[Correlations between secondary hypogammaglobulinaemia, infections and mortality and the need for preventive immunoglobulin replacement in patients with chronic lymphoid leukaemia]. / A másodlagos hypogammaglobulinaemia, a fertozések és a halálozás összefüggései és a preventív immunglobulin-pótlás szükségessége krónikus lymphoid leukaemiás betegekben.

Immune status was investigated in 186 patients with chronic lymphoid leukaemia between January 2012 and March 2015. Incidences of infections and mortality were analysed in patients who did not receive prophylactic immunoglobulin therapy. Immunoglobulin G (IgG) levels were normal (7-17.8 g/L) or decreased in 62.37% and 35.48% of patients, respectively. We measured high immunoglobulin levels only in a few cases (2.15%). Immunoglobulin levels became increasingly lower in more advanced disease stages (Rai stages). The number of infections was inversely proportional to that. Hypogammaglobulinaemia proved to be more important than disease progression in terms of the development of infections. The most common infections were upper respiratory tract (33.07%) and sepsis (18.90%). Two months after chemotherapy, initially normal immunoglobulin levels decreased by an average of 21%, and at the same time the incidence of infections increased. The most common cause of death was sepsis: 30% occurred at low immunoglobulin levels, while 20% at normal immunoglobulin levels. According to literature, prophylactic immunoglobulin treatment is indicated in patients with chronic lymphoid leukaemia and immunodeficiency for decreasing both morbidity and mortality. According to recommendations in literature, replacement treatment must be administered in severe or moderately severe recurrent bacterial infections. Immunoglobulin prophylaxis may be provided as low dose (10 g), fix dose (18 g) or individually customized higher dose (300-400 mg/kg body weight) treatment. According to recommendations, higher dose immunoglobulin prophylaxis, administered every three weeks on six occasions, is more efficient when customized. With this dose, infection-free condition may be achieved in 50% of patients. Orv Hetil. 2019; 160(38): 1487-1494.

Detection of high-risk thrombophilia with an automated, global test: the Coagulation Inhibitor Potential assay.

: The diagnosis of thrombophilia is a cost-consuming and time-consuming process, as each defect should be separately investigated. The Coagulation Inhibitor Potential (CIP) assay is a promising new global test, sensitive for most of the hereditary thrombophilias, developed for manual methodology. We adapt the original method to an optical coagulation analyser. By this automation, the test will be easier, faster and more precise, and it also allows carrying out 18 measurements simultaneously. The CIP assay was performed in 126 healthy subjects and 193 patients with different types of hereditary thrombophilia conditions. Detected with conventional laboratory tests high-risk thrombophilia was present in 70 patients: deficiencies of antithrombin (AT) (n = 12), protein C (PC) (n = 14), protein S (PS) (n = 6), homozygous factor V Leiden (FVL) mutation (n = 9) and combined types (n = 29). Low-risk thrombophilia was present in 123 patients: heterozygous FVL (n = 115) and FII G2010A mutation (n = 8). Significantly lower median CIP values were found for AT-,PC-, PS deficiencies, homozygous and heterozygous FVL mutations and combined thrombophilias (P < 0.01) as compared with healthy controls. There was no significant difference between the heterozygous FIIG20210A (P = 0.669) thrombophilia group and the healthy controls. The best performance of the test was achieved at the cut-off value of 90.0 U (area: 0.981) with 96% sensitivity and 92% specificity in the high-risk thrombophilia group estimated by receiver operating characteristic analysis. The new method seems to be appropriate and reliable for the detection of AT-, PC- and PS deficiencies, homozygous FVL mutation and also for combined deficiencies. The automated CIP test is insensitive to FII G2010A mutation.

Efficacy and Tolerability of a 2-Year Rituximab Maintenance Therapy in Patients with Advanced Follicular Lymphoma after Induction of Response with Rituximab-Containing First Line-Regimens (HUSOM Study).

Follicular lymphoma is a lymphoid malignancy commonly showing slow progression which makes the treatment of the disease challenging. Rituximab monotherapy and rituximab added to standard chemotherapy has been proven to increase survival among patients with advanced stage of the disease. However, the benefit of a rituximab maintenance therapy after induction was still unclear at the time of the initiation of this study. HUSOM was a phase III open-label, single-arm, multi-centre study aimed to assess the efficacy and the safety of the 12 cycles of rituximab (375 mg/m2 every 8 weeks) maintenance therapy in patients had already presented partial or complete response to R-CVP or R-CHOP. Efficacy endpoints such as event-free survival and overall survival were estimated. Adverse events were recorded during the entire course of the study. A total number of 124 patients were enrolled by 15 Hungarian study sites. Out of these, 86 patients received 12 cycles of rituximab and 69 patients completed the 3-year follow-up phase as well. The probabilities of the event free survival and progression at 4.3 years were estimated to be 70.3% and 74.4%, respectively. The overall and the disease free survival at 4 years were estimated to be 90.7% and 87.9%, respectively. A total number of 85 adverse events were reported during the study out of which 5 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those reported by controlled clinical trials (EORTC 20981, PRIMA) conducted in parallel with the HUSOM study.

Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center.

INTRODUCTION: Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. PATIENTS AND METHODS: Non-related AT deficient patients (n=156) and their family members (total n=246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. RESULTS: Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. CONCLUSION: Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.

[The role of autologous hemopoietic stem cell transplantation in T-cell lymphoma. Hungarian data]. / Autológ haemopoeticus ossejt-transzplantáció szerepe T-sejtes lymphomában. Magyar adatok.

T-cell lymphoma is a poor prognostic hematological malignancy. The generally used - not sufficiently effective - induction chemotherapy should be improved with consolidative autologous hemopoetic stem cell transplantation. The authors describe the role, place and effectiveness of transplantation in this disorder. One hundred thirty three autologous stem cell transplantations were performed in the last 22 years in Hungary. Detailed results are available from the last 6 years. In this period 43 transplantations were carried out in 4 Hungarian centers. Carmustine-etoposide-cytosine arabinoside-melphalan (BEAM) conditioning regimen was used in 95%. The transplantation was done mainly in complete remission (84%), 1 year after transplantation 65% of patients were still in complete remission. Eleven patients died, 82% of them have progressive disease. Brentuximab vedotin has already proved the effectiveness, several other chemoterapeutics, monoclonal antibodies, kinase inhibitors are under investigation. In certain cases allogeneic stem cell transplantation has real indication among therapeutic options. Orv Hetil. 2017; 158(41): 1615-1619.

[Actual questions about the prevention of venous thromboembolism in cancer patients receiving chemotherapy]. / A kórházi és az ambuláns kemoterápiában részesülo onkológiai betegek vénásthromboembolia-profilaxisának aktuális kérdései.

Cancer patients have a 2-7 fold increased risk of venous thromboembolism compared with the general population and, since 1990, this is associated with significant morbidity and mortality. This review summarizes the current knowledge on venous thromboembolism and cancer. Notably, the risk of venous thromboembolism varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of venous thromboembolism than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors, cytokines and growth factors may directly and indirectly enhance venous thromboembolism. Chemotherapy produces ~6,5 fold increase in venous thromboembolism incidence in cancer patients compared to the general population. Prevention of this complication is challenging. The authors review the development of guidelines concerning venous thromboembolism prevention in hospitalized and also in ambulatory cancer patients treated with chemotherapy. Current guidelines recommend the use of low-molecular-weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent venous thromboembolism in cancer patients.

Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant women.

INTRODUCTION: Normal pregnancy is associated with hypercoagulable state. Elevated markers of coagulation and fibrinolytic system activation indicate increased thrombin activity and increased fibrinolysis following fibrin formation throughout pregnancy. These changes exceed the biological variability in most cases. Haemostatic reference intervals are generally based on samples from non-pregnant women. Thus, they may not be relevant to pregnant women, a problem that may hinder accurate diagnosis and treatment of haemostatic disorders during pregnancy. The aim of the study was to follow the changes of haemostatic parameters and to establish gestational age-specific reference intervals during normal pregnancy. MATERIALS AND METHODS: Blood samples of 83 pregnant women were collected at gestational weeks 16, 26 and 36. Fibrinogen, D-dimer, and C-Reactive Protein (CRP) were examined. Reference intervals were calculated for fibrinogen, D-dimer tests with two different methods (mean±2 SD or median and 2.5th and 97.5th percentiles with 90% confidence intervals). RESULTS: fibrinogen and D-dimer increased progressively throughout pregnancy. Mean fibrinogen levels were higher than the maximum of the conventional reference interval, already in the 16th week of pregnancy. D-dimer levels were at or above the conventional cutoff point (250ng/mL) throughout the pregnancy in 42% of pregnant women, while in the 36th week 98% of them displayed elevated D-dimer levels. CRP did not increase in normal pregnancy. CONCLUSIONS: There seems to be an emerging need to reconsider fibrinogen and D-dimer values from a different aspect in pregnancy compared to non-pregnant reference intervals. New reference ranges are suggested to be established in pregnancy.

[Questionnaire for assessing the risk of venous thromboembolism in hospitalized surgical and non-surgical patients in the 4th Hungarian antithrombotic guideline entitled "Risk reduction and treatment of venous thromboembolism"]. / Vénásthromboembolia-kockázati kérdôív kórházban kezelt sebészeti és nem sebészeti betegek részére "A thromboemboliák kockázatának csökkentése és kezelése" címu, 4. magyar antithromboticus irányelvben.

A large proportion of hospitalized surgical and medical patients are at risk for venous thromboembolism. Depending on the type of surgical intervention, venous thrombosis develops in 15-60% of surgical patients without prophylaxis. Although venous thromboembolism is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic events and 70 to 80% of fatal pulmonary embolisms occur in nonsurgical patients. International and national registries show that the majority of at-risk surgical patients actually received the appropriate thromboembolic prophylaxis. However, despite of international and national recommendations, prophylaxis was not provided for a large proportion of at-risk medical patients. The rate of medical patients receiving prophylaxis should be increased, and appropriate thrombosis prophylaxis should be offered to at-risk medical patients. The thrombosis risk assessment is an important tool to identify patients at increased risk for venous thromboembolism, to simplify decision making on prophylaxis administration, and to improve the adherence to guidelines. When the risk is recognized, if there is no contraindication, prophylaxis should be ordered. The 4th Hungarian Antithrombotic Guideline entitled "Risk reduction and treatment of thromboembolism" calls attention to the importance of risk assessment and for the first time it includes and recommends risk assessment models for hospitalized surgical and medical patients. The risk assessment models are presented and the evidence based data for the different risk factors included in these models are reviewed.

[Results of ENDORSE-2-HUNGARIA study. Repeated assessment of the prevalence of venous thromboembolism risk and prophylaxis in acute hospital care setting]. / Az ENDORSE-2-HUNGARIA vizsgálat eredményei. Az akut kórházi betegek vénásthromboembolia-kockázatának és -profilaxisának ismételt hazai felmérése.

ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study in 2006, was a multinational cross-sectional survey designed to assess the prevalence of venous thromboembolism (VTE) risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive appropriate prophylaxis. From the 358 randomly selected hospitals across 32 countries in the global registry, 9 Hungarian centers were included. According to the Hungarian results, the use of appropriate prophylaxis was more common in surgical patients but much less common in medical patients comparing to the worldwide average. ENDORSE 2-HUNGARY was a local survey to compare the prophylactic habits after two years and two months time period. In both surveys, the 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines were used to assess venous thromboembolism risk and to determine whether patients were receiving recommended prophylaxis. The one day survey ENDORSE 2-HUNGARY was repeated beside seven already audited hospitals, and in two newly recruited hospitals. A total of 886 patients were assessed for thrombosis risk on the basis of hospital chart review. Of these patients 59.0% (N=523) were judged at risk for VTE, including 100% (N=327) surgical and 35.1% (N=196) medical patients. 67.9% (N=355) of the total at-risk patients received ACCP-recommended VTE prophylaxis. Among surgical patients, 84.4% (N=276) received recommended prophylaxis compared with 40.3% (N=79) of medical patients. Results of the ENDORSE in 2006 and 2009 were compared, as well. The rate of appropriate prophylaxis use in at-risk patients did not changed significantly in surgical patients, however, a significant, 43.9% increase was found in medical patients (p=0.002), that proves the success of lectures presenting the facts and focusing to increase medical prophylaxis during the time period between the two studies. 59.7% of at-risk medical patients and 15.6% of surgical patients were unprotected against thrombosis in 2009. We should further increase the rate of at-risk patients receiving appropriate prophylaxis. We should reinforce the rationale for the increase of awareness of VTE risk in hospitalized medical patients, and to enhance the prophylaxis practice among healthcare professionals.

[Results of ENDORSE study in Hungary. Multinational, cross-sectional study to assess the prevalence of venous thromboembolism risk and prophylaxis in acute hospital care setting]. / Az ENDORSE vizsgálat magyarországi eredményei: az akut kórházi betegek vénásthromboembolia-kockázatának és -profilaxisának nemzetközi, keresztmetszeti felmérése.

Information about the risk of venous thromboembolism and prophylactic practices around the world is limited. ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study is a multinational cross-sectional survey designed to assess the prevalence of venous thromboembolism (VTE) risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive appropriate prophylaxis. All hospital inpatients aged 40 years or above admitted to a medical ward, or those aged 18 years or above admitted to a surgical ward, in 358 randomly selected hospitals across 32 countries were assessed for risk of VTE on the basis of hospital chart review. The 2004 American College of Chest Physicians evidence-based consensus guidelines were used to assess venous thromboembolism risk and to determine whether patients were receiving recommended prophylaxis. Nine Hungarian centers were included in the international survey, and a total of 1300 patients were assessed for thrombosis risk in Hungary. Of these patients 39.9% (N=519) were judged at risk for VTE, including 58.2% (N=253) surgical and 30.8% (N=266) medical patients. 56.6% (N=294) of the total at-risk patients received ACCP-recommended VTE prophylaxis. Among major surgery patients 86.6% (N=219) received recommended prophylaxis compared with 28.2% (N=75) of medical patients. In Hungary more than two-thirds of at-risk hospitalized medical patients did not receive appropriate prophylaxis. ENDORSE results reinforced that a large proportion of hospitalized surgical and medical patients are at risk for VTE worldwide as well as in Hungary. The rate of at-risk patients receiving appropriate prophylaxis should be urgently increased.

[Frequency of coagulopathies in cases with post-tonsillectomy bleeding]. / Coagulopathiák gyakoriságának vizsgálata tonsillectomiákat követo utóvérzések eseteiben.

INTRODUCTION: The most serious complication of tonsillectomy is haemorrhage. Primary post-tonsillectomy bleeding occurs during the first 24 hours following the procedure as a consequence of inadequate suturing/ligation of the feeding arteries. Secondary post-tonsillectomy bleeding occurs most frequently between the 5-8. postoperative days. The role of different risk factors has intensively been examined in the background of secondary post-tonsillectomy bleedings, however, their real role is rather confusing. AIM: The aim of the present study was to examine whether preoperative haematological screening in order to detect hidden coagulopathies in the background of post-tonsillectomy bleedings is reasonable or not. METHOD: Of the 115 patients who were admitted to the Department of Otorhinolaryngology, Head and Neck Surgery, Medical School, University of Pécs, between 2002 and 2004, 107 patients (59 female, 48 male, average age 29+/-10.9 years) were asked to undergo screening of the following factors: thrombocytes, bleeding time using the Ivy method, thrombin time, activated partial prothrombin time, prothrombin/INR ratio, fibrinogen level. RESULTS: Of the 58 patients who accepted the invitation 28 (49%) presented with abnormal screening results. Isolated factor determination was recommended to all of them, however, only 19 patients (68%) turned up for the second screening. In 2 cases--3.4% of the re-examined patients--unknown coagulopathy was diagnosed: isolated factor VII underproduction in 1 patient and combined factor VII and XII underproduction also in 1 patient. Three female patients presented with a surprising isolated factor IX overproduction which proned them to thrombosis: all 3 patients had been on oral anticoncipients. CONCLUSIONS: From this study several conclusions can be drown for the practising physician: 1. the universal preoperative haematological screening does not seem to be cost-effective; 2. in cases of children, especially if the family history and also both the preoperative history and detailed physical examination are suspicious (e.g. recurrent mild nasal bleedings!) hidden coagulopathy needs to be ruled out; 3. in our study activated partial thromboplastin time seemed to be the most sensitive screening parameter; 4. due to the fact that coagulopathies are inherited diseases, the diagnosis of a patient with a particular hidden coagulopathy can contribute to the exploration of further family members; 5. the vast majority of secondary post-tonsillectomy bleedings were observed after procedures which had been carried out with "hot" techniques: bipolar forceps or bipolar scissors; 6. Ivy's method is the recommended method of choice to examine the bleeding time.

[Multidrug resistance in chronic lymphocytic leukemia]. / Multidrogrezisztencia-vizsgálatok krónikus lymphoid leukaemiában.

INTRODUCTION: New prognostic factors discovered in chronic lymphocytic leukemia have recently got into the center of clinical interest. While the predictive value of cytogenetical abnormalities, immunoglobulin heavy chain gene mutation status, CD38 and ZAP70 expression is already well known, the significance of multi-drug resistance in chronic lymphocytic leukemia is not well characterized. AIMS: The goal of this study was to characterize the multidrug resistance features in 82 patients with chronic lymphocytic leukemia at the genetical, expression- and functional level and to compare it with the patient's clinical behavior (survival and response to therapy). METHODS: Light Cycler Real Time PCR based "Single Nucleotide Polymorphism" analysis of the MDR1 gene, as a biological predictor of the expression level of P-glycoprotein was tested in 66 patients with chronic lymphocytic leukemia. P-glycoprotein expression and MDR-function was detected in 82 cases by flow cytometry (by use of anti-P-glycoprotein monoclonal antibody and calcein-verapamil functional test). Response to therapy was analyzed by statistical Fisher-test in the treated 35 patients. The survival analysis (Log-rank test) was performed on the whole population ( n = 82). RESULTS: No significant correlation was found between the three levels of multidrug resistance (genetics, phenotype, function) in our patients with chronic lymphocytic leukemia. P-glycoprotein positive cases (n = 9) were predominantly non-responders (8/9, 89%). There must be, however, other mechanisms causing non-response (total non-responders: 13/35 treated cases). Most of P-glycoprotein negative CLL patients (n = 26) responded well (21/26, 80%) to chemotherapy (responders: 22/35 treated CLL) (p < 0,001). The tendency was the same in the average expected survival rate between P-glycoprotein positive and negative patients (84 vs 203 months) but the difference was not significant (p = 0,106). CONCLUSIONS: This study proved the clinical prognostic significance of P-glycoprotein expression of leukaemic cells predicting the chemotherapy response and partially estimating the general survival of patients suffering from chronic lymphocytic leukemia.

Primary bone marrow T-cell anaplastic large cell lymphoma with triple M gradient.

We present a case of a 60-year-old male patient with primary bone marrow anaplastic large cell lymphoma. He was admitted to the hospital with the symptoms of anemia and fever. There was no evidence of lymphadenopathy or splenomegaly. Immunoelectrophoresis showed the presence of a triple M gradient (double IgM and an IgG), with the IgG and one of the IgM paraproteins functioning as a cryoglobulin. The patient had no hepatitis C virus infection. Bone marrow biopsy showed massive CD30-positive, ALK-negative large lymphoid cell infiltration of T-cell origin with anaplastic morphology. PCR analysis of lymphoid cells separated from the bone marrow demonstrated the presence of a B/T hybrid genotype disorder with no evidence of the t(2;5), nor t(1;2) translocations. The patient entered a period of remission following CHOP chemotherapy. The patient subsequently died of sepsis as a consequence of serious humoral immunodeficiency.

[Complex analysis of prognostic factors in chronic lymphocytic leukemia]. / Prognosztikai faktorok komplex vizsgálata krónikus lymphocytás leukémiában.

INTRODUCTION: Many new prognostic factors established in recent years in chronic lymphocytic leukemia. May help predicting survival. AIMS: The goal of the present study was to determine the frequency and the correlation of these novel prognostic factors in samples of 419 leukemia patients. METHODS: The mutation status of the IgH gene was evaluated in 160 cases. RESULTS: In 62% of cases, non-mutated IgH gene was found, the heavy chain family usage was different in mutated and non-mutated cases. The CD38 expression demonstrated 78% concordance with the mutation status, the ZAP-70 expression failed to show any correlation. Cytogenetic abnormalities were seen in 76% of cases, the most frequent were del(13q) (57%), trisomy 12 (15%), del(11q) (12%) and del(17p) (6%). 95% of cases with del(11q) harbored non-mutated, 74% of cases with del(13q) as the sole anomaly demonstrated mutated IgH genes. CONCLUSIONS: The parameters analysed are not independent of each other, utilization of them in the clinical routine needs careful planning.

Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood.

Several methods are used to analyse platelet function in whole blood. A new device to measure whole blood platelet aggregation has been developed, called multiple electrode platelet aggregometry (MEA). Our aim was to evaluate MEA in comparison with the single platelet counting (SPC) method for the measurement of platelet aggregation and platelet inhibition by aspirin or apyrase in diluted whole blood. Platelet aggregation induced by different concentrations of ADP, collagen and TRAP-6 and platelet inhibition by apyrase or aspirin were determined in citrateor hirudin-anticoagulated blood by MEA and SPC. MEA indicated that spontaneous platelet aggregation was lower, and stimulated platelet aggregation was higher in hirudin- than citrate-anticoagulated blood. In hirudin-anticoagulated, but not citrate-anticoagulated blood, spontaneous platelet aggregation measured by MEA was inhibited by apyrase. For MEA compared with SPC the dose response-curves of agonist-induced platelet aggregation in citrate- and hirudin-blood showed similar EC50 values for TRAP, and higher EC50 values for ADP (non-significant) and collagen (p < 0.05). MEA and the SPC method gave similar results concerning platelet-inhibition by apyrase and aspirin. MEA was more sensitive than SPC to the inhibitory effect of aspirin in collagen-induced aggregation. In conclusion, MEA is an easy, reproducible and sensitive method for measuring spontaneous and stimulated platelet aggregation, and evaluating antiplatelet drugs in diluted whole blood. The use of hirudin as an anticoagulant is preferable to the use of citrate. MEA is a promising technique for experimental and clinical applications.

Karyotype complexity and VH gene status in B-cell chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia-related genomic changes were analyzed by karyotyping, fluorescence in situ hybridization, and V(H) gene sequencing in a prospective clinical evaluation. The V(H) mutational status correlated with high-risk cytogenetic aberrations while no such relation could be demonstrated for specific VH gene usage (V(3-21) and V(1-69)). Complex karyotypes were highly indicative of disease progression.

[Cytogenetic and molecular monitoring of chronic myeloid leukemia]. / A krónikus myeloid leukaemia citogenetikai es molekuláris monitorozása.

The t(9;22) translocation, which results in a fusion protein with abnormal tyrosine-kinase activity, plays a central role in the pathogenesis of chronic myeloid leukemia. The selective inhibition of this chimeric protein with imatinib-mesylate is an efficient therapeutic option, haematologic and cytogenetic responses can be achieved in most of the patients. The primary goal of monitoring the disease is to assess the efficiency of the therapy, to highlight those patients, whose survival may be improved by modifying treatment. Three methods are widely used for the genetic monitoring of chronic myeloid leukemia. With karyotyping, the proliferating bone marrow cells can be evaluated. The use of fluorescent in situ hybridization makes the cytogenetic analysis of each cell within the sample possible. Real-time quantitative polymerase chain reaction is capable of quantifying residual leukemia far below the sensitivity of cytogenetics. The results of these three methods have different biological meanings, thus, for the interpretation of the results, the knowledge of the characteristics, the benefits and the draw-backs of the methods is required. The present study shows the most important characteristics of these methods based on the literature and data acquired from 1165 samples of 197 patients detected by the authors.

In vitro effect of the potent poly(ADP-ribose) polymerase (PARP) inhibitor INO-1001 alone and in combination with aspirin, eptifibatide, tirofiban, enoxaparin or alteplase on haemostatic parameters.

It has been shown that PARP inhibition is protective in several models of ischemia-reperfusion injury including cardiac, cerebral and renal ones. Due to their ability to reduce myocardial necrosis and to improve myocardial function PARP inhibitors emerged as candidates for treating various cardiovascular diseases including acute myocardial ischemia. Since the pathophysiology of acute ischemic cardiac diseases involves haemostatic impairment and the therapeutic regimen includes antithrombotic drugs, we investigated the effect of the potent poly(ADP-ribose) polymerase (PARP) inhibitor INO-1001 alone and in combination with platelet aggregation inhibitors (aspirin, eptifibatide and tirofiban), unfractionated heparin, low molecular weight heparin (enoxaparin) or the recombinant fibrinolytic drug (alteplase), on various haemostatic parameters in vitro. ADP- and epinephrine-induced platelet aggregation was evaluated by optical aggregometry in the presence or absence of different concentrations of INO-1001, in combination with aspirin, tirofiban, eptifibatide or saline on ten healthy volunteers' platelet rich plasma (PRP). Activated partial thromboplastin time, Anti-Xa activity and euglobulin lysis time were determined in the presence or absence of different concentrations of INO-1001, in combination with sodium heparin, enoxaparin or alteplase, respectively. INO-1001, on its own does not affect the measured platelet, and haemostatic functions, i.e. does not reduce the respective anti-platelet, anti-coagulant and thrombolytic activity of therapeutically relevant concentrations of aspirin, tirofiban, eptifibatide, enoxaparin and alteplase in vitro. INO-1001 enhanced the effects of heparins above therapeutic ranges; the magnitude of this effect was negligible. Consequently, the PARP inhibitor INO-1001 can be safely applied together with the drugs tested.

[Type I antithrombin deficiency as a cause of arterial and venous thrombosis in a family with severe thrombophilia]. / I-es tipusú antitrombinhiány artériás es vénás thrombosisok hátterében egy súlyosan thrombophiliás családban.

INTRODUCTION: In rare cases of thromboembolic diseases developing in young age, venous and arterial thromboembolism can occur simultaneously. AIMS: To detect the venous and the arterial risk factors in a severe thrombophilic family. A 47-years-old female with severe atherosclerosis and recurrent deep vein thrombosis, and 6 members of her family were analysed. METHODS: The following haemostatic and molecular genetic investigations were performed: besides the rutin haemostatic parameters, risk factors for venous thrombembolic disease, risk factors for venous and arterial thrombosis (plasma homocysteine level, MTHFR C677T polymorphism) were determined. This panel was completed with the measurement of lipoprotein (a), von Willebrand factor, plasminogen activator inhibitor-1 antigen, serum total cholesterin, HDL cholesterin, C reactive protein and PIA2 variant. The propositus was proven to have type I antithrombin deficiency, elevated homocysteine level, homozygous MTHFR C677T polymorphism, elevated Lp(a), vWF:Ag, and PAI-1:Ag levels. RESULTS: All family members had a combination of cardiovascular risk factors (in 4 cases elevated homocysteine level, in 3 cases elevated Lp(a), in 2 cases elevated vWF:Ag, in 4 cases increased PAI-1 level). These risk factors were combined in three cases with type I antithrombin deficiency. Despite of the presence of atherosclerotic risk factors in the family, arterial thrombotic disease could be detected only in two patients with antithrombin deficiency. CONCLUSIONS: The results of the investigated family indicate that in case of combination of venous and arterial thromboembolic risk factors, antithrombin deficiency may contribute to the manifestation of arterial thromboembolic diseases.