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PCSK9-inhibitors belong to the new class of hypolipidemic agents. They enhance catabolism of low density lipoprotein cholesterol (LDL-C) through inhibiting activity of proprotein convertase subtilisin/kexin type 9 (PCSK9). They are monoclonal antibodies (alirocumab, evolocumab etc). Under clinical development are also other types of PCSK9-inhibitors which act at a subcellular level. The treatment with PCSK9-inhibitors can be beneficially combined with lipoprotein apheresis (LA). If such treatment using PCSK9-inhibitors is possible with regard to an individual patients genotype, the combination of LA and PCSK9-inhibitors leads to slowing the space of LDL-C increase between individual procedures of apheresis and enables attaining of the lowest possible values of LDL-cholesterolemia for the longest possible period of time. Due to high efficiency of PCSK9-inhibitors lowering LDL-C, but also their lower cost as compared to therapeutic LA, PCSK9-inhibitors now take precedence over the use of extracorporeal lipoprotein apheresis which, nonetheless, still remains the final method for hypolipidemic treatment of patients with severe hypercholesterolemia, who are resistant to conventional therapy while not reaching the target lipid values and at high cardiovascular risk. They belong to extracorporeal elimination methodologies which remove low density lipoprotein (LDL) cholesterol from circulating blood. LA in combination with higher doses of statins and ezetimib currently represents the most efficient method of treatment of homozygous and statin-refractory heterozygous familial hypercholesterolemia (FH). Residual cardiovascular risk in these patients still remains high, in particular because, despite the aforementioned treatment, the target values for lipids according to present recommendations cannot be reached. The combination of LA with the new drugs is promising, primarily due to its potential for further lowering of LDL-cholesterolemia between the individual apheresis procedures. Preliminary results of the ongoing studies indicate that the new hypolipidemic drugs in combination with LA, or when used separately, will substantially enrich and improve the treatment of refractory FH.Key words: alirocumab - atherosclerosis - evolocumab - hypercholesterolemia - cardiovascular disease - lipoprotein apheresis.

Lipoprotein apheresis (LA) is an effective treatment method the patients with severe hypercholesterolemia, resistant to the standard therapy. LA is an extracorporeal elimination technique, which specifically removes low density lipoprotein (LDL) cholesterol from the circulation. At present, lipoprotein apheresis, combined with high-dose statin and ezetimibe therapy, is the best available means of treating patients with homozygous and statin refractory heterozygous familial hypercholesterolaemia (FH). However, the extent of cholesterol-lowering achieved is often insufficient to meet the targets set by current guidelines. The recent advent of new classes of lipid-lowering agents provides new hope that the latter objective may now be achievable. These compounds act either by reducing low density lipoprotein (LDL) cholesterol production by inhibiting apolipoprotein B synthesis with an antisense oligonucleotide (mipomersen), or by inhibiting microsomal triglyceride transfer protein (lomitapid), or by enhancing LDL catabolism via monoclonal antibody-mediated inhibition of the activity of proprotein convertase subtilisin/kexin 9 (PCSK9-alirocumab, evolocumab etc). The promising is the combination of LDL-apheresis with new drugs, namely for its potential to further decrease of LDL-cholesterol between apheresis. Depending on the outcome of current trials, it seems likely that these compounds, used alone or combined with lipoprotein apheresis, will markedly improve the management of refractory FH.

LDL-apheresis is an extracorporeal elimination technique, which specifically removes LDL-cholesterol from the circulation. There are six methods for the selective LDL-cholesterol removal these days. The main indications for LDL-apheresis are the diagnosis of homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia which is refractory the standard care and intolerance of routine care, and also patients with lipoprotein(a) increase resistant to the farmacotherapy. There is still debate which LDL-cholesterolemia is indication for LDL-apheresis therapy, and the recommendation differs among various countries. Despite large randomized trials are missing, there are several good quality studies to conclude, that the beneficial cardiovascular effects of LDL-apheresis in severe hypercholesterolemia are important and beneficial.

Assessment of the treatment procedures and their results is increasingly important in current medicine. The emphasis is put on an effective use of the health technologies (HTA). Unlike randomised studies, which involve strictly selected groups of patients who meet inclusion and exclusion criterias, the multicentre clinical registries provide a real-life picture of the treatment safety and effectiveness. Well prepared registries involve both research database and a friendly user interface enabling collection of parametric and easily analyzable data. Although there are some technological aspects aiming to ensure a maximum quality of entered data, cooperation with the users and data managers is essential. Such a registry, otherwise meaningful, must provide answers to previously defined medical hypotheses. Regular feedback to users (so called benchmarking or reporting) is considered to be of key importance. The Czech TAVI Registry (CTR) is a good example of reaching all of the above defined criterias. This registry contains data of approximately 95 % of all transcatheter aortic valve implantations (TAVI) performed in the Czech Republic. It is based on a general system aimed at the design of clinical trials, namely the TrialDB2 (a database system for clinical registries developed by the Institute of Biostatistics and Analyses at the Masaryk University (IBA MU). CTR has been run as an English-language version under the auspices of the Czech Society of Cardiology and represents one of the top-quality registries maintained by IBA MU. This paper presents the currently available database systems and some reports from this particular registry.

Introduction: Patients with serious aortic stenoses treated by conservative therapy have significantly worse life expectancy. Besides the surgical aortic valve replacement (AVR) as the gold standard of therapy, the transcatheter aortic valve implantation (TAVI) is indicated in patients at very high risk or who are contraindicated to AVR. The role of learning-curve in TAVI has to be established., Aim: Assessment of the results of consecutive TAVI procedures based on the experience of the team., Methods: 58 high-risk consecutive patients with the average age of 82.2 years were divided into 3 groups based on the TAVI order ( 20., 21.-40., 41.-58.). After the Edwards SAPIEN implantation via transfemoral or transapical approaches, all patients were followed for minimum 30 days. Data from the national registry (Czech TAVI Registry) were used for the retrospective analysis. Comparison of the groups was done by using the Kruskal-Wallis test, Mann-Whitney U test and χ2 test., Results: Significantly shorter procedural time (p < 0.001), hospitalization (p = 0.033) and a lower amount of contrast medium (p < 0.001) was observed during the time. There was no difference in the rate of clinical complications at 30 days., Conclusions: Increasing experience of the TAVI implantation team is associated with significantly shorter procedural time, hospitalization and a lower amount of contrast medium. Overall very good clinical results during 30 days were not affected by the team experience.

Tumourous diseases are associated with haemorrhagic as well as thrombotic complications. The most frequent cause of haemorrhagic states in tumourous diseases is thrombocytopenic haemorrhage, consumption coagulopathy and activated fibrinolysis. Trousseau described in 1865 a mutual association between tumourous diseases and venous thromboembolism. As many as 15-20% patients with venous thromboembolism have an undetected malignity which is a prevalence of 2-3% in the population. From this ensues the relative risk of a newly diagnosed malignity which is higher during the first year after venous thromboembolism. The prevalence varies between 2% and 6%. Migrating thrombophlebitiis (saltans and migrans) are a relatively specific sign in tumours, in particular in pancreatic tumours. In the pathogenesis of venous thromboembolisms in tumourous diseases in particular the following factors play a part: elevated coagulation parameters, reduced fibrinolysis, frequent immobilization, surgical operations in the case-history, chemotherapy, hormonal therapy and central venous catheters. The authors present a brief review of changes of haemostasis in tumourous diseases, their possible diagnosis and possible pharmacological prevention and treatment of thromboembolisms.

In a group of 993 patients with serious medical diseases an important deficiency of antithrombin III was found in patients with hepatic insufficiency, pulmonary embolism and with disseminated intravascular coagulation. Acquired antithrombin III deficiency in these conditions develops when the antithrombin production in the liver is low and also in patients with shock syndrome and disseminated intravascular coagulation. Assessment of antithrombin III is of diagnostic and prognostic value in thrombotic and prethrombotic conditions and its results is decisive for adequate substitution. Adequate AT III substitution without concurrent heparin administration in patients with septicaemia and manifestations of DIC improves the prognosis of patients with an increased endothelial resistance.

The authors revealed some changes in the platelet activity in patients with invasive cardiological procedures. Changes of the platelet function were manifested by an enhanced aggregation of platelets in vivo, an increased secretion from alpha granules and increased release of prostaglandin metabolites from platelets and from the vascular wall. Acetylsalicylic acid (ASA) suppressed the formation of circulating platelet aggregates in vivo, but the platelet activity was manifested by another mechanism, independent on ASA. The authors recorded therefore an increase of prostaglandin metabolites and PF4 even in patients who were treated with ASA before the invasive examination.

Extracorporeal elimination of LDL-cholesterol is at present an important part of comprehensive treatment of patients with very high cholesterol levels. An absolute indication for their use are patients with the homozygous form of familial hypercholesterolaemia. Treatment is, after individual consideration, indicated also patient with severe heterozygous familial hypercholesterolaemia, with a positive family history of IHD, if it is not possible to reduce LDL-cholesterol by diet and hypolipidaemic agents below 5.2 mmol/l; also patients with severe IHD and severe hypercholesterolaemia, included in secondary prevention where it is not possible to reduce LDL-cholesterol by diet and pharmacotherapy below 3,4 mmol/l. Another indication for treatment by LDL apheresis are patients where cardiosurgery cannot be performed because of angiosclerosis. These are patients with severe hypercholesterolaemia which does not respond to drugs and with diffuse changes of the coronary circulation in young age, which cannot be treated by angioplasty or coronary bypass, and also patients after a coronary bypass with a refractory disorder of the lipid metabolism. LDL apheresis is furthermore indicated in patients with severe hyperlipidaemic crises which eventually develop into necrosis of the pancreas. Long-term LDL-apheresis leads to regression of manifestations of xanthomatosis of the skin and tendons, it prevents progression and starts regression of atherosclerosis in patients with severe hypercholesterolaemia. In homozygotes with familial hypercholesterolaemia treatment by LDL-apheresis leads to prolongation of life and improves the quality of life. In heterozygotes neither prolongation of the life span nor a lower incidence of IHD is observed, while the quality of life improves and regression of atherosclerosis occurs. A combination of LDL-apheresis, dietary provisions and hypolipidaemic treatment in heterozygotes is the most effective method to reduce the LDL-cholesterol level. Extracorporeal elimination of LDL-cholesterol can be done by non-selective centrifuging or membrane plasmapheresis. More recent methods of LDL-apheresis are more selective and effective. They use active columns or capsules to remove atherogenic particles from plasma. These methods include cascade filtration, immunoadsorption heparin-induced LDL precipitation, thermofiltration and dextran-induced LDL precipitation.

The authors examined some indicators of platelet activity in patients with hypertension stage II (according to WHO). They revealed an increased platelet activity which was manifested by an increased concentration of platelet factor 4 (50.2 +/- 28.2 ng/ml) and thromboxane B2 (49.9 +/- 20.1 pg/ml) in plasma. The increase of indicators of platelet activation associated with hypertension is a molecular marker of activation of haemostasis and according to data in the literature it is an indicator of vascular complications in hypertension. It is not clear whether the increased platelet functions in hypertension is primary or an induced change.

The authors used the Simplate test (Organon Teknika) to examine the bleeding time from an incision in 15 healthy blood donors and found normal values of 3.45 +/- 0.90 min. The authors proved a close correlation between the improvement of the number of platelets in 10 patients with thrombocytopenia, treated with thrombocyte infusions and the improvement of the bleeding time when using the Simplate R test after one hour and after 24 hours following thrombocyte administration. Examination of the bleeding time by means of the Simplate R test (Organon Teknika) was well tolerated by the authors' patients and the test does not produce any side-effects.

The authors draw attention to the leukostasis syndrome which develops in haematological patients in case of enormous leucocyte proliferation. It occurs most frequently in chronic myelosis but may occur also in other types of leukaemia. The diagnosis is not easy. Most frequently disorders of the microcirculation develop in the lungs and brain. These are frequently very urgent clinical situations which can be resolved by leukapheresis. The authors described a patient where during chronic lymphadenosis proliferation of lymphocytes occurred to values of 1432 x 10(9)/l. After leukapheresis and cytostatic treatment rapid improvement of the condition occurred and the leucocyte values were approximately 30 x 10(9)/l. The patient's condition improved for a long period of time and became stabilized.

The authors made 184 thrombocytaphereses for the preparation of thrombocyte concentrates on a Travenol CS-3000 separator. They evaluate indicators on which the thrombocyte yield depends: it was found that the yield is higher in donors with a higher number of platelets and that it increases with the period of separation. The mean thrombocyte yield was 2.91 +/- 0.84 x 10(11). It corresponded to the average lower platelet number of donors--182 x 10(9)/L. In those donors where the number of platelets was higher than 180 x 10(9)/L, the yield was 3.21 x 10(9)/L. The undesirable presence of leucocytes (in 98% lymphocytes) increases in relation to the number of leucocytes in the donor and their decline after separation. It was lower in longer separations. The authors discuss the possibility to increase the thrombocyte yield without contamination with leucocytes.

Severe inhibition of haematopoiesis is a serious disease from the prognostic aspect. The authors evaluated a group of 26 patients of whom one survived for more than five years. The mean life span is 154 days. The most frequent cause of death are infectious complications, in particular septicaemia. Investigation of the aetiology of the disease was negative in 46% of the cases, in the remainder drugs were suspected most frequently, in particular antibiotics. It is very important to prevent the development of secondary inhibition of haematopoiesis, in particular by careful indication of myelotoxic drugs. In case of necessity, these drugs should be administered for a short time, in the lowest effective doses with check-ups of the haemogram. Hope for affected patients in future is transplantation of bone marrow and the early administration of antilymphocytic globulin.

The authors performed 1252 haemaphereses, incl. 689 plasmaphereses. They divide the side-reactions as follows: Technical reaction: these do not threaten the donor directly; these reactions were recorded in 4.4%. Clinical reactions--total 6.8%. a) early, b) late. The authors recorded one severe reaction during plasmapheresis, there was however, no fatality. The most frequent reactions were: general symptoms, failure to withdraw blood because of poor state of the veins and hypotension. The authors analyze the importance of the observed reactions. They used continual separators where in general the incidence of reactions is smaller. They investigated also late reactions, in particular after development of infections in donors or in the staff working with the separator. Repeated donors were subjected to detailed immunological examination, no abnormalities were, however, recorded.