Thrombogenic Properties Research Articles

Prethrombin-1 as a Drug Substance Promoting Hemostasis with Reduced Risk of Thrombosis.

Prethrombin-1 is a Gla-domain lacking enzymatically inactive split product that results from the cleavage of fragment 1 from prothrombin by thrombin in a feedback reaction. A prethrombin-1 preparation derived from human plasma was tested for its hemostatic and thrombogenic properties. Animal models of nail clipping (for rabbits) and tail clipping (for mice) were developed to measure blood loss in FVIII-inhibitor or rivaroxaban anticoagulated rabbits and mice, respectively. A modified Wessler test was used in rabbits to assess the thrombogenic potential by Wessler score and clot weight. Studies were performed in groups of three to six for prethrombin-1 dose escalation and comparison with prothrombin, Beriplex®, FEIBA®, and saline as a control. Data were analyzed using t-statistics or the Mann Whitney U test as applicable. Prethrombin-1 has excellent hemostatic properties in anticoagulated mouse and rabbit bleeding models. Wessler tests suggest that in contrast to activated and nonactivated prothrombin complexes, prethrombin-1 has negligible thrombogenic potential. The thrombin zymogen prethrombin-1 promotes hemostasis with reduced risk of thrombosis. Prethrombin-1 may have potential to become a life-saving treatment for patients who bleed or are at risk of bleeding.

Three-dimensional fluid-structure interaction simulation of the Wheatley aortic valve.

Valvular heart diseases (such as stenosis and regurgitation) are recognized as a rapidly growing cause of global deaths and major contributors to disability. The most effective treatment for these pathologies is the replacement of the natural valve with a prosthetic one. Our work considers an innovative design for prosthetic aortic valves that combines the reliability and durability of artificial valves with the flexibility of tissue valves. It consists of a rigid support and three polymer leaflets which can be cut from an extruded flat sheet, and is referred to hereafter as the Wheatley aortic valve (WAV). As a first step towards the understanding of the mechanical behavior of the WAV, we report here on the implementation of a numerical model built with the ICFD multi-physics solver of the LS-DYNA software. The model is calibrated and validated using data from a basic pulsatile-flow experiment in a water-filled straight tube. Sensitivity to model parameters (contact parameters, mesh size, etc.) and to design parameters (height, material constants) is studied. The numerical data allow us to describe the leaflet motion and the liquid flow in great detail, and to investigate the possible failure modes in cases of unfavorable operational conditions (in particular, if the leaflet height is inadequate). In future work the numerical model developed here will be used to assess the thrombogenic properties of the valve under physiological conditions.

Thrombus Aspirates From Patients With Acute Ischemic Stroke Are Infiltrated by Viridans Streptococci.

Acute ischemic stroke may be due to embolism from ruptured atherosclerotic carotid arteries. DNA of oral bacteria, mainly the viridans streptococci group, has been detected in thrombus aspirates of patients with ischemic stroke as well as in carotid endarterectomy samples. Because viridans streptococci are known to possess thrombogenic properties, we studied whether their presence in thrombus aspirates and in carotid artery specimens can be confirmed using bacterial immunohistochemistry. Thrombus aspirates from 61 patients with ischemic stroke (70.5% men; mean age, 66.8 years) treated with mechanical thrombectomy, as well as carotid endarterectomy samples from 20 symptomatic patients (65.0% men; mean age, 66.2 years) and 48 carotid artery samples from nonstroke autopsy cases (62.5% men; mean age, 66.4 years), were immunostained with an antibody cocktail against 3 species (Streptococcus sanguinis, Streptococcus mitis, and Streptococcus gordonii) of viridans streptococci. Of the thrombus aspirates, 84.8% were immunopositive for viridans streptococci group bacteria, as were 80.0% of the carotid endarterectomy samples, whereas immunopositivity was observed in 31.3% of the carotid artery samples from nonstroke autopsies. Most streptococci were detected inside neutrophil granulocytes, but there were also remnants of bacterial biofilm as well as free bacterial infiltrates in some samples. Oral streptococci were found in aspirated thrombi of patients with acute ischemic stroke as well as in carotid artery samples. Our results suggest that viridans streptococci group bacteria may play a role in the pathophysiology of ischemic stroke.

Effect of Atomic-Layer-Deposited Hydroxyapatite Coating on Surface Thrombogenicity of Titanium

This study aimed to evaluate the surface characteristics of a nanocrystalline hydroxyapatite coating made through atomic layer deposition (ALD-HA) on titanium surfaces and to investigate its effect on blood coagulation and platelet adhesion. Grade 2 square titanium discs (0.7 cm, 1 mm thick) were used (n = 108). Half of the substrates (n = 54) were coated with ALD-HA, and the other half were used as the non-coated control. Surface free energy (SFE), contact angle (CA), surface roughness (Ra), and chemical composition were evaluated. Blood thrombogenic properties were assessed on ALD-HA and non-coated surfaces using the kinetic clotting time method. The platelets’ adhesion and morphology were also evaluated. The ALD-HA-coated surfaces demonstrated significantly higher polar SFE (p < 0.001) and lower CA (p < 0.001) values compared to the non-coated surfaces. In addition, the surface roughness was significantly lower for the ALD-HA (p < 0.001) than for the non-coated surfaces. Platelets adhered to both surfaces; however, there was variability in platelet morphologies in different areas with higher platelet density on the ALD-HA surfaces. There was no significant difference in the overall absorbance values of the hemolyzed hemoglobin for both substrates, and the total clotting time was achieved at 60 min. It can be concluded that the ALD-HA coating of titanium can enhance surface wettability, increase surface free energy, and support blood coagulation and platelet adhesion.

Fibrin Adsorption on Cardiovascular Biomaterials and Medical Devices.

Medical devices that are inserted in blood vessels always risk eliciting thrombosis, and the surface properties of such devices are thus of major importance. The initiating step for surface-induced pathological coagulation has been associated with adsorption of fibrinogen protein on biomaterial surfaces and subsequent polymerization into an insoluble fibrin clot. This issue gives rise to an inherent challenge in biomaterial design as varied surface materials must fulfill specialized roles while also minimizing thrombotic complications from spontaneous fibrin(ogen) recruitment. We have aimed to characterize the thrombogenic properties of state-of-the-art cardiovascular biomaterials and medical devices by quantifying the relative surface-dependent adsorption and formation of fibrin followed by analysis of the resulting morphologies. We identified stainless steel and amorphous fluoropolymer as comparatively preferable biomaterials based on their low fibrin(ogen) recruitment, in comparison to other metallic and polymeric biomaterials, respectively. In addition, we observed a morphological trend that fibrin forms fiber structures on metallic surfaces and fractal branched structures on polymeric surfaces. Finally, we used vascular guidewires as clotting substrates and found that fibrin adsorption depends on parts of the guidewire that are exposed, and we correlated the morphologies on uncoated guidewires with those formed on raw stainless-steel biomaterials.

Features of remodeling of newly formed vascular tissue based on biodegradable vascular prostheses implanted in the carotid artery of sheep: morphogenetic analysis

Tissue-engineered vascular prostheses developed for prosthesis of small-diameter arteries have high biocompatibility and coverage of their patency after implantation into the vascular bed, and should also show a high probability of forming on their basis a newly formed tissue that is largely susceptible to native vascular tissue.Aim: To evaluate the expected patency of biodegradable vascular prostheses with athrombogenic drug coating in large laboratory animal models.Material and Methods. Vascular prostheses Ø 4 mm were fabricated by electrospinning from a polymer composition of 5% polyhydrosibutyrate/valeriate (PHBV) and 10% polycaprolactone (PCL) and a complex of proangiogenic tissues (GFmix): vascular endothelial growth (VEGF), rare fibroblast growth (bFGF) and chemoattractant molecule (SDF-1α). To induce thromboresistant properties of grafts, an athrombogenic modification of the surface of parts of the fabricated prostheses with heparin and iloprost was carried out. Modified prostheses were implanted in the carotid artery for a period of 12 months. The group with autoarterial implantation acted as a control.Results. In 12 months after implantation, the patency of auto-arterial grafts was 87.5%. The patency of PHBV/PCL/GFmix with heparin and iloprost reached 50% at the time of implantation. The biodegradable frame made of reinforced prostheses was almost completely resorbed with the formation of aneurysms throughout. In the modified prostheses, the main elements of the newly formed vascular tissue are present. There is no formation in the walls of the prostheses.Conclusion. The results showed that biodegradable vascular prostheses PHBV/PCL/GFmixHep/Ilo have a high final patency, which allows us to consider them suitable for the formation of newly formed vascular tissue on their basis. However, due to the aneurysm formation, a long-term execution of the bone tissue of the prosthesis and the thrombogenic properties of the inner surface are required.

TNX-1500, a crystallizable fragment–modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival

The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa–dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma receptor IIa while retaining certain other effector functions and pharmacokinetics comparable with natural antibodies. Here, we report that TNX-1500 treatment is not associated with platelet activation in vitro and consistently inhibits kidney allograft rejection in vivo without clinical or histologic evidence of prothrombotic phenomena. We conclude that TNX-1500 retains efficacy similar to that of 5c8 to prevent kidney allograft rejection while avoiding previously identified pathway-associated thromboembolic complications.

Preclinical Evaluation of a New Anti-COVID-19 Intravenous Immunoglobulin

Introduction. Using of immunoglobulins containing SARS-CoV-2 neutralizing antibodies may be an effective and safe tool for COVID-19 treatment. An intravenous immunoglobulin COVID-globulin from donor blood plasma containing SARS-CoV-2 neutralizing antibodies was developed at Joint-Stock Company Nacimbio.Aim. A pilot study of the safety of the "COVID-globulin".Materials and methods. When studying the safety of the preparation in animals the following parameters were evaluated: general toxicity, thrombogenic potential, influence on hematological and biochemical parameters, blood clotting and hemolytic activity, determination of local irritant action, pyrogenic properties, bacterial endotoxins, allergic effect of the drug preparation and its physicochemical characteristics.Results and discussion. Safety studies of "COVID-globulin" in animals showed no signs of intoxication, local irritant action and thrombogenic properties. Macroscopic and histological examination of the organs of rats treated with COVID-globulin showed no signs of necrosis, inflammation, atypia, or any significant pathological changes. Hematological and biochemical parameters of the blood of laboratory animals after the administration of "COVID-globulin" corresponded to the reference values. Administration of COVID-globulin to rabbits did not activate blood clot formation. The IgG subclasses distribution in the preparation corresponded to that in human plasma. The activity of the Fc-function of the immunoglobulin molecule was more than 130 % compared to the reference standard preparation, the concentration of the prekallikrein activator in the COVID-globulin ranged from 4.2 to 4.8 IU/ml, anticomplementary activity was less than 1 unit complement per 1 mg of protein.Conclusion. The results of all studies have demonstrated a high level of safety of the developed COVID-globulin preparation, which meets the safety requirements for human immunoglobulins for intravenous administration by national regulatory documents and the European Pharmacopoeia.

Comparative study of predisposition to thrombosis with administration of known systemic hemostatic agents and fibrin monomer in the experiment

Aim. To compare predisposition to thrombosis caused by administration of known systemic hemostatic agents and fibrin monomer under the conditions of normal coagulation versus drug-induced hypocoagulation in the experiment.Materials and methods. The prothrombotic effect of intravenous (IV) administration of various systemic hemostatic agents was compared in a series of in vivo experiments. These agents included fibrin monomer (FM) (0.25 mg / kg), prothrombin complex concentrate (PCC) (40 IU / kg) or recombinant factor VIIa (rFVIIa) (270 mcg / kg). The studies were conducted under the conditions of hypocoagulation induced by the administration of warfarin (per os at a dose of 0.4–0.5 mg / kg / day for 14 days) or dabigatran etexilate (per os at a single dose of 15–20 mg / kg). Hemostatic system parameters were evaluated using thromboelastometry and calibrated automated thrombography.Results. It was found that PCC reversed anticoagulant effects and led to an overcompensated increase in the density characteristics of the blood clot along with an excessive increase in thrombin generation in the groups of animals with warfarin-induced coagulopathy. The use of PCC and rFVIIa in the groups of animals with dabigatran-induced hypocoagulation also resulted in an increase in blood thrombogenic properties. In the administration of PCC, it was manifested though an increased D-dimer level and in administration of rFVIIa – through an increase in the clot density characteristics. At the same time, replacement of these hemostatic agents with FM did not affect the hemostatic system parameters.Conclusion. FM at a dose of 0.25 mg / kg, as opposed to PCC and rFVIIa, is safer in terms of the risk of thrombosis.

Monoclonal Gammopathy of Thrombotic Significance.

The current review provides an overview of the thrombotic risk observed in patients with MG who do not otherwise require treatment. We discuss clinical and biomarker studies that highlight the heterogenous hemostatic profile observed in these patients and how knowledge has evolved over the past 20 years. Biomarker studies suggest shared biologic features between multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS), which involves both hypercoagulability and platelet activation. Hemostatic abnormalities identified in MGUS patients cannot be translated into clinical practice as they lack correlation to clinical events. The prothrombotic phenotype of MGUS patients has not been ascertained yet, but novel data on coagulation markers are promising. We also review rare conditions associated with the thrombogenic properties of the monoclonal protein that predispose to arterial, venous or microthrombotic events and demonstrate that the M-protein can be linked to clinically significant thrombotic events. Cryoglobulinemia, cryofibrinogenemia, cryo-crystaloglobulinemia and MG-related antiphospholipid syndrome are reviewed. We propose the new umbrella term "monoclonal gammopathy of thrombotic significance" (MGTS) to refer to significant, recurrent thrombotic events in patients with MGUS that provide a rationale for targeting the underlying plasma cell clone. Identifying MGUS patients at high risk for thrombotic events is currently a challenge.

Semi-Quantitative Method of Assessing the Thrombogenicity of Biomaterials Intended for Long-Term Blood Contact

Biomaterials used in cardiosurgical implants and artificial valves that have long-term contact with blood pose a great challenge for researchers due to the induction of thrombogenicity. So far, the assessment of the thrombogenicity of biomaterials has been performed with the use of highly subjective descriptive methods, which has made it impossible to compare the results of various experiments. The aim of this paper was to present a new semi-quantitative method of thrombogenicity assessment based on scanning electron microscope (SEM) images of an adhered biological material deposited on the surfaces of prepared samples. The following biomaterials were used to develop the proposed method: Bionate 55D polyurethane, polyether-ether ketone, Ti6Al7Nb alloy, sintered yttria-stabilized zirconium oxide (ZrO2 + Y2O3), collagen-coated glass, and bacterial cellulose. The samples were prepared by incubating the biomaterials with platelet-rich plasma. In order to quantify the thrombogenic properties of the biomaterials, a TR parameter based on the fractal dimension was applied. The obtained results confirmed that the use of the fractal dimension enables the quantitative assessment of thrombogenicity and the proper qualification of samples in line with an expert's judgment. The polyurethanes showed the best thrombogenic properties of the tested samples: Bionate 55D (TR = 0.051) and PET-DLA 65% (average TR = 0.711). The ceramics showed the worst thrombogenic properties (TR = 1.846). All the tested materials were much less thrombogenic than the positive control (TR = 5.639).

Contribution of ADAMTS13‐independent VWF regulation in sickle cell disease

BackgroundVon Willebrand factor (VWF) is elevated in sickle cell disease (SCD) and contributes to vaso‐occlusion through its thrombogenic properties. VWF is regulated by ADAMTS13, a plasma protease that cleaves VWF into less bioactive multimers. Independent investigations have shown VWF to be elevated in SCD, whereas measurements of ADAMTS13 have been variable. ObjectivesWe assessed ADAMTS13 activity using multiple activity assays and measured levels of alternative VWF‐cleaving proteases in SCD. Methods/ PatientsPlasma samples were collected from adult patients with SCD (n = 20) at a single institution when presenting for routine red cell exchange transfusion therapy. ADAMTS13 activity was measured by FRETS‐VWF73, Technozym ADAMTS‐13 Activity ELISA kit and a full‐length VWF digestion reaction. Alternative VWF‐cleaving proteases were identified by ELISA. A cell culture model was used to study the impact of SCD stimuli on endothelial ADAMTS13 and alternative VWF‐cleaving proteases. ResultsADAMTS13 activity was found to be moderately deficient across the SCD cohort as assessed by activity assays using a VWF A2 domain peptide substrate. However, SCD plasma showed preserved ability to digest full‐length VWF, suggesting assay‐discrepant results. Neutrophil and endothelial‐derived proteases were found to be elevated in SCD plasma. Matrix metalloproteinase 9 specifically showed preferential cleavage of full‐length VWF. Upregulation of alternative VWF‐cleaving proteases occurred in endothelial cells exposed to SCD stimuli such as heme and hypoxia. ConclusionsThis is the first demonstration of accessory plasma enzymes contributing to the regulation of VWF in a specific disease state and may have implications for assessing the VWF/ADAMTS13 axis in other settings.

Lipoprotein(a) and SARS-CoV-2 infections: Risk for ischemic heart disease and thromboembolic events

Background and Aims : SARS-CoV-2 positive patients show high frequency of thromboembolic complications. Comorbidities like ischemic heart disease (IHD) associate with worse outcome. Since lipoprotein(a) [Lp(a)] is a strong risk factor for IHD and has possibly thrombogenic properties, we investigated in UK Biobank whether SARS-CoV-2 infections alter the Lp(a)-driven risk for IHD and thromboembolic events.

Development and characterization of anti-SARS-CoV-2 intravenous immunoglobulin from COVID-19 convalescent plasma.

Background: The authors describe the developmental process of intravenous anti-COVID-19 hyperimmune immunoglobulin from anti-SARS-CoV-2 neutralizing antibody-containing plasma. Furthermore, the authors investigated its safety and protective activity in animal models. Materials & methods: The manufacturing process included standard ethanol fractionation, chromatographic purification steps and virus removal or inactivation. Results: The authors produced pure and safe immunoglobulin for intravenous administration, with 98.1 ± 6.5 mg/ml protein content, of which 97.6 ± 0.7% was IgG. The concentration factor of SARS-CoV-2 neutralizing antibodies was 9.4 ± 1.4-times. Safety studies in animals showed no signs of acute/chronic toxicity or allergenic or thrombogenic properties. Intravenous anti-COVID-19 hyperimmune immunoglobulin protected immunosuppressed hamsters against SARS-Cov-2. Conclusion: The obtained results can allow the start of clinical trials to study the safety and efficacy in healthy adults.

Thrombosis in patients with hereditary fibrinogen deficiency

Introduction. In most cases, in patients with hereditary fibrinogen deficiency, clinical manifestations are represented by bleeding of varying intensity and localization. However, the clinical picture of hereditary fibrinogen deficiency can also be represented by thrombosis.Aim — to characterize the detected mutations in fibrinogen genes and to analyze prothrombotic factors in patients with hereditary hypofibrinogenemia and thrombosis.Materials and methods. Forty-nine patients with hereditary hypofibrinogenemia were observed, of which 46 patients had no history of thrombosis and 3 patients had a confirmed history of thrombosis. These 3 patients made up the study group.Results. Heterozygous mutations were found in all 3 patients in the fibrinogen gamma chain gene (FGG), one of them had a previously undescribed deletion g.2653_2684+211del, p.(Asp167Glufs*2), which removes 32 terminal nucleotides of the fifth exon of the FGG gene and leads to the formation of a stop codon in place of amino acid 168. In two other patients, there were missense mutations c.1140T>A, p.(Cys365Ser) and c.1114A>T, p.(Asp356Val), which can determine the thrombogenic properties of the altered protein structure of fibrinogen. Other prothrombotic factors were also identified: genetic polymorphisms of low thrombotic risk, surgery, taking combined oral contraceptives.Conclusion. Hereditary fibrinogen deficiency does not play a protective role in relation to the development of thrombosis and may cause the development of thrombosis, which is associated with its multifunctional role in the hemostasis system. The pathogenesis of thrombosis in patients with hereditary hypofibrinogenemia is multifactorial and may be associated with the characteristics of the main protein defect and the coexistence of hereditary and acquired thrombotic risk factors (surgical interventions, taking combined oral contraceptives, etc.).

Lipoprotéine(a) et risque cardiovasculaire

AbstractDiscovered 60 years ago, lipoprotein (a) was very quickly recognized as an independent cardiovascular risk factor when its genetically determined concentration was high. Lp(a) is a lipoprotein containing apolipoprotein B100 like LDL but distinguished by the presence of an apolipoprotein (a) molecule. This apo(a) exhibits a very great structural heterogeneity as a function of the number of copies of the “kringle IV2” motif, making it possible to distinguish between small isoforms and large isoforms. The plasma concentration of Lp(a) is inversely proportional to the size of the apo(a) present in the Lp(a). The atherogenic properties of Lp(a) are linked to the LDL fraction, its thrombogenic properties are due to the anti- fibrinolytic action of apo(a) due to its partial homology with plasminogen. More recently a role in vascular calcification has also been demonstrated. During the 2000s, interest in Lp(a) declined considerably. Lp(a) is now back in the spotlight because its dosage makes it possible to improve the identification and management of subjects at high cardiovascular risk and because new therapies to reduce the synthesis of apo(a) look promising.

Case Report: Deep Vein Thrombosis Following a Wild Bee Sting

Deep vein thrombosis is one of the rare reactions that can occur after bee envenomation. A 40-year-old female presented at our facility for evaluation and management of a left lower limb swelling two weeks after suffering a bee sting. She was diagnosed with deep vein thrombosis (DVT). The development of DVT was attributed to thrombogenic properties of bee venom and endothelial injury caused by released inflammatory cytokines. The patient’s mainstay treatment was with anticoagulants.

Modified Surface Composition and Biocompatibility of Core-Shell Nitinol Nanoparticles Fabricated via Laser Ablation of Differently Passivized Targets

Nitinol is a versatile alloy known for its shape memory effect and thus finds multiple applications in biomedical devices and implants. The biomedical applications of nitinol-based devices are, however, limited because of concerns related to leaching and its associated cytotoxicity. In particular, nitinol nanoparticles (NPs), despite being highly promising for biomedical applications such as nano-actuators and biomolecular delivery agents are not explored, owing to the same concerns. Moreover, nitinol nanoparticles and their biological interactions are not fully characterized, and the available literature on their toxicity portrays a divided picture. Surface passivation of nitinol using multiple methods has been explored in the past to reduce the leaching of nickel in implants while also improving the thrombogenic properties. In this work, we reported the preparation of passivized nitinol NPs by laser ablation of nitinol targets, followed by different surface treatments. The effect of different treatments in reducing nickel leaching and its influence on biocompatibility were studied. The biocompatibility and multi-faceted interaction of nitinol NPs with osteoblast cells and associated toxicity were explored. Homogenous nitinol NPs were found to be generated at 25 W of laser power. Also, surface modification using hydrogen peroxide, anodization, and acid etching was found to be effective in waning the nickel leaching and improving biocompatibility. In view of the observed results of cellular interactions, we discussed the possible routes of cellular toxicity of these NPs. The prospective applications of such passivized NPs in the biomedical field are also discussed in this work.

Value of Genetic Testing for Lipoprotein(a) Variants

Value of Genetic Testing for Lipoprotein(a) Variants

Lipoprotein(a)-The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation.

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients.