Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation

Background: Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG) and plasmin generation (PG). Objective: To determine differences in TG and PG between HA patients before and during a pharmacokinetic study and identify best parameters to develop a pharmacodynamic model. Methods: Twenty-five HA patients (baseline FVIII < 1-9 IU/dL) underwent a pharmacokinetic study with a single dose of 25-50 IU/kg standard half-life FVIII concentrate. At baseline and after administration of FVIII TG and PG parameters were measured with the NHA. Results: FVIII activity level increased from median 1.0 IU/dL (interquartile range < 1.0-6.0) to 71 IU/dL (62-82) 15 minutes after administration and decreased to 15 IU/dL (10-26) at 24 hours. TG was enhanced simultaneously, with thrombin peak height (TPH) increasing from 22nM (15-35) to 222nM (159-255), and thrombin potential (TP) from 404nM/min (undetectable-876) to 1834nM/min (1546-2353). Twenty-four hours after infusion, TG parameters remained high (TPH 73nM [58.5-126.3]; TP 1394nM/min [1066-1677]) compared to FVIII activity level. PG showed hyperfibrinolysis in severe HA patients compared to mild patients and controls, which normalized after FVIII supplementation. Conclusion: HA patients showed clear differences in baseline TG and PG despite having comparable FVIII activity levels. These results reveal a discrepancy between FVIII activity level and TG, in which the latter may be a better parameter to monitor individualized treatment in HA patients

Combining factor VIII levels and thrombin/plasmin generation: A population pharmacokinetic-pharmacodynamic model for patients with haemophilia A

Aims: Prophylactic treatment of haemophilia A patients with factor VIII (FVIII) concentrate focuses on maintaining a minimal trough FVIII activity level to prevent bleeding. However, due to differences in bleeding tendency, the pharmacokinetic (PK)-guided dosing approach may be suboptimal. An alternative approach could be the addition of haemostatic pharmacodynamic (PD) parameters, reflecting a patient's unique haemostatic balance. Our aim was to develop a population PK/PD model, based on FVIII activity levels and Nijmegen Haemostasis Assay (NHA) patterns, a global haemostatic assay that measures thrombin/plasmin generation simultaneously. Methods: PK/PD measurements were collected from 30 patients treated with standard half-life FVIII concentrate. The relationship between FVIII activity levels and the thrombin/plasmin generation parameters (thrombin potential, thrombin peak height and plasmin peak height), were described by sigmoidal Emax functions. Results: The obtained EC50 value was smallest for the normalized thrombin potential (11.6 IU/dL), followed by normalized thrombin peak height (56.6 IU/dL) and normalized plasmin peak height (593 IU/dL), demonstrating that normalized thrombin potential showed 50% of the maximal effect at lower FVIII activity levels. Substantial inter-individual variability in the PD parameters, such as EC50 of thrombin potential (86.9%) was observed, indicating that, despite similar FVIII activity levels, haemostatic capacity varies significantly between patients. Conclusion: These data suggest that dosing based on patients' individual PK/PD parameters may be beneficial over dosing solely on individual PK parameters. This model could be used as proof-of-principle to examine the application of PK/PD-guided dosing. However, the relation between the PD parameters and bleeding has to be better defined

Meaningful work – Mismatches between employees’ work and sense of self

Meaningful work has been a growing area of research during the last few decades. People’s attitudes towards their work have been changed and people expect their work to provide possibilities to actualize themselves as well as serve a greater good. Meaningful work is a subjective experience of individuals that is influenced by several factors. In this research, the topic is approached through the literature covering meaningful work and identity. In this study, meaningful work is examined in individuals’ career transitions. The aim of this research is to explore what kind of mismatches people find between their work and identities and to understand, how people reflect those mismatches. The purpose was to interview individuals who have considered or done career transitions due to their mismatching work experiences. The topic is approached through people’s individual-level experiences in order to form a holistic picture of the phenomenon. The research is approached through qualitative study methods. The material is collected by interviewing 12 individuals. The interviewees were selected based on their mismatching work experiences by purposive sampling methods. The interviews were semi-structured interviews and they were conducted during the spring of 2020 by remote access. The data were transcribed and analyzed by obeying the principles of interpretative phenomenological analysis (IPA). The findings of this study were examined through the research questions. The findings show that the mismatches between work and identity are encapsulated in four main themes: organizational procedures, management of the organization, purpose of the organization, and organizational ideology and message. Furthermore, the study focuses on the way in which the interviewees’ reflected their mismatches. The responses divided into two main themes. The first theme was the self-related aspect that contains individuals’ personalities, possibilities to be themselves as well as their personal growth stories. The second theme that emerged was the work-related aspect which refers to the needs that interviewees expected from their workplaces. The work-related aspect divided into the need for transparency, the need for appreciation, the reciprocal relationships, and the integrity between work and free time. The study results strive to give individual-level views of the experience of meaningful work. The main results of this research are that meaningful work experiences are parallel with the existing literature. However, the study gives an in-depth view of the phenomenon on the individual level. Furthermore, the research proposes that individuals’ personal and professional identities are converging with each other. The interviewees hoped that they could actualize themselves similarly inside and outside work. Also, the interviewees experienced that they wanted to find a job through which they could influence on things they found important. However, further research is needed.Merkityksellinen työ on aihe, jonka tutkimus on lisääntynyt erityisesti viime vuosina. Ihmisten asenteet työtä kohtaan ovat muuttuneet ja työltä haetaan asioita, joiden avulla yksilö voi toisaalta toteuttaa itseään ja toisaalta vaikuttaa johonkin itseään suurempaan. Merkityksellinen työ on yksilöllinen kokemus, johon vaikuttavat monet tekijät. Tässä tutkimuksessa aiheeseen perehdytään merkitykselliseen työhön ja identiteettiin liittyvän kirjallisuuden pohjalta. Tutkimuksessa on tarkasteltu merkityksellistä työtä yksilöiden urasiirtymävaiheissa. Tutkimuksen tavoitteena on selvittää, millaisia ristiriitoja yksilöiden työn ja identiteetin välillä ilmenee sekä ymmärtää, miten nämä ristiriidat koetaan. Tavoite pyritään saavuttamaan haastattelemalla henkilöitä, jotka ovat harkinneet uranvaihtoa tai vaihtaneet työpaikkaa heidän identiteetin ja työpaikan välisen ristiriidan vuoksi. Aihetta lähestytään haastateltavien henkilökohtaisten työkokemusten kautta, jotta ilmiöstä voitaisiin muodostaa mahdollisimman kokonaisvaltainen kuva. Tutkimus on toteutettu laadullisin tutkimusmenetelmin. Tutkimusaineisto kerättiin haastattelemalla 12 henkilöä, jotka valittiin harkinnanvaraisesti heidän ristiriitaisten työkokemustensa perusteella. Haastattelut toteutettiin puolistrukturoituina haastatteluina keväällä 2020 etäyhteyden välityksellä. Tutkimusaineisto litteroitiin ja analysoitiin tulkitsevan fenomenologisen analyysin periaatteita noudattaen. Tutkimuksen löydöksiä tarkastellaan tutkimuskysymysten kautta. Aineistosta ilmenee useita ristiriitoja, jotka tiivistyvät neljään teemaan: organisaation toimintatavat, organisaation johto, organisaation tavoite ja organisaation viesti. Seuraava osio keskittyy siihen, kuinka haastateltavat tarkastelivat näitä ristiriitoja. Vastauksista tunnistetaan kaksi teemaa: henkilöön itseensä liittyvät syyt, jotka jakautuivat yksilön persoonallisuuteen, mahdollisuuteen olla oma itsensä sekä henkilökohtaiseen kasvutarinaan. Toisena teemana aineistossa ilmeni työpaikkaan liittyvät syyt. Työpaikkaan liittyvät syyt nousevat esiin tarpeina, joita haastateltavat kaipaavat työpaikoiltaan. Näitä syitä ovat tarve läpinäkyvyydelle, tarve arvostukselle, tarve molemminpuoliselle suhteelle sekä tarve työn ja vapaa-ajan yhdenmukaistamiselle. Tutkimustulokset pyrkivät antamaan yksilötason näkökulmaa merkityksellisen työn kokemuksesta. Tämän tutkimuksen merkittävimpinä tuloksina ilmenee, että yksilöiden käsitykset merkityksellisestä työstä ovat hyvin samankaltaisia olemassa olevan kirjallisuuden kanssa. Tutkimus kuitenkin syventää merkityksellisen työn kokemusta yksilötasolla. Lisäksi tutkimus antaa viitteitä siitä, että haastateltavat haluavat heidän persoonallisten ja ammatillisten identiteettien olevan lähempänä toisiaan. Haastateltaville oli tärkeää, että he pystyivät kokonaisvaltaisesti toteuttamaan itseään niin töissä kuin vapaa-ajalla. Lisäksi haastateltavat kokivat, että he halusivat työn, jonka avulla he pystyivät vaikuttamaan asioihin, jotka katsoivat henkilökohtaisesti tärkeiksi. Jatkotutkimusta kuitenkin tarvitaan