The Past Decade: Fibrinogen

This paper reviews the advances in understanding of fibrinogen structure and function, its genetic and environmental determinants, role in the process of hemostasis, platelet aggregation, plasma viscosity and erythrocyte aggregation, cellular and matrix interactions, inflammation, wound healing, tumor development, atherogenesis and involvement in pathogenesis of diseases, that have been made over the past decade. Future studies will seek to define precise mechanisms of complex gene-environment interactions that influence fibrinogen levels and its complex role in the pathogenesis of fibrinogen-associated diseases

Thrombopoietin receptor agonist romiplostim in refractory thrombocytopenia as a bridging therapy to the second allogeneic stem cell transplantation

Thrombopoietin (TPO) receptor agonist romiplostim mimic the action of TPO and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. In this work, we present a patient with a Ph-negative chronic myeloid leukemia (CML) with refractory thrombocytopenia treated with romiplostim as a bridging therapy to the second allogeneic stem cell transplantation (alloSCT). A 56-year old male patient was diagnosed with an atypical Ph-negative CML. One year after the diagnosis he underwent alloSCT from HLA-matched unrelated donor, but had early graft rejection, with severe bleeding diathesis, anemia and thrombocytopenia refractory to transfusion therapy. In addition to daily platelet transfusions (sometimes 2 times per day), he received tranexamic acid and intravenous immunoglobulins. Since the severe thrombocytopenia persisted, romiplostim was introduced as subcutaneous once per week treatment. After two weeks of romiplostim therapy, platelet count increased and the need for platelet transfusions decresed, and he was further followed up in outpatient setting receiving romiplostim as a bridging therapy to his second alloSCT that he received latter. This work describe an unusual use of the TPO receptor agonist as a bridging therapy between two alloSCTs to treat severe refractory thrombocytopenia

BOLESNICA S MANJKOM FXII, JAK2-MUTACIJA POZITIVNOM KRONIČNOM MIJELOPROLIFERATIVNOM NEOPLAZMOM I PONAVLJANIM ROMBOEMBOLIJSKIM INCIDENTIMA

Introduction and Aim: Factor XII (FXII) deficiency is a rare disorder associated with a prolonged coagulation test (aPTT) indicating bleeding diathesis but without clinically major bleeding tendencies. In opposite to this laboratory finding, it is clinically associated with an increased risk of developing thromboembolic events. The aim of this case report is to present a female patient with severe FXII deficiency, very prolonged aPTT, recurrent thromboembolic events and diagnosis of JAK2-mutation positive chronic myeloproliferative neoplasm (MPN), without hemorrhagic diathesis despite dual anticoagulation and antiaggregation therapy. We also performed review of the literature regarding FXII deficiency, its clinical significance and open questions regarding that rare coagulation disorder. Case Report: We present a female patient born in 1959, with a history of severe obesity and arterial hypertension, which in 2010 developed deep vein thrombosis (DVT) of the right arm during hormone replacement therapy. Laboratory findings showed prolonged aPTT. Warfarin was introduced into therapy for two years, followed by treatment with acetylsalicylic acid, without hemorrhagic complications. In January 2014, after cholecystectomy she developed pulmonary embolism, DVT of the right leg, with very prolonged aPTT verified again (>150 s), clinically without signs of hemorrhagic diathesis. She was treated with low molecular weight heparin with bridging to warfarin and was referred to a hematologist due to prolonged aPTT. Extended diagnostic workup revealed low activity of FXII (<0.02 KIU/L), elevated activity of FVIII (2.52-3.5 KIU/L) and VWF (VWF:RCo 251%, VWF:Ag 317%). Also JAK2V617F mutation was found indicating chronic MPN, and acetylsalicylic acid therapy was started along with warfarin, and later cytoreductive therapy with hydroxyurea was initiated because of JAK2-mutation positive chronic MPN. During subsequent 4-year follow-up, the patient was without thromboembolic incidents, adequately anticoagulated, without hemorrhagic diathesis despite dual anticoagulation and antiaggregation therapy and permanently prolonged aPTT. Conclusion: Repeating prolonged aPTT in a person with no signs of bleeding diathesis requires diagnostic workup for the possible lack of contact factors including FXII. The presented patient with acquired and hereditary thrombophilia and recurrent thrombotic incidents has an indication for long term dual anticoagulant and antiaggregation therapy that is well tolerated without bleeding complications.Uvod i cilj: Manjak faktora XII (FXII) je rijedak poremećaj povezan s produženim testom koagulacije (APTV) laboratorijski ukazujući na moguću sklonost krvarenju, no bez klinički značajnih krvarenja. Suprotno laboratorijskom nalazu, klinički je povezan s povećanim rizikom razvoja tromboembolijskih incidenata. Cilj ovoga rada je prikazati bolesnicu s teškim manjkom FXII, izrazito produženim APTV-om, ponavljajućim tromboembolijskim incidentima i dijagnozom JAK2-mutacija pozitivne kronične mijeloproliferativne neoplazme (MPN) bez hemoraške dijateze unatoč dvojnoj antikoagulacijskoj i antiagregacijskoj terapiji. Također je učinjen pregled literature o manjku FXII i njegovom kliničkom značenju, s otvorenim pitanjima o ovom rijetkom koagulacijskom poremećaju. Prikaz bolesnice: Prikazujemo bolesnicu rođenu 1959. godine s anamnezom izrazite pretilosti i arterijske hipertenzije. Bolesnica je 2010. godine imala duboku vensku trombozu (DVT) desne ruke tijekom uzimanja hormonske nadomjesne terapije. Tada se u laboratorijskim nalazima verifi cirao produženi APTV. Primala je varfarin tijekom dvije godine nakon čega je uvedena terapija acetilsalicilnom kiselinom, bez hemoraških komplikacija. U siječnju 2014. nakon kolecistektomije dolazi do razvoja masivne plućne embolije, DVT desne noge uz ponovno verificiran vrlo produženi APTV (>150 s), klinički bez znakova hemoraške dijateze. Liječena je niskomolekularnim heparinom s premoštavanjem na varfarin. Upućena je hematologu zbog produženog APTV-a, a učinjenom se ekstenzivnom obradom utvrde vrlo niska aktivnost FXII (<0,02 KIU/L), povišena aktivnost FVIII (2,52 KIU/L) i VWF (VWF:RCo 251 %, VWF:Ag 317 %) te točkasta mutacija V617F u genu za JAK2, nakon čega je uvedena i acetilsalicilna kiselina uz varfarin, a kasnije i citoreduktivna terapija hidroksiurejom zbog JAK2-mutacija pozitivne kronične MPN. Tijekom iduće 4 godine praćenja bolesnica je bez novih tromboembolijskih incidenata, dostatno antikoagulirana, bez hemoraških incidenata unatoč dvojnoj antikoagulacijskoj i antiagregacijskoj terapiji i trajno izrazito produženom APTV-u. Zaključak: Ponavljajući produženi APTV u osobe koja nema znakove krvarenja zahtijeva obradu na mogući manjak kontaktnih faktora uključujući FXII. U prikazane bolesnice sa stečenom i nasljednom trombofi lijom i ponavljajućim trombotskim incidentima indicirana je dugotrajna dvojna antikoagulantna i antiagregacijska terapija koju dobro podnosi bez krvarećih komplikacija

Prädiktoren zur Gewichtsbestimmung bei Neugeborenen

Recent observations that there is a secular variation in newborn weight and length call for their continuous assessment, as well as evaluating factors that influence them. The influence of maternal age, weight and height, as well as the number of previous deliveries, abortions and the number of cigarettes smoked per day on newborn weight and length was examined. Data were collected from 181 healthy pregnant women from Zagreb, Croatia, who delivered healthy newborns in term. Multiple regression, correlation coefficients and variance analysis were performed to assess the significance of tested variables on observed fetal features. Maternal age has no significant influence on birth weight, even though mothers younger than 20 and older than 30 tend to have lighter children. Both the numbers of previous deliveries and abortions showed no significant correlation to newborn weight. The number of cigarettes smoked per day during pregnancy and maternal pre-pregnancy weight were found to have significant correlation to newborn weight and length. Maternal height correlated significantly with newborn weight and length, but when multiple regression was performed, controlling for other parameters, no significant influence on newborn weight was found. These results indicate that smoking cessation and im-provement in maternal nutritional status (expressed as body weight) are the two modifiable factors that play a significant role in the reduction of low birth weight children, and thus the reduction of perinatal mortality.Novija zapažanja da postoje sekularna odstupanja u težini i duljini novorođenčadi zahtijevaju stalnu provjeru, kao i vrijednosti koje na njih utječu.Stoga se ispitivao utjecaj majčine dobi, težine i visine, kao i broj prijašnjih poroda, abortusa te broj popušenih cigareta na dan, na težinu i duljinu novorođene djece.Podaci su prikupljani od 181 zdrave trudnice iz Zagreba, Hrvatske, koje su rodile zdravu novorođenčad u terminu.Izvedene su regresijska analiza, korelacija koeficijenata i analiza varijance kako bi se utvrdila značajnost provjeravanih varijabli na opažanim karakteristikama fetusa.Majčina dob ne utječe značajno na težinu novorođenog djeteta, premda su majke mlađe od dvadeset godina i starije od 30 sklone rađanju djece s manjom porođajnom težinom.Broj prijašnjih poroda kao i prekida trudnoće nije značajno povezan s težinom novorođenčeta. Međutim, broj dnevno popušenih cigareta tijekom trudnoće te težina majki prije trudnoće bile su značajno korelirane s težinom i duljinom novorođenog djeteta.Visina majki također je bila značajno povezana s težinom i duljinom djeteta, ali nakon regresijske analize, kontrolom ostalih parametara, nije zamijećen značajan utjecaj na djetetovu težinu.Ovi nalazi pokazuju da su prestanak pušenja i poboljšanje majčine prehrane (izražene u tjelesnoj težini) dva modificirajuća faktora koji imaju važnu ulogu u smanjivanju broja djece s niskom porođajnom tjelesnom težinom te tako smanjuju i perinatalni mortalitet.Jüngsten Beobachtungen zufolge gibt es unter Neugeborenen außerordentlich große Schwankungen in Körpergewicht und Größe. Dies wie auch die Umstände, die dazu führen, erfordern eine ständige Kontrolle. Die vorliegende Untersuchung galt daher den Auswirkungen, die das Alter der Mutter, deren Körpergewicht und Größe, die Zahl der früheren Geburten und Abtreibungen, die Zahl der pro Tag gerauchten Zigaretten auf das Körpergewicht und die Größe von Neugeborenen haben. Die ermittelten Angaben stammen von 181 Schwangeren aus Zagreb, Kroatien, die innerhalb des Geburtstermins gesunde Babys zur Welt brachten. Es wurden eine Regressionsanalyse, eine Koeffizienten-Korrelation und eine Varianzanalyse angewandt, um die Auswirkung der geprüften Variablen auf die an den Föten beobachteten Charakteristiken zu untersuchen. Das Gewicht des Neugeborenen wird nur unwesentlich durch das Alter der Mutter beeinflußt, auch wenn Frauen unter 20 sowie Frauen über 30 Jahren dazu neigen, Kinder mit geringerem Körpergewicht zu gebären. Ebensowenig steht die Zahl früherer Geburten und Schwangerschaftsabbrüche in einem wesentlichen Zusammenhang mit dem Körpergewicht des Neugeborenen. Dafür erwies sich jedoch, daß die tägliche Zahl der während der Schwangerschaft gerauchten Zigaretten sowie das Körpergewicht der Mutter vor der Schwangerschaft in wesentlichem Bezug zu Körpergewicht und Größe des Neugeborenen stehen. Dasselbe gilt für die Körpergröße der Mutter, doch konnte – nach angewandter Regressionsanalyse und einer Kontrolle der übrigen Parameter – kein ausschlaggebender Einfluß auf das Körpergewicht des Säuglings nachgewiesen werden. Diese Angaben zeigen, daß die Einstellung des Rauchens und eine verbesserte Ernährungsweise der Mutter (ausgedrückt im Körpergewicht) zwei modifizierende Faktoren darstellen, die nachhaltig dazu beitragen können, die Zahl der untergewichtigen Neugeborenen und somit das Ausmaß der Säuglingssterblichkeit einzudämmen