mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary myelofibrosis. To date, several
...mutations were identified, with only frameshift mutations linked to the diseased phenotype. It is of diagnostic and prognostic importance to properly define the type of
mutation and subclassify it according to its structural similarities to the classical mutations, a 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2 mutation), using a statistical approximation algorithm (AGADIR). Today, the knowledge on the pathogenesis of
-positive MPN is expanding and several cellular mechanisms have been recognized that finally cause a clonal hematopoietic expansion. In this review, we discuss the current basis of the cellular effects of
mutants and the understanding of its implementation in the current diagnostic laboratorial and medical practice. Different methods of
detection are explained and a diagnostic algorithm is shown that aids in the approach to
-positive MPN. Finally, contemporary methods joining artificial intelligence in accordance with molecular-genetic biomarkers in the approach to MPN are presented.
S transfuzijo povezana reakcija presadka proti gostitelju (angl. Transfusion associated graft versus host disease, TA-GvHD) je redek, vendar resen in življenje ogrožajoč zaplet po transfuziji krvnih ...pripravkov. Posledica, kolikor do nje pride, je bolnikova smrt v več kot 90 % primerov. Po transfuziji krvi se osebi z imunsko pomanjkljivostjo limfociti T iz darovalčeve krvi odzovejo na celične in tkivne antigene prejemnika krvi. Zato darovalčevi limfociti T aktivirajo in uničijo tarčne celice v tkivih prejemnika. Vzrok, da se imunske celice prejemnika ne odzovejo tako, da bi onemogočile darovalčeve limfocite T, je pomanjkljivost imunskega odziva pri prejemniku in le izjemoma vprašanje skladnosti HLA med prejemnikom in darovalcem.
Obsevanje krvnih pripravkov z ionizirajočimi žarki je najbolj učinkovita metoda za preprečevanje TA-GvHD. Patogensko inaktiviranje s psoralenom in UVA-žarki je enakovredno obsevanju, vendar se zaenkrat uporablja samo za trombocitne pripravke. Zato je pomembno, da lečeči zdravnik prepozna bolnike, pri katerih lahko nastane TA-GvHD in za njih naroča zgolj obsevane krvne pripravke. Obsevamo eritrocite, granulocite ter trombocite, kadar niso patogensko inaktivirani. Sveže zmrznjene plazme, krioprecipitata, zdravil iz krvi, kot so albumin, imunoglobulini, faktorji strjevanja krvi ... ter eritrocitov po odmrzovanju ne obsevamo, ker je vsebnost limfocitov T zanemarljiva. Priporočen osrednji obsevalni odmerek je znotraj 25–50 Gy.
1 Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan, Department of Medicine and Medical Specialities, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Luigi ...Villa Foundation, Milan, Italy;
2 Laboratory for Thrombosis Research, IRC, KULeuven Campus Kortrijk, Kortrijk, Belgium;
3 Internal Medicine, Unit Department of Medical and Surgical Sciences, University of Padua, Padua, Italy;
4 Department of Haematology, University Medical Center, Ljubljana, Slovenija;
5 Department of Hematology and Stem Cell Transplantation, National Medical Center, Budapest, Hungary;
6 emostasis Department and Hemophilia Center, National Blood Transfusion Institute, Belgrade, Serbia;
7 Haemostasis and Thrombosis Unit, Haematology Research Centre, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
8 Division of Hematology and Bone Marrow Transplantation, Vittorio Emanuele Ferrarotto-S.Bambino Hospital, University of Catania, Catania, Italy;
9 Hematology Institute, Catholic University, Rome, Italy
Correspondence: Flora Peyvandi, MD, PhD, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, University of Milan, Via Pace, 9, 20122, Milan, Italy. E-mail: flora.peyvandi{at}unimi.it
Background: From 20 to 50% of patients who survive an acute episode of the acquired form of thrombotic thrombocytopenic purpura relapse but clinical and laboratory markers of recurrence are not well established.
Design and Methods: In 109 patients enrolled in an international registry we evaluated, in the frame of a retrospective cohort study, the predictive role of the metalloprotease ADAMTS13 as measured in plasma during remission. Anti-ADAMTS13 antibodies and von Willebrand factor were also evaluated in a smaller number of the same patients.
Results: Median values of ADAMTS13 activity and antigen were significantly lower in patients with recurrent thrombotic thrombocytopenic purpura than in those with no recurrence (activity: 12% vs. 41%; p =0.007; antigen: 36% vs. 58%; p =0.003). A severe deficiency of ADAMTS13 activity (10% or less) was associated with a higher likelihood of recurrence (odds ratio 2.9; 95% confidence interval 1.3 to 6.8; p =0.01). Anti-ADAMTS13 antibodies were also more prevalent in patients with recurrent thrombotic thrombocytopenic purpura (odds ratio 3.1; 95% confidence interval 1.4 to 7.3; p =0.006). The presence during remission of both severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies increased the likelihood of recurrence 3.6 times (95% confidence interval 1.4 to 9.0; p =0.006). The presence of ultralarge von Willebrand factor multimers and of associated diseases or conditions did not increase recurrence.
Conclusions: Survivors of an acute episode of acquired thrombotic thrombocytopenic purpura with severely reduced levels of ADAMTS13 and/or with anti-ADAMTS13 antibodies during remission have an approximately three-fold greater likelihood of developing another episode of thrombotic thrombocytopenic purpura than patients with higher protease activity and no antibody.
Key words: thrombotic thrombocytopenic purpura, ADAMTS13, von Willebrand factor, risk factors, recurrence.
Related Article
Acquired thrombotic thrombocytopenic purpura: ADAMTS13 activity, anti-ADAMTS13 autoantibodies and risk of recurrent disease
Bernhard Lämmle, Johanna A. Kremer Hovinga, James N. George
Haematologica 2008 93: 172-177.
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Extramedullary plasmacytoma of the head and neck is a rare indolent neoplasm. Radiotherapy is often the preferred treatment option with excellent local control and survival. The risk of local ...recurrence or transformation to multiple myeloma is 10–30%. In our case-cohort, thorough, sensitive initial evaluation for disseminated clonal disease and the incorporation of surgery led to excellent results with no recurrences or systemic progression.
The current guidelines for prevention of infections in hematopoietic stem cell transplantation (HSCT) do not specify which central venous catheter (CVC) insertion site should be preferred in ...allogeneic HSCT recipients-internal jugular vein (IJV) or subclavian vein (SCV). We designed a multicenter prospective observational study comparing the risk of infectious and non-infectious complications between the two most common sites of CVC insertion (IJV and SCV) in allogeneic HSCT. There were in total 232 consecutive patients (86 IJV and 146 SCV) who underwent adult allogeneic HSCT reported from 11 centers in 8 countries. The center independent analysis of central line associated/related blood stream infections with ECDC criteria has shown statistically significant difference favoring SCV (23% IJV vs 13% SCV (OR 2.03 (1.01-4.06), p = 0.047)). The differences in CLABSI per 1000 days of CVC use favored SCV over IJV (7.93/1000 days IJV vs 2.79/1000 days SCV, p = 0.002). The frequency of all non-infectious complications was similar in both arms-13% IJV and 12% SCV (OR 1.1 (0.5-2.5), p = 0.8). This multicenter prospective study showed statistically significant lower confirmed number of CLABSI per 1000 days of CVC use without higher risk of noninfectious complications related to the subclavian insertion site in allogeneic HSCT recipients.
Background: Iron deficiency anaemia (IDA) is the most prevalent type of anaemia and a common cause for patient referrals to the haematology outpatient clinic. The aim of this study was to determine ...the number of patients with IDA treated at the Haematology Outpatient Clinic of the UMC Ljubljana in the period of two years, as well as to inquire into the causes for their referrals to the clinic, patient characteristics, their complete blood count results at initial examination, the prescribed therapy, the number and the causes of their follow-up visits. We draw special attention to the IDA onset mechanism, the microcytic anaemia therapy principles and the indications prompting a referral of an IDA patient to the haematology specialist. Methods: We undertook a retrospective analysis of the medical records of patients who were referred to the Haematology outpatient clinic of the UMC Ljubljana for examination in the two-year period between 1 January 2014 and 31 December 2015 and had been diagnosed with IDA on the basis of their clinical picture and their CBC values. Data were collected with the Hipokrat IT system and statistically evaluated with Microsoft Excel. Results: In the period relevant for our research, 277 patients of those who were referred to the Haematology outpatient clinic for medical examination were diagnosed with IDA. 11.6 % of these patients were male and 88.4 % female; 62.1 % of the female patients were of childbearing age. IDA was specified as the referral diagnosis in the cases of no more than 39 % of the patients referred to the specialist outpatient clinic, whilst the medical condition of the remaining percentage of patients was not identified by the referring doctor. Comorbidities were observed in 50.2 % of the patients, and for 62.5 % of the patients a follow-up appointment was scheduled by the treating haematologist. Of all patients, 63.5 % were treated with an intravenous iron preparation during their first examination at the outpatient clinic and a transfusion of erythrocytes was administered during such an examination to 4.3 % of the patients. Conclusion: Patients with IDA were often treated at our Haematology Outpatient Clinic in the relevant two-year period. The data indicates a poor recognition rate of this prevalent type of anaemia. IDA is not a blood disorder and the referral of IDA patients to the Haematology Outpatient Clinic is justified in the case of severe microcytic anaemia, when the patient does not respond to the oral or intravenous iron replacement therapy or if a concomitant change in the CBC persists despite the effective treatment with iron preparations.
Slabokrvnost je najbolj pogost simptom v nosečnosti. Zaradi razvoja zarodka in hitre rasti ploda se močno povečajo potrebe organizma po železu in vitaminih. Zato je slabokrvnost zaradi pomanjkanja ...železa daleč najbolj razširjena oblika slabokrvnosti v nosečnosti. Anemija v nosečnosti je opredeljena z ravnijo hemoglobina (Hb), ki je manjša od 110 g/L. V normalni nosečnosti se sestava krvi pomembno spremeni. Povečanje celokupnega volumna krvi in hemostatske spremembe so fiziološke spremembe, ki omogočajo, da porodnica brez posledic prenese normalno izgubo krvi med porodom. Plazemski volumen se v nosečnosti poveča za 50 %, masa eritrocitov pa za 18 – 25 %, odvisno od razpoložljivega železa. Te spremembe povzročijo razredčitev koncentracije hemoglobna, kar poznamo kot fiziološko slabokrvnost v nosečnosti. Fiziološka slabokrvnost doseže vrh v 32. tednu nosečnosti. Zaradi fizioloških sprememb odkrijemo s presejalnimi testi v nosečnosti mnogo slabokrvnosti, ki bi sicer ostale neodkrite. Povečane ali spremenjene prehranske in presnovne zahteve v nosečnosti povzročijo, da je slabokrvnost zaradi pomanjkanja železa (sideropenična anemija) bolj pogosta. Prva nepravilnost v biokemičnih izvidih, ki kaže na pomanjkanje železa v nosečnosti, je zmanjšana koncentracija feritina (na pomanjkanje železa lahko sklepamo že, ko je vrednost feritina manjša od 20–30 g/L). Feritin je stabilen in zadovoljivo zrcali zaloge železa, za razliko od vrednosti serumskega železa. Zato učinkovito dodajanje železovih pripravkov in s tem preprečevanje sideropeničnih anemij lahko pričnemo že zelo zgodaj. Tako na zelo enostaven način učinkovito preprečimo nastanek zapletov v nosečnosti, ob porodu in v poporodnem obdobju. Slabokrvnost v nosečnosti je povezana s višjo pogostnostjo za prezgodnji porod, nizko porodno težo, z nujnostjo uporabe transfuzije ob in po porodu ter s poporodno depresijo.
Incidenca levkemij, odkritih v nosečnosti, znaša od 1/10.000 do 1/100.000. Nemalokrat je ob odkritju bolezni z zdravljenjem s citostatiki potrebno začeti takoj. Citostatiki so za plod teratogeni, ...zato moramo pred pričetkom zdravljenja pretehtati vse možnosti in izbrati najbolj sprejemljivo. Predstavljamo primera akutne mieloične levkemije (AML) in kronične mieloične levkemije (KML), odkrita v nosečnosti, ki smo ju obravnavali v Univerzitetnem kliničnem centru v Ljubljani. Gre za edina primera v zadnjih desetih letih v Sloveniji.Bolnico z AML, podvrsta akutna promielocitna levkemija (APL), smo ob začetku 2. trimesečja nosečnosti zdravili z daunorubicinom in all-transretinoično kislino (ATRA). Glede na našo izkušnjo se zdi, da so priporočila za zdravljenje APL v nosečnosti realna, izvedljiva in predvsem varna za bolnico in plod.Pri bolnici s KML, ki je prvič prišla k nam tik pred porodom, je bila v ospredju izrazita levkocitoza 335 × 109/L, trombocitoza in splenomegalija. Zavračala je vse načine zdravljenja, v prvi vrsti levkoferezo. Kljub vsemu je brez porodnih zapletov rodila zdravega otroka. Porod je bil zaradi povečane vranice in posledične nevarnosti za njeno rupturo dokončan s carskim rezom. Na osnovi naše izkušnje lahko zaključimo, da ni moč priporočiti, pri kako velikem številu levkocitov je za mati in plod koristno začeti zdraviti z levkoferezo. Enako tudi ni jasno, kakšno tveganje za rupturo vranice v teh primerih predstavlja poskus vaginalnega poroda. Uganka ostaja tudi vprašanje, kolikokrat se zaradi levkemij različnih oblik poveča tveganje za trombembolični dogodek v nosečnosti, ki že sama po sebi nagiba k trobozam.
The purpose of this article was to present a case of successful long term treatment with azacitidine in patient with Chronic Myelomonocytic Leukemia (CMML) and discussing possible contributing ...factors for its long term efficacy. Data from our case were compared with similar data available in the literature. Effective treatment with azacitidine resulted in overall survival of 11 years 5 months and we showed that applying multiple cycles of treatment is feasible. Our patient received 71 cycles of treatment with total duration of 7 years and 3 months. Our report about a patient with CMML and a good clinical course revealed, that long term treatment with azacitidine is feasible in some patients. Initially low bone marrow blast count, a relatively small malignant CMML clone, reduction of spleen size and fast platelet response seemed to be factors determining long term response to treatment in our patient. More data on CMML treatment by Hypomethylating Agents and their analysis are needed in order to make firm conclusions.
The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the ...interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-κB) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells’ interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.
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