Tukostaipumus ja suora trombiinin estäjä lepirudiini : kliinisiä ja monitorointinäkökulmia

Thrombophilia (TF) predisposes both to venous and arterial thrombosis at a young age. TF may also impact the thrombosis or stenosis of hemodialysis (HD) vascular access in patients with end-stage renal disease (ESRD). When involved in severe thrombosis TF may associate with inappropriate response to anticoagulation. Lepirudin, a potent direct thrombin inhibitor (DTI), indicated for heparin-induced thrombocytopenia-related thrombosis, could offer a treatment alternative in TF. Monitoring of narrow-ranged lepirudin demands new insights also in laboratory. The above issues constitute the targets in this thesis. We evaluated the prevalence of TF in patients with ESRD and its impact upon thrombosis- or stenosis-free survival of the vascular access. Altogether 237 ESRD patients were prospectively screened for TF and thrombogenic risk factors prior to HD access surgery in 2002-2004 (mean follow-up of 3.6 years). TF was evident in 43 (18%) of the ESRD patients, more often in males (23 vs. 9%, p=0.009). Known gene mutations of FV Leiden and FII G20210A occurred in 4%. Vascular access sufficiently matured in 226 (95%). The 1-year thrombosis- and stenosis-free access survival was 72%. Female gender (hazards ratio, HR, 2.5; 95% CI 1.6-3.9) and TF (HR 1.9, 95% CI 1.1-3.3) were independent risk factors for the shortened thrombosis- and stenosis-free survival. Additionally, TF or thrombogenic background was found in relatively young patients having severe thrombosis either in hepatic veins (Budd-Chiari syndrome, BCS, one patient) or inoperable critical limb ischemia (CLI, six patients). Lepirudin was evaluated in an off-label setting in the severe thrombosis after inefficacious traditional anticoagulation without other treatment options except severe invasive procedures, such as lower extremity amputation. Lepirudin treatments were repeatedly monitored clinically and with laboratory assessments (e.g. activated partial thromboplastin time, APTT). Our preliminary studies with lepirudin in thrombotic calamities appeared safe, and no bleeds occurred. An effective DTI lepirudin calmed thrombosis as all patients gradually recovered. Only one limb amputation was performed 3 years later during the follow-up (mean 4 years). Furthermore, we aimed to overcome the limitations of APTT and confounding effects of warfarin (INR of 1.5-3.9) and lupus anticoagulant (LA). Lepirudin responses were assessed in vitro by five specific laboratory methods. Ecarin chromogenic assay (ECA) or anti-Factor IIa (anti-FIIa) correlated precisely (r=0.99) with each other and with spiked lepirudin in all plasma pools: normal, warfarin, and LA-containing plasma. In contrast, in the presence of warfarin and LA both APTT and prothrombinase-induced clotting time (PiCT®) were limited by non-linear and imprecise dose responses. As a global coagulation test APTT is useful in parallel to the precise chromogenic methods ECA or Anti-FIIa in challenging clinical situations. Lepirudin treatment requires multidisciplinary approach to ensure appropriate patient selection, interpretation of laboratory monitoring, and treatment safety. TF seemed to be associated with complicated thrombotic events, in venous (BCS), arterial (CLI), and vascular access systems. TF screening should be aimed to patients with repeated access complications or prior unprovoked thromboembolic events. Lepirudin inhibits free and clot-bound thrombin which heparin fails to inhibit. Lepirudin seems to offer a potent and safe option for treatment of severe thrombosis. Multi-centered randomized trials are necessary to assess the possible management of complicated thrombotic events with DTIs like lepirudin and seek prevention options against access complications.Veren poikkeava tukostaipumus altistaa nuorena ilmaantuville laskimotukoksille ja harvemmin valtimotukoksille. Väitöskirjan tavoite oli kartoittaa tukostaipumuksen merkitystä vaikeiden tukosten yhteydessä ja dialyysiveritien tukos- ja ahtaumakomplikaatioissa vaikeaa kroonista munuaisten vajaatoimintaa sairastavilla potilailla. Selvitimme myös suoran trombiinin estäjän lepirudiinin tehoa vaikeiden perinteiselle hepariinihoidolle vastaamattomien tukosten hoidossa. Lepirudiinin virallinen käyttöaihe on nykyisin hepariinin aiheuttaman verihiutaleiden määrän laskuun liittyvän tukoksen hoito. Lepirudiinin kapea terapeuttinen alue edellyttää luotettavaa annosvasteen monitorointia. Nykyisin käytetyn menetelmän, aktivoitu osittainen hyytymisaika (APTT), puutteiden vuoksi selvitimme neljän muun spesifisen monitorointimenetelmän soveltumista lepirudiinin annosvasteiden arvioimiseen, myös kliinisesti tärkeiden sekoittavien tekijöiden, varfariinin (INR 1.5-3.9) ja lupus antikoagulantin (LA) yhteydessä. Kaikkiaan 237:lta potilaalta määritettiin verikokein tukostaipumusta ja tukoksille altistavia tekijöitä ennen dialyysiveritieleikkausta vuosina 2002-2004 (seuranta-aika ka. 3.6 v). Tukostaipumus todettiin 43:lla (18%) potilaista, useimmiten miehillä (23 vs. 9%, p=0.009). Tunnetut geenimutaatiot FV Leiden and FII G20210A esiintyivät 4%:lla, poikkeamatta normaaliväestöstä. Veriteiden tukos- ja ahtaumavapaa elinkaari 1-vuoden kohdalla oli 72%. Naissukupuoli (hasardisuhde, 2.5; 95% LV 1.6-3.9) ja poikkeava tukostaipumus (hasardisuhde 1.9, 95% LV 1.1-3.3) olivat itsenäisiä riskitekijöitä tukosten ja ahtaumien lyhentämälle veritien elinkaarelle. Poikkeava tukostaipumus todettiin myös suhteellisen nuorilla potilailla, joilla oli vaikea tukos (maksalaskimon tukos, Budd-Chiari oireyhtymä, BCS sekä 6 kriittinen verisuonikirurgiaan soveltumaton alaraajaiskemia). Lepirudiinin tavanomaisten käyttöaiheiden ulkopuolista tehoa ja turvallisuutta arvioitiin näiden erittäin vaikeiden tukosten hoidossa tilanteessa, jossa muita parantavia hoitomahdollisuuksia ei ollut ja hoitovaste perinteiselle antikoagulaatiolle oli heikko. Lepirudiinihoito osoittautui turvalliseksi ja tehokkaaksi. Vuotokomplikaatioita ei ilmaantunut ja kaikki potilaat toipuivat. Ainoastaan yksi alaraaja amputoitiin 3 vuotta myöhemmin 4 vuoden seuranta-aikana. Lepirudiinin annosvasteen arvio oli luotettavinta kromogeenisillä menetelmillä (ecarin chromogenic assay, ECA ja anti-Factor IIa), jotka korrelloivat erinomaisesti sekä keskenään (r=0.99) että lepirudiinipitoisuuksien kanssa kaikissa olosuhteissa: normaaliplasmassa, varfariinia ja LA-sisältävissä plasmoissa. APTT ja protrombiinin indusoima hyytymisaika (PiCT®) kuvastivat epälineaarisesti lepirudiinin annosvastetta. Kyseiset menetelmät eivät soveltuneet käytettäviksi LA:a sisältävässä plasmassa. Poikkeava tukostaipumus assosioitui hankaliin laskimo- (BCS) ja valtimotukoksiin (kriittinen alaraajaiskemia) sekä dialyysiveritien tukoksiin. Tukostaipumuksen kartoittaminen kannattaa suunnata potilaisiin, joilla on historiassa riskitekijöitä kuten aiemman veritien tukkeutuminen tai ilman altistetta ilmantunut laskimo- tai valtimotukos. Lepirudiini estää vapaata ja myös hyytymään sitoutunutta trombiinia toisin kuin hepariini, mikä osin selittänee sen tehoa hepariinihoidolle huonosti vastanneissa tukoksissa. Veren hyytymisjärjestelmän globaalisen mittarin APTT:n käyttö sitä tarkempien kromogeenisten monitorointimenetelmien rinnalla on avuksi haastavissa kliinisissä tilanteissa. Moniammatillinen yhteistyö laboratorion ja kliinikkojen välillä on ensiarvoisen tärkeää lepirudiinihoitojen toteutuksessa ja vasteiden arvioinnissa. Siten turvataan tehokas tukosten hoito, mutta estetään vuoto-ongelmia. Monikeskuksiset tutkimukset ovat tarpeen suorien trombiinin estäjien merkityksen arvioinnissa vaikeiden tukosten hoidossa sekä dialyysiveritien tukosten ja ahtaumien ehkäisyssä ja hoidossa

Tunnistatko amiodaronin haittavaikutukset?

Amiodaroni on erittäin tehokas, mutta potentiaalisesti toksinen rytmihäiriölääke. Jokaisen potilaita hoitavan lääkärin tulee osata epäillä sen haittavaikutuksia. Niiden hoito ja amiodaronilääkityksen jatkaminen arvioidaan erikoissairaanhoidossa

Cancer risk and mortality after solid organ transplantation : A population-based 30-year cohort study in Finland

Cancer is a significant cause of morbidity and mortality after solid organ transplantation (SOT) and related to lifelong immunosuppression. This retrospective registry study assessed for the first time in Finland population-based cancer risk and cancer mortality after all SOTs (lung and childhood transplantations included) as standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs). Data from transplant registries were linked with the data of Finnish Cancer Registry and Statistics Finland. We followed 6548 consecutive first SOT recipients from 1 January 1987 to 31 December 2016 translating to 66 741 person-years (median follow-up time 8.9 years [interquartile range 4.0-15.1]). In total, 2096 cancers were found in 1483 patients (23% of all patients). Majority of cancers (53%) were nonmelanoma skin cancers (NMSCs). The overall SIR was 3.6 (95% confidence interval [CI]: 3.5-3.8) and the SIR excluding NMSCs was 2.2 (95% CI: 2.0-2.3). SIR for all cancers was highest for heart (5.0) and lowest for liver (2.7) recipients. Most common cancer types after NMSCs were non-Hodgkin lymphoma (NHL), SIR 9.9 (95% CI: 8.5-11.4) and kidney cancer, SIR 7.3 (95% CI: 6.0-8.8). Cancer-related deaths were 17% (n = 408) of all deaths after first month post transplantation. SMR for all cancers was 2.5 (95% CI: 2.2-2.7) and for NHL 13.6 (95% CI: 10.7-16.8). Notably, overall SIR for cancer was lower in later period (2000-2016), 3.0 (95% CI: 2.8-3.2), than in earlier period (1987-1999), 4.3 (95% CI: 4.0-4.5), P < .001. Decrease in cancer incidence was temporally associated with major changes in immunosuppression in the 2000s.Peer reviewe

Trends and burden of diabetes in patients with atrial fibrillation during 2007-2018 : A Finnish nationwide cohort study

Aims: We assessed the temporal trends in the prevalence of diabetes and in its associations with outcomes among patients with atrial fibrillation (AF). Methods: The registry-based FinACAF study covered all patients with incident AF in Finland between 2007 and 2018. Ischemic stroke (IS) and mortality rates were computed using Poisson regression model. Results: We identified 229 565 patients (50.0% female; mean age 72.7 years; mean follow-up 4.0 years) patients with incident AF. The prevalence of diabetes increased steadily from 15.5% in 2007 to 26.3% in 2018. A decrease in IS and mortality rates was observed during the study period both in patients with and without diabetes. Diabetes was associated with IS and mortality (adjusted incidence rate ratios with 95% confidence intervals 1.22 (1.17-1.26) and 1.32 (1.29-1.34), respectively). The impact of diabetes on IS risk remained stable, while its effect on mortality increased slightly during the observation period. Conclusions: The prevalence of diabetes has increased considerably among patients with AF between 2007 and 2018. There have been substantial improvements in the prognosis of AF patients with diabetes. However, diabetes remains a significant risk factor for IS and mortality in this patient population.Peer reviewe

Temporal trends of gender disparities in oral anticoagulant use in patients with atrial fibrillation

Aims: To investigate sex-specific temporal trends in the initiation of oral anticoagulant (OAC) therapy among patients diagnosed with atrial fibrillation (AF) in Finland between 2007 and 2018.Methods: The registry-linkage Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) Study included all patients with incident AF in Finland from 2007 to 2018. The primary outcome was the initiation of any OAC therapy.Results: We identified 229,565 patients with new-onset AF (50.0% women; mean age 72.7 years). The initiation of OAC therapy increased continuously during the observation period. While women were more likely to receive OAC therapy overall, after adjusting for age, stroke risk factors and other confounding factors, female sex was associated with a marginally lower initiation of OACs (unadjusted and adjusted hazard ratios comparing women to men: 1.08 (1.07-1.10) and 0.97 (0.96-0.98), respectively). Importantly, the gender disparities in OAC use attenuated and reached parity by the end of the observation period. Furthermore, when only patients eligible for OAC therapy according to the contemporary guidelines were included in the analyses, the gender inequalities in OAC initiation appeared minimal. Implementation of direct OACs for stroke prevention was slightly slower among women.Conclusion: This nationwide retrospective cohort study covering all patients with incident AF in Finland from 2007 to 2018 observed that although female sex was initially associated with a lower initiation of OAC therapy, the sex-related disparities resolved over the course of the study period.Peer reviewe