Jaroslav Maly

Prothrombotic changes due to an increase in thyroid hormone levels.

OBJECTIVE With increasing free thyroxine levels, a gradually rising risk of venous thromboembolism has been described in case-control studies. However, reports on the influence of thyroid hormones on haemostasis, while suggesting a hypercoagulable state in thyrotoxicosis, have often been inconclusive. This study evaluates multiple markers of haemostasis and fibrinolysis in a paired design, making it more sensitive to changes in thyroid hormone levels. DESIGN We analysed multiple variables in patients who shifted from severe hypothyroidism to mild hyperthyroidism during thyroid cancer treatment. Those with possible residual disease were excluded. METHODS Ninety patients following total thyroidectomy were tested on two occasions: i) before radioiodine remnant ablation and ii) 6 weeks later, on levothyroxine (lT4) suppression treatment, and the results were compared using the Wilcoxons test for paired data. RESULTS During lT4 treatment, significant increases (all P<0.001) in fibrinogen (from median 3.4 to 3.8 g/l), von Willebrand factor (from 85 to 127%), factor VIII (from 111 to 148%) and plasminogen activator inhibitor 1 (from 6.5 to 13.9 μg/l) were observed. In addition, the activation times of platelet adhesion and aggregation stimulated with collagen and epinephrine (EPI)/ADP, i.e. closure times in platelet function analyser (PFA-100), were significantly shortened (P<0.001): for EPI from median 148 to 117 s and for ADP from 95 to 80 s. Changes in other tests were less prominent or insignificant. CONCLUSIONS An increase in thyroid hormone levels shifts the haemostatic balance towards a hypercoagulable, hypofibrinolytic state. This may contribute to the increased cardiovascular morbidity and mortality observed even in mild thyrotoxicosis.

Cardiac troponin I seems to be superior to cardiac troponin T in the early detection of cardiac injury associated with anthracycline treatment.

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 Information@Karger.de www.karger.com liver and renal function during the study. Cardiac evaluation was performed at baseline (before CT), the day after the first CT with anthracyclines (mean cumulative dose 135.8 ± 28.5 mg/m2, median 150), the day after the last CT with anthracyclines (mean cumulative dose 472.1 ± 115.0 mg/m2, median 423), and approximately 6 months after completion of CT. Concentrations of cardiac troponins diagnostic for cardiotoxicity of oncology treatment have not yet been established. In our study, values above the reference range recommended by the manufacturer were considered elevated. The cut-off value for cTnT was 0.01 μg/l (Roche Diagnostics), and for cTnI 0.40 μg/l (Randox Laboratories Ltd.). Echocardiographic evaluation was performed on a Hewlett Packard Image Point machine by an experienced echocardiographer who was blinded to the cardiac troponin data. Parameters of systolic and diastolic left ventricular (LV) function were assessed. Systolic LV dysfunction was defined as LV ejection fraction (LVEF) ≤ 55%. Diastolic LV dysfunction was defined as E/A inversion and a E wave deceleration time above 220 ms on the transmitral Doppler curve (impaired relaxation). Statistical analysis was performed with Statistica for Windows, version 5.0 (StatSoft, Tulsa, OK, USA). Analysis of variance test was used. Correlations were evaluated with normal and Spearman correlation tests. The values are expressed as mean ± standard deviation (SD). Probability values (p) of < 0.01 were considered statistically significant. The results are summarized in table 1. Of the cardiac troponins, only cTnI became positive on the days after the first and last CT with anthracyclines, which was observed in a total of 4 (17.4%) patients. Positivity of cTnI correlated with systolic and diastolic LV dysfunction on echocardiography: r = 0.712; p < 0.00001 and r = 0.591; p < 0.0001, Cardiac toxicity is among the undesirable side effects of oncology treatment. Of the cytostatics, anthracyclines represent the greatest risk for development of cardiotoxicity [1]. Various methods have been recommended for monitoring cardiotoxicity in oncology [2, 3]. Echocardiography and electrocardiography are routinely used, and recently, the applicability of cardiac troponins in the detection of cancer therapy-induced cardiotoxicity has been investigated [4]. In some studies, administration of anthracyclines did not cause any elevation of cardiac troponins [5–7]. In other studies, cardiac troponins became positive after anthracycline treatment, correlated with disease severity, and were suggested as predictors of subsequent major cardiac events during follow-up [8–10]. The results of clinical studies are inconsistent, and cardiac troponins have not been established in clinical practice for monitoring cardiotoxicity in oncology. The aim of our study was to evaluate acute and chronic cardiotoxicity of anthracyclines with cardiac troponins. We used current immunoassays for cardiac troponin T (cTnT; Roche Diagnostics, Mannheim, Germany) and cardiac troponin I (cTnI; Randox Laboratories Ltd., Crumlin, Co. Antrim, UK), and correlated the results with echocardiography findings. A total of 23 patients (mean age 47.0 ± 11.1 years; 14 males, 9 females) with acute leukemia were studied. The patients were treated with 3–6 cycles of conventional chemotherapy (CT) containing anthracyclines at a total cumulative dose of 472.1 ± 115.0 mg/m2; to calculate the total cumulative anthracycline dose, we applied conversion factors derived from the maximum recommended cumulative doses for the individual agents used (idarubicin, daunorubicin, mitoxantrone). Six patients were treated for arterial hypertension; other patients had no history of cardiovascular disease. All patients had normal Cardiac Troponin I Seems to Be Superior to Cardiac Troponin T in the Early Detection of Cardiac Injury Associated with Anthracycline Treatment

Prevalence of hypercoagulable disorders in inflammatory bowel disease

Abstract Objective. Inflammatory bowel disease (IBD) can be associated with hypercoagulable disorders. Aim of this single-center, prospective study was an in-depth evaluation of acquired hypercoagulable states in IBD patients. Methods. A total of 110 patients with Crohns disease (CD) (aged 19–69; mean 40.5, median 38.5 years), 43 with ulcerative colitis (UC) (aged 17–72; mean 42, median 36 years), and 30 controls were enrolled. Full blood count, serum C-reactive protein (CRP), proteins C and S, activated protein C (APC) resistance, thrombin–antithrombin complex (TAT), F1+F2 fragments, tissue factor pathway inhibitor (TFPI) total and truncated, TFPI-factor Xa, tissue plasminogen activator (tPA) and PAI-I antigen were investigated in peripheral blood samples. Results. Only 18 of 153 (11.8%) IBD patients had hemocoagulation parameters within normal range. Significant difference between IBD patients and controls was found in thrombocyte volume (p < 0.001), protein C (p = 0.025), protein S (p = 0.003), APC resistance (p < 0.001), F1+F2 fragments (p < 0.001), and tPA (p = 0.002). In CD patients who were divided into two subgroups according to serum CRP values (non-active disease: <5 mg/L; active disease ≥5 mg/L), thrombocyte count was significantly lower (p = 0.001), thrombocyte volume was significantly higher (p = 0.002), F1+F2 fragments were significantly lower (p = 0.007) and tPA was significantly higher (p = 0.038) in the subgroup with CRP <5 mg/L. In UC patients, no significant difference depending on CRP was found. Conclusions. Acquired hypercoagulable abnormalities in IBD patients are frequent. Patients with active CD, but not UC, displayed significantly different hemocoagulable parameters, when compared to non-active CD/UC subjects. In patients with active CD (with increased serum CRP concentration) and patients with active extensive UC found at endoscopy (despite low CRP values), prophylactic anticoagulation therapy should be considered.

Biomarkers for the early detection of anthracycline-induced cardiotoxicity: current status

BACKGROUND Cardiotoxicity is a well-known and potentially serious complication of anticancer therapy. Anthracycline-based chemotherapy represents the greatest risk. Early detection of cardiotoxicity is crucial for applying preventive and supportive therapeutic strategies. METHODS AND RESULTS Various methods have been recommended for monitoring of cardiotoxicity. In our conditions, echocardiography and electrocardiography are routinely used. However, this approach shows low sensitivity for the early prediction of cardiomyopathy when the possibilities of appropriate management could still improve the patients outcome. Recently, biomarkers of cardiac injury have been investigated in the assessment of chemotherapy-induced cardiotoxicity. Cardiospecific biomarkers, such as cardiac troponins, show high diagnostic efficacy in the early subclinical phase of the disease before the clinical onset of cardiomyopathy. Increase in their concentrations correlates with disease severity. As for natriuretic peptides, some studies, including ours, have shown promising results. Definitive evidence of their diagnostic and prognostic role in this context is still lacking and natriuretic peptides have not been routinely used for monitoring of cardiotoxicity in clinical practice. Other perspective biomarkers of cardiotoxicity in oncology are under study, especially heart-type fatty acid-binding protein (H-FABP) and glycogen phosphorylase BB (GPBB). Our studies using GPBB have provided encouraging results. However, the available data are limited and their practical use in this context cannot be recommended until their clinical efficacy is clearly defined. CONCLUSIONS This review covers the current status of biomarkers for the early detection of anthracycline-induced cardiotoxicity. The authors present in brief, their own experience with multiple biomarkers in the detection of cardiotoxicity.

Angiopoietin-2 mRNA expression is increased in chronic lymphocytic leukemia patients with poor prognostic features

Abstract Several studies have demonstrated the potential prognostic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Elevated expression of angiopoietin-2 (Ang-2), an angiogenic cytokine, was recently reported in CLL. However, data regarding prognostic significance of Ang-2 in CLL are limited. Therefore, we quantitated Ang-2 mRNA in purified mononuclear cells of 33 untreated CLL patients and compared the transcript levels to traditional as well as modern prognostic factors in patients with CLL (clinical stage, disease course, IgVH mutation status, CD38, and ZAP-70 expression). Elevated Ang-2 mRNA concentrations were detected in 12 cases; 21 patients had very low or undetectable levels of Ang-2 transcript. There was significant association between high Ang-2 mRNA levels and unmutated IgVH genes (n=27, P=0·010) and with CD38 expression (n=32, P=0·011), but not with ZAP-70 expression (n=32, P=0·784), Rai stage (n=33, P=0·305) or stable versus progressive clinical course (n=33, P=0·443). There was a trend towards shorter progression-free survival in patients with high Ang-2 expression; however, it did not reach statistical significance (P=0·090). Our pilot data show that Ang-2 mRNA is differentially expressed in patients with CLL and its increased expression appears to be associated with poor prognostic features. Further studies are needed to confirm the results in a larger patient cohort.

Risk of Thrombosis in Patients Homozygous and Heterozygous for Factor V Leiden in the East Bohemian Region

A retrospective investigation on the frequency of thrombotic events in 227 heterozygous and 16 homozygous carriers for the factor V R506Q mutation (factor V Leiden) from 102 unrelated families in the East Bohemian region is reported. A majority of 130 of the 227 (57%) heterozygous and a minority of 5 of 16 (31 %) homozygous carriers for the factor V R506Q mutation remained asymptomatic. Deep venous thrombosis without pulmonary embolism in a minority was the main and the most frequent clinical manifestation in 97 of 243 carriers for the factor V R506Q mutation. Deep venous throm bosis occurred in 92 of 227 (41%) heterozygous and in 11 of 16 (69%) homozygous carriers of the factor V R506Q. Spontane ous thrombosis prevailed in symptomatic men. Thrombosis in women usually occurs during risk situations well known to elicit venous thrombosis. Oral contraceptives and pregnancy were significantly the most frequent risk factors in female car riers of the factor V R506Q mutation, which in fact can readily explain the lower average age for the first thrombotic event of 30.6 years in women compared to 37.1 years in men.

The decrease of mean platelet volume after extracorporeal LDL-cholesterol elimination

OBJECTIVE Mean platelet volume is arousing increasing interest as a new independent cardiovascular risk factor. Large platelets are likely to be more reactive. If mean platelet volume would drop after LDL-lowering therapy, decreased MPV could be one of the markers of successful therapy. Therefore, we investigated mean platelet volume after extracorporeal LDL-cholesterol elimination. METHODS Mean platelet volume was investigated in patients with severe familial hypercholesterolemia long-term treated (3-12 years) by LDL-apheresis (immunoapheresis) or cascade filtration. Plasma was obtained by centrifugation. Adsorbers Lipopak 400 were used for immunoapheresis and filters Evaflux 4A were used for cascade filtration. 95 pair samples were measured (before and after the procedures) in a group of 12 patients--each patient 8 times in 4 years. RESULTS Mean platelet volume before the procedures was 10.891 fl, CI 10.25-11.53. Mean platelet volume after the procedures decreased--10.478 fl, CI 09.84-11.11. The difference is statistically significant (p = 0.036). Mean platelet volume did not correlate with age, sex, platelet count, duration of therapy. At the same time, we used rheohemapheresis in the therapy of 40 patients with age-related macular degeneration. But mean platelet volume was not changed. CONCLUSION Mean platelet volume is easily available and is often disregarded, and sometimes may suggest the need for a careful assessment in patients with familial hypercholesterolemia. Mean platelet volume could be one of the markers of therapeutic efficacy in patients with familial hypercholesterolemia treated by extracorporeal LDL-cholesterol elimination that is simple and inexpensive.

New biomarkers of myocardial injury and assessment of cardiac toxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia

No Abstract available

Significant change in ZAP-70 expression during the course of chronic lymphocytic leukemia.

Introduction:  It is widely accepted that expression of ZAP‐70 in chronic lymphocytic leukemia (CLL) remains stable in time. However, data supporting this notion are surprisingly scarce. Therefore, we assessed expression of ZAP‐70 in serial samples taken during the course of the disease.

Good Short-Term but not Long-Term Reproducibility of the Antiplatelet Efficacy Laboratory Assessment

Background: The antiplatelet effect of acetylsalicylic acid (ASA) varies among individual patients. We assessed the short-term reproducibility (STR) and long-term reproducibility (LTR) of light transmission aggregometry (LTA). Methods: Residual platelet reactivity was measured twice using LTA in a group of 207 consecutive patients (56 females, mean age 67 ± 9 years) on ASA therapy in 10 ± 6 months interval. The STR was assessed in 15 patients (6 females, mean age 61 ± 7 years) with 10 measurements on 2 consecutive days. Results: There was no correlation between both measurements in the long-term part of the study, and also Bland-Altman plot showed a diverging pattern. However, LTA STR was good with a correlation coefficient of .800 (P < .05) confirmed by Bland-Altman plot. Conclusions: Although short-term intraindividual reproducibility of LTA assessment of platelet reactivity is very good, in the long-term perspective the antiplatelet ASA effectivity may be influenced by additional variables and repeated measurements are warranted.