predictor of mortality (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.05 to 1.28 for each decrease of 1 g/dl). Hb level remained an independent predictor of all-cause mortality when cancer patients were excluded from the analysis (adjusted HR 0.81; 95% CI, 0.66 to 0.99; p = 0.04). Moreover, patients with anaemia showed a higher risk of fatal PE (unadjusted HR 1.19, 95% CI 1.04 to 1.37). In conclusion, in patients with acute symptomatic PE, anaemia severity is associated with worsened survival.

[Anti-factor Xa activity of enoxaparin for thromboprophylaxis in nonsurgical patients is dependent on body mass]. / La actividad anti-Xa depende del peso en pacientes médicos que reciben tromboprofilaxis con enoxaparina.

OBJECTIVE: Thromboprophylaxis with a fixed dose of low-molecular-weight heparin is recommended for hospitalized acutely ill medical patients. The purpose of this study was to assess whether the anti-factor Xa (anti-Xa) activity of enoxaparin prescribed for venous thromboembolism prophylaxis depends on body mass index (BMI) in patients hospitalized for an acute respiratory disease. PATIENTS AND METHODS: All patients admitted to the respiratory medicine department (January-December 2006) for an acute respiratory disease, and for whom pharmacologic thromboprophylaxis was indicated, were included in the study. Anti-Xa activity was measured 4 hours after administration of enoxaparin on the third day of hospitalization. The primary outcome was anti-Xa activity in relation to BMI. RESULTS: One hundred twelve patients were enrolled. Mean anti-Xa activity decreased with each BMI quartile (0.28, 0.23, 0.15, and 0.13 U/mL for quartiles 1, 2, 3, and 4, respectively). In the multivariate analysis, BMI was the only predictor of inadequate anti-Xa activity (odds ratio, 1.14; 95% confidence interval, 10.5-1.24; P< .002) after adjustment for age, sex, and serum creatinine levels. Two episodes of symptomatic proximal deep vein thrombosis were diagnosed in the month after hospitalization; both occurred in patients who had inadequate anti-Xa activity. CONCLUSIONS: Anti-Xa activity is dependent on BMI in hospitalized acute medical patients receiving enoxaparin for thromboprophylaxis.

Platelet dysfunction in primary thrombocythemia using the platelet function analyzer, PFA-100.

We measured platelet function by standard aggregometric tests and by the PFA-100 (Dade Behring, Newark, DE) in samples from 55 patients with primary thrombocythemia (PT) and 26 healthy volunteers. Platelet function was evaluated in platelet-rich plasma by aggregation tests. PFA-100 studies (closure time) were performed in citrated whole blood using collagen-adenosine diphosphate (ADP) and collagen-epinephrine cartridges. Plasma levels of von Willebrand factor (vWF) also were measured. The mean +/- SD closure time for patients vs volunteers for the collagen-epinephrine cartridge was prolonged (210.8 +/- 62.2 vs 118.1 +/- 19.6 seconds; P < .001); results were abnormal for 38 patients (69%). Results with the collagen-ADP cartridge also were abnormal in patients (134.3 +/- 58.4 seconds) vs volunteers (87.3 +/- 15.6 seconds; P < .001); closure time was prolonged in 23 patients (42%). A decreased response to epinephrine (38.4% +/- 34.2% vs 82.5% +/- 10.3%; P < .001), the main defect detected by platelet aggregation tests, affected 32 patients (58%). Platelet response to collagen also was abnormal (52.0% +/- 34.6% vs 86.0% +/- 10.1%; P < .01) but affected only 21 patients (38%). vWF levels for patients were normal. The results seem to confirm that platelet function in patients with PT is abnormal and show that platelet function can be assessed by an easy, reproducible, and sensitive method, the PFA-100. Closure time usually was prolonged; this feature could be applied in the diagnosis of PT.

Aging and oral anticoagulant therapy using acenocoumarol.

We evaluated the influence of aging, gender and indications of anticoagulant therapy on acenocoumarol requirements in 1845 patients from 30 to 99 years old receiving acenocoumarol therapy who were monitored in our hospital outpatient anticoagulation clinic from March 1993 through September 1999. The patients were stratified in seven age groups, comprising older than 80 years and the five decades between 30 years and 80 years. We found a progressive decrease in the acenocoumarol requirements from 30 years to 80 years (rho=-0.98), which was estimated as 2.7 mg/week per decade (11.5% per decade). This decrease was not the consequence of a different range of anticoagulation or differences in body weight. We did not find correlation between the decrease of acenocoumarol requirements and different biochemical parameters including, creatinine, calcium and alanine aminotransferase. We detected a progressive decrease in levels of serum total proteins but changes in this parameter did not correlate with the amount of acenocoumarol requirements. The dose of acenocoumarol (mg/week per patient) of those patients suffering from venous thromboembolism were higher than the remainder of the patients (18.4 +/- 9.3 versus 14.5 +/- 7.8, P <0.0001). This finding was also detected, after stratifying the patients by decades, from 60 years to 80 years. In conclusion, requirements of acenocoumarol decrease with aging; this decrease represents an important amount from 30 years to 80 years and it should be kept in mind to choose the initial dose of acenocoumarol. Patients with venous thromboembolism required a higher dose of acenocoumarol.

Tissue plasminogen activator plasma levels as a potential diagnostic aid in acute pulmonary embolism.

CONTEXT: Pulmonary embolism (PE) is a potentially fatal and frequent complication of deep venous thrombosis, and the most reliable techniques for the diagnosis of PE are not universally available and have other limitations. OBJECTIVE: To determine the efficacy of 4 different fibrinolysis system parameters, namely, tissue plasminogen activator (tPA), tissue plasminogen activator inhibitor type 1 (PAI-1), plasmin-antiplasmin complexes (PAP), and D-dimer, in the diagnosis of acute PE. SETTING: A 350-bed university hospital serving an area with 280,000 inhabitants. PATIENTS: Sixty-six consecutive outpatients with clinically suspected PE. The diagnosis of PE was based on ventilation-perfusion (V/Q) lung scan in combination with clinical assessment, lower limb study, and (when required) pulmonary angiography. MAIN OUTCOME MEASURES: At the moment of clinical suspicion, a sample of venous blood was obtained to measure levels of tPA, PAI-1, PAP, and D-dimer using an enzyme-linked immunosorbent assay method. RESULTS: Twenty-seven patients (41%) were classified as PE positive (high clinical probability and V/Q lung scan [n = 12], nondiagnostic V/Q lung scan and high clinical probability [n = 1], inconclusive V/Q lung scan and positive lower limb examination for deep venous thrombosis [n = 11], and positive pulmonary angiography [n = 3]), and 39 patients (59%) were classified PE negative. The sensitivity/negative predictive value for tPA, using a cutoff of 8.5 ng/mL, and PAI-1, using a cutoff of 15 ng/mL, were 100%/100% and 100%/100%, respectively. A tPA level lower than 8.5 ng/mL occurred in 13 (19.7%; all PE negative) of 66 patients with suspected PE, and PAI-1 levels were lower than 15 ng/mL in 9 (13.6%; all PE negative) of 66 patients with suspected PE. The D-dimer, using a cutoff of 500 ng/mL, showed a sensitivity and negative predictive value of 92.6% and 87.5%, respectively. CONCLUSIONS: Our data indicate that tPA and PAI-1 levels are potentially useful in ruling out PE, although tPA seems to be the better parameter. The sensitivity levels and negative predictive values for the rapid enzyme-linked immunosorbent assay for D-dimer used in this investigation were low compared with previous studies using the same test.

Dos nuevos casos de hepatitis E autóctonos / Two new cases of autochthonous hepatitis E

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