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Összefoglaló. A szerzők a SARS-CoV-2 vírus okozta járványnak (COVID–19) a haemostasist érintő, klinikailag fontosabb szempontjait tekintik át röviden. Felhívják a figyelmet a thromboemboliás szövődmények súlyossága és gyakorisága mögött levő patomechanizmus jellegzetességére, vagyis a Virchow-triász három alkotója időben egyszerre történő aktiválódására. A továbbiakban a kórállapotot és -lefolyást jelző fontosabb haemostasis laboratóriumi leleteket érintik, majd rátérnek a megelőzés és a kezelés kérdéseire, mely utóbbiakat a betegség súlyossági csoportokra történő bontásában tárgyalják, a jelenlegi nemzetközi irányelvekre támaszkodva. Végezetül egy összefoglaló táblázatban, a nemzetközi ajánlásokon alapuló, de a hazai szempontokat is figyelembe vevő, általánosan elfogadható antikoagulálási útmutatót igyekeznek adni, hangsúlyozva a kezelés személyre szabásának fontosságát. Summary. In the present paper the most important, clinically relevant haemostatic effects of SARS-Cov-2 virus infection (COVID-19) is reviewed and an awareness is raised of the unique pathomechanism which allows a concurrent activation of each side of the Virchows’ triad responsible for the aggressivity of thrombotic events in the disease. Subsequently characteristic haemostatic prognostic and staging laboratory results are discussed followed by a brief survey of anticoagulant prophylaxis and therapy in the different severity stages of the disease. Finally a brief guidance is given based on various international guidelines with an adoption of current Hungarian situation and emphasizing the importance of personalized decisions.

Hereditary hemorrhagic telangiectasia (HHT) is a rare germline vascular malformation syndrome with a prevalence of 1:5000-1:10,000 [...].

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Introduction Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. Patients and methods Non-related AT deficient patients (n = 156) and their family members (total n = 246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. Results Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH 7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. Conclusion Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.

Deep vein thrombosis (DVT), pulmonary embolism (PE), or with the common name venous thromboembolism (VTE) are frequent manifestations of pathologic hemostasis in malignancies, thereby contributing to the large number of patients despite recent developments in thrombosis prevention. In the present paper up-to-date practice of diagnosis and therapy will be discussed partly based on the author's previous publications on epidemiology and prophylaxis of VTE in oncological patients.A malignus betegségeket gyakran kíséri a hemosztázis zavara, amely többnyire mélyvénás trombózisban (MVT), pulmonális embóliában (PE), együttes megnevezéssel vénás tromboembóliában (VTE) nyilvánul meg, nem kis mértékben hozzájárulva a hatékonyabb megelõzés ellenére sem csökkenõ betegszámhoz. A szerzõ a jelen munkában a VTE korszerû diagnózisának és kezelésének fontosabb általános és onkológiai szempontjait tekinti át, támaszkodva saját korábbi, az epidemiológiai adatokat és a profilaxis kérdését tárgyaló közleményeire.

A 38-year-old alcoholic man with severe iron deficient anaemia, and bloody-mucous stool was found to have haemorrhoidal bleeding. In spite of intravenous iron supplements haemoglobin levels were falling. He was admitted because of deteriorating condition, jaundice, severe anaemia (haemoglobin, 38 g/l) and iron deficiency. Except of toxic (alcohol) agent all other causes of liver disease could be excluded. Sclero-, and medical therapy, and abstinency resulted in a rapid improvement in his condition and subsequently rectal bleeding also disappeared. Bleeding from the upper gastrointestinal tract is a well known and serious complication in liver cirrhosis, however, a voluminous blood loss resulting in a life-threatening anaemia from lower gastrointestinal tract or haemorrhoids, as it was detected in this patient, is quite rare. Sclerotherapy seems to be an effective method with only minor complications when compared with other invasive techniques. However, the patient’s compliance even in liver cirrhosis with haemorrhoidal nodes is essential for a long-time success. Orv. Hetil., 2013, 154, 382–386.

P-selectin receptor is expressed in platelets and endothelial cells in a cell-activation-dependent manner. Platelet P-selectin (CD62) levels may become elevated in a number of vasoocclusive diseases, including arteriosclerosis, atherothrombosis, and diabetes mellitus (DM). Nonarteritic anterior ischemic optic neuropathy (NAION) is associated with a sudden loss of vision due to the vascular insufficiency of ciliary arteries supplying the optic nerve. In this study, our aim was to investigate the presence of increased platelet reactivity in the development of NAION. Twenty-one NAION patients, 39 healthy control subjects, and 44 patients suffering from diabetes mellitus (DM) were examined in our case-control, pilot study. Platelet activation was investigated by flow cytometric analysis of the mean fluorescence intensity (MFI) of CD62 on platelets. These results were compared among the different study groups. NAION patients showed considerably although not signifactly (p = 0.2017) higher P-selectin MFI values (71.98 ± 40.30) versus healthy subjects (55.48 ± 20.95), insulin-dependent DM patients (50.02 ± 13.08), and non-insulin-dependent DM subjects (54.72 ± 24.74). However, logistic regression analysis resulted in a statistically significant adjusted effect on the odds of NAION when CD62 MFI values were logarithmically transformed (OR: 3.86, 95 % CI: 1.10 to 13.53, p = 0.0346). Elevated platelet CD62 positivity may be related to NAION, suggesting a possible role of enlarged platelet activity in the generation of this type of ischemic optic neuropathy.

Blood vessels supplying ocular structures originate from the internal carotid artery, so the blood supply of the eyes and the brain are closely connected. The various branches of the ophthalmic artery (central retinal artery, short and long posterior ciliary arteries, lacrimal artery, anterior ciliary artery) originating from the internal carotid artery and the corresponding veins are responsible for supplying the region indicated by their name. In rare cases, when the ophthalmic artery is absent, the medial meningeal artery performs the same task. The uvea is supplied by the ciliary artery, and the retina gets its blood supply from the branches of the central retinal artery. The posterior ciliary arteries (that supply the optic disc) and the central retinal artery (that supplies the medial two-thirds of the retina) are the first arteries to branch off the ophthalmic artery that enters through the optic foramen. The central retinal artery divides into superior temporal, inferior temporal and nasal branches. The next vessels to branch off are the long posterior ciliary arteries that supply the peripheral parts of the choroidea, the ciliary body and the iris. The last branch is that of the anterior ciliary arteries. Venous drainage from the retina is carried out by the central retinal vein and its smaller branches that have the same name and course as the corresponding arteries. The vorticose veins drain the choroidea towards the inferior and superior ophthalmic vein and the cavernous sinus. The capillary network between the retinal arteries and veins serves to ensure overly efficient oxygen and nutrient exchange. It is only the macula lutea (responsible for acute vision) and the fovea centralis that have no capillaries. Another special feature of these vessels is that retinal blood vessels have the same structure as cervical ones, and it is also true for uveal and extracranial vessels. These veins and arteries are located very close to each other, sometimes in the same adventitia sheath.

Background Antithrombin (AT) is a key regulator of the coagulation. In type II deficiency, the heparin-binding-site defect (type II HBS) is considered to be relatively low thrombosis risk. Objectives Our aims were to search for SERPINC1 mutation(s) and to describe the clinical and laboratory phenotype of a large number of AT Budapest3 (ATBp3, p.Leu131Phe) carriers and confirm the presence of a founder effect. Patients/methods AT-deficient patients were recruited and carriers of ATBp3, n = 102 (63 families) were selected. To investigate the founder effect, eight intragenic single nucleotide polymorphisms, a 5'-length dimorphism, and five microsatellite markers were detected. Clinical and laboratory data of the patients were collected and analyzed. Results In AT deficiency, 16 different causative mutations were found, and the great majority of patients were of type II HBS subtype. Most of them (n = 102/118, 86.5%) carried the ATBp3 mutation. The ATBp3 mutant allele was associated with one single haplotype, while different haplotypes were detected in the case of normal allele. The anti-factor Xa-based AT activity assay that we used could detect all ATBp3 patients with high sensitivity in our cohort. ATBp3 homozygosity (n = 26) was associated with thrombosis at a young age and conferred a high thrombotic risk. Half of the heterozygotes (n = 41/76, 53.9%) also had venous and/or arterial thrombosis, and pregnancy complications were also recorded. Conclusion In Hungary, the founder mutation, ATBp3, is the most common AT deficiency. Our study is the first in which the clinical characterization of ATBp3 mutation was executed in a large population.

Atherosclerosis is a systemic disease affecting the coronary, carotid, intracerebral, renal and peripherial arteries. The early morphological and functional impairments could be detected in the second or third decades of life and their progression depend on the number and severity of risk factors and individual susceptility. Although the vascular risk factors (smoking, overweight, age, unhealthy diet, lack of physical exercise, hypertension, diabetes mellitus, chronic kidney disease and dyslipidemia) are the same and common in the different vascular diseases, the present clinical routine artificially classifies the diagnosis and therapy of different vascular diseases into different subfields of medicine with the negative impact of possible polypragmasia. Recently, worldwide health surveys (e.g. REACH registry) have proven the usefulness of a holistic approach in the diagnosis and therapy of multiorgan-affected vascular patients. This review summarizes the multidisciplinary advances and future perspective of vascular diseases. Orv. Hetil., 2012, 153, 483–498.

Absztrakt A perioperatív antithromboticus megelőzés, illetve a tartósan antithromboticus kezelésben részesülő betegek műtéti ellátása (ún. áthidaló kezelés) mind a vénás thromboemboliák (VTE) megelőzése, mind a műtéti vérzéses szövődmények számának és súlyosságának csökkentése szempontjából kiemelt jelentőségű feladat. A nagyszámú irodalom és a nyomukban született ajánlások – érthető módon – elsősorban a hagyományos, általában többnapos hospitalizációt igénylő, nyílt műtétek különféle formáival foglalkoznak, sokkal kevesebb figyelem jutott ez ideig az egynapos sebészet során fellépő VTE kockázataira, illetve megelőzésére. A szerzők áttekintik az egynapos sebészeti eljárásokhoz kapcsolódó VTE epidemiológiáját, ismertetik az új nemzetközi, illetve a 4. Magyar Antithrombotikus Irányelv ajánlásait. Ezek lényege: amennyiben a műtétre kerülő betegnél egyidejűleg szerzett vagy veleszületett thrombosisra hajlamosító tényezők igazolhatók, az általános, nem gyógyszeres thrombosismegelőzési módszereken túlmenően egynapos sebészeti eljárások során is indokolt a gyógyszeres (kis molekulatömegű heparin) profilaxis.

A kórházban kezelt sebészeti és belgyógyászati betegekben jelentős a vénásthromboembolia-rizikó. Profilaxis nélkül, a műtét típusától függően, a sebészeti beavatkozások kapcsán a betegek 15–60%-ában alakul ki mélyvénás trombózis vagy tüdőembólia, és az utóbbi ma is vezető kórházi halálok. Bár a vénás thromboemboliát leggyakrabban a közelmúltban végzett műtéttel vagy traumával hozzák kapcsolatba, a szimptómás thromboemboliás események 50–70%-a és a fatális tüdőembóliák 70–80%-a nem a sebészeti betegekben alakul ki. Nemzetközi és hazai felmérések alapján a nagy kockázattal rendelkező sebészeti betegek többsége megkapja a szükséges trombózisprofilaxist. Azonban profilaxis nélkül marad a rizikóval rendelkező belgyógyászati betegek jelentős része, a konszenzuson alapuló nemzetközi és hazai irányelvi ajánlások ellenére. A belgyógyászati betegek körében növelni kell a profilaxisban részesülők arányát és el kell érni, hogy trombózisrizikó esetén a betegek megkapják a hatásos megelőzést. A beteg trombóziskockázatának felmérése fontos eszköze a vénás thromboembolia által veszélyeztetett betegek felderítésének, megkönnyíti a döntést a profilaxis elrendeléséről és javítja az irányelvi ajánlások betartását. A trombózisveszély megállapításakor, ha nem ellenjavallt, profilaxist kell alkalmazni. „A thromboemboliák kockázatának csökkentése és kezelése” című, 4. magyar antithromboticus irányelv felhívja a figyelmet a vénástrombózis-rizikó felmérésének szükségességére, és elsőként tartalmazza a kórházban fekvő belgyógyászati és sebészeti betegek kockázati kérdőívét. Ismertetjük a kockázatbecslő kérdőíveket és áttekintjük a kérdőívekben szereplő rizikófaktorokra vonatkozó bizonyítékokon alapuló adatokat.

A nem insulinoma eredetű tartós (perzisztáló) hyperinsulinaemiával járó hypoglykaemia oka a felnőttek körében ritkán előforduló nesidioblastosis. A nesidioblastosis hátterében álló inzulinszekréciós zavar molekuláris eltéréseken alapul. Morfológiailag különböző pancreassziget-, illetve béta-sejt-eltérések jellemzik, az inzulinhiperszekréció hátterében azonban körülhatárolható térfoglalás nem mutatható ki. A diagnózis alappillére az alacsony vércukorszint, a normoglykaemia intravénásan alkalmazott glükóz adásával történő fenntarthatósága, illetve az emelkedett inzulin- és C-peptid-szint. A hormontermelő tumor kizárásához mind invazív, mind nem invazív képalkotó módszerek szükségesek. A tartós, illetve ismétlődő hypoglykaemia káros hatásai gyógyszeres és/vagy sebészi kezeléssel előzhetők meg. Esetismertetés: A szerzők két betegük esetét ismertetik, akiknél felnőttkorban jelentkeztek a súlyos tünetekkel járó hypoglykaemiás epizódok. Nőbetegük „klasszikus” hypoglykaemiás tünetei 34 éves korban léptek fel: izzadás, szédülés, remegés, idegesség, illetve életveszélyes neuroglycopeniás jelek. Második, férfi betegük 22 éves, akinek fő panasza a hypoglykaemia ritka és szokatlan tünete, a nagyfokú éhségérzet mellett jelentkező puffadás volt. Az éhezési próbák mindkét esetben pozitívak voltak, vagyis hypoglykaemiás tünetek miatt fel kellett azokat függeszteni. Az inzulin- és a C-peptid-szintek magasak voltak, vénás inzulinszint-meghatározás az a. lienalis több pontjából és a képalkotó eljárások (komputertomográfia, mágneses rezonancia, pozitronemissziós tomográfia, angiográfia) nem tudtak igazolni térfoglalást. Az adatok alapján – szövettan hiányában is – a legvalószínűbb a felnőttkori nesidioblastosis diagnózisa. Diazoxid adásával mindkét esetben majdnem teljes tünetmentességet értek el, és neuroglycopeniás esemény a kezelés kezdete óta nem fordult elő. Következtetések: Ismeretlen eredetű hypoglykaemia esetén, ha a képalkotó eljárásokkal nincs körülírt képlet, a laboratóriumi adatok viszont egyértelműen emelkedett inzulinszekrécióra utalnak, gondolni kell nesidioblastosis lehetőségére. A sebészi beavatkozás veszélye pancreaselégtelenség éppúgy lehet, mint a betegség fennmaradása a hasnyálmirigy reszekciója miatt. Diazoxid adásával viszont tartós tünetmentesség érhető el ezen ritka kórképben, ezért érdemes elsőként ezt megkísérelni.

A 25-year-old woman who developed transient neurological abnormalities after scuba diving is reported. The subsequent day she experienced transient left-side monocular blindness. Arterial ocular occlusion in apparently healthy young women is unusual, and a search for the cause of this devastating vascular event is mandatory. Occlusion of the left branch retinal artery, total occlusion of the left internal carotid artery, and a petrous apex epidermoid were found, together with a shortened prothrombin time (INR: 0.73), a slightly elevated serum cholesterol level (6.1 mmol/l) and combined thrombophilia (elevated FVIIIC plus type 2 sticky platelet syndrome). This case underlines the complex mechanism of thromboembolic diseases, and the importance of the acquired trigger (in the present case scuba diving) in addition to the long-term anatomical and biochemical risk factors.

Introduction Protein C (PC) is a major anticoagulant and numerous distinct mutations in its coding gene result in quantitative or qualitative PC deficiency with high thrombosis risk. Homozygous or compound heterozygous PC deficiency usually leads to life-threatening thrombosis in neonates. Patients and Methods The molecular consequences of 3 different missense mutations of two patients have been investigated. The first patient suffered from neonatal purpura fulminans and was a compound heterozygote for p.Asp77Gly and p.Ala163Glu mutations. The second patient had severe deep venous thrombosis in young adulthood and carried the p.Ala163Val mutation. The fate of mutant proteins expressed in HEK cells was monitored by ELISA, by Western blotting, by investigation of polyubiquitination and by functional assays. Their intracellular localization was examined by immunostaining and confocal laser scanning microscopy. Molecular modeling and dynamics simulations were also carried out. Results and Conclusions The 163Val and 163Glu mutants had undetectable levels in the culture media, showed intracellular co-localization with the 26S proteasome and were polyubiquitinated. The 77Gly mutant was secreted to the media showing similar activity as the wild type. There was no difference among intracellular PC levels of wild type and mutant proteins. The 163Val and 163Glu mutations caused significant changes in the relative positions of the EGF2 domains suggesting misfolding with the consequence of secretion defect. No major structural alteration was observed in case of 77Gly mutant; it might influence the stability of protein complexes in which PC participates and may have an impact on the clearance of PC requiring further research.

Nonarteritic anterior ischemic optic neuropathy (NAION) is an ischemic infarction of the optic nerve head, frequently leading to sudden, mostly irreversible loss of vision. In this study blood thrombophilic factors, as well as cardiovascular risk factors were investigated for their relevance to this pathology. Trombophilic risk factors so far not evaluated were included in the study.37 NAION patients (4 with sequential second eye involvement) and 81 matched control subjects were examined. From blood, protein C, protein S, antithrombin, von Willebrand antigen levels (vWFAg), and factor V (Leiden) mutation, factor VIIIC level, plasminogen activity, lipoprotein (a) and fibrinogen levels, and presence of anticardiolipin antibodies were investigated. Possibly relevant pathologies [e.g. diabetes mellitus (DM), hypertension, and ischemic heart disease] were also registered.Elevated Lp(a) and vWFAg levels, DM, F V (Leiden), hypercholesterolemia, and hyperfibinogenemia proved to be significant risk factors associated with NAION. Forward stepwise logistic regression analysis revealed that high Lp(a), DM, and FV (Leiden) were the main predictive components, with odds ratios 16.88 (p=0.012), 5.78 (p=0.022) and 4.44 (p=0.033), respectively.Based on our results it appears that thrombophilia is likely to contribute to the development of NAION besides vascular damage due to the presence of cardiovascular risk factors. Further data are needed, however, to justify the suggested use of secondary prophylaxis using anticoagulant/antiplatelet therapy.

Purpose: Protein C is a major component of the natural anticoagulant pathway. Resistance of coagulation factor V (FV) to activated protein C (APC), mostly due to FV Leiden mutation, is the most common cause of inherited thrombophilia. The aim of this retrospective study was to determine the prevalence of APC resistance and Leiden mutation in patients with non-arteritic anterior ischaemic optic neuropathy (NAION). Methods: A total of 25 patients with NAION were examined between 1997 and 2002. The patients were screened for APC resistance and FV Leiden mutation as well as for acquired risk factors of vascular disease such as diabetes mellitus, hypercholesterolaemia, hypertonia and ischaemic heart disease. A control group of subjects without ocular vascular disease and with homogenous distribution of the same risk factors was used for comparison. Results: Six of the 25 patients (24%) with NAION had APC resistance due to the heterozygous Leiden mutation of FV. The frequency of the same genetic mutation in the control group was only 5.9%. Odds ratio calculations showed that patients with the Leiden mutation were at a significantly higher risk of NAION than control patients (p ≤ 0.021). Conclusion: The high frequency of Leiden mutation in NAION suggests a pathogenic role of the mutation in the disease.

Development of autoantibody against coagulation factor V (FV) is a rare clinical condition with hemorrhagic complications of varying severity. The aim of this study was to establish the pathomechanism of an acquired FV deficiency and characterize the FV inhibitor responsible for the clinical symptoms. A 78-year-old female was admitted to hospital with severe gastrointestinal bleeding. General clotting tests and determination of clotting factors were performed by standard methods. FV antigen and FV containing immune complexes were measured by ELISA. The FV molecule was investigated by Western blotting and by sequencing the f5 gene. The binding of patient's IgG to FV and activated FV (FVa) was demonstrated in an ELISA system and its effect on the procoagulant activity of FVa was tested in clotting tests and in a chromogenic prothrombinase assay. Localization of the epitope for the antibody was performed by blocking ELISA. FV activity was severely suppressed both in plasma and platelets. FV antigen levels were normal by ELISA using polyclonal anti-FV antibody or monoclonal antibody against the connecting region of FV, but depressed when HV1 monoclonal antibody against the C2 domain in the FV light-chain was used as capture antibody. The FV molecule was found intact. An IgG reacting with both FV and FVa was present in the patient's plasma and its binding to FV was inhibited by HV1 antibody. FV-containing immune complexes were detected in the patient's plasma and platelet lysate. The patient's IgG inhibited the procoagulant function of FVa. An anti-FV IgG was present in the patient's plasma and platelets. The autoantibody reacted with an epitope in the C2 domain of FV light chain and neutralized the procoagulant function of FVa.

The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.).A szerzők a felnőttkorban kiteljesedő ritka kórképekre hívják fel a figyelmet. Ezek részben nem genetikai eredetűek, hanem egy adott régióban, populációban vagy abszolút értelemben is ritka fertőzéses, anyagcsere-, autoimmun, daganatos, környezeti ártalmak okozta betegségek. Azonban a genetikai kórokú kórképek jelentős része is – beleértve a tárolási betegségeket (például Tay–Sachs-kór és Gaucher-kór felnőttkori formája), az enzimhiányokat (például az ureaciklus betegségein belül az ornitin-transzkarbamiláz deficiencia), a ritka thrombophiliákat (például homozigóta V. faktor Leiden-mutáció, antitrombindeficientia), egyes ritka, monogénes öröklésű betegségeket, mint a Huntington-chorea – csak kései gyermekkorban vagy felnőttkorban manifesztálódnak, érintve az orvoslás valamennyi területét. Az általánosan elfogadott becslés szerint a mintegy 6–8 ezer ritka betegségnek legalább a fele tehát a felnőttellátók (belgyógyászat, neurológia stb.), illetve „korsemleges” szakterületek (például szemészet, fül-orr-gégészet, bőrgyógyászat stb.) feladata. Orv. Hetil., 2014, 155(9), 334–340.

A szerzők a felnőttkorban kiteljesedő ritka kórképekre hívják fel a figyelmet. Ezek részben nem genetikai eredetűek, hanem egy adott régióban, populációban vagy abszolút értelemben is ritka fertőzéses, anyagcsere-, autoimmun, daganatos, környezeti ártalmak okozta betegségek. Azonban a genetikai kórokú kórképek jelentős része is – beleértve a tárolási betegségeket (például Tay–Sachs-kór és Gaucher-kór felnőttkori formája), az enzimhiányokat (például az ureaciklus betegségein belül az ornitin-transzkarbamiláz deficiencia), a ritka thrombophiliákat (például homozigóta V. faktor Leiden-mutáció, antitrombindeficientia), egyes ritka, monogénes öröklésű betegségeket, mint a Huntington-chorea – csak kései gyermekkorban vagy felnőttkorban manifesztálódnak, érintve az orvoslás valamennyi területét. Az általánosan elfogadott becslés szerint a mintegy 6–8 ezer ritka betegségnek legalább a fele tehát a felnőttellátók (belgyógyászat, neurológia stb.), illetve „korsemleges” szakterületek (például szemészet, fül-orr-gégészet, bőrgyógyászat stb.) feladata. Orv. Hetil., 2014, 155(9), 334–340.

Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) is located in the activation peptide (AP) just 3 amino acids away from the thrombin cleavage site. This mutation has been associated with a protective effect against occlusive arterial diseases and venous thrombosis; however, its biochemical consequences have not been explored. In the current study it was demonstrated that the intracellular stability and the plasma concentration of FXIII of different Val34Leu genotypes are identical, which suggests that there is no difference in the rate of synthesis and externalization of wild-type and mutant FXIII-A. In contrast, the release of AP by thrombin from the Leu34 allele proceeded significantly faster than from its wild-type Val34 counterpart. By molecular modeling larger interaction energy was calculated between the Leu34 variant and the respective domains of thrombin than between the Val34 variant and thrombin. In agreement with these findings, the activation of mutant plasma FXIII by thrombin was faster and required less thrombin than that of the wild-type variant. Full thrombin activation of purified plasma FXIII of different genotypes, however, resulted in identical specific transglutaminase activities. Similarly, the mean specific FXIII activity in the plasma was the same in the groups with wild-type, heterozygous, and homozygous variants. Faster activation of the Leu34 allele hardly could be associated with its presumed protective effect against venous thrombosis. No such protective effect was observed in a large group of patients with familial thrombophilia.

A 38-year-old alcoholic man with severe iron deficient anaemia, and bloody-mucous stool was found to have haemorrhoidal bleeding. In spite of intravenous iron supplements haemoglobin levels were falling. He was admitted because of deteriorating condition, jaundice, severe anaemia (haemoglobin, 38 g/l) and iron deficiency. Except of toxic (alcohol) agent all other causes of liver disease could be excluded. Sclero-, and medical therapy, and abstinence resulted in a rapid improvement in his condition and subsequently rectal bleeding also disappeared. Bleeding from the upper gastrointestinal tract is a well known and serious complication in liver cirrhosis, however, a voluminous blood loss resulting in a life-threatening anaemia from lower gastrointestinal tract or haemorrhoids, as it was detected in this patient, is quite rare. Sclerotherapy seems to be an effective method with only minor complications when compared with other invasive techniques. However, the patient's compliance even in liver cirrhosis with haemorrhoidal nodes is essential for long-term success.

SummaryDrugs can be electro-encapsulated within platelets and targeted to damaged blood vessels by exploiting the platelet’s natural haemostatic properties to adhere to collagen and other vessel wall constituents revealed by injury. A rat aorta balloon angioplasty model has been used to study the effect on platelet deposition of giving iloprost loaded platelets i.v. during the balloon injury. After labelling the circulating platelets with 111-Indium before balloon injury, time course studies showed maximum platelet deposition on the injured aorta occurred at about 1 h post-injury and the deposition remained stable over the next 2-3 h. When iloprost-loaded platelets were given i.v. during injury and the circulating platelet pool labelled with 111-Indium 30 min later, platelet deposition, measured at 2 h postinjury, was substantially and significantly reduced compared with control platelet treatment. Some antiproliferative effects of iloprost-loaded platelets given i.v. during injury have also been observed. Whereas the incorporation of [3H]-thymidine into aorta intima-media DNA at 3 days post injury was 62-fold higher in balloon injured rats than in control sham operated rats, thymidine incorporation into intima/media of rats which had received iloprost loaded platelets during injury was reduced as compared with rats subjected only to the injury procedure. The reduction was only of near significance, however, but at 14 days after injury the total DNA content of the aorta intima/media of rats given iloprost loaded platelets during injury was significantly reduced. Although iloprost loaded platelets can clearly inhibit excessive platelet deposition, other encapsulated agents may have greater anti-proliferative effects. These studies have shown that drug loaded platelets can be targeted to injured arteries, where they may be retained as depots for local release. We believe this novel drug delivery protocol may have therapeutic potential in reducing the incidence of occlusion and restenosis after angioplasty and thrombolysis treatment. Electro-encapsulation of drugs into platelets is a simple procedure and, using autologous and fully biocompatible and biodegradable platelets as delivery vehicles, might overcome some of the immunological and toxicological problems which have been encountered with other delivery vectors such as liposomes, microbeads, synthetic microcapsules and antibodies.

Objectives: There have been few reports on the association of rheumatoid arthritis (RA) with anti-neutrophil cytoplasmic antigen (ANCA)-associated systemic vasculitides. Methods: Here we present four cases of RA overlapping with Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). All these cases had both the diagnosis of RA and that of ANCA-associated vasculitis. Results: After we tried corticosteroids, multiple immunosuppressive drugs, sometimes plasmapheresis, rituximab was introduced to 3 out of 4 cases. Rituximab therapy was found to be effective in these three overlap cases. In the fourth case, rituximab was and will be considered; however, the patient has not given consent. Conclusion: To our knowledge, this is the first report on RA+CSS association. Common pathogenic background, such as genetic predisposition and ANCA may account for the development of RA+vasculitis overlaps. In DMARD-refractory cases, such as the ones presented here, biologics, especiall...

Purpose Von Hippel-Lindau disease is an autosomal dominantly inherited highly penetrant tumor syndrome predisposing to retinal and central nervous system hemangioblastomas, renal cell carcinoma and pheochromocytoma among other less frequent complications. Our goal was to establish genotype-phenotype correlation in Hungarian von Hippel-Lindau patients. Methods Fourteen members (9 patients and 5 healthy family members) of 6 unrelated families with type 1 VHL disease underwent clinical and molecular genetic examination. The effect of a novel missense mutation was predicted using molecular modeling. Results Retinal angioma was detected in seven patients; six patients had central nervous system hemangioblastoma and three patients developed RCC. Molecular genetic investigations detected four novel (c.232A>T, c.340+1G>A, c.163G>T, c.555C>A) and two previously described (c.583C>T and c.472C>G) germline mutations in the VHL gene, including four mutations leading to protein truncation and two missense mutations. Conclusion RCC only associated to MLTP among our patients, in accordance with previous findings. The novel c.163G>T mutation associated to bilateral RCC and retinal angioma in a 15-years-old male patient, which is the earliest occurrence of RCC in VHL disease reported so far. Molecular modeling of the VHL-Elongin C complex predicted that the c.232A>T mutation responsible for the p.Asn78Tyr amino acid exchange remarkably changes the 77-83 loop structure of the VHL protein destabilizing the VHL protein and the VHL- Elongin C complex. Therefore it is predicted to cause type I phenotype, as seen in our patient indeed. Our results can be useful for genetic counseling and follow-up of VHL patients.

Venous occlusion was used in 8 patients with liver cirrhosis and in 10 normals to investigate the pathomechanism of long-term elevation of plasma von Willebrand factor antigen (vWFAg) in liver cirrhosis. The following parameters were determined at baseline, and immediately, 60 min and 24 h after 10 min venous occlusion: vWFAg, ristocetin cofactor (RiCoF), in vitro platelet retention (Adeplat T), and tissue-type plasminogen activator (t-PA). Every baseline value in the liver cirrhosis group was significantly higher than in the controls. In both groups the 10-min values were significantly higher than their corresponding baseline results. Hence, comparing the two groups, in liver cirrhosis a significantly higher release of vWFAg and t-PA could be observed. These findings suggest on the one hand that the increased release contributes substantially to the sustained elevation of plasma vWF level in liver cirrhosis. On the other hand, the results indicate that not only the vascular surface of the diseased liver but most probably the total endothelium plays an important role in this phenomenon.

Central retinal vein occlusion (CRVO) occurring simultaneously in both eyes is a rare condition, in such cases usually associated with severe systemic disease. Overall, only 10% of all CRVO patients are younger than 40 years. A relatively young patient reported with simultaneous bilateral CRVO associated with chronic kidney disease and malignant hypertension. A case of a 35-year-old male patient presented with the complaint of decreased vision in both eyes. Ophthalmic examination revealed bilateral CRVO. Chronic kidney disease leading to malignant hypertension and hyperviscosity was diagnosed as the underlying cause. Clinical support and medical therapy effectively controlled the hypertension, leading to improvement of both the systemic and ocular changes. To the best of our knowledge, this is the first case report of simultaneous bilateral CRVO in a young patient associated with chronic renal failure and malignant hypertension. Primary care providers, either ophthalmologists or physicians, need to consider both common and atypical risk factors for retinal vein occlusion, in order to prevent further ocular morbidity and systemic complications.

Perioperative antithrombotic prophylaxis as well as surgical and invasive procedures done in anticoagulated patients ("bridging") have primary importance as regards prevention of venous thromboembolism (VTE) and reducing haemorrhagic complications. It is understandable that overwhelming majority of publications are dealing with major surgery (when usually several days hospitalization is required) while much less papers focus on one-day surgery cases. In this paper a brief survey on VTE epidemiology and prevention is carried out based on the new international and the 4th Hungarian Antithrombotic Guideline. The new protocols suggest that beside general measures a perioperative pharmaceutical antithrombotic prophylaxis is necessary if concomittant inherited and/or acquired thrombophilia is present.

A large proportion of hospitalized surgical and medical patients are at risk for venous thromboembolism. Depending on the type of surgical intervention, venous thrombosis develops in 15-60% of surgical patients without prophylaxis. Although venous thromboembolism is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic events and 70 to 80% of fatal pulmonary embolisms occur in nonsurgical patients. International and national registries show that the majority of at-risk surgical patients actually received the appropriate thromboembolic prophylaxis. However, despite of international and national recommendations, prophylaxis was not provided for a large proportion of at-risk medical patients. The rate of medical patients receiving prophylaxis should be increased, and appropriate thrombosis prophylaxis should be offered to at-risk medical patients. The thrombosis risk assessment is an important tool to identify patients at increased risk for venous thromboembolism, to simplify decision making on prophylaxis administration, and to improve the adherence to guidelines. When the risk is recognized, if there is no contraindication, prophylaxis should be ordered. The 4th Hungarian Antithrombotic Guideline entitled "Risk reduction and treatment of thromboembolism" calls attention to the importance of risk assessment and for the first time it includes and recommends risk assessment models for hospitalized surgical and medical patients. The risk assessment models are presented and the evidence based data for the different risk factors included in these models are reviewed.

SummaryA novel approach to site-directed delivery of drugs in vivo using blood platelets as carrier vehicles is being investigated. In this context some initial studies are reported on the effect of platelet encapsulated anti-platelet drugs on platelet aggregation and adhesion to fibrillar collagen and injured arteries in vitro. The stable prostacyclin analogue lloprost has been encapsulated within human and pig platelets by high voltage electroporation (Hughes and Crawford 1989 and 1990). After resealing the platelets, the packaged drug has a negligible effect upon platelet adhesion to a surface of fibrillar collagen or to damaged aorta (stripped to the tunica media to simulate deep injury). The rate of platelet recruitment to the collagen shows no dose dependency with respect to intracellular lloprost concentrations. After high lloprost loading, as few as 2% drug loaded platelets in a mixture with control (sham encapsulated) platelets, inhibit agonist-induced platelet aggregation >50%. The prior deposition of a “lawn” of Iloprost-loaded platelets onto fibrillar collagen or damaged aorta has a substantial inhibitory effect (50–70%) upon the secondary recruitment of normal platelets compared with recruitment to a “lawn” of normal platelets. This inhibition of secondary recruitment occurs even in the presence of a platelet activator. If reduction of platelet recruitment to a vessel wall lesion results in a decrease in the local concentration of platelet granule-derived smooth muscle cell chemotactic and proliferative factors, this site-directed drug delivery may well have application for the prevention of restenosis following balloon angioplasty procedures.

A 75-year-old man presented with painful oral and groin ulcers. The lack of any infections and the location of the ulcers suggested Behcet's disease. Subsequently, pancytopenia developed and bone marrow examination revealed myelodysplastic syndrome. Cytogenetic examination revealed 7q- and 20q- but not 8+. Immunosuppressive therapy with cyclosporine and corticosteroid resulted in a dramatic improvement in both clinical signs and hematologic abnormalities.

A krónikus lymphoid leukaemia (CLL) növeli a különböző szolid tumorok kialakulásának veszélyét, transzformálódhat egyéb lymphoid eredetű malignus betegségbe, myeloid jellegű malignus kórkép azonban ritkán társul CLL-hez. A szerzők egy kezeletlen CLL-es betegük kórtörténetét ismertetik, akiben hat évvel a CLL felismerését követően myelodysplasticus szindróma [refrakter anaemia gyűrűs („ringed”) sideroblastokkal] alakult ki. A myelodysplasticus szindróma kialakulásával és progressziójával a CLL háttérbe szorulását észlelték. A kórtörténet és irodalom ismertetése mellett áttekintik a CLL-hez társuló malignus myeloid betegségek patogenezisének lehetőségeit.

We report the case of a 39-year-old Hungarian woman who cyclically experienced painful, erythematous, patchy skin lesions on her face and chest. Because of her irregular menses and hysterectomy performed later on to manage endometriosis, it was difficult to link her symptoms to the menstrual cycle. But on the basis of the cyclic nature of the rash and the previous negative results - acne vulgaris, psoriasis, atopic dermatitis, lichen planus, systemic lupus erythematosus and infections were ruled out - autoimmune progesterone dermatitis was suspected. As progesterone is not available in aqueous solution for intradermal allergen test in Hungary, we performed progesterone provocation vaginally. The patient developed the usual skin lesions to vaginal progesterone exposure, which confirmed the diagnosis. The patient became symptom free to gonadotropine-analogue treatment and remained so even after the cessation of the therapy after 6 months. To our knowledge, this is the first case in the medical literature, in which autoimmune progesterone dermatitis was proved by vaginal progesterone provocation.

Valeria Nagy1, Lili Takacs1, Zita Steiber1, György Pfliegler2, Andras Berta11Department of Ophthalmology, 2Division of Rare Diseases, University of Debrecen Medical and Health Science Center, Debrecen, HungaryBackground: Retinal artery occlusion (RAO) is an ischemic vascular damage of the retina, which frequently leads to sudden, mostly irreversible loss of vision. In this study, blood thrombophilic factors as well as cardiovascular risk factors were investigated for their relevance to this pathology. Thrombophilic risk factors so far not evaluated were included in the study.Patients and methods: 28 RAO patients and 81 matched control subjects were examined. From blood samples, protein C, protein S, antithrombinopathy, and factor V (Leiden) mutation (FV), factor II gene polymorphism, factor VIII C level, plasminogen activity, lipoprotein(a) and fibrinogen levels, hyperhomocysteinemia and presence of anticardiolipin – antiphospholipid antibodies were investigated. Possibly relevant pathologies such as diabetes mellitus, hypertension, and ischemic heart disease were also registered. Statistical analysis by logistic regression was performed with 95% confidence intervals.Results: In the group of patients with RAO only the incidence of hypertension (OR: 3.33, 95% CI: 1.30–9.70, p = 0.014) as an average risk factor showed significant difference, but thrombophilic factors such as hyperfibrinogenemia (OR: 2.9, 95% CI: 1.29–6.57, p = 0.010) and the presence of FV (Leiden mutation) (OR: 3.9, 95% CI: 1.43–10.96, p = 0.008) increased the chances of developing this disease.Conclusions: Our results support the assumption that thrombophilia may contribute to the development of RAO besides vascular damage due to the presence of cardiovascular risk factors. Further studies are needed, however, to justify the possible use of secondary prophylaxis in form of anticoagulant/antiplatelet therapy.Keywords: retinal arterial occlusion, risk factors, thrombophilia

Introduction: congenital FXIII deficiency is a rare bleeding disorder with a high risk of spontaneous intracranial haemorrhage. Life-long preventive supplementation is mandatory if FXIII activity is Aim: to report the effective use of rFXIII for the treatment of a major bleeding in a patient with severe inherited FXIII-A deficiency. Patient and methods: a 19-year-old man exhibiting severe bleeding phenotype without clear diagnosis was referred to our haemostasis centre. After presenting negative haemostasis screening tests he was evaluated for FXIII deficiency by the determination of FXIII activity, FXIII-A2B2, FXIII-A and FXIII-B concentrations and by mutation analysis. Results: severe FXIII-A deficiency was established and prophylaxis with rFXIII was planned. Prior to the start of the prophylaxis he was hospitalized due to a large intramuscular hematoma (19.0x8.3x7.7 cm) in the right thigh and rFXIII, in the prophylactic dose (35 IU/kg) was administered for therapy. Following the administration of rFXIII, the pain disappeared and the swelling of the thigh considerable decreased. Complete resolution of the hematoma occurred without any additional FXIII supplementation. Results of the pharmacokinetic assessment were comparable with those described in the literature. Conclusion: rFXIII can be successfully used in acute bleeding episode of severe congenital FXIII deficiency. Disclosures No relevant conflicts of interest to declare.

Hermansky-Pudlak syndrome is characterised by oculocutaneous albinism and haemorrhagic diathesis. The bleeding tendency that is associated with this autosomal recessive disease is caused by storage-pool deficiency and has been reported to be controllable by prophylactic administration of 1-desamino 8D-arginine (desmopressin, DDAVP). The DDAVP prophylaxis at the first delivery of our patient did not prevent the severe haemorrhagic sequeal requiring transfusion of packed red cells and platelets, but the same preventive measure was successful at her second childbirth. Response to prophylactic DDAVP administration varies between as well as within patients with Hermansky-Pudlak syndrome.

Introduction Pregnancy is associated with an increased risk of venous thromboembolism (VTE) which is even more pronounced in the presence of inherited thrombophilia. Despite the well-established relation between thrombophilic pregnancies and VTE, there is no consensus on the optimal approach for thromboprophylaxis in this population. There is growing evidence that thrombin generation correlates with the overall procoagulant state of the plasma leading to elevated thrombosis risk. The aim of this study was to evaluate thrombin generation over the course of pregnancy in women with inherited thrombophilia compared to healthy pregnant women. We also aimed to investigate the effectiveness of low molecular weight heparin (LMWH) prophylaxis in pregnancy by measuring thrombin generation and anti-Factor-Xa activity. Methods In this cohort study women with severe (n=8) and mild (n=47) thrombophilia were followed throughout their pregnancies. In addition, healthy pregnant women (n=15) were recruited as control subjects. Thrombin generation was evaluated in each trimester as well as 5 days after delivery and 8 weeks postpartum (baseline). In order to assess the effect of LMWH therapy at each stage of the pregnancy, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration of the drug (peak and trough effect). Thrombin generation was determined using Technothrombin TGA assay system, and the results were evaluated with the provided software. For analysis, the median peak thrombin and endogenous thrombin potential were determined. The anti-Factor-Xa activity was measured by a commercially available chromogenic assay. Results In all the 3 study groups, both peak thrombin and endogenous thrombin potential were increased over the course of pregnancy compared to the non-pregnant state. Peak thrombin and endogenous thrombin potential were higher in the severe thrombophilia group than in the other 2 groups in every trimester and also after delivery. There was no distinct difference in thrombin generation between the mild group and the controls. In women undergoing LMWH prophylaxis a decrease was observed in both the peak thrombin and endogenous thrombin potential after the drug was administered. Over the course of pregnancy the extent of this decrease reduced in a stepwise fashion. The difference between the 2 measurements (before and after LMWH) was smallest in the third trimester and increased again after delivery. Anti-Factor-Xa activity appeared to be enhanced at the peak effect of LMWH. However, the difference between the anti-Factor-Xa activity before and after LMWH administration remained unchanged over the progression of pregnancy. None of the women suffered from VTE or had any bleeding complications during the observation period. Conclusions Our results show that thrombin generation is increased during pregnancy, with higher levels in women with severe thrombophilic defects. In addition, our data demonstrate a decrease in the effect of LMWH with advancing stages of pregnancy. Until now no studies evaluated prospectively the effect of LMWH prophylaxis on thrombin generation over pregnancy. Our findings contribute to the ongoing debate about the necessity and intensity of thromboprophylaxis during pregnancy, providing new information about the coagulable state of mild and severe thrombophilic pregnant women. The decreasing antithrombotic effect of LMWH over pregnancy suggests a need for dose adjustment in late gestational weeks. Furthermore, our results imply that thrombin generation as a global coagulation test may demonstrate more sensitively the effect of LMWH than the anti-Factor-Xa activity assay. Disclosures: No relevant conflicts of interest to declare.