Search

INTRODUCTION: Chronic liver disease is an important complication observed in haemophilia patients due to viral infections transmitted during treatment with factor concentrates. Our objective was to examine synthetic liver function parameters [fibrinogen, factor V (FV), albumin and Glu-plasminogen] in haemophilia B (HB) patients. METHODS: The study group consisted of 41 HB patients, aged 2-84 years, divided into two groups according to age: HB1≤18 years (N=15) and HB2>18 years (N=26), and 41 healthy male controls (HMC) aged 6-76 years. The Clauss method was used for the determination of fibrinogen concentrations (Dade Thrombin, Sysmex CS5100, Siemens) whereas FV activities were measured by the one-stage clotting assay (Atellica COAG360, Siemens). Albumin concentrations were measured using the bromocresol green colorimetric method (Cobas c501, Roche Diagnostics), whereas Glu-plasminogen was assayed using the ELISA method (Technoclone). The MedCalc® Software was used for statistical analysis. RESULTS: Higher median fibrinogen concentration (3.1 g/L) was encountered in HB patients (range: 2.7-3.6 g/L), compared to the HMC group (median 2.5 g/L ; range: 2.3-2.8 g/L), resulting in a statistically significant difference (P

Aim: The aim of this study was to present the first Croatian experience with eltrombopag (a peroral thrombopoietin receptor agonist) as the novel treatment option for aplastic anemia (AA). Patients and Methods: This was a retrospective analysis on the use of eltrombopag for adult patients with acquired AA among Croatian hematology centers. Results: Between 2015 and 2019, thirteen adult patients (nine female (69%), median age 59 (26-79) years) with acquired AA were treated with eltrombopag: six of them had severe AA, six very severe AA, and one had paroxysmal nocturnal hemoglobinuria with severe AA fenotype. All patients received eltrombopag after at least one previous line of treatment, either as a monotherapy or in combination with cyclosporine +/- low dose methylprednisolone. Hematological response was achieved in seven (54%) patients: complete remission in four, partial remission in two, and minimal response in one patient, while six (46%) patients were refractory. Median duration of eltrombopag administration was four (1,5-40) months. Median dose of eltrombopag was 150 mg per day and adverse events were consistent with the known safety data of the drug. Sixty-nine percent of the patients were still alive at a median follow up of 16 (2-48) months. One patient who achieved minimal response relapsed after eight months of treatment and developed new cytogenetic change (trisomy 8). Four patients died, seven (1-12) months after discontinuation of eltrombopag therapy, due to comorbidities and infections. Conclusion: Presented data from Croatian hematology centers in the real-world setting confirm that eltrombopag is an interesting new modality to treat adult patients with acquired severe AA, especially for those who are refractory to prior immunosuppressive therapy and/or unsuitable for allogeneic hematopoietic stem cell transplantation., Cilj istraživanja: Cilj je ovog rada prikaz prvih hrvatskih iskustava pri primjeni eltrombopaga (peroralnog agonista trombopoetinskih receptora), nove opcije u liječenju aplastične anemije (AA). Ispitanici i metode: U ovu retrospektivnu analizu uključeni su odrasli bolesnici sa stečenom AA, liječeni eltrombopagom u hrvatskim hematološkim centrima. Rezultati: Od 2015. do 2019. eltrombopagom je liječeno 13-ero bolesnika s AA (9 žena (69%), medijan dobi 59 (26 – 79) godina): 6-ero ih je imalo tešku aplastičnu anemiju, 6-ero vrlo tešku, a 1 paroksizmalnu noćnu hemoglobinuriju s fenotipom teške AA. Svi su primili eltrombopag nakon prethodne, najmanje jedne linije terapije, i to ili kao monoterapiju ili u kombinaciji s ciklosporinom s niskom dozom metilprednizolona ili bez nje. Hematološki odgovor postiglo je 7-ero (54%) bolesnika: kompletnu remisiju njih četvero, parcijalnu remisiju dvoje, minimalan odgovor jedna bolesnica, a 6-ero (46%) bolesnika bilo je refraktorno. Medijan trajanja primjene eltrombopaga bio je 4 mjeseca (1,5 – 40 mjeseci). Primijenjena srednja doza eltrombopaga bila je 150 mg na dan, a opisane nuspojave bile su u skladu s poznatim podatcima o sigurnosti lijeka. Medijan praćenja iznosio je 16 (2 – 48) mjeseci, a u tom je razdoblju 69% bolesnika i dalje živo. U bolesnice, koja je postigla minimalan odgovor, nakon 8 mjeseci liječenja nastao je relaps AA i razvila se nova citogenska promjena (trisomija 8). Četiri su bolesnika umrla 7 (1 – 12) mjeseci poslije prekida terapije eltrombopagom, i to zbog komorbiditeta i infekcija. Zaključak: Prikazani podatci iz rutinskoga kliničkog rada hrvatskih hematoloških centara potvrđuju da je eltrombopag zanimljiva nova opcija liječenja odraslih bolesnika sa stečenom teškom AA, posebno onih koji su refraktorni na prethodnu imunosupresivnu terapiju i/ili nisu prikladni za transplantaciju alogenih krvotvornih matičnih stanica.

Introduction: Coronavirus disease 2019 (COVID-19) can lead to systemic activation of coagulation and thrombotic complications. Post–COVID-19 syndrome may involve sustained intrapulmonary activation of coagulation with ongoing pulmonary microthrombosis as a consequence. Aim: To evaluate clinical and epidemiological characteristics, as well as risk factors for venous thromboembolism (VTE) in patients following COVID-19 in Croatia. Materials and Methods: A retrospective analysis of 15 patients hospitalized in University Hospital “Sveti Duh”, Zagreb, Croatia, with a diagnosis of venous thromboembolism after COVID- 19 infection from December 2020 to January 2021. Inclusion criteria were: age of at least 18 years, a positive PCR test for a severe acute respiratory syndrome coronavirus 2 from a nasopharyngeal swab and a confi rmed diagnosis of deep vein thrombosis or pulmonary embolism. Results: We included 15 (n=15) patients (with median age 61 years, 53% men, 13% required hospital treatment for COVID-19 and 40% developed COVID-19 pneumonia). The median time from positive PCR test for Sars-Cov 2 virus to thrombotic event was 20 days (interquartile range, 1-32). Median MEWS score for COVID-19 disease was 1, 5 (interqaurtile range 0-4), and only women had high MEWS scores (3 or higher), while men had lower MEWS scores ranging from 0 to 2. 46% of patients presented with a deep vein thrombosis, 40% with a segmental pulmonary embolism, and 14% with a massive pulmonary embolism. 73% of patients had arterial hypertension, 33% had body mass index (BMI) over 30 kg/m2, 20% had asthma, 13% malignant diseaseas, and 13% diabetes. Thromboprophylaxis was used in 33% of patients during acute COVID-19 disease. All patients have been tested for thrombophilia, and results are expected. Conclusions: The risk of venous thromboembolism in patients with COVID-19 and post-COVID-19 syndrome is high. Our results show that venous thromboembolism following COVID- 19 occurs in women who have suff ered from a more severe form of the COVID-19 disease (according to MEWS score), in contrast to men, in whom it occurs more often after milder clinical pictures of COVID- 19. Our results show that arterial hypertension and high BMI are the most common risk factors for VTE following COVID-19. There is a need to improve prophylactic strategy to prevent VTE.

Background: Acquired haemophilia A (AHA) is a rare autoimmune disease, caused by antibodies (inhibitors) against coagulation FVIII and characterized by spontaneous hemorrhage in patients with no previous history of bleeding. Risk factors for the occurrence of AHA include advanced age and underlying diseases (malignancy, autoimmune disorders, pregnancy, and the postpartum period). Aims: The aim is to analyze treatment outcomes of patients with acquired hemophilia A during the last ten years at the University Hospital Center Zagreb. Methods: We analyzed retrospectively treatment outcomes of patients with AHA in the Department of Hematology, University Hospital Center Zagreb from 2010-2020. Response to treatment was assessed as partial (PR) or complete remission (CR). Results: We analyzed the outcomes of twenty patients (11 (55%) male, 9 (45%) female), median age was 68 (33-81) years, and with median FVIII activity 5 (1 – 15) IU/dL and median inhibitor titer at the time of AHA diagnosis was 9 (2, 3 – 2000) BU/ml. Severe bleeding had 75 % patients requiring erythrocyte transfusion. In 12 patients (60%) were identified underlying diseases: malignancies 2 (oligodendroglioma, B-CLL), autoimmune diseases 9, (autoimmune haemolytic anaemia - 2, rheumatoid arthritis - 2, polymyalgia rheumatica - 3, pemphigus -1 and myasthenia- 1. One patient had postpartal AHA. The last female patient with myasthenia was diagnosed in December 2020. and she developed COVID19 bilateral pneumonia with ARDS. 90% of patients recieved hemostatic treatment (65 % - aPCC, 10% aPCC and rFVIIa, 25 % - rFVIIa). All patients were treated with immunosuppressive therapy, combination ofcyclophosphamide and steroids in 18/20, steroids alone in 2/20 patients, while 3/20 patients (15%) were treated in the second line therapy. The response rate to the first line eradication therapy was 90%. Inhibitor eradication time was 18 (3-300) days, time to achieve CR was 32 (15-300) days. At follow up of 31 (1-90) months 13 patients (65%) are alive, 7 (35%) dead. No death was due to bledding. Two patients died of pneumonia, two deaths were associated with sepsis, one with progressive malignant disease and one with cardiogenic shock. One female patient died of COVID19 at the age of 55 years, 25 days after AHA was diagnosed. Higher inhibitor activity, known underlying cause of AHA with advanced age, comorbidities were unfavourable factors of survival. Summary/Conclusion: Our treatment outcomes are very similar to the large European Registries, with the quite high response rate of eradication therapy in the first line treatment (90%). Infective complications and comorbidities were the leading causes of death. Patients with AHA and COVID19 could have a worse outcome due to immunosuppressive therapy.

The aim of this study was to explore differences in well-being indicators among persons with severe haemophilia based on their marital status. The research was conducted in Croatia, using the paper-pen method, and assessing various aspects of life with haemophilia. Our findings support the premise that marriage can contribute to the well- being of men with haemophilia. Single men suffering from severe haemophilia could benefit from psychosocial support directed to enhancing their social connectedness and personal feeling of accomplishment.

Cilj istraživanja: Cilj je ovog rada prikaz prvih hrvatskih iskustava pri primjeni eltrombopaga (peroralnog agonista trombopoetinskih receptora), nove opcije u liječenju aplastične anemije (AA). ----- Ispitanici i metode: U ovu retrospektivnu analizu uključeni su odrasli bolesnici sa stečenom AA, liječeni eltrombopagom u hrvatskim hematološkim centrima. ----- Rezultati: Od 2015. do 2019. eltrombopagom je liječeno 13-ero bolesnika s AA (9 žena (69%), medijan dobi 59 (26 – 79) godina): 6-ero ih je imalo tešku aplastičnu anemiju, 6-ero vrlo tešku, a 1 paroksizmalnu noćnu hemoglobinuriju s fenotipom teške AA. Svi su primili eltrombopag nakon prethodne, najmanje jedne linije terapije, i to ili kao monoterapiju ili u kombinaciji s ciklosporinom s niskom dozom metilprednizolona ili bez nje. Hematološki odgovor postiglo je 7-ero (54%) bolesnika: kompletnu remisiju njih četvero, parcijalnu remisiju dvoje, minimalan odgovor jedna bolesnica, a 6-ero (46%) bolesnika bilo je refraktorno. Medijan trajanja primjene eltrombopaga bio je 4 mjeseca (1,5 – 40 mjeseci). Primijenjena srednja doza eltrombopaga bila je 150 mg na dan, a opisane nuspojave bile su u skladu s poznatim podatcima o sigurnosti lijeka. Medijan praćenja iznosio je 16 (2 – 48) mjeseci, a u tom je razdoblju 69% bolesnika i dalje živo. U bolesnice, koja je postigla minimalan odgovor, nakon 8 mjeseci liječenja nastao je relaps AA i razvila se nova citogenska promjena (trisomija 8). Četiri su bolesnika umrla 7 (1 – 12) mjeseci poslije prekida terapije eltrombopagom, i to zbog komorbiditeta i infekcija. ----- Zaključak: Prikazani podatci iz rutinskoga kliničkog rada hrvatskih hematoloških centara potvrđuju da je eltrombopag zanimljiva nova opcija liječenja odraslih bolesnika sa stečenom teškom AA, posebno onih koji su refraktorni na prethodnu imunosupresivnu terapiju i/ili nisu prikladni za transplantaciju alogenih krvotvornih matičnih stanica., Aim: The aim of this study was to present the first Croatian experience with eltrombopag (a peroral thrombopoietin receptor agonist) as the novel treatment option for aplastic anemia (AA). ----- Patients and Methods: This was a retrospective analysis on the use of eltrombopag for adult patients with acquired AA among Croatian hematology centers. ----- Results: Between 2015 and 2019, thirteen adult patients (nine female (69%), median age 59 (26-79) years) with acquired AA were treated with eltrombopag: six of them had severe AA, six very severe AA, and one had paroxysmal nocturnal hemoglobinuria with severe AA fenotype. All patients received eltrombopag after at least one previous line of treatment, either as a monotherapy or in combination with cyclosporine +/- low dose methylprednisolone. Hematological response was achieved in seven (54%) patients: complete remission in four, partial remission in two, and minimal response in one patient, while six (46%) patients were refractory. Median duration of eltrombopag administration was four (1,5-40) months. Median dose of eltrombopag was 150 mg per day and adverse events were consistent with the known safety data of the drug. Sixty-nine percent of the patients were still alive at a median follow up of 16 (2-48) months. One patient who achieved minimal response relapsed after eight months of treatment and developed new cytogenetic change (trisomy 8). Four patients died, seven (1-12) months after discontinuation of eltrombopag therapy, due to comorbidities and infections. ----- Conclusion: Presented data from Croatian hematology centers in the real-world setting confirm that eltrombopag is an interesting new modality to treat adult patients with acquired severe AA, especially for those who are refractory to prior immunosuppressive therapy and/or unsuitable for allogeneic hematopoietic stem cell transplantation.

Cilj: Stečena hemofi lija A (SHA) je rijetki stečeni poremećaj zgrušavanja zbog pojave autoprotutijela, najčešće na FVIII i potencijalno smrtonosan ukoliko se rano ne prepozna i liječi. Cilj je prikazati rezultate liječenja stečene hemofi lije tijekom desetogodišnjeg razdoblja u KBC Zagreb. Metode: Analizirani su retrospektivno rezultati liječenja bolesnika sa SHA u Zavodu za hematologiju, KBC Zagreb od 2010–2020. Rezultati: Liječeno je 19 bolesnika, 11 muškaraca (58%) i 8 žena (42%). Medijan dobi iznosio je 68 godina (raspon 33–81 godina), medijan aktivnosti FVIII 5% (raspon 1–15%), inhibitora 6, 8 BIU/dL (raspon 1– 2000 IU/dL). Transfuziju eritrocita trebalo je 14 bolesnika (73, 7%). Kod 58% bolesnika bio je poznat uzrok SHA (oligodendrogliom, B-CLL i AIHA toplih protutijela, AIHA toplih protutijela, AIHA hladnih protutijela, reumatoidni artritis kod 2 bolesnika te pemfi gus kod jedne bolesnice, polimijalgija reumatika u 3 bolesnika, i jedna postpartalna SHA). Hemostatsku terapiju primilo je 17 bolesnika (89, 4%). APCC (FEIBA) primalo je 12 bolesnika (70, 6%), rFVIIa (NovoSeven) 5 bolesnika (29, 4%). Svi su bolesnici primali eradikacijsku terapiju, ciklofosfamid i kortikosteroid 17 bolesnika (89, 4%), 2 bolesnika kortikosteroid (10, 6%), a rituksimab 3 bolesnika u 2. liniji (15, 8%). Medijan eradikacije inhibitora iznosio je 18 dana (raspon 3–300), a za postizanje KR 32, 5 dana (raspon 15–300). Medijan preživljenja od trenutka dijagnoze je 21, 5 mjeseci (1–90 mj). Prva linija liječenja dovela je do KR u 18 bolesnika (94, 4%) bolesnika. Troje bolesnika (15, 8%) dožvjelo je relaps (dvoje bolesnika 1. relaps, a jedna bolesnica 2. relaps) te su ponovno postigli KR kombinacijom kortikosteroida i ciklofosfamida (2 bolesnika) a jedna bolesnica na rituksimab. U praćenju je umrlo 6 bolesnika (31, 5%). Nitko nije umro od posljedica krvarenja. Uzroci smrti su sepsa kod 2 bolesnika, pneumonija, kardiogeni šok, kardiorespiratorni arest te infarkt miokarda kod ostala 4 bolesnika. Viša aktivnost inhibitora bila je povezana s poznatim predležećim uzrokom te je uz dob, komorbiditete nepovoljno utjecala na preživljenje, a infekcije su uz komorbiditet (kardiovaskularne bolesti) glavni neposredni uzrok smrtnosti. Zaključak: Rezultati 10-godišnjeg liječenja stečene hemofi lije u KBC Zagreb u skladu su s rezultatima europskih registara uz visoku stopu kompletnog odgovora (>80%) ali i uspješno liječenje relapsa.

Uvod: Postpartalna stečena hemofi lija A je rijetak poremećaj. Nastaje uslijed pojave protutijela na koagulantni FVIII i uzrokuje pad aktivnosti FVIII i krvarenje. Opisani su slučajevi i transplacentarnog prijelaza protutijela u novorođenče pa dovodi do pada aktivnosti FVIII (kao u našem slučaju) a može i do krvarenja. Cilj: U ovom radu prikazujemo mladu babinjaču s razvojem, postpartalne stečene hemofi lije A. Rezultati: Bolesnica u dobi od 34. godine prvorotkinja urednog tijeka trudnoće osim blage hipertenzije. Pred porod zamijećeni obostrani pleuralni izljevi. Porod se dovršava carskim rezom da bi po zahvatu nastupilo teško krvarenje. Bolesnica je stabilizirana primjenom brojnih transfuzija eritrocita i trombocita, rFVIIa, plazme. Po stabilizaciji krvarenja premješta se u našu ustanovu i pri dolasku se dijagnosticira postpartalna stečena hemofi lija A. Titar inhibitora iznosi je 33 BU a aktivnost FVIII 5%. Započinje se liječenje aPCC uz imunosupresiju. Dva dana kasnije ulazi u hemoraški šok uslijed krvarenja u trbušnu šupljinu i uterus. Pristupi se eksplorativnoj laparotomiji s postavljanjem novih šavi na mjestu dehiscijencije ranijih. Postoperacijski i dalje krvari uz kontinuirane nadoknade eritrocita i trombocita, rFVIIa, traneksamičnu kiselinu. Kako se krvarenje ne zaustavlja bolesnica je ponovno podvrgnuta detamponadi, histerektomiji te endovaskularnoj embolizaciji ogranaka obje AII. Posoperativno se zbog prisutnog krvarenja primjenjuje sekvencijska terapija (rFVIIa i aPCC), imunoglobulinima i visokim dozanam kortikosteroida na što krvarenje prestaje. Zbog nižih vrijednosti FXIII isti je nadoknađivan. Kontrolni CT abdomena nalazi regresiju hemoragiziranog sadržaja i parcijalnu trombozu 8 mm na utoku desne renalne arterije u donju šuplju venu. Mjesec dana od carskog reza inhibitori nestaju i normalizira se aktivnost FVIII. Deset dana po otpustu iz bolnice ponovno dolazi zbog rektoragije i pada aktivnosti FVIII i pojavu inhibitora (30 BU).Liječi se imunoupresivnom terapijom (rituximabom), gamaglobulinima uz kortikosteroide i rFVIIa i kroz 10 dana dolazi do normalizacije aktivnsoti FVIII i nestanka inhibitora. Zaključak: Postpartalna, stečena hemofi lija A je teško stanje s intraktabilnim krvarenjem. Operativni zahvati u toj situaciji predstavljaju poseban izazov za uspostavljanje hemostaze. Bilateralni izljevi su često prvi znaci ovog teškog poremećaja koagulacije

Background/Aims Traditionally used laboratory methods, i.e. one-stage or chromogenic assays for FVIII activity determination do not always and accurately reflect bleeding severity in haemophilia A (HA) patients. As global haemostasis assays provide overall haemostatic status estimation, we investigated the ability of three global assays for identifying bleeding phenotype both in severe and non-severe HA patients, as well as their usefulness in laboratory management of HA patients with discrepant bleeding phenotype. Materials and Methods Overall haemostasis potential (OHP), aPTT-clot waveform analysis (aPTT-CWA), endogenous thrombin potential (ETP) and FVIII activity were measured in 30 severe and 32 non- severe HA patients and 27 male controls. For classification of HA patients regarding bleeding phenotype, we used a scoring method that included three clinical parameters: age at first joint bleed, number of target joints and number of joint/muscle bleeds per year. Bleeding scores ≤4 and ≥5 suggested mild and severe beeding phenotype, respectively. Results All global assays correlated significantly with FVIII activity (P

Background: Cardiovascular and thromboembolic events are the leading causes of morbidity and mortality for patients with myeloproliferative disorders (MPN). Aims: This retrospective study aimed to evaluate the incidence and the risk factors for the arterial and venous thrombosis in treated patients with MPN. Methods: The study included 329 adult MPN patients, 184 (56%) female, treated at University Hospital Center Zagreb, Department of Internal medicine, Division of Hematology and Zadar General Hospital, Hematology Unit. Patients were aged 24-85 years (median 68), and were diagnosed as having essential thrombocythemia (ET) (n = 149, 45%), polycythaemia vera (PV)(n = 94, 29%), primary myelofibrosis (PMF)(n = 69, 21%) and unclassifiable MPN (n = 17, 5%). Diagnosis were made according to the 2008 WHO Classification. JAK-2 mutation status was either established or revised in our center, but was unknown in 55 (17%) patients. Data about treatment and cardiovascular and thromboembolic incidents was retrieved from medical records. Results: Forty patients (12%) developed thrombosis after median of 36 (range 1-240) months from the time of diagnosis. Fifteen (5%) patients developed venous thrombosis, twenty-four (7%) arterial, while one (0, 3%) patient both type of thrombosis. Regarding the disease type, thrombosis was described in 16 patients with ET (11%), 18 with PV (19%) and 6 with PMF (8%). The risk of thrombosis was the highest in patients with previous thrombotic events, but did not correlate with the type of therapy (cytoreductive and/or antiagreggation) nor the JAK-2 status. Summary/Conclusion: The risk of both arterial and venous thrombosis was found to be increased in patients with MPN even after introducing appropriate treatment. The highest risk of post treatment thrombosis was found in patients with previously diagnosed thrombotic events.

Sažetak. Unatrag nekoliko godina u hematologiji i onkologiji globalno sve češći problem postaje prikladna opskrba „starijim i manje zanimljivim“ kemoterapeuticima. Zbog povremene nestašice karmustina, jednog od osnovnih kemoterapeutika pri kondicioniranju prije autologne transplantacije krvotvornih matičnih stanica (ATKS) u oboljelih od limfoma, u našem se centru od 2016. godine on zamjenjuje bendamustinom. U ovom radu retrospektivno analiziramo tijek ATKS-a u 41 bolesnika koji su primili bendamustin u sklopu protokola BeEAM te ga uspoređujemo s tijekom ATKS-a u 40 bolesnika koji su primili karmustin u sklopu protokola BEAM. Medijan oporavka vrijednosti neutrofila (> 0,5 × 109/l) u skupini koja je primila bendamustin iznosio je 11 dana, dok je u skupini kondicioniranoj karmustinom iznosio 10 dana. Medijan oporavka vrijednosti trombocita (> 20 × 109/l) bio je duži kod skupine koja je primala bendamustin (16 prema 13 dana) te su ti bolesnici bili duže ovisni o transfuzijama eritrocita (7 prema 5 dana). Infektivne komplikacije nisu bile češće nakon primjene bendamustina, ali smo nakon primjene karmustina imali veću pojavu mukozitisa II. – III. stupnja (35% prema 12%). Nakon primjene bendamustina zabilježen je jedan slučaj nefrotoksičnosti i kardiotoksičnosti terapije, dok kod primjene karmustina te komplikacije nisu zabilježene. Pri upotrebi bendamustina kod kondicioniranja u naših bolesnika u ovom trenutku nije utvrđena znatnija hematološka toksičnost u odnosu prema karmustinu, ali su prisutni dulji period oporavka vrijednosti trombocita te niža incidencija mukozitisa., Summary. Inadequate supply of „old and less interesting“ chemotherapeutic agents is becoming a global issue in hemato-oncology today. In 2016 we were faced with occasional carmustin shortage, one of the most commonly used in autologous transplant conditioning regimens for lymphoma in our centre, so we decided to use bendamustin instead. We performed a retrospective analysis of 41 patients treated at our centre who had received bendamustin within BeEAM protocol and compared them with 40 patients who had received carmustin within BEAM protocol. Both protocols were used as conditioning protocols before autologous stem cell transplantation. Neutrophil recovery median following transplantation (ANC>0,5x109/l) was 11 days in the bendamustin group in comparison to 10 days in the carmustin group.Platelets recovery median following transplantation (PLT>20x109/l) was longer in the bendamustin group (16 vs.13 days) as was blood transfusion dependency (7 vs. 5 days). Infectious complications were not more frequent after bendamustin, but grade II–III mucositis was more frequent in patients who received carmustin (35% vs.12%). Following bendamustin we had one reported case of nephrotoxicity and cardiac toxicity, not reported with carmustin. Bendamustin has shown similar hematologic toxicity compared to carmustin but a longer platelet recovery period and a lower mucositis incidence.

Hemophilia A has been considered as a bleeding disorder that is not only a consequence of the defect in the coagulation system, but also of the impaired down-regulation of the fibrinolytic system. To examine correlation between activities and/or concentrations of most important fibrinolytic parameters with overall hemostasis potential (OHP) and fibrin clot permeability (FCP) in hemophilia A patients. Activities of FXIII, plasminogen, plasmin inhibitor, plasminogen activator inhibitor–1 (PAI-1) (Siemens Healthcare Diagnostics, Germany) and thrombin-activatable fibrinolysis inhibitor (TAFI) (Diagnostica Stago, France), as well as activated/inactivated TAFI antigen (TAFIa/ai) (Diagnostica Stago) and prothrombin fragment F1+2 concentrations (PF1+2) (Siemens) were tested in plasma samples of 63 hemophilia A patients (30 severe, 33 non-severe). OHP method, based on repeated spectrophotometric registration of fibrin-aggregation in plasma, after addition of small amounts of exogenous thrombin, tissue plasminogen activator and calcium, gave beside OHP parameter (area under the fibrin aggregation curve) 3 supplementary parameters: overall coagulation potential (OCP), overall fibrinolytic potential (OFP) and clot lysis time (CLT). Permeability coefficients (Ks), providing information on fibrin network porosity, were obtained by FCP method, flow measurement technique along with visualisation by electron microscopy scanning. Among fibrinolytic and OHP parameters significant but weak correlation (P< ; 0.05) was found only for OCP with TAFI and PF1+2 (r=0.252 and 0.266, respectively). Regarding FCP, significant correlation of Ks was found with FXIII, plasmin inhibitor and PF1+2 (r=-0.466, - 0.432 and -0.599, respectively). There was no correlation between Ks and OHP parameters. Obtained correlation between fibrinolytic parameters and parameters that assess coagulation activity and fibrin network porosity confirmed the association between these two processes in patients with hemophilia A.

Measurement of FVIII activity allows diagnosis of hemophilia A and categorization of disease severity, but has poor correlation with clinical phenotype. New laboratory methods that assess global hemostasis have been developed, with intention to better diagnose and monitor hemophilia A patients. To assess overall coagulation and fibrinolytic activity in hemophilia A patients using non- standard laboratory methods: overall hemostasis potential (OHP), aPTT-waveform analysis (aPTT- WA) and endogenous thrombin potential (ETP). Total of 63 hemophilia A patients (30 severe and 33 non-severe) and 27 healthy male subjects as control group were tested. OHP method, based on repeated spectrophotometric registration of the fibrin-aggregation in plasma, after addition of small amounts of exogenous thrombin, tissue-type plasminogen activator and calcium, provides besides OHP parameter (area under the fibrin aggregation curve) supplemetary parameters: overall coagulation potential (OCP), overall fibrinolytic potential (OFP) and clot lysis time (CLT). In-house aPTT- WA was performed on BCS with Actin FS (Siemens Healthcare Diagnostics, Germany), obtaining 3 quantitative waveform parameters from 2 different evaluation modes, drifting baseline (DB) and point of inflexion (PI): DELTA (aPTT- PI minus aPTT-DB), RATIO1 (aPTT- PI/aPTT-DB) and RATIO2 (DELTA/aPTT-DB). ETP method, setting C was performed on BCS-XP (Siemens), giving 4 parameters: area under the thrombin generation curve (AUC), peak thrombin concentration (Cmax), time to peak thrombin concentration (t- max) and time to signal beginning (t-lag). Obtained results revealed statistically significant difference (P< ; 0.05) for all parameters between analyzed groups, except for CLT between severe and non-severe group. Global assays can serve as a useful laboratory tool for assessing overall coagulation and fibrinolysis activity, providing at the same time additional information about hemophilia A patients.

Radna skupina za bolesti hemostaze i tromboze Hrvatske kooperativne grupe za hematološke bolesti (KROHEM), Referentni centar Ministarstva zdravlja Republike Hrvatske za nasljedne i stečene bolesti hemostaze te Hrvatsko hematološko društvo Hrvatskoga liječničkog zbora izradili su Hrvatske smjernice za dijagnostiku i liječenje odraslih bolesnika s primarnom imunosnom trombocitopenijom (ITP). Detaljnim kliničkim i laboratorijskim pregledom treba isključiti niz čestih uzroka sekundarne trombocitopenije. Predlaže se individualizirani pristup liječenju, gdje se odluka o početku aktivnog liječenja temelji na ozbiljnosti i riziku od krvarenja, broju trombocita, životnom stilu, dobi bolesnika i komorbiditetima. Prva linija terapije ITP-a jesu glukokortikoidi, s primjenom intravenskih imunoglobulina ili bez nje. U drugoj terapijskoj liniji predlaže se splenektomija ili liječenje agonistima trombopoetinskih receptora. Kod splenektomiranih bolesnika s relapsom ITP-a preporučuje se liječenje agonistima trombopoetinskih receptora. Alternativno se sugerira mogućnost primjene rituksimaba i drugih imunosupresiva u drugoj ili kasnijoj terapijskoj liniji.

Uvod: Tromboza je jedna od najčešćih komplikacija u bolesnika s Ph(-) mijeloproliferativnim neoplazmama, a razlozi zbog kojih nastaje još uvijek su predmet istraživanja. Cilj: Otkriti postoji li razlika u učestalosti i vrsti tromboze u V617F JAK2–pozitivnih bolesnika ovisno o njihovoj dijagnozi, dobi, spolu te opterećenju mutiranim alelom. Materijali i metode: U ovo istraživanje bila su uključena 182 V617F JAK2–pozitivna bolesnika - policitemija vera (PV) 63 bolesnika, esencijalna trombocitoza (ET) 83 bolesnika i primarna mijelofibroza (PM) 36 bolesnika. Bolesnici su bili podijeljeni prema dijagnozi, spolu, dobi pri dijagnozi te nastanku prve tromboze. Mutacija V617F JAK2 kvantificirana je iz uzorka granulocitne DNK periferne krvi metodom PCR-a u stvarnom vremenu prema Larsenu i sur. Br J Haematol 2007 ; 136:745. Rezultati: Od 182 bolesnika, 66 bolesnika razvilo je trombozu (36 %), pri čemu je arterijska tromboza bila dvostruko učestalija od venske tromboze u sve 3 grupe bolesnika. U skupini bolesnika s ET bilo je više žena (udjel žena = 0, 71), p< 0, 001. Statistički važna razlika za dob pri dijagnozi (p

Introduction and objectives: The fact, proven by many research, is that in their lives persons with haemophilia are often faced with severe or slight pain. In this paper we tried to examine relation between it’s severity and frequency, as well as discover what is the pain frequency and intensity’s influence on the life satisfaction among persons with haemophilia. Methods: Survey among adults with haemophilia was conducted in Croatia (N=135). General life satisfaction was assessed on a 5-point rating scale, whereas 10-point scales, extracted from the Personal Wellbeing Index – PWI (Cummins, 2002), were used to measure satisfaction with material and social aspects of life and life accomplishments. Pain frequency was measured on a 4-point scale, while pain intensity and its influence on mood, mobility, sleeping, work and recreation was measured on 5-point scales. Results: Negative correlation with life satisfaction is shown by both pain intensity (r=-0, 243 ; p=0, 005) and frequency (r=-0, 348 ; p=0, 000), while the regression analysis pointed only to pain frequency as significant predictor of life satisfaction (β=-0.347 ; p=0.003 / β=0.001 ; p=0.990). In relation to some other determinants of life satisfaction, such as 3 domains of the personal well-being scale: life accomplishments (β=0.288 ; p=0.005), material conditions (β=0.240 ; p=0.010) and social relationships (β=0.191 ; p=0.020), pain frequency remained significant predictor of life satisfaction (β=-0.207 ; p=0.036) and pain intensity insignificant (β=0, 137 ; p=0.166). In addition, we also separately analysed the influence of pain on various aspects of daily functioning: mood, mobility, sleeping, work, and recreation. All deficiencies caused by pain are in negative correlation with life satisfaction, but observed concurrently, in a regression model, sleep deprivation will take priority and remain the only significant predictor of (lesser) general life satisfaction (β=-0.403 ; p=0.002). Conclusion: The negative correlation of pain intensity and frequency with daily functioning and life satisfaction makes evident, as expected, that the presence of pain degrades the level of life satisfaction among persons with haemophilia. Additional analyses point to the probability of becoming relatively accustomed to pain in certain contexts ; however, it seems that this is not possible if the pain causes sleep deprivation.

Hemofilija je rijetka nasljedna bolest poremećaja zgrušavanja krvi koja se klinički manifestira spontanim, prekomjernim i ponavljajućim krvarenjima najčešće u zglobove i mišiće. Uzrokovana je manjkom faktora zgrušavanja VIII (hemofilija A) ili IX (hemofilija B). Ključan čimbenik uspješnoga liječenja jest adherencija bolesnika. Postoje tri skupine čimbenika koji utječu na adherenciju: čimbenici vezani za bolesnika, čimbenici vezani za liječnika i čimbenici vezani za zdravstveni sustav. Čimbenici vezani za bolesnika dijele se na sociodemografske čimbenike, kliničke čimbenike i psihološke čimbenike. Prisutnost simptoma depresije također može utjecati na adherenciju. Cilj ovoga istraživanja jest ispitati povezanost simptoma depresije s adherencijom u bolesnika s umjerenom ili teškom hemofilijom koji su na profilaktičnoj terapiji, neovisno o različitim sociodemografskim, psihološkim i kliničkim čimbenicima. U istraživanje je uključeno 82 odrasla ispitanika s umjerenom ili teškom hemofilijom A ili B na profilaktičnoj terapiji. Istraživanje je provedeno u Centru za hemofiliju i trombofiliju Klinike za unutarnje bolesti Kliničkog bolničkog centra Zagreb te u Centru za hemofiliju Kliničkog zavoda za hematologiju Sveučilišnog kliničkog centra Ljubljana. Sociodemografski podaci prikupljeni su putem upitnika, klinički podaci preuzeti su iz medicinskog kartona, adherencija se određivala pomoću VERITAS-Pro instrumenta, psihološki čimbenici pomoću SF-36v2 upitnika zdravstvenog statusa, a simptomi depresije pomoću Beckovog inventara depresije – drugo izdanje. Neadherentno je bilo 14 (17 %) ispitanika. Ukupno je 11 (14 %) ispitanika na Beckovom inventaru depresije – drugo izdanje imalo rezultat 12 ili više, što je prema hrvatskoj standardizaciji granični rezultat za blagu depresiju. Simptomi depresije predviđali su VERITAS-Pro ukupan rezultat i rezultat na podskali pamćenje uz kontrolu sociodemografskih čimbenika. Provedeno istraživanje pruža vrijedne informacije o adherenciji prema profilaktičnom liječenju u hemofiliji kod bolesnika iz Hrvatske i Slovenije, kao i o brojnim čimbenicima te adherencije. Primjenom validirane mjere za ispitivanje simptoma depresije dobivena je niža učestalost simptoma depresije nego u prethodnim istraživanjima koja nisu koristila validiranu mjeru, ali su se simptomi depresije svejedno pokazali važnim prediktorom adherencije. Haemophilia is a rare inherited bleeding disorder. Clinical manifestations of haemophilia are spontaneous, excessive and recurring bleedings mostly in joints and muscles. Haemophilia is caused by the deficiency of the clotting factor VIII (haemophilia A) or IX (haemophilia B). Adherence to medication is the key factor for successful treatment. There are three groups of factors that affect adherence: patient related factors, physician related factors and healthcare related factors. Patient related factors are divided into sociodemographic factors, clinical factors and psychological factors. Depressive symptoms may also have an impact on adherence. The aim of this study was to investigate the association of symptoms of depression with adherence to prophylactic therapy independent of various sociodemographic, psychosocial and clinical characteristics of patients with moderate or severe haemophilia. A total of 82 patients with mild or severe haemophilia A or B, aged 18 or older who were currently using prophylactic treatment were included in the study. The study was conducted in the National Haemophilia Centre at University Hospital Centre Zagreb, Croatia and in the National Haemophilia Centre at University Medical Centre Ljubljana, Slovenia. Sociodemographic data were collected using a questionnaire, clinical data were obtained from the medical records, adherence was assessed with VERITAS-Pro, psychosocial characteristics with SF-36v2 and depressive symptoms with Beck Depression Inventory II (BDI-II). Only 14 (17%) participants were nonadherent. A total of 11 (14%) participants had on BDI-II scores of 12 or more which is, according to Croatian standardization, the cut-off score for mild depression. Depressive symptoms were a significant predictor of VERIAS-Pro Total Score and VERITAS-Pro subscale Remember after controlling for sociodemographic variables.This study provides valuable information about adherence to prophylactic treatment in patients with haemophilia from Croatia and Slovenia, as well as information about various factors that have an impact on adherence. In this study the validated instrument for measuring depressive symptoms was used and the prevalence of depressive symptoms was lower than in the previous studies that have not used validated instruments. Although the prevalence of depressive symptoms was lower, they were still an important predictor of adherence.

Uvod i svrha rada: Neke studije sugeriraju da bolesnici s hemofilijom (BSH) imaju veću prevalenciju urolitijaze u usporedbi s općom muškom populacijom iste dobne skupine. Kod odraslih BSH nedostaje spoznaja o čimbenicima rizika za urolitijazu. Svrha je rada istražiti prevalenciju/pojavnost urolitijaze kod odraslih BSH te pridružene čimbenike rizika.----- Metode: U ovo presječno istraživanje uključena su 92 odrasla BSH liječena u jednom centru, KBC-u Zagreb. Ultrazvuk urotrakta bila je metoda izbora za dokazivanje urolitijaze, dok se svim ispitanicima uzimala anamneza te uzorci za laboratorijske pretrage krvi i urina.----- Rezultati: Prevalencija urolitijaze znatno je viša kod BSH nego u hrvatskoj populaciji (10,9 % vs. 5,9 %; P = 0,042). Također je vjerojatnost doživljenja/pojave urolitijaze tijekom života znatno viša nego u općoj populaciji (25 % vs. 12 %; P = 0,001). Trenutačna prisutnost urolitijaze i ranija anamneza urolitijaze nisu bile statistički značajno povezane s tipom hemofilije ili težinom hemofilije kao niti s načinom liječenja ili vrstom lijeka (plazmatski ili rekombinatni faktori) (P > 0,05). U multivarijatnoj analizi neovisni prediktori trenutačne prisutnosti urolitijaze (P < 0,05) bili su arterijska hipertenzija, prisutnost inhibitora, hiperkalciurija, povišen serumski bilirubin (P < 0,05), dok su hematurija (P = 0,051) i ranije infekcije mokraćnog sustava (P = 0,059) prepoznati kao relevantni čimbenici. Slično su arterijska hipertenzija, prisutnost inhibitora i pozitivna anamneza hematurije u anamnezi prepoznati kao nezavisni prediktori u anamnezi urolitijaze (P < 0,05), dok je ranije liječenje HCV bilo na granici statističke značajnosti (P = 0,085). ----- Zaključak: Odrasli BSH imaju češću urolitijazu koja se može smatrati još jednom bolešću povezanom s hemofilijom. Čimbenici rizika ukazuju na neimunološko i imunološko oštećenje bubrega te hiperkalciuriju kao glavne etiološke mehanizme nastanka bubrežnih kamenaca u ovih bolesnika., Introduction and aim: Patients with haemophilia (PWH) could have higher prevalence of urolithiasis according to some studies compared with age-matched males. There is a lack of data regarding risk factors for urolithiasis in adult PWH patients. The aim of this work is to investigate the prevalence of urolithiasis in adult PWH and associated risk factors. ----- Methods: We cross-sectionally evaluated 92 adult PWH, from one centre, UHC Zagreb. Presence of urolithiasis was assessed by ultrasound, while all patients had a medical history and samples were taken for blood and urine laboratory tests.----- Results: Prevalence of urolithiasis was significantly higher among PWH than reported prevalence in Croatian population (10,9 % vs. 5,9 %; P = 0,042). Similarly, occurrence of urolithiasis during course of disease was significantly higher than estimated lifetime cumulative incidence of urolithiasis in Croatian population (25 % vs 12 %; P = 0,001). Neither current presence of urolithiasis, nor urolithiasis previously recorded during course of the disease showed statistically significant associations with type of hemophilia, severity of hemophilia, use of plasma derived factors or recombinant factors (P > 0,05 for all associations). In multivariate analyses, arterial hypertension, presence of inhibitors, hypercalciuria and serum bilirubin were identified as independent predictors of current urolithiasis (P < 0,05), whereas haematuria (P = 0,051) and prior urinary infections (P = 0,059) were also recognized as relevant factors. Similarly, arterial hypertension, presence of inhibitors and history of macrohematuria were recognized as independent predictors of history of urolithiasis (P < 0,05). ----- Conclusion: Adult PWH have more frequent urolithiasis which can be considered as haemophilia-related disease. Risk factors indicate non-immunological and immunological kidney damage and hypercalciuria as the main etiological mechanisms of urolithiasis in these patients.